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| Publications of Ahmad Hariri :chronological alphabetical combined listing:%% Journal Articles @article{fds372228, Author = {Lay-Yee, R and Hariri, AR and Knodt, AR and Barrett-Young, A and Matthews, T and Milne, BJ}, Title = {Social isolation from childhood to mid-adulthood: is there an association with older brain age?}, Journal = {Psychological medicine}, Volume = {53}, Number = {16}, Pages = {7874-7882}, Year = {2023}, Month = {December}, url = {http://dx.doi.org/10.1017/s0033291723001964}, Abstract = {<h4>Background</h4>Older brain age - as estimated from structural MRI data - is known to be associated with detrimental mental and physical health outcomes in older adults. Social isolation, which has similar detrimental effects on health, may be associated with accelerated brain aging though little is known about how different trajectories of social isolation across the life course moderate this association. We examined the associations between social isolation trajectories from age 5 to age 38 and brain age assessed at age 45.<h4>Methods</h4>We previously created a typology of social isolation based on onset during the life course and persistence into adulthood, using group-based trajectory analysis of longitudinal data from a New Zealand birth cohort. The typology comprises four groups: 'never-isolated', 'adult-only', 'child-only', and persistent 'child-adult' isolation. A brain age gap estimate (brainAGE) - the difference between predicted age from structural MRI date and chronological age - was derived at age 45. We undertook analyses of brainAGE with trajectory group as the predictor, adjusting for sex, family socio-economic status, and a range of familial and child-behavioral factors.<h4>Results</h4>Older brain age in mid-adulthood was associated with trajectories of social isolation after adjustment for family and child confounders, particularly for the 'adult-only' group compared to the 'never-isolated' group.<h4>Conclusions</h4>Although our findings are associational, they indicate that preventing social isolation, particularly in mid-adulthood, may help to avert accelerated brain aging associated with negative health outcomes later in life.}, Doi = {10.1017/s0033291723001964}, Key = {fds372228} } @article{fds373508, Author = {Knodt, AR and Elliott, ML and Whitman, ET and Winn, A and Addae, A and Ireland, D and Poulton, R and Ramrakha, S and Caspi, A and Moffitt, TE and Hariri, AR}, Title = {Test-retest reliability and predictive utility of a macroscale principal functional connectivity gradient.}, Journal = {Human brain mapping}, Volume = {44}, Number = {18}, Pages = {6399-6417}, Year = {2023}, Month = {December}, url = {http://dx.doi.org/10.1002/hbm.26517}, Abstract = {Mapping individual differences in brain function has been hampered by poor reliability as well as limited interpretability. Leveraging patterns of brain-wide functional connectivity (FC) offers some promise in this endeavor. In particular, a macroscale principal FC gradient that recapitulates a hierarchical organization spanning molecular, cellular, and circuit level features along a sensory-to-association cortical axis has emerged as both a parsimonious and interpretable measure of individual differences in behavior. However, the measurement reliabilities of this FC gradient have not been fully evaluated. Here, we assess the reliabilities of both global and regional principal FC gradient measures using test-retest data from the young adult Human Connectome Project (HCP-YA) and the Dunedin Study. Analyses revealed that the reliabilities of principal FC gradient measures were (1) consistently higher than those for traditional edge-wise FC measures, (2) higher for FC measures derived from general FC (GFC) in comparison with resting-state FC, and (3) higher for longer scan lengths. We additionally examined the relative utility of these principal FC gradient measures in predicting cognition and aging in both datasets as well as the HCP-aging dataset. These analyses revealed that regional FC gradient measures and global gradient range were significantly associated with aging in all three datasets, and moderately associated with cognition in the HCP-YA and Dunedin Study datasets, reflecting contractions and expansions of the cortical hierarchy, respectively. Collectively, these results demonstrate that measures of the principal FC gradient, especially derived using GFC, effectively capture a reliable feature of the human brain subject to interpretable and biologically meaningful individual variation, offering some advantages over traditional edge-wise FC measures in the search for brain-behavior associations.}, Doi = {10.1002/hbm.26517}, Key = {fds373508} } @article{fds370718, Author = {Strauman, TJ and Hariri, AR}, Title = {Revising a Self-Regulation Phenotype for Depression Through Individual Differences in Macroscale Brain Organization.}, Journal = {Current directions in psychological science}, Volume = {32}, Number = {4}, Pages = {267-275}, Year = {2023}, Month = {August}, url = {http://dx.doi.org/10.1177/09637214221149742}, Abstract = {<i>Self-regulation</i> denotes the processes by which people initiate, maintain, and control their own thoughts, behaviors, or emotions to produce a desired outcome or avoid an undesired outcome. Self-regulation brings the influence of distal factors such as biology, temperament, and socialization history onto cognition, motivation, and behavior. Dysfunction in self-regulation represents a contributory causal factor for psychopathology. Accordingly, we previously proposed a risk phenotype model for depression drawing from regulatory focus theory and traditional task-based fMRI studies. In this article, we revise and expand our risk phenotype model using insights from new methodologies allowing quantification of individual differences in task-free macroscale brain organization. We offer a set of hypotheses as examples of how examination of intrinsic macroscale brain organization can extend and enrich investigations of self-regulation and depression. In doing so, we hope to promote a useful heuristic for model development and for identifying transdiagnostic risk phenotypes in psychopathology.}, Doi = {10.1177/09637214221149742}, Key = {fds370718} } @article{fds371656, Author = {Whitman, ET and Knodt, AR and Elliott, ML and Abraham, WC and Cheyne, K and Hogan, S and Ireland, D and Keenan, R and Leung, JH and Melzer, TR and Poulton, R and Purdy, SC and Ramrakha, S and Thorne, PR and Caspi, A and Moffitt, TE and Hariri, AR}, Title = {Functional topography of the neocortex predicts covariation in complex cognitive and basic motor abilities.}, Journal = {Cerebral cortex (New York, N.Y. : 1991)}, Volume = {33}, Number = {13}, Pages = {8218-8231}, Year = {2023}, Month = {June}, url = {http://dx.doi.org/10.1093/cercor/bhad109}, Abstract = {Although higher-order cognitive and lower-order sensorimotor abilities are generally regarded as distinct and studied separately, there is evidence that they not only covary but also that this covariation increases across the lifespan. This pattern has been leveraged in clinical settings where a simple assessment of sensory or motor ability (e.g. hearing, gait speed) can forecast age-related cognitive decline and risk for dementia. However, the brain mechanisms underlying cognitive, sensory, and motor covariation are largely unknown. Here, we examined whether such covariation in midlife reflects variability in common versus distinct neocortical networks using individualized maps of functional topography derived from BOLD fMRI data collected in 769 45-year-old members of a population-representative cohort. Analyses revealed that variability in basic motor but not hearing ability reflected individual differences in the functional topography of neocortical networks typically supporting cognitive ability. These patterns suggest that covariation in motor and cognitive abilities in midlife reflects convergence of function in higher-order neocortical networks and that gait speed may not be simply a measure of physical function but rather an integrative index of nervous system health.}, Doi = {10.1093/cercor/bhad109}, Key = {fds371656} } @article{fds362550, Author = {Cobb, AR and Rubin, M and Stote, DL and Baldwin, BC and Lee, H-J and Hariri, AR and Telch, MJ}, Title = {Hippocampal volume and volume asymmetry prospectively predict PTSD symptom emergence among Iraq-deployed soldiers.}, Journal = {Psychological medicine}, Volume = {53}, Number = {5}, Pages = {1906-1913}, Year = {2023}, Month = {April}, url = {http://dx.doi.org/10.1017/s0033291721003548}, Abstract = {<h4>Background</h4>Evidence suggests a link between smaller hippocampal volume (HV) and post-traumatic stress disorder (PTSD). However, there has been little prospective research testing this question directly and it remains unclear whether smaller HV confers risk or is a consequence of traumatization and PTSD.<h4>Methods</h4>U.S. soldiers (<i>N</i> = 107) completed a battery of clinical assessments, including structural magnetic resonance imaging pre-deployment. Once deployed they completed monthly assessments of traumatic-stressors and symptoms. We hypothesized that smaller HV would potentiate the effects of traumatic stressors on PTSD symptoms in theater. Analyses evaluated whether total HV, lateral (right <i>v.</i> left) HV, or HV asymmetry (right - left) moderated the effects of stressor-exposure during deployment on PTSD symptoms.<h4>Results</h4>Findings revealed no interaction between total HV and average monthly traumatic-stressors on PTSD symptoms <i>b</i> = -0.028, <i>p</i> = 0.681 [95% confidence interval (CI) -0.167 to 0.100]. However, in the context of greater exposure to average monthly traumatic stressors, greater right HV was associated with fewer PTSD symptoms <i>b</i> = -0.467, <i>p</i> = 0.023 (95% CI -0.786 to -0.013), whereas greater left HV was unexpectedly associated with greater PTSD symptoms <i>b</i> = 0.435, <i>p</i> = 0.024 (95% CI 0.028-0.715).<h4>Conclusions</h4>Our findings highlight the importance of considering the complex role of HV, in particular HV asymmetry, in predicting the emergence of PTSD symptoms in response to war-zone trauma.}, Doi = {10.1017/s0033291721003548}, Key = {fds362550} } @article{fds370934, Author = {Barrett-Young, A and Abraham, WC and Cheung, CY and Gale, J and Hogan, S and Ireland, D and Keenan, R and Knodt, AR and Melzer, TR and Moffitt, TE and Ramrakha, S and Tham, YC and Wilson, GA and Wong, TY and Hariri, AR and Poulton, R}, Title = {Associations Between Thinner Retinal Neuronal Layers and Suboptimal Brain Structural Integrity in a Middle-Aged Cohort.}, Journal = {Eye and brain}, Volume = {15}, Pages = {25-35}, Year = {2023}, Month = {January}, url = {http://dx.doi.org/10.2147/eb.s402510}, Abstract = {<h4>Purpose</h4>The retina has potential as a biomarker of brain health and Alzheimer's disease (AD) because it is the only part of the central nervous system which can be easily imaged and has advantages over brain imaging technologies. Few studies have compared retinal and brain measurements in a middle-aged sample. The objective of our study was to investigate whether retinal neuronal measurements were associated with structural brain measurements in a middle-aged population-based cohort.<h4>Participants and methods</h4>Participants were members of the Dunedin Multidisciplinary Health and Development Study (n=1037; a longitudinal cohort followed from birth and at ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, 32, 38, and most recently at age 45, when 94% of the living Study members participated). Retinal nerve fibre layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) thickness were measured by optical coherence tomography (OCT). Brain age gap estimate (brainAGE), cortical surface area, cortical thickness, subcortical grey matter volumes, white matter hyperintensities, were measured by magnetic resonance imaging (MRI).<h4>Results</h4>Participants with both MRI and OCT data were included in the analysis (RNFL n=828, female n=413 [49.9%], male n=415 [50.1%]; GC-IPL n=825, female n=413 [50.1%], male n=412 [49.9%]). Thinner retinal neuronal layers were associated with older brain age, smaller cortical surface area, thinner average cortex, smaller subcortical grey matter volumes, and increased volume of white matter hyperintensities.<h4>Conclusion</h4>These findings provide evidence that the retinal neuronal layers reflect differences in midlife structural brain integrity consistent with increased risk for later AD, supporting the proposition that the retina may be an early biomarker of brain health.}, Doi = {10.2147/eb.s402510}, Key = {fds370934} } @article{fds365599, Author = {Knodt, AR and Meier, MH and Ambler, A and Gehred, MZ and Harrington, H and Ireland, D and Poulton, R and Ramrakha, S and Caspi, A and Moffitt, TE and Hariri, AR}, Title = {Diminished Structural Brain Integrity in Long-term Cannabis Users Reflects a History of Polysubstance Use.}, Journal = {Biological psychiatry}, Volume = {92}, Number = {11}, Pages = {861-870}, Year = {2022}, Month = {December}, url = {http://dx.doi.org/10.1016/j.biopsych.2022.06.018}, Abstract = {<h4>Background</h4>Cannabis legalization and use are outpacing our understanding of its long-term effects on brain and behavior, which is fundamental for effective policy and health practices. Existing studies are limited by small samples, cross-sectional measures, failure to separate long-term from recreational use, and inadequate control for other substance use. Here, we address these limitations by determining the structural brain integrity of long-term cannabis users in the Dunedin Study, a longitudinal investigation of a population-representative birth cohort followed to midlife.<h4>Methods</h4>We leveraged prospective measures of cannabis, alcohol, tobacco, and other illicit drug use in addition to structural neuroimaging in 875 study members at age 45 to test for differences in both global and regional gray and white matter integrity between long-term cannabis users and lifelong nonusers. We additionally tested for dose-response associations between continuous measures of cannabis use and brain structure, including careful adjustments for use of other substances.<h4>Results</h4>Long-term cannabis users had a thinner cortex, smaller subcortical gray matter volumes, and higher machine learning-predicted brain age than nonusers. However, these differences in structural brain integrity were explained by the propensity of long-term cannabis users to engage in polysubstance use, especially with alcohol and tobacco.<h4>Conclusions</h4>These findings suggest that diminished midlife structural brain integrity in long-term cannabis users reflects a broader pattern of polysubstance use, underlining the importance of understanding comorbid substance use in efforts to curb the negative effects of cannabis on brain and behavior as well as establish more effective policy and health practices.}, Doi = {10.1016/j.biopsych.2022.06.018}, Key = {fds365599} } @article{fds367351, Author = {Meier, MH and Caspi, A and Ambler, A and Hariri, AR and Harrington, H and Hogan, S and Houts, R and Knodt, AR and Ramrakha, S and Richmond-Rakerd, LS and Poulton, R and Moffitt, TE}, Title = {Preparedness for healthy ageing and polysubstance use in long-term cannabis users: a population-representative longitudinal study.}, Journal = {The lancet. Healthy longevity}, Volume = {3}, Number = {10}, Pages = {e703-e714}, Year = {2022}, Month = {October}, url = {http://dx.doi.org/10.1016/s2666-7568(22)00201-x}, Abstract = {<h4>Background</h4>Cannabis is often characterised as a young person's drug. However, people who began consuming cannabis in the 1970s and 1980s are no longer young and some have consumed it for many years. This study tested the preregistered hypothesis that long-term cannabis users show accelerated biological ageing in midlife and poorer health preparedness, financial preparedness, and social preparedness for old age.<h4>Methods</h4>In this longitudinal study, participants comprised a population-representative cohort of 1037 individuals born in Dunedin, New Zealand, between April, 1972, and March, 1973, and followed to age 45 years. Cannabis, tobacco, and alcohol use and dependence were assessed at ages 18 years, 21 years, 26 years, 32 years, 38 years, and 45 years. Biological ageing and health, financial, and social preparedness for old age were assessed at age 45 years. Long-term cannabis users were compared using independent samples t tests with five groups: lifelong cannabis non-users, long-term tobacco users, long-term alcohol users, midlife recreational cannabis users, and cannabis quitters. In addition, regression analyses tested dose-response associations for continuously measured persistence of cannabis dependence from age 18 years to 45 years, with associations adjusted for sex, childhood socioeconomic status, childhood IQ, low childhood self-control, family substance dependence history, and persistence of alcohol, tobacco, and other illicit drug dependence.<h4>Findings</h4>Of 997 cohort members still alive at age 45 years, 938 (94%) were assessed at age 45 years. Long-term cannabis users showed statistically significant accelerated biological ageing and were less equipped to manage a range of later-life health, financial, and social demands than non-users. Standardised mean differences between long-term cannabis users and non-users were large: 0·70 (95% CI 0·46 to 0·94; p<0·0001) for biological ageing, -0·72 (-0·96 to -0·49, p<0·0001) for health preparedness, -1·08 (-1·31 to -0·85; p<0·0001) for financial preparedness, and -0·59 (-0·84 to -0·34, p<0·0001) for social preparedness. Long-term cannabis users did not fare better than long-term tobacco or alcohol users. Tests of dose-response associations suggested that cannabis associations could not be explained by the socioeconomic origins, childhood IQ, childhood self-control, and family substance-dependence history of long-term cannabis users. Statistical adjustment for long-term tobacco, alcohol, and other illicit drug dependence suggested that long-term cannabis users' tendency toward polysubstance dependence accounted for their accelerated biological ageing and poor financial and health preparedness, although not for their poor social preparedness (β -0·10, 95% CI -0·18 to -0·02; p=0·017).<h4>Interpretation</h4>Long-term cannabis users are underprepared for the demands of old age. Although long-term cannabis use appears detrimental, the greatest challenge to healthy ageing is not use of any specific substance, but rather the long-term polysubstance use that characterises many long-term cannabis users. Substance-use interventions should include practical strategies for improving health and building financial and social capital for healthy longevity.<h4>Funding</h4>The National Institute on Aging and the UK Medical Research Council. The Dunedin Research Unit is supported by the New Zealand Health Research Council and the New Zealand Ministry of Business, Innovation and Employment.}, Doi = {10.1016/s2666-7568(22)00201-x}, Key = {fds367351} } @article{fds366147, Author = {Kim, MJ and Knodt, AR and Hariri, AR}, Title = {Meta-analytic activation maps can help identify affective processes captured by contrast-based task fMRI: the case of threat-related facial expressions.}, Journal = {Social cognitive and affective neuroscience}, Volume = {17}, Number = {9}, Pages = {777-787}, Year = {2022}, Month = {September}, url = {http://dx.doi.org/10.1093/scan/nsac010}, Abstract = {Meta-analysis of functional magnetic resonance imaging (fMRI) data is an effective method for capturing the distributed patterns of brain activity supporting discrete cognitive and affective processes. One opportunity presented by the resulting meta-analysis maps (MAMs) is as a reference for better understanding the nature of individual contrast maps (ICMs) derived from specific task fMRI data. Here, we compared MAMs from 148 neuroimaging studies representing emotion categories of fear, anger, disgust, happiness and sadness with ICMs from fearful > neutral and angry > neutral faces from an independent dataset of task fMRI (n = 1263). Analyses revealed that both fear and anger ICMs exhibited the greatest pattern similarity to fear MAMs. As the number of voxels included for the computation of pattern similarity became more selective, the specificity of MAM-ICM correspondence decreased. Notably, amygdala activity long considered critical for processing threat-related facial expressions was neither sufficient nor necessary for detecting MAM-ICM pattern similarity effects. Our analyses suggest that both fearful and angry facial expressions are best captured by distributed patterns of brain activity, a putative neural correlate of threat. More generally, our analyses demonstrate how MAMs can be leveraged to better understand affective processes captured by ICMs in task fMRI data.}, Doi = {10.1093/scan/nsac010}, Key = {fds366147} } @article{fds367352, Author = {Sugden, K and Caspi, A and Elliott, ML and Bourassa, KJ and Chamarti, K and Corcoran, DL and Hariri, AR and Houts, RM and Kothari, M and Kritchevsky, S and Kuchel, GA and Mill, JS and Williams, BS and Belsky, DW and Moffitt, TE and Alzheimer's Disease Neuroimaging Initiative*}, Title = {Association of Pace of Aging Measured by Blood-Based DNA Methylation With Age-Related Cognitive Impairment and Dementia.}, Journal = {Neurology}, Volume = {99}, Number = {13}, Pages = {e1402-e1413}, Year = {2022}, Month = {September}, url = {http://dx.doi.org/10.1212/wnl.0000000000200898}, Abstract = {<h4>Background and objectives</h4>DNA methylation algorithms are increasingly used to estimate biological aging; however, how these proposed measures of whole-organism biological aging relate to aging in the brain is not known. We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Framingham Heart Study (FHS) Offspring Cohort to test the association between blood-based DNA methylation measures of biological aging and cognitive impairment and dementia in older adults.<h4>Methods</h4>We tested 3 "generations" of DNA methylation age algorithms (first generation: Horvath and Hannum clocks; second generation: PhenoAge and GrimAge; and third generation: DunedinPACE, Dunedin Pace of Aging Calculated from the Epigenome) against the following measures of cognitive impairment in ADNI: clinical diagnosis of dementia and mild cognitive impairment, scores on Alzheimer disease (AD) / Alzheimer disease and related dementias (ADRD) screening tests (Alzheimer's Disease Assessment Scale, Mini-Mental State Examination, and Montreal Cognitive Assessment), and scores on cognitive tests (Rey Auditory Verbal Learning Test, Logical Memory test, and Trail Making Test). In an independent replication in the FHS Offspring Cohort, we further tested the longitudinal association between the DNA methylation algorithms and the risk of developing dementia.<h4>Results</h4>In ADNI (<i>N</i> = 649 individuals), the first-generation (Horvath and Hannum DNA methylation age clocks) and the second-generation (PhenoAge and GrimAge) DNA methylation measures of aging were not consistently associated with measures of cognitive impairment in older adults. By contrast, a third-generation measure of biological aging, DunedinPACE, was associated with clinical diagnosis of Alzheimer disease (beta [95% CI] = 0.28 [0.08-0.47]), poorer scores on Alzheimer disease/ADRD screening tests (beta [Robust SE] = -0.10 [0.04] to 0.08[0.04]), and cognitive tests (beta [Robust SE] = -0.12 [0.04] to 0.10 [0.03]). The association between faster pace of aging, as measured by DunedinPACE, and risk of developing dementia was confirmed in a longitudinal analysis of the FHS Offspring Cohort (<i>N</i> = 2,264 individuals, hazard ratio [95% CI] = 1.27 [1.07-1.49]).<h4>Discussion</h4>Third-generation blood-based DNA methylation measures of aging could prove valuable for measuring differences between individuals in the rate at which they age and in their risk for cognitive decline, and for evaluating interventions to slow aging.}, Doi = {10.1212/wnl.0000000000200898}, Key = {fds367352} } @article{fds364214, Author = {Farber, MJ and Gee, DG and Hariri, AR}, Title = {Normative range parenting and the developing brain: A scoping review and recommendations for future research.}, Journal = {The European journal of neuroscience}, Volume = {55}, Number = {9-10}, Pages = {2341-2358}, Year = {2022}, Month = {May}, url = {http://dx.doi.org/10.1111/ejn.15003}, Abstract = {Studies of early adversity such as trauma, abuse, and neglect highlight the critical importance of quality caregiving in brain development and mental health. However, the impact of normative range variability in caregiving on such biobehavioral processes remains poorly understood. Thus, we lack an essential foundation for understanding broader, population-representative developmental mechanisms of risk and resilience. Here, we conduct a scoping review of the extant literature centered on the question, "Is variability in normative range parenting associated with variability in brain structure and function?" After removing duplicates and screening by title, abstract, and full-text, 23 records were included in a qualitative review. The most striking outcome of this review was not only how few studies have explored associations between brain development and normative range parenting, but also how little methodological consistency exists across published studies. In light of these limitations, we propose recommendations for future research on normative range parenting and brain development. In doing so, we hope to facilitate evidence-based research that will help inform policies and practices that yield optimal developmental trajectories and mental health as well as extend the literature on the neurodevelopmental impact of early life stress.}, Doi = {10.1111/ejn.15003}, Key = {fds364214} } @article{fds364180, Author = {Kim, MJ and Elliott, ML and Knodt, AR and Hariri, AR}, Title = {A Connectome-wide Functional Signature of Trait Anger.}, Journal = {Clinical psychological science : a journal of the Association for Psychological Science}, Volume = {10}, Number = {3}, Pages = {584-592}, Year = {2022}, Month = {May}, url = {http://dx.doi.org/10.1177/21677026211030240}, Abstract = {Past research on the brain correlates of trait anger has been limited by small sample sizes, a focus on relatively few regions-of-interest, and poor test-retest reliability of functional brain measures. To address these limitations, we conducted a data-driven analysis of variability in connectome-wide functional connectivity in a sample of 1,048 young adult volunteers. Multi-dimensional matrix regression analysis showed that self-reported trait anger maps onto variability in the whole-brain functional connectivity patterns of three brain regions that serve action-related functions: bilateral supplementary motor area (SMA) and the right lateral frontal pole. We then demonstrate trait anger modulates the functional connectivity of these regions with canonical brain networks supporting somatomotor, affective, self-referential, and visual information processes. Our findings offer novel neuroimaging evidence for interpreting trait anger as a greater propensity to provoked action, supporting ongoing efforts to understand its utility as a potential transdiagnostic marker for disordered states characterized by aggressive behavior.}, Doi = {10.1177/21677026211030240}, Key = {fds364180} } @article{fds364143, Author = {Meier, MH and Caspi, A and R Knodt and A and Hall, W and Ambler, A and Harrington, H and Hogan, S and M Houts and R and Poulton, R and Ramrakha, S and Hariri, AR and Moffitt, TE}, Title = {Long-Term Cannabis Use and Cognitive Reserves and Hippocampal Volume in Midlife.}, Journal = {The American journal of psychiatry}, Volume = {179}, Number = {5}, Pages = {362-374}, Year = {2022}, Month = {May}, url = {http://dx.doi.org/10.1176/appi.ajp.2021.21060664}, Abstract = {<h4>Objective</h4>Cannabis use is increasing among midlife and older adults. This study tested the hypotheses that long-term cannabis use is associated with cognitive deficits and smaller hippocampal volume in midlife, which is important because midlife cognitive deficits and smaller hippocampal volume are risk factors for dementia.<h4>Methods</h4>Participants are members of a representative cohort of 1,037 individuals born in Dunedin, New Zealand, in 1972-1973 and followed to age 45, with 94% retention. Cannabis use and dependence were assessed at ages 18, 21, 26, 32, 38, and 45. IQ was assessed at ages 7, 9, 11, and 45. Specific neuropsychological functions and hippocampal volume were assessed at age 45.<h4>Results</h4>Long-term cannabis users showed IQ decline from childhood to midlife (mean=-5.5 IQ points), poorer learning and processing speed relative to their childhood IQ, and informant-reported memory and attention problems. These deficits were specific to long-term cannabis users because they were either not present or were smaller among long-term tobacco users, long-term alcohol users, midlife recreational cannabis users, and cannabis quitters. Cognitive deficits among long-term cannabis users could not be explained by persistent tobacco, alcohol, or other illicit drug use, childhood socioeconomic status, low childhood self-control, or family history of substance dependence. Long-term cannabis users showed smaller hippocampal volume, but smaller hippocampal volume did not statistically mediate cannabis-related cognitive deficits.<h4>Conclusions</h4>Long-term cannabis users showed cognitive deficits and smaller hippocampal volume in midlife. Research is needed to ascertain whether long-term cannabis users show elevated rates of dementia in later life.}, Doi = {10.1176/appi.ajp.2021.21060664}, Key = {fds364143} } @article{fds364171, Author = {Bourassa, KJ and Moffitt, TE and Ambler, A and Hariri, AR and Harrington, H and Houts, RM and Ireland, D and Knodt, A and Poulton, R and Ramrakha, S and Caspi, A}, Title = {Association of Treatable Health Conditions During Adolescence With Accelerated Aging at Midlife.}, Journal = {JAMA pediatrics}, Volume = {176}, Number = {4}, Pages = {392-399}, Year = {2022}, Month = {April}, url = {http://dx.doi.org/10.1001/jamapediatrics.2021.6417}, Abstract = {<h4>Importance</h4>Biological aging is a distinct construct from health; however, people who age quickly are more likely to experience poor health. Identifying pediatric health conditions associated with accelerated aging could help develop treatment approaches to slow midlife aging and prevent poor health in later life.<h4>Objective</h4>To examine the association between 4 treatable health conditions in adolescence and accelerated aging at midlife.<h4>Design, setting, and participants</h4>This cohort study analyzed data from participants in the Dunedin Study, a longitudinal investigation of health and behavior among a birth cohort born between April 1, 1972, and March 31, 1973, in Dunedin, New Zealand, and followed up until age 45 years. Participants underwent an assessment at age 45 years and had data for at least 1 adolescent health condition (asthma, smoking, obesity, and psychological disorders) and outcome measure (pace of aging, gait speed, brain age, and facial age). Data analysis was performed from February 11 to September 27, 2021.<h4>Exposures</h4>Asthma, cigarette smoking, obesity, and psychological disorders were assessed at age 11, 13, and 15 years.<h4>Main outcomes and measures</h4>The outcome was a midlife aging factor composite score comprising 4 measures of biological aging: pace of aging, gait speed, brain age (specifically, BrainAGE score), and facial age.<h4>Results</h4>A total of 910 participants (459 men [50.4%]) met the inclusion criteria, including an assessment at age 45 years. Participants who had smoked daily (0.61 [95% CI, 0.43-0.79] SD units), had obesity (0.82 [95% CI, 0.59-1.06] SD units), or had a psychological disorder diagnosis (0.43 [95% CI, 0.29-0.56] SD units) during adolescence were biologically older at midlife compared with participants without these conditions. Participants with asthma were not biologically older at midlife (0.02 [95% CI, -0.14 to 0.19] SD units) compared with those without asthma. These results remained unchanged after adjusting for childhood risk factors such as poor health, socioeconomic disadvantage, and adverse experiences.<h4>Conclusions and relevance</h4>This study found that adolescent smoking, obesity, and psychological disorder diagnoses were associated with older biological age at midlife. These health conditions could be treated during adolescence to reduce the risk of accelerated biological aging later in life.}, Doi = {10.1001/jamapediatrics.2021.6417}, Key = {fds364171} } @article{fds364966, Author = {Kragel, PA and Hariri, AR and LaBar, KS}, Title = {The Temporal Dynamics of Spontaneous Emotional Brain States and Their Implications for Mental Health.}, Journal = {Journal of cognitive neuroscience}, Volume = {34}, Number = {5}, Pages = {715-728}, Year = {2022}, Month = {March}, url = {http://dx.doi.org/10.1162/jocn_a_01787}, Abstract = {Temporal processes play an important role in elaborating and regulating emotional responding during routine mind wandering. However, it is unknown whether the human brain reliably transitions among multiple emotional states at rest and how psychopathology alters these affect dynamics. Here, we combined pattern classification and stochastic process modeling to investigate the chronometry of spontaneous brain activity indicative of six emotions (anger, contentment, fear, happiness, sadness, and surprise) and a neutral state. We modeled the dynamic emergence of these brain states during resting-state fMRI and validated the results across two population cohorts-the Duke Neurogenetics Study and the Nathan Kline Institute Rockland Sample. Our findings indicate that intrinsic emotional brain dynamics are effectively characterized as a discrete-time Markov process, with affective states organized around a neutral hub. The centrality of this network hub is disrupted in individuals with psychopathology, whose brain state transitions exhibit greater inertia and less frequent resetting from emotional to neutral states. These results yield novel insights into how the brain signals spontaneous emotions and how alterations in their temporal dynamics contribute to compromised mental health.}, Doi = {10.1162/jocn_a_01787}, Key = {fds364966} } @article{fds368528, Author = {Reuben, A and Moffitt, TE and Abraham, WC and Ambler, A and Elliott, ML and Hariri, AR and Harrington, H and Hogan, S and Houts, RM and Ireland, D and Knodt, AR and Leung, J and Pearson, A and Poulton, R and Purdy, SC and Ramrakha, S and Rasmussen, LJH and Sugden, K and Thorne, PR and Williams, B and Wilson, G and Caspi, A}, Title = {Improving risk indexes for Alzheimer's disease and related dementias for use in midlife.}, Journal = {Brain communications}, Volume = {4}, Number = {5}, Pages = {fcac223}, Year = {2022}, Month = {January}, url = {http://dx.doi.org/10.1093/braincomms/fcac223}, Abstract = {Knowledge of a person's risk for Alzheimer's disease and related dementias (ADRDs) is required to triage candidates for preventive interventions, surveillance, and treatment trials. ADRD risk indexes exist for this purpose, but each includes only a subset of known risk factors. Information missing from published indexes could improve risk prediction. In the Dunedin Study of a population-representative New Zealand-based birth cohort followed to midlife (<i>N</i> = 938, 49.5% female), we compared associations of four leading risk indexes with midlife antecedents of ADRD against a novel benchmark index comprised of nearly all known ADRD risk factors, the Dunedin ADRD Risk Benchmark (DunedinARB). Existing indexes included the Cardiovascular Risk Factors, Aging, and Dementia index (CAIDE), LIfestyle for BRAin health index (LIBRA), Australian National University Alzheimer's Disease Risk Index (ANU-ADRI), and risks selected by the Lancet Commission on Dementia. The Dunedin benchmark was comprised of 48 separate indicators of risk organized into 10 conceptually distinct risk domains. Midlife antecedents of ADRD treated as outcome measures included age-45 measures of brain structural integrity [magnetic resonance imaging-assessed: (i) machine-learning-algorithm-estimated brain age, (ii) log-transformed volume of white matter hyperintensities, and (iii) mean grey matter volume of the hippocampus] and measures of brain functional integrity [(i) objective cognitive function assessed via the Wechsler Adult Intelligence Scale-IV, (ii) subjective problems in everyday cognitive function, and (iii) objective cognitive decline measured as residualized change in cognitive scores from childhood to midlife on matched Weschler Intelligence scales]. All indexes were quantitatively distributed and proved informative about midlife antecedents of ADRD, including algorithm-estimated brain age (<i>β</i>'s from 0.16 to 0.22), white matter hyperintensities volume (<i>β</i>'s from 0.16 to 0.19), hippocampal volume (<i>β</i>'s from -0.08 to -0.11), tested cognitive deficits (<i>β</i>'s from -0.36 to -0.49), everyday cognitive problems (<i>β</i>'s from 0.14 to 0.38), and longitudinal cognitive decline (<i>β</i>'s from -0.18 to -0.26). Existing indexes compared favourably to the comprehensive benchmark in their association with the brain structural integrity measures but were outperformed in their association with the functional integrity measures, particularly subjective cognitive problems and tested cognitive decline. Results indicated that existing indexes could be improved with targeted additions, particularly of measures assessing socioeconomic status, physical and sensory function, epigenetic aging, and subjective overall health. Existing premorbid ADRD risk indexes perform well in identifying linear gradients of risk among members of the general population at midlife, even when they include only a small subset of potential risk factors. They could be improved, however, with targeted additions to more holistically capture the different facets of risk for this multiply determined, age-related disease.}, Doi = {10.1093/braincomms/fcac223}, Key = {fds368528} } @article{fds364215, Author = {Miles, AE and Dos Santos and FC and Byrne, EM and Renteria, ME and McIntosh, AM and Adams, MJ and Pistis, G and Castelao, E and Preisig, M and Baune, BT and Schubert, KO and Lewis, CM and Jones, LA and Jones, I and Uher, R and Smoller, JW and Perlis, RH and Levinson, DF and Potash, JB and Weissman, MM and Shi, J and Lewis, G and Penninx, BWJH and Boomsma, DI and Hamilton, SP and Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, and Sibille, E and Hariri, AR and Nikolova, YS}, Title = {Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk.}, Journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, Volume = {46}, Number = {13}, Pages = {2304-2311}, Year = {2021}, Month = {December}, url = {http://dx.doi.org/10.1038/s41386-021-01189-x}, Abstract = {Studies in post-mortem human brain tissue have associated major depressive disorder (MDD) with cortical transcriptomic changes, whose potential in vivo impact remains unexplored. To address this translational gap, we recently developed a transcriptome-based polygenic risk score (T-PRS) based on common functional variants capturing 'depression-like' shifts in cortical gene expression. Here, we used a non-clinical sample of young adults (n = 482, Duke Neurogenetics Study: 53% women; aged 19.8 ± 1.2 years) to map T-PRS onto brain morphology measures, including Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index, as well as broad MDD risk, indexed by self-reported family history of depression. We conducted side-by-side comparisons with a PRS independently derived from a Psychiatric Genomics Consortium (PGC) MDD GWAS (PGC-PRS), and sought to link T-PRS with diagnosis and symptom severity directly in PGC-MDD participants (n = 29,340, 59% women; 12,923 MDD cases, 16,417 controls). T-PRS was associated with smaller amygdala volume in women (t = -3.478, p = 0.001) and lower prefrontal gyrification across sexes. In men, T-PRS was associated with hypergyrification in temporal and occipital regions. Prefrontal hypogyrification mediated a male-specific indirect link between T-PRS and familial depression (b = 0.005, p = 0.029). PGC-PRS was similarly associated with lower amygdala volume and cortical gyrification; however, both effects were male-specific and hypogyrification emerged in distinct parietal and temporo-occipital regions, unassociated with familial depression. In PGC-MDD, T-PRS did not predict diagnosis (OR = 1.007, 95% CI = [0.997-1.018]) but correlated with symptom severity in men (rho = 0.175, p = 7.957 × 10<sup>-4</sup>) in one cohort (N = 762, 48% men). Depression-like shifts in cortical gene expression have sex-specific effects on brain morphology and may contribute to broad depression vulnerability in men.}, Doi = {10.1038/s41386-021-01189-x}, Key = {fds364215} } @article{fds368901, Author = {Carlisi, CO and Moffitt, TE and Knodt, AR and Harrington, H and Langevin, S and Ireland, D and Melzer, TR and Poulton, R and Ramrakha, S and Caspi, A and Hariri, AR and Viding, E}, Title = {Association of subcortical gray-matter volumes with life-course-persistent antisocial behavior in a population-representative longitudinal birth cohort.}, Journal = {Development and psychopathology}, Pages = {1-11}, Year = {2021}, Month = {October}, url = {http://dx.doi.org/10.1017/s0954579421000377}, Abstract = {Neuropsychological evidence supports the developmental taxonomy theory of antisocial behavior, suggesting that abnormal brain development distinguishes life-course-persistent from adolescence-limited antisocial behavior. Recent neuroimaging work confirmed that prospectively-measured life-course-persistent antisocial behavior is associated with differences in cortical brain structure. Whether this extends to subcortical brain structures remains uninvestigated. This study compared subcortical gray-matter volumes between 672 members of the Dunedin Study previously defined as exhibiting life-course-persistent, adolescence-limited or low-level antisocial behavior based on repeated assessments at ages 7-26 years. Gray-matter volumes of 10 subcortical structures were compared across groups. The life-course-persistent group had lower volumes of amygdala, brain stem, cerebellum, hippocampus, pallidum, thalamus, and ventral diencephalon compared to the low-antisocial group. Differences between life-course-persistent and adolescence-limited individuals were comparable in effect size to differences between life-course-persistent and low-antisocial individuals, but were not statistically significant due to less statistical power. Gray-matter volumes in adolescence-limited individuals were near the norm in this population-representative cohort and similar to volumes in low-antisocial individuals. Although this study could not establish causal links between brain volume and antisocial behavior, it constitutes new biological evidence that all people with antisocial behavior are not the same, supporting a need for greater developmental and diagnostic precision in clinical, forensic, and policy-based interventions.}, Doi = {10.1017/s0954579421000377}, Key = {fds368901} } @article{fds364144, Author = {Lam, M and Chen, C-Y and Ge, T and Xia, Y and Hill, DW and Trampush, JW and Yu, J and Knowles, E and Davies, G and Stahl, EA and Huckins, L and Liewald, DC and Djurovic, S and Melle, I and Christoforou, A and Reinvang, I and DeRosse, P and Lundervold, AJ and Steen, VM and Espeseth, T and Räikkönen, K and Widen, E and Palotie, A and Eriksson, JG and Giegling, I and Konte, B and Hartmann, AM and Roussos, P and Giakoumaki, S and Burdick, KE and Payton, A and Ollier, W and Chiba-Falek, O and Koltai, DC and Need, AC and Cirulli, ET and Voineskos, AN and Stefanis, NC and Avramopoulos, D and Hatzimanolis, A and Smyrnis, N and Bilder, RM and Freimer, NB and Cannon, TD and London, E and Poldrack, RA and Sabb, FW and Congdon, E and Conley, ED and Scult, MA and Dickinson, D and Straub, RE and Donohoe, G and Morris, D and Corvin, A and Gill, M and Hariri, AR and Weinberger, DR and Pendleton, N and Bitsios, P and Rujescu, D and Lahti, J and Le Hellard and S and Keller, MC and Andreassen, OA and Deary, IJ and Glahn, DC and Huang, H and Liu, C and Malhotra, AK and Lencz, T}, Title = {Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.}, Journal = {Neuropsychopharmacology}, Volume = {46}, Number = {10}, Pages = {1788-1801}, Year = {2021}, Month = {September}, url = {http://dx.doi.org/10.1038/s41386-021-01023-4}, Abstract = {Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.}, Doi = {10.1038/s41386-021-01023-4}, Key = {fds364144} } @article{fds364145, Author = {Elliott, ML and Knodt, AR and Hariri, AR}, Title = {Striving toward translation: strategies for reliable fMRI measurement.}, Journal = {Trends in cognitive sciences}, Volume = {25}, Number = {9}, Pages = {776-787}, Year = {2021}, Month = {September}, url = {http://dx.doi.org/10.1016/j.tics.2021.05.008}, Abstract = {fMRI has considerable potential as a translational tool for understanding risk, prioritizing interventions, and improving the treatment of brain disorders. However, recent studies have found that many of the most widely used fMRI measures have low reliability, undermining this potential. Here, we argue that many fMRI measures are unreliable because they were designed to identify group effects, not to precisely quantify individual differences. We then highlight four emerging strategies [extended aggregation, reliability modeling, multi-echo fMRI (ME-fMRI), and stimulus design] that build on established psychometric properties to generate more precise and reliable fMRI measures. By adopting such strategies to improve reliability, we are optimistic that fMRI can fulfill its potential as a clinical tool.}, Doi = {10.1016/j.tics.2021.05.008}, Key = {fds364145} } @article{fds347350, Author = {Romer, AL and Knodt, AR and Sison, ML and Ireland, D and Houts, R and Ramrakha, S and Poulton, R and Keenan, R and Melzer, TR and Moffitt, TE and Caspi, A and Hariri, AR}, Title = {Replicability of structural brain alterations associated with general psychopathology: evidence from a population-representative birth cohort.}, Journal = {Molecular psychiatry}, Volume = {26}, Number = {8}, Pages = {3839-3846}, Year = {2021}, Month = {August}, url = {http://dx.doi.org/10.1038/s41380-019-0621-z}, Abstract = {Transdiagnostic research has identified a general psychopathology factor-often called the 'p' factor-that accounts for shared variation across internalizing, externalizing, and thought disorders in diverse samples. It has been argued that the p factor may reflect dysfunctional thinking present in serious mental illness. In support of this, we previously used a theory-free, data-driven multimodal neuroimaging approach to find that higher p factor scores are associated with structural alterations within a cerebello-thalamo-cortical circuit (CTCC) and visual association cortex, both of which are important for monitoring and coordinating information processing in the service of executive control. Here we attempt to replicate these associations by conducting region-of-interest analyses using data from 875 members of the Dunedin Longitudinal Study, a five-decade study of a population-representative birth cohort, collected when they were 45 years old. We further sought to replicate a more recent report that p factor scores can be predicted by patterns of distributed cerebellar morphology as estimated through independent component analysis. We successfully replicated associations between higher p factor scores and both reduced gray matter volume of the visual association cortex and fractional anisotropy of pontine white matter pathways within the CTCC. In contrast, we failed to replicate prior associations between cerebellar structure and p factor scores. Collectively, our findings encourage further focus on the CTCC and visual association cortex as core neural substrates and potential biomarkers of general psychopathology.}, Doi = {10.1038/s41380-019-0621-z}, Key = {fds347350} } @article{fds347349, Author = {Elliott, ML and Belsky, DW and Knodt, AR and Ireland, D and Melzer, TR and Poulton, R and Ramrakha, S and Caspi, A and Moffitt, TE and Hariri, AR}, Title = {Brain-age in midlife is associated with accelerated biological aging and cognitive decline in a longitudinal birth cohort.}, Journal = {Molecular psychiatry}, Volume = {26}, Number = {8}, Pages = {3829-3838}, Year = {2021}, Month = {August}, url = {http://dx.doi.org/10.1038/s41380-019-0626-7}, Abstract = {An individual's brainAGE is the difference between chronological age and age predicted from machine-learning models of brain-imaging data. BrainAGE has been proposed as a biomarker of age-related deterioration of the brain. Having an older brainAGE has been linked to Alzheimer's, dementia, and mortality. However, these findings are largely based on cross-sectional associations which can confuse age differences with cohort differences. To illuminate the validity of brainAGE as a biomarker of accelerated brain aging, a study is needed of a large cohort all born in the same year who nevertheless vary on brainAGE. In the Dunedin Study, a population-representative 1972-73 birth cohort, we measured brainAGE at age 45 years, as well as the pace of biological aging and cognitive decline in longitudinal data from childhood to midlife (N = 869). In this cohort, all chronological age 45 years, brainAGE was measured reliably (ICC = 0.81) and ranged from 24 to 72 years. Those with older midlife brainAGEs tended to have poorer cognitive function in both adulthood and childhood, as well as impaired brain health at age 3. Furthermore, those with older brainAGEs had an accelerated pace of biological aging, older facial appearance, and early signs of cognitive decline from childhood to midlife. These findings help to validate brainAGE as a potential surrogate biomarker for midlife intervention studies that seek to measure dementia-prevention efforts in midlife. However, the findings also caution against the assumption that brainAGE scores represent only age-related deterioration of the brain as they may also index central nervous system variation present since childhood.}, Doi = {10.1038/s41380-019-0626-7}, Key = {fds347349} } @article{fds356131, Author = {Gehred, MZ and Knodt, AR and Ambler, A and Bourassa, KJ and Danese, A and Elliott, ML and Hogan, S and Ireland, D and Poulton, R and Ramrakha, S and Reuben, A and Sison, ML and Moffitt, TE and Hariri, AR and Caspi, A}, Title = {Long-term Neural Embedding of Childhood Adversity in a Population-Representative Birth Cohort Followed for 5 Decades.}, Journal = {Biological psychiatry}, Volume = {90}, Number = {3}, Pages = {182-193}, Year = {2021}, Month = {August}, url = {http://dx.doi.org/10.1016/j.biopsych.2021.02.971}, Abstract = {<h4>Background</h4>Childhood adversity has been previously associated with alterations in brain structure, but heterogeneous designs, methods, and measures have contributed to mixed results and have impeded progress in mapping the biological embedding of childhood adversity. We sought to identify long-term differences in structural brain integrity associated with childhood adversity.<h4>Methods</h4>Multiple regression was used to test associations between prospectively ascertained adversity during childhood and adversity retrospectively reported in adulthood with structural magnetic resonance imaging measures of midlife global and regional cortical thickness, cortical surface area, and subcortical gray matter volume in 861 (425 female) members of the Dunedin Study, a longitudinal investigation of a population-representative birth cohort.<h4>Results</h4>Both prospectively ascertained childhood adversity and retrospectively reported adversity were associated with alterations in midlife structural brain integrity, but associations with prospectively ascertained childhood adversity were consistently stronger and more widely distributed than associations with retrospectively reported childhood adversity. Sensitivity analyses revealed that these associations were not driven by any particular adversity or category of adversity (i.e., threat or deprivation) or by childhood socioeconomic disadvantage. Network enrichment analyses revealed that these associations were not localized but were broadly distributed along a hierarchical cortical gradient of information processing.<h4>Conclusions</h4>Exposure to childhood adversity broadly is associated with widespread differences in midlife gray matter across cortical and subcortical structures, suggesting that biological embedding of childhood adversity in the brain is long lasting, but not localized. Research using retrospectively reported adversity likely underestimates the magnitude of these associations. These findings may inform future research investigating mechanisms through which adversity becomes embedded in the brain and influences mental health and cognition.}, Doi = {10.1016/j.biopsych.2021.02.971}, Key = {fds356131} } @article{fds364967, Author = {Romer, AL and Hariri, AR and Strauman, TJ}, Title = {Regulatory focus and the p factor: Evidence for self-regulatory dysfunction as a transdiagnostic feature of general psychopathology.}, Journal = {Journal of psychiatric research}, Volume = {137}, Pages = {178-185}, Year = {2021}, Month = {May}, url = {http://dx.doi.org/10.1016/j.jpsychires.2021.02.051}, Abstract = {A general psychopathology ('p') factor captures transdiagnostic features of mental illness; however, the meaning of the p factor remains unclear. Regulatory focus theory postulates that individuals regulate goal pursuit either by maximizing gains (promotion) or minimizing losses (prevention). As maladaptive goal pursuit has been associated with multiple categorical disorders, we examined whether individual differences in promotion and prevention goal pursuit are associated with p as well as internalizing- and externalizing-specific factors using structural equation modeling of data from 1330 volunteers aged 18-22. Unsuccessful attainment of promotion and prevention goals was related to increased levels of p. Over and above relations with the p factor, unsuccessful attainment of promotion goals was associated with higher internalizing-specific psychopathology, whereas unsuccessful attainment of prevention goals was related to higher externalizing-specific psychopathology. These associations also were separable from related personality traits. After controlling for sex differences in the composition of the psychopathology factors, there were no sex differences in the relations between promotion and prevention goal pursuit and p and specific internalizing and externalizing factors. These findings suggest higher general psychopathology reflects poorer overall self-regulation of goal pursuit and that maladaptive promotion and prevention orientations also are associated with internalizing- and externalizing-specific psychopathology, respectively.}, Doi = {10.1016/j.jpsychires.2021.02.051}, Key = {fds364967} } @article{fds364968, Author = {Elliott, ML and Knodt, AR and Caspi, A and Moffitt, TE and Hariri, AR}, Title = {Need for Psychometric Theory in Neuroscience Research and Training: Reply to Kragel et al. (2021).}, Journal = {Psychological science}, Volume = {32}, Number = {4}, Pages = {627-629}, Year = {2021}, Month = {April}, url = {http://dx.doi.org/10.1177/0956797621996665}, Doi = {10.1177/0956797621996665}, Key = {fds364968} } @article{fds364216, Author = {Pfeiffer, JR and Bustamante, AC and Kim, GS and Armstrong, D and Knodt, AR and Koenen, KC and Hariri, AR and Uddin, M}, Title = {Associations between childhood family emotional health, fronto-limbic grey matter volume, and saliva 5mC in young adulthood.}, Journal = {Clinical epigenetics}, Volume = {13}, Number = {1}, Pages = {68}, Year = {2021}, Month = {March}, url = {http://dx.doi.org/10.1186/s13148-021-01056-y}, Abstract = {<h4>Background</h4>Poor family emotional health (FEH) during childhood is prevalent and impactful, and likely confers similar neurodevelopmental risks as other adverse social environments. Pointed FEH study efforts are underdeveloped, and the mechanisms by which poor FEH are biologically embedded are unclear. The current exploratory study examined whether variability in 5-methyl-cytosine (5mC) and fronto-limbic grey matter volume may represent pathways through which FEH may become biologically embedded.<h4>Results</h4>In 98 university students aged 18-22 years, retrospective self-reported childhood FEH was associated with right hemisphere hippocampus (b = 10.4, p = 0.005), left hemisphere amygdala (b = 5.3, p = 0.009), and right hemisphere amygdala (b = 5.8, p = 0.016) volumes. After pre-processing and filtering to 5mC probes correlated between saliva and brain, analyses showed that childhood FEH was associated with 49 5mC principal components (module eigengenes; MEs) (p<sub>range</sub> = 3 × 10<sup>-6</sup> to 0.047). Saliva-derived 5mC MEs partially mediated the association between FEH and right hippocampal volume (Burlywood ME indirect effect b = - 111, p = 0.014), and fully mediated the FEH and right amygdala volume relationship (Pink4 ME indirect effect b = - 48, p = 0.026). Modules were enriched with probes falling in genes with immune, central nervous system (CNS), cellular development/differentiation, and metabolic functions.<h4>Conclusions</h4>Findings extend work highlighting neurodevelopmental variability associated with adverse social environment exposure during childhood by specifically implicating poor FEH, while informing a mechanism of biological embedding. FEH-associated epigenetic signatures could function as proxies of altered fronto-limbic grey matter volume associated with poor childhood FEH and inform further investigation into primarily affected tissues such as endocrine, immune, and CNS cell types.}, Doi = {10.1186/s13148-021-01056-y}, Key = {fds364216} } @article{fds364162, Author = {Elliott, ML and Caspi, A and Houts, RM and Ambler, A and Broadbent, JM and Hancox, RJ and Harrington, H and Hogan, S and Keenan, R and Knodt, A and Leung, JH and Melzer, TR and Purdy, SC and Ramrakha, S and Richmond-Rakerd, LS and Righarts, A and Sugden, K and Thomson, WM and Thorne, PR and Williams, BS and Wilson, G and Hariri, AR and Poulton, R and Moffitt, TE}, Title = {Disparities in the pace of biological aging among midlife adults of the same chronological age have implications for future frailty risk and policy.}, Journal = {Nature aging}, Volume = {1}, Number = {3}, Pages = {295-308}, Year = {2021}, Month = {March}, url = {http://dx.doi.org/10.1038/s43587-021-00044-4}, Abstract = {Some humans age faster than others. Variation in biological aging can be measured in midlife, but the implications of this variation are poorly understood. We tested associations between midlife biological aging and indicators of future frailty-risk in the Dunedin cohort of 1037 infants born the same year and followed to age 45. Participants' Pace of Aging was quantified by tracking declining function in 19 biomarkers indexing the cardiovascular, metabolic, renal, immune, dental, and pulmonary systems across ages 26, 32, 38, and 45 years. At age 45 in 2019, participants with faster Pace of Aging had more cognitive difficulties, signs of advanced brain aging, diminished sensory-motor functions, older appearance, and more pessimistic perceptions of aging. People who are aging more rapidly than same-age peers in midlife may prematurely need supports to sustain independence that are usually reserved for older adults. Chronological age does not adequately identify need for such supports.}, Doi = {10.1038/s43587-021-00044-4}, Key = {fds364162} } @article{fds364217, Author = {Mareckova, K and Hawco, C and Santos, FCD and Bakht, A and Calarco, N and Miles, AE and Voineskos, AN and Sibille, E and Hariri, AR and Nikolova, YS}, Title = {Correction: Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms.}, Journal = {Translational psychiatry}, Volume = {11}, Number = {1}, Pages = {152}, Year = {2021}, Month = {March}, url = {http://dx.doi.org/10.1038/s41398-021-01277-y}, Doi = {10.1038/s41398-021-01277-y}, Key = {fds364217} } @article{fds364969, Author = {Romer, AL and Elliott, ML and Knodt, AR and Sison, ML and Ireland, D and Houts, R and Ramrakha, S and Poulton, R and Keenan, R and Melzer, TR and Moffitt, TE and Caspi, A and Hariri, AR}, Title = {Pervasively Thinner Neocortex as a Transdiagnostic Feature of General Psychopathology.}, Journal = {The American journal of psychiatry}, Volume = {178}, Number = {2}, Pages = {174-182}, Year = {2021}, Month = {February}, url = {http://dx.doi.org/10.1176/appi.ajp.2020.19090934}, Abstract = {<h4>Objective</h4>Neuroimaging research has revealed that structural brain alterations are common across broad diagnostic families of disorders rather than specific to a single psychiatric disorder. Such overlap in the structural brain correlates of mental disorders mirrors already well-documented phenotypic comorbidity of psychiatric symptoms and diagnoses, which can be indexed by a general psychopathology or <i>p</i> factor. The authors hypothesized that if general psychopathology drives the convergence of structural alterations common across disorders, then 1) there should be few associations unique to any one diagnostic family of disorders, and 2) associations with the <i>p</i> factor should overlap with those for the broader diagnostic families.<h4>Methods</h4>Analyses were conducted on structural MRI and psychopathology data collected from 861 members of the population-representative Dunedin Multidisciplinary Health and Development Study at age 45.<h4>Results</h4>Study members with high scores across three broad diagnostic families of disorders (externalizing, internalizing, thought disorder) exhibited highly overlapping patterns of reduced global and widely distributed parcel-wise neocortical thickness. Study members with high <i>p</i> factor scores exhibited patterns of reduced global and parcel-wise neocortical thickness nearly identical to those associated with the three broad diagnostic families.<h4>Conclusions</h4>A pattern of pervasively reduced neocortical thickness appears to be common across all forms of mental disorders and may represent a transdiagnostic feature of general psychopathology. As has been documented with regard to symptoms and diagnoses, the underlying brain structural correlates of mental disorders may not exhibit specificity, and the continued pursuit of such specific correlates may limit progress toward more effective strategies for etiological understanding, prevention, and intervention.}, Doi = {10.1176/appi.ajp.2020.19090934}, Key = {fds364969} } @article{fds364181, Author = {Richmond-Rakerd, LS and Caspi, A and Ambler, A and d'Arbeloff, T and de Bruine, M and Elliott, M and Harrington, H and Hogan, S and Houts, RM and Ireland, D and Keenan, R and Knodt, AR and Melzer, TR and Park, S and Poulton, R and Ramrakha, S and Rasmussen, LJH and Sack, E and Schmidt, AT and Sison, ML and Wertz, J and Hariri, AR and Moffitt, TE}, Title = {Childhood self-control forecasts the pace of midlife aging and preparedness for old age.}, Journal = {Proceedings of the National Academy of Sciences of the United States of America}, Volume = {118}, Number = {3}, Pages = {e2010211118}, Year = {2021}, Month = {January}, url = {http://dx.doi.org/10.1073/pnas.2010211118}, Abstract = {The ability to control one's own emotions, thoughts, and behaviors in early life predicts a range of positive outcomes in later life, including longevity. Does it also predict how well people age? We studied the association between self-control and midlife aging in a population-representative cohort of children followed from birth to age 45 y, the Dunedin Study. We measured children's self-control across their first decade of life using a multi-occasion/multi-informant strategy. We measured their pace of aging and aging preparedness in midlife using measures derived from biological and physiological assessments, structural brain-imaging scans, observer ratings, self-reports, informant reports, and administrative records. As adults, children with better self-control aged more slowly in their bodies and showed fewer signs of aging in their brains. By midlife, these children were also better equipped to manage a range of later-life health, financial, and social demands. Associations with children's self-control could be separated from their social class origins and intelligence, indicating that self-control might be an active ingredient in healthy aging. Children also shifted naturally in their level of self-control across adult life, suggesting the possibility that self-control may be a malleable target for intervention. Furthermore, individuals' self-control in adulthood was associated with their aging outcomes after accounting for their self-control in childhood, indicating that midlife might offer another window of opportunity to promote healthy aging.}, Doi = {10.1073/pnas.2010211118}, Key = {fds364181} } @article{fds364146, Author = {d'Arbeloff, T and Elliott, ML and Knodt, AR and Sison, M and Melzer, TR and Ireland, D and Ramrakha, S and Poulton, R and Caspi, A and Moffitt, TE and Hariri, AR}, Title = {Midlife Cardiovascular Fitness Is Reflected in the Brain's White Matter.}, Journal = {Frontiers in aging neuroscience}, Volume = {13}, Pages = {652575}, Year = {2021}, Month = {January}, url = {http://dx.doi.org/10.3389/fnagi.2021.652575}, Abstract = {Disappointing results from clinical trials designed to delay structural brain decline and the accompanying increase in risk for dementia in older adults have precipitated a shift in testing promising interventions from late in life toward midlife before irreversible damage has accumulated. This shift, however, requires targeting midlife biomarkers that are associated with clinical changes manifesting only in late life. Here we explored possible links between one putative biomarker, distributed integrity of brain white matter, and two intervention targets, cardiovascular fitness and healthy lifestyle behaviors, in midlife. At age 45, fractional anisotropy (FA) derived from diffusion weighted MRI was used to estimate the microstructural integrity of distributed white matter tracts in a population-representative birth cohort. Age-45 cardiovascular fitness (VO<sub>2</sub>Max; <i>N</i> = 801) was estimated from heart rates obtained during submaximal exercise tests; age-45 healthy lifestyle behaviors were estimated using the Nyberg Health Index (<i>N</i> = 854). Ten-fold cross-validated elastic net predictive modeling revealed that estimated VO<sub>2</sub>Max was modestly associated with distributed FA. In contrast, there was no significant association between Nyberg Health Index scores and FA. Our findings suggest that cardiovascular fitness levels, but not healthy lifestyle behaviors, are associated with the distributed integrity of white matter in the brain in midlife. These patterns could help inform future clinical intervention research targeting ADRDs.}, Doi = {10.3389/fnagi.2021.652575}, Key = {fds364146} } @article{fds364970, Author = {Rasmussen, LJH and Caspi, A and Ambler, A and Danese, A and Elliott, M and Eugen-Olsen, J and Hariri, AR and Harrington, H and Houts, R and Poulton, R and Ramrakha, S and Sugden, K and Williams, B and Moffitt, TE}, Title = {Association Between Elevated suPAR, a New Biomarker of Inflammation, and Accelerated Aging.}, Journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, Volume = {76}, Number = {2}, Pages = {318-327}, Year = {2021}, Month = {January}, url = {http://dx.doi.org/10.1093/gerona/glaa178}, Abstract = {<h4>Background</h4>To understand and measure the association between chronic inflammation, aging, and age-related diseases, broadly applicable standard biomarkers of systemic chronic inflammation are needed. We tested whether elevated blood levels of the emerging chronic inflammation marker soluble urokinase plasminogen activator receptor (suPAR) were associated with accelerated aging, lower functional capacity, and cognitive decline.<h4>Methods</h4>We used data from the Dunedin Study, a population-representative 1972-1973 New Zealand birth cohort (n = 1037) that has observed participants to age 45 years. Plasma suPAR levels were analyzed at ages 38 and 45 years. We performed regression analyses adjusted for sex, smoking, C-reactive protein, and current health conditions.<h4>Results</h4>Of 997 still-living participants, 875 (88%) had plasma suPAR measured at age 45. Elevated suPAR was associated with accelerated pace of biological aging across multiple organ systems, older facial appearance, and with structural signs of older brain age. Moreover, participants with higher suPAR levels had greater decline in physical function and cognitive function from childhood to adulthood compared to those with lower suPAR levels. Finally, improvements in health habits between ages 38 and 45 (smoking cessation or increased physical activity) were associated with less steep increases in suPAR levels over those years.<h4>Conclusions</h4>Our findings provide initial support for the utility of suPAR in studying the role of chronic inflammation in accelerated aging and functional decline.}, Doi = {10.1093/gerona/glaa178}, Key = {fds364970} } @article{fds354222, Author = {Gianaros, PJ and Kraynak, TE and Kuan, DC-H and Gross, JJ and McRae, K and Hariri, AR and Manuck, SB and Rasero, J and Verstynen, TD}, Title = {Affective brain patterns as multivariate neural correlates of cardiovascular disease risk.}, Journal = {Social cognitive and affective neuroscience}, Volume = {15}, Number = {10}, Pages = {1034-1045}, Year = {2020}, Month = {November}, url = {http://dx.doi.org/10.1093/scan/nsaa050}, Abstract = {This study tested whether brain activity patterns evoked by affective stimuli relate to individual differences in an indicator of pre-clinical atherosclerosis: carotid artery intima-media thickness (CA-IMT). Adults (aged 30-54 years) completed functional magnetic resonance imaging (fMRI) tasks that involved viewing three sets of affective stimuli. Two sets included facial expressions of emotion, and one set included neutral and unpleasant images from the International Affective Picture System (IAPS). Cross-validated, multivariate and machine learning models showed that individual differences in CA-IMT were partially predicted by brain activity patterns evoked by unpleasant IAPS images, even after accounting for age, sex and known cardiovascular disease risk factors. CA-IMT was also predicted by brain activity patterns evoked by angry and fearful faces from one of the two stimulus sets of facial expressions, but this predictive association did not persist after accounting for known cardiovascular risk factors. The reliability (internal consistency) of brain activity patterns evoked by affective stimuli may have constrained their prediction of CA-IMT. Distributed brain activity patterns could comprise affective neural correlates of pre-clinical atherosclerosis; however, the interpretation of such correlates may depend on their psychometric properties, as well as the influence of other cardiovascular risk factors and specific affective cues.}, Doi = {10.1093/scan/nsaa050}, Key = {fds354222} } @article{fds364139, Author = {Reuben, A and Elliott, ML and Abraham, WC and Broadbent, J and Houts, RM and Ireland, D and Knodt, AR and Poulton, R and Ramrakha, S and Hariri, AR and Caspi, A and Moffitt, TE}, Title = {Association of Childhood Lead Exposure With MRI Measurements of Structural Brain Integrity in Midlife.}, Journal = {JAMA}, Volume = {324}, Number = {19}, Pages = {1970-1979}, Year = {2020}, Month = {November}, url = {http://dx.doi.org/10.1001/jama.2020.19998}, Abstract = {<h4>Importance</h4>Childhood lead exposure has been linked to disrupted brain development, but long-term consequences for structural brain integrity are unknown.<h4>Objective</h4>To test the hypothesis that childhood lead exposure is associated with magnetic resonance imaging (MRI) measurements of lower structural integrity of the brain in midlife.<h4>Design, setting, and participants</h4>The Dunedin Study followed a population-representative 1972-1973 birth cohort in New Zealand (N = 564 analytic sample) to age 45 years (until April 2019).<h4>Exposures</h4>Childhood blood lead levels measured at age 11 years.<h4>Main outcomes and measures</h4>Structural brain integrity at age 45 years assessed via MRI (primary outcomes): gray matter (cortical thickness, surface area, hippocampal volume), white matter (white matter hyperintensities, fractional anisotropy [theoretical range, 0 {diffusion is perfectly isotropic} to 100 {diffusion is perfectly anisotropic}]), and the Brain Age Gap Estimation (BrainAGE), a composite index of the gap between chronological age and a machine learning algorithm-estimated brain age (0 indicates a brain age equivalent to chronological age; positive and negative values represent an older and younger brain age, respectively). Cognitive function at age 45 years was assessed objectively via the Wechsler Adult Intelligence Scale IV (IQ range, 40-160, standardized to a mean of 100 [SD, 15]) and subjectively via informant and self-reports (z-score units; scale mean, 0 [SD, 1]).<h4>Results</h4>Of 1037 original participants, 997 were alive at age 45 years, of whom 564 (57%) had received lead testing at age 11 years (302 [54%] male) (median follow-up, 34 [interquartile range, 33.7-34.7] years). Mean blood lead level at age 11 years was 10.99 (SD, 4.63) μg/dL. After adjusting for covariates, each 5-μg/dL higher childhood blood lead level was significantly associated with 1.19-cm2 smaller cortical surface area (95% CI, -2.35 to -0.02 cm2; P = .05), 0.10-cm3 smaller hippocampal volume (95% CI, -0.17 to -0.03 cm3; P = .006), lower global fractional anisotropy (b = -0.12; 95% CI, -0.24 to -0.01; P = .04), and a BrainAGE index 0.77 years older (95% CI, 0.02-1.51 years; P = .05) at age 45 years. There were no statistically significant associations between blood lead level and log-transformed white matter hyperintensity volume (b = 0.05 log mm3; 95% CI, -0.02 to 0.13 log mm3; P = .17) or mean cortical thickness (b = -0.004 mm; 95% CI, -0.012 to 0.004 mm; P = .39). Each 5-μg/dL higher childhood blood lead level was significantly associated with a 2.07-point lower IQ score at age 45 years (95% CI, -3.39 to -0.74; P = .002) and a 0.12-point higher score on informant-rated cognitive problems (95% CI, 0.01-0.23; P = .03). There was no statistically significant association between childhood blood lead levels and self-reported cognitive problems (b = -0.02 points; 95% CI, -0.10 to 0.07; P = .68).<h4>Conclusions and relevance</h4>In this longitudinal cohort study with a median 34-year follow-up, higher childhood blood lead level was associated with differences in some MRI measures of brain structure that suggested lower structural brain integrity in midlife. Because of the large number of statistical comparisons, some findings may represent type I error.}, Doi = {10.1001/jama.2020.19998}, Key = {fds364139} } @article{fds364218, Author = {Mareckova, K and Hawco, C and Dos Santos and FC and Bakht, A and Calarco, N and Miles, AE and Voineskos, AN and Sibille, E and Hariri, AR and Nikolova, YS}, Title = {Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms.}, Journal = {Translational psychiatry}, Volume = {10}, Number = {1}, Pages = {410}, Year = {2020}, Month = {November}, url = {http://dx.doi.org/10.1038/s41398-020-01093-w}, Abstract = {Convergent data from imaging and postmortem brain transcriptome studies implicate corticolimbic circuit (CLC) dysregulation in the pathophysiology of depression. To more directly bridge these lines of work, we generated a novel transcriptome-based polygenic risk score (T-PRS), capturing subtle shifts toward depression-like gene expression patterns in key CLC regions, and mapped this T-PRS onto brain function and related depressive symptoms in a nonclinical sample of 478 young adults (225 men; age 19.79 +/- 1.24) from the Duke Neurogenetics Study. First, T-PRS was generated based on common functional SNPs shifting CLC gene expression toward a depression-like state. Next, we used multivariate partial least squares regression to map T-PRS onto whole-brain activity patterns during perceptual processing of social stimuli (i.e., human faces). For validation, we conducted a comparative analysis with a PRS summarizing depression risk variants identified by the Psychiatric Genomics Consortium (PGC-PRS). Sex was modeled as moderating factor. We showed that T-PRS was associated with widespread reductions in neural response to neutral faces in women and to emotional faces and shapes in men (multivariate p < 0.01). This female-specific reductions in neural response to neutral faces was also associated with PGC-PRS (multivariate p < 0.03). Reduced reactivity to neutral faces was further associated with increased self-reported anhedonia. We conclude that women with functional alleles mimicking the postmortem transcriptomic CLC signature of depression have blunted neural activity to social stimuli, which may be expressed as higher anhedonia.}, Doi = {10.1038/s41398-020-01093-w}, Key = {fds364218} } @article{fds364140, Author = {d'Arbeloff, T and Cooke, M and Knodt, AR and Sison, M and Melzer, TR and Ireland, D and Poulton, R and Ramrakha, S and Moffitt, TE and Caspi, A and Hariri, AR}, Title = {Is cardiovascular fitness associated with structural brain integrity in midlife? Evidence from a population-representative birth cohort study.}, Journal = {Aging}, Volume = {12}, Number = {20}, Pages = {20888-20914}, Year = {2020}, Month = {October}, url = {http://dx.doi.org/10.18632/aging.104112}, Abstract = {Improving cardiovascular fitness may buffer against age-related cognitive decline and mitigate dementia risk by staving off brain atrophy. However, it is unclear if such effects reflect factors operating in childhood (neuroselection) or adulthood (neuroprotection). Using data from 807 members of the Dunedin Study, a population-representative birth cohort, we investigated associations between cardiovascular fitness and structural brain integrity at age 45, and the extent to which associations reflected possible neuroselection or neuroprotection by controlling for childhood IQ. Higher fitness, as indexed by VO<sub>2</sub>Max, was not associated with average cortical thickness, total surface area, or subcortical gray matter volume including the hippocampus. However, higher fitness was associated with thicker cortex in prefrontal and temporal regions as well as greater cerebellar gray matter volume. Higher fitness was also associated with decreased hippocampal fissure volume. These associations were unaffected by the inclusion of childhood IQ in analyses. In contrast, a higher rate of decline in cardiovascular fitness from 26 to 45 years was not robustly associated with structural brain integrity. Our findings are consistent with a neuroprotective account of adult cardiovascular fitness but suggest that effects are not uniformly observed across the brain and reflect contemporaneous fitness more so than decline over time.}, Doi = {10.18632/aging.104112}, Key = {fds364140} } @article{fds364219, Author = {Avinun, R and Israel, S and Knodt, AR and Hariri, AR}, Title = {Little evidence for associations between the Big Five personality traits and variability in brain gray or white matter.}, Journal = {NeuroImage}, Volume = {220}, Pages = {117092}, Year = {2020}, Month = {October}, url = {http://dx.doi.org/10.1016/j.neuroimage.2020.117092}, Abstract = {Attempts to link the Big Five personality traits of Openness-to-Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism with variability in trait-like features of brain structure have produced inconsistent results. Small sample sizes and heterogeneous methodology have been suspected in driving these inconsistencies. Here, using data collected from 1,107 university students (636 women, mean age 19.69 ± 1.24 years), representing the largest sample to date of unrelated individuals, we tested for associations between the Big Five personality traits and measures of cortical thickness and surface area, subcortical volume, and white matter microstructural integrity. In addition to replication analyses based on a prior study, we conducted exploratory whole-brain analyses. Four supplementary analyses were also conducted to examine 1) possible associations with lower-order facets of personality; 2) modulatory effects of sex; 3) effect of controlling for non-target personality traits; and 4) parcellation scheme effects. Our analyses failed to identify significant associations between the Big Five personality traits and brain morphometry, except for a weak association between greater surface area of the superior temporal gyrus and lower conscientiousness scores. As the latter association is not supported by previous studies, it should be treated with caution. Our supplementary analyses mirrored these predominantly null findings, suggesting they were not substantively biased by our analytic choices. Collectively, these results indicate that if there are associations between the Big Five personality traits and brain structure, they are likely of very small effect size and will require very large samples for reliable detection.}, Doi = {10.1016/j.neuroimage.2020.117092}, Key = {fds364219} } @article{fds350143, Author = {Elliott, ML and Knodt, AR and Ireland, D and Morris, ML and Poulton, R and Ramrakha, S and Sison, ML and Moffitt, TE and Caspi, A and Hariri, AR}, Title = {What Is the Test-Retest Reliability of Common Task-Functional MRI Measures? New Empirical Evidence and a Meta-Analysis.}, Journal = {Psychological science}, Volume = {31}, Number = {7}, Pages = {792-806}, Year = {2020}, Month = {July}, url = {http://dx.doi.org/10.1177/0956797620916786}, Abstract = {Identifying brain biomarkers of disease risk is a growing priority in neuroscience. The ability to identify meaningful biomarkers is limited by measurement reliability; unreliable measures are unsuitable for predicting clinical outcomes. Measuring brain activity using task functional MRI (fMRI) is a major focus of biomarker development; however, the reliability of task fMRI has not been systematically evaluated. We present converging evidence demonstrating poor reliability of task-fMRI measures. First, a meta-analysis of 90 experiments (<i>N</i> = 1,008) revealed poor overall reliability-mean intraclass correlation coefficient (ICC) = .397. Second, the test-retest reliabilities of activity in a priori regions of interest across 11 common fMRI tasks collected by the Human Connectome Project (<i>N</i> = 45) and the Dunedin Study (<i>N</i> = 20) were poor (ICCs = .067-.485). Collectively, these findings demonstrate that common task-fMRI measures are not currently suitable for brain biomarker discovery or for individual-differences research. We review how this state of affairs came to be and highlight avenues for improving task-fMRI reliability.}, Doi = {10.1177/0956797620916786}, Key = {fds350143} } @article{fds364220, Author = {Baranger, DAA and Few, LR and Sheinbein, DH and Agrawal, A and Oltmanns, TF and Knodt, AR and Barch, DM and Hariri, AR and Bogdan, R}, Title = {Borderline Personality Traits Are Not Correlated With Brain Structure in Two Large Samples.}, Journal = {Biological psychiatry. Cognitive neuroscience and neuroimaging}, Volume = {5}, Number = {7}, Pages = {669-677}, Year = {2020}, Month = {July}, url = {http://dx.doi.org/10.1016/j.bpsc.2020.02.006}, Abstract = {<h4>Background</h4>Borderline personality disorder is associated with severe psychiatric presentations and has been linked to variability in brain structure. Dimensional models of borderline personality traits (BPTs) have become influential; however, associations between BPTs and brain structure remain poorly understood.<h4>Methods</h4>We tested whether BPTs are associated with regional cortical thickness, cortical surface area, and subcortical volumes (n = 152 brain structure metrics) in data from the Duke Neurogenetics Study (n = 1299) and Human Connectome Project (n = 1099). Positive control analyses tested whether BPTs are associated with related behaviors (e.g., suicidal thoughts and behaviors, psychiatric diagnoses) and experiences (e.g., adverse childhood experiences).<h4>Results</h4>While BPTs were robustly associated with all positive control measures, they were not significantly associated with any brain structure metrics in the Duke Neurogenetics Study or Human Connectome Project, or in a meta-analysis of both samples. The strongest findings from the meta-analysis showed a positive association between BPTs and volumes of the left ventral diencephalon and thalamus (p values < .005 uncorrected, p values > .1 false discovery rate-corrected). Contrasting high and low BPT decile groups (n = 552) revealed no false discovery rate-significant associations with brain structure.<h4>Conclusions</h4>We find replicable evidence that BPTs are not associated with brain structure despite being correlated with independent behavioral measures. Prior reports linking brain morphology to borderline personality disorder may be driven by factors other than traits (e.g., severe presentations, comorbid conditions, severe childhood adversity, or medication) or reflect false positives. The etiology or consequences of BPTs may not be attributable to brain structure measured via magnetic resonance imaging. Future studies of BPTs will require much larger sample sizes to detect these very small effects.}, Doi = {10.1016/j.bpsc.2020.02.006}, Key = {fds364220} } @article{fds343722, Author = {Puetz, VB and Viding, E and Gerin, MI and Pingault, J-B and Sethi, A and Knodt, AR and Radtke, SR and Brigidi, BD and Hariri, AR and McCrory, E}, Title = {Investigating patterns of neural response associated with childhood abuse v. childhood neglect - Corrigendum.}, Journal = {Psychological medicine}, Volume = {50}, Number = {8}, Pages = {1408}, Year = {2020}, Month = {June}, url = {http://dx.doi.org/10.1017/s0033291719001752}, Abstract = {<h4>Background</h4>Childhood maltreatment is robustly associated with increased risk of poor mental health outcome and changes in brain function. The authors investigated whether childhood experience of abuse (e.g. physical, emotional and sexual abuse) and neglect (physical and emotional deprivation) was differentially associated with neural reactivity to threat.<h4>Methods</h4>Participants were drawn from an existing study and allocated to one of four groups based on self-report of childhood maltreatment experience: individuals with childhood abuse experiences (n = 70); individuals with childhood neglect experiences (n = 87); individuals with combined experience of childhood abuse and neglect (n = 50); and non-maltreated individuals (n = 207) propensity score matched (PSM) on gender, age, IQ, psychopathology and SES. Neural reactivity to facial cues signalling threat was compared across groups, allowing the differential effects associated with particular forms of maltreatment experience to be isolated.<h4>Results</h4>Brain imaging analyses indicated that while childhood abuse was associated with heightened localised threat reactivity in ventral amygdala, experiences of neglect were associated with heightened reactivity in a distributed cortical fronto-parietal network supporting complex social and cognitive processing as well as in the dorsal amygdala. Unexpectedly, combined experiences of abuse and neglect were associated with hypo-activation in several higher-order cortical regions as well as the amygdala.<h4>Conclusions</h4>Different forms of childhood maltreatment exert differential effects in neural threat reactivity: while the effects of abuse are more focal, the effects of neglect and combined experiences of abuse are more distributed. These findings are relevant for understanding the range of psychiatric outcomes following childhood maltreatment and have implications for intervention.}, Doi = {10.1017/s0033291719001752}, Key = {fds343722} } @article{fds347193, Author = {Baranger, DAA and Demers, CH and Elsayed, NM and Knodt, AR and Radtke, SR and Desmarais, A and Few, LR and Agrawal, A and Heath, AC and Barch, DM and Squeglia, LM and Williamson, DE and Hariri, AR and Bogdan, R}, Title = {Convergent Evidence for Predispositional Effects of Brain Gray Matter Volume on Alcohol Consumption.}, Journal = {Biological psychiatry}, Volume = {87}, Number = {7}, Pages = {645-655}, Year = {2020}, Month = {April}, url = {http://dx.doi.org/10.1016/j.biopsych.2019.08.029}, Abstract = {<h4>Background</h4>Alcohol use has been reliably associated with smaller subcortical and cortical regional gray matter volumes (GMVs). Whether these associations reflect shared predisposing risk factors or causal consequences of alcohol use remains poorly understood.<h4>Methods</h4>Data came from 3 neuroimaging samples (N = 2423), spanning childhood or adolescence to middle age, with prospective or family-based data. First, we identified replicable GMV correlates of alcohol use. Next, we used family-based and longitudinal data to test whether these associations may plausibly reflect a predispositional liability for alcohol use or a causal consequence of alcohol use. Finally, we used heritability, gene-set enrichment, and transcriptome-wide association study approaches to evaluate whether genome-wide association study-defined genomic risk for alcohol consumption is enriched for genes that are preferentially expressed in regions that were identified in our neuroimaging analyses.<h4>Results</h4>Smaller right dorsolateral prefrontal cortex (DLPFC) (i.e., middle and superior frontal gyri) and insula GMVs were associated with increased alcohol use across samples. Family-based and prospective longitudinal data suggest that these associations are genetically conferred and that DLPFC GMV prospectively predicts future use and initiation. Genomic risk for alcohol use was enriched in gene sets that were preferentially expressed in the DLPFC and was associated with replicable differential gene expression in the DLPFC.<h4>Conclusions</h4>These data suggest that smaller DLPFC and insula GMV plausibly represent genetically conferred predispositional risk factors for, as opposed to consequences of, alcohol use. DLPFC and insula GMV represent promising biomarkers for alcohol-consumption liability and related psychiatric and behavioral phenotypes.}, Doi = {10.1016/j.biopsych.2019.08.029}, Key = {fds347193} } @article{fds364147, Author = {Wallace, GL and Richard, E and Peng, CS and Knodt, AR and Hariri, AR}, Title = {Subclinical eating disorder traits are correlated with cortical thickness in regions associated with food reward and perception.}, Journal = {Brain imaging and behavior}, Volume = {14}, Number = {2}, Pages = {346-352}, Year = {2020}, Month = {April}, url = {http://dx.doi.org/10.1007/s11682-018-0007-x}, Abstract = {Behavioral traits associated with various forms of psychopathology are conceptualized as dimensional, varying from those present in a frank disorder to subclinical expression. Demonstrating links between these behavioral traits and neurobiological indicators, such as brain structure, provides one form of validation for this view. However, unlike behavioral dimensions associated with other forms of psychopathology (e.g., autism spectrum disorder, attention deficit hyperactivity disorder, antisocial disorders), eating disorder traits have not been investigated in this manner in spite of the potential that such an approach has to elucidate etiological mechanisms. Therefore, we examined for the first time neural endophenotypes of Anorexia Nervosa and Bulimia via dimensional traits (measured using the Eating Disorders Inventory-3) in a large subclinical sample of young adults (n = 456 and n = 247, respectively; ages = 18-22 years) who each provided a structural magnetic resonance imaging scan. Cortical thickness was quantified at 81,924 vertices across the cortical surface. We found: 1) increasing eating disorder traits correlated with thinner cortex in the insula and orbitofrontal cortex, among other regions, and 2) using these regions as seeds, increasing eating disorder trait scores negatively modulated structural covariance between these seed regions and other cortical regions linked to regulatory and sensorimotor functions (e.g., frontal and temporal cortices). These findings parallel those found in the clinical literature (i.e., thinner cortex in these food-related regions in individuals with eating disorders) and therefore provide evidence supporting the dimensional view of behavioral traits associated with eating disorders. Extending this approach to genetic and neuroimaging genetics studies holds promise to inform etiology.}, Doi = {10.1007/s11682-018-0007-x}, Key = {fds364147} } @article{fds364971, Author = {Caspi, A and Houts, RM and Ambler, A and Danese, A and Elliott, ML and Hariri, A and Harrington, H and Hogan, S and Poulton, R and Ramrakha, S and Rasmussen, LJH and Reuben, A and Richmond-Rakerd, L and Sugden, K and Wertz, J and Williams, BS and Moffitt, TE}, Title = {Longitudinal Assessment of Mental Health Disorders and Comorbidities Across 4 Decades Among Participants in the Dunedin Birth Cohort Study.}, Journal = {JAMA network open}, Volume = {3}, Number = {4}, Pages = {e203221}, Year = {2020}, Month = {April}, url = {http://dx.doi.org/10.1001/jamanetworkopen.2020.3221}, Abstract = {<h4>Importance</h4>Mental health professionals typically encounter patients at 1 point in patients' lives. This cross-sectional window understandably fosters focus on the current presenting diagnosis. Research programs, treatment protocols, specialist clinics, and specialist journals are oriented to presenting diagnoses, on the assumption that diagnosis informs about causes and prognosis. This study tests an alternative hypothesis: people with mental disorders experience many different kinds of disorders across diagnostic families, when followed for 4 decades.<h4>Objective</h4>To describe mental disorder life histories across the first half of the life course.<h4>Design, setting, and participants</h4>This cohort study involved participants born in New Zealand from 1972 to 1973 who were enrolled in the population-representative Dunedin Study. Participants were observed from birth to age 45 years (until April 2019). Data were analyzed from May 2019 to January 2020.<h4>Main outcomes and measures</h4>Diagnosed impairing disorders were assessed 9 times from ages 11 to 45 years. Brain function was assessed through neurocognitive examinations conducted at age 3 years, neuropsychological testing during childhood and adulthood, and midlife neuroimaging-based brain age.<h4>Results</h4>Of 1037 original participants (535 male [51.6%]), 1013 had mental health data available. The proportions of participants meeting the criteria for a mental disorder were as follows: 35% (346 of 975) at ages 11 to 15 years, 50% (473 of 941) at age 18 years, 51% (489 of 961) at age 21 years, 48% (472 of 977) at age 26 years, 46% (444 of 969) at age 32 years, 45% (429 of 955) at age 38 years, and 44% (407 of 927) at age 45 years. The onset of the disorder occurred by adolescence for 59% of participants (600 of 1013), eventually affecting 86% of the cohort (869 of 1013) by midlife. By age 45 years, 85% of participants (737 of 869) with a disorder had accumulated comorbid diagnoses. Participants with adolescent-onset disorders subsequently presented with disorders at more past-year assessments (r = 0.71; 95% CI, 0.68 to 0.74; P < .001) and met the criteria for more diverse disorders (r = 0.64; 95% CI, 0.60 to 0.67; P < .001). Confirmatory factor analysis summarizing mental disorder life histories across 4 decades identified a general factor of psychopathology, the p-factor. Longitudinal analyses showed that high p-factor scores (indicating extensive mental disorder life histories) were antedated by poor neurocognitive functioning at age 3 years (r = -0.18; 95% CI, -0.24 to -0.12; P < .001), were accompanied by childhood-to-adulthood cognitive decline (r = -0.11; 95% CI, -0.17 to -0.04; P < .001), and were associated with older brain age at midlife (r = 0.14; 95% CI, 0.07 to 0.20; P < .001).<h4>Conclusions and relevance</h4>These findings suggest that mental disorder life histories shift among different successive disorders. Data from the present study, alongside nationwide data from Danish health registers, inform a life-course perspective on mental disorders. This perspective cautions against overreliance on diagnosis-specific research and clinical protocols.}, Doi = {10.1001/jamanetworkopen.2020.3221}, Key = {fds364971} } @article{fds344832, Author = {Avinun, R and Nevo, A and Radtke, SR and Brigidi, BD and Hariri, AR}, Title = {Divergence of an association between depressive symptoms and a dopamine polygenic score in Caucasians and Asians.}, Journal = {European archives of psychiatry and clinical neuroscience}, Volume = {270}, Number = {2}, Pages = {229-235}, Year = {2020}, Month = {March}, url = {http://dx.doi.org/10.1007/s00406-019-01040-x}, Abstract = {A recent study reported a negative association between a putatively functional dopamine (DA) polygenic score, indexing higher levels of DA signaling, and depressive symptoms. We attempted to replicate this association using data from the Duke Neurogenetics Study. Our replication attempt was made in a subsample of 520 non-Hispanic Caucasian volunteers (277 women, mean age 19.78 ± 1.24 years). The DA polygenic score was based on the following five loci: rs27072 (SLC6A3/DAT1), rs4532 (DRD1), rs1800497 (DRD2/ANKK1), rs6280 (DRD3), and rs4680 (COMT). Because the discovery sample in the original study consisted mostly of Asian participants, we also conducted a post hoc analysis in a smaller subsample of Asian volunteers (N = 316, 179 women, mean age 19.61 ± 1.32 years). In the primary sample of non-Hispanic Caucasians, a linear regression analysis controlling for sex, age, socioeconomic status (SES), body mass index, genetic ancestry, and both early and recent life stress, revealed that higher DA polygenic scores were associated with higher self-reported symptoms of depression. This was in contrast to the original association of higher DA polygenic scores and lower depressive symptoms. However, the direction of the association in our Asian subsample was consistent with this original finding. Our results also suggested that compared to the Asian subsample, the non-Hispanic Caucasian subsample was characterized by higher SES, lower early and recent life stress, and lower depressive symptoms. These differences may have contributed to the observed divergence in associations. Collectively, the current findings add to evidence that specific genetic associations may differ between populations and further encourage explicit modeling of race/ethnicity in examining the polygenic nature of depressive symptoms and depression.}, Doi = {10.1007/s00406-019-01040-x}, Key = {fds344832} } @article{fds364972, Author = {Carlisi, CO and Moffitt, TE and Knodt, AR and Harrington, H and Ireland, D and Melzer, TR and Poulton, R and Ramrakha, S and Caspi, A and Hariri, AR and Viding, E}, Title = {Associations between life-course-persistent antisocial behaviour and brain structure in a population-representative longitudinal birth cohort.}, Journal = {The lancet. Psychiatry}, Volume = {7}, Number = {3}, Pages = {245-253}, Year = {2020}, Month = {March}, url = {http://dx.doi.org/10.1016/s2215-0366(20)30002-x}, Abstract = {<h4>Background</h4>Studies with behavioural and neuropsychological tests have supported the developmental taxonomy theory of antisocial behaviour, which specifies abnormal brain development as a fundamental aspect of life-course-persistent antisocial behaviour, but no study has characterised features of brain structure associated with life-course-persistent versus adolescence-limited trajectories, as defined by prospective data. We aimed to determine whether life-course-persistent antisocial behaviour is associated with neurocognitive abnormalities by testing the hypothesis that it is also associated with brain structure abnormalities.<h4>Methods</h4>We used structural MRI data collected at 45 years of age from participants in the Dunedin Study, a population-representative longitudinal birth cohort of 1037 individuals born between April 1, 1972, and March 31, 1973, in Dunedin, New Zealand, who were resident in the province and who participated in the first assessment at 3 years of age. Participants underwent MRI, and mean global cortical surface area and cortical thickness were extracted for each participant. Participants had been previously subtyped as exhibiting life-course-persistent, adolescence-limited, or no history of persistent antisocial behaviour (ie, a low trajectory group) based on informant-reported and self-reported conduct problems from the ages of 7 years to 26 years. Study personnel who processed the MRI images were masked to antisocial group membership. We used linear estimated ordinary least squares regressions to compare each antisocial trajectory group (life-course persistent and adolescence limited) with the low trajectory group to examine whether antisocial behaviour was related to abnormalities in mean global surface area and mean cortical thickness. Next, we used parcel-wise linear regressions to identify antisocial trajectory group differences in surface area and cortical thickness. All results were controlled for sex and false discovery rate corrected.<h4>Findings</h4>Data from 672 participants were analysed, and 80 (12%) were classified as having life-course-persistent antisocial behaviour, 151 (23%) as having adolescence-limited antisocial behaviour, and 441 (66%) as having low antisocial behaviour. Individuals on the life-course-persistent trajectory had a smaller mean surface area (standardised β=-0·18 [95% CI -0·24 to -0·11]; p<0·0001) and lower mean cortical thickness (standardised β=-0·10 [95% CI -0·19 to -0·02]; p=0·020) than did those in the low group. Compared with the low group, the life-course-persistent group had reduced surface area in 282 of 360 anatomically defined parcels and thinner cortex in 11 of 360 parcels encompassing circumscribed frontal and temporal regions associated with executive function, affect regulation, and motivation. Widespread differences in brain surface morphometry were not observed for the adolescence-limited group compared with either non-antisocial behaviour or life-course-persistent groups.<h4>Interpretation</h4>These analyses provide initial evidence that differences in brain surface morphometry are associated with life-course-persistent, but not adolescence-limited, antisocial behaviour. As such, the analyses are consistent with the developmental taxonomy theory of antisocial behaviour and highlight the importance of using prospective longitudinal data to define different patterns of antisocial behaviour development.<h4>Funding</h4>US National Institute on Aging, Health Research Council of New Zealand, New Zealand Ministry of Business, Innovation and Employment, UK Medical Research Council, Avielle Foundation, and Wellcome Trust.}, Doi = {10.1016/s2215-0366(20)30002-x}, Key = {fds364972} } @article{fds364172, Author = {Burr, DA and d'Arbeloff, T and Elliott, ML and Knodt, AR and Brigidi, BD and Hariri, AR}, Title = {Functional connectivity predicts the dispositional use of expressive suppression but not cognitive reappraisal.}, Journal = {Brain and behavior}, Volume = {10}, Number = {2}, Pages = {e01493}, Year = {2020}, Month = {February}, url = {http://dx.doi.org/10.1002/brb3.1493}, Abstract = {<h4>Introduction</h4>Previous research has identified specific brain regions associated with regulating emotion using common strategies such as expressive suppression and cognitive reappraisal. However, most research focuses on a priori regions and directs participants how to regulate, which may not reflect how people naturally regulate outside the laboratory.<h4>Method</h4>Here, we used a data-driven approach to investigate how individual differences in distributed intrinsic functional brain connectivity predict emotion regulation tendency outside the laboratory. Specifically, we used connectome-based predictive modeling to extract functional connections in the brain significantly related to the dispositional use of suppression and reappraisal. These edges were then used in a predictive model and cross-validated in novel participants to identify a neural signature that reflects individual differences in the tendency to suppress and reappraise emotion.<h4>Results</h4>We found a significant neural signature for the dispositional use of suppression, but not reappraisal. Within this whole-brain signature, the intrinsic connectivity of the default mode network was most informative of suppression tendency. In addition, the predictive performance of this model was significant in males, but not females.<h4>Conclusion</h4>These findings help inform how whole-brain networks of functional connectivity characterize how people tend to regulate emotion outside the laboratory.}, Doi = {10.1002/brb3.1493}, Key = {fds364172} } @article{fds364142, Author = {Detloff, AM and Hariri, AR and Strauman, TJ}, Title = {Neural signatures of promotion versus prevention goal priming: fMRI evidence for distinct cognitive-motivational systems.}, Journal = {Personality neuroscience}, Volume = {3}, Pages = {e1}, Year = {2020}, Month = {February}, url = {http://dx.doi.org/10.1017/pen.2019.13}, Abstract = {Regulatory focus theory (RFT) postulates two cognitive-motivational systems for personal goal pursuit: the promotion system, which is associated with ideal goals (an individual's hopes, dreams, and aspirations), and the prevention system, which is associated with ought goals (an individual's duties, responsibilities, and obligations). The two systems have been studied extensively in behavioral research with reference to differences between promotion and prevention goal pursuit as well as the consequences of perceived attainment versus nonattainment within each system. However, no study has examined the neural correlates of each combination of goal domain and goal attainment status. We used a rapid masked idiographic goal priming paradigm and functional magnetic resonance imaging to present individually selected promotion and prevention goals, which participants had reported previously that they were close to attaining ("match") or far from attaining ("mismatch"). Across the four priming conditions, significant activations were observed in bilateral insula (Brodmann area (BA) 13) and visual association cortex (BA 18/19). Promotion priming discriminantly engaged left prefrontal cortex (BA 9), whereas prevention priming discriminantly engaged right prefrontal cortex (BA 8/9). Activation in response to promotion goal priming was also correlated with an individual difference measure of perceived success in promotion goal attainment. Our findings extend the construct validity of RFT by showing that the two systems postulated by RFT, under conditions of both attainment and nonattainment, have shared and distinct neural correlates that interface logically with established network models of self-regulatory cognition.}, Doi = {10.1017/pen.2019.13}, Key = {fds364142} } @article{fds364134, Author = {Lee, MR and Shin, JH and Deschaine, S and Daurio, AM and Stangl, BL and Yan, J and Ramchandani, VA and Schwandt, ML and Grodin, EN and Momenan, R and Corral-Frias, NS and Hariri, AR and Bogdan, R and Alvarez, VA and Leggio, L}, Title = {A role for the CD38 rs3796863 polymorphism in alcohol and monetary reward: evidence from CD38 knockout mice and alcohol self-administration, [11C]-raclopride binding, and functional MRI in humans.}, Journal = {The American journal of drug and alcohol abuse}, Volume = {46}, Number = {2}, Pages = {167-179}, Year = {2020}, Month = {January}, url = {http://dx.doi.org/10.1080/00952990.2019.1638928}, Abstract = {<i>Background</i>: Cluster of differentiation 38 (CD38) is a transmembrane protein expressed in dopaminergic reward pathways in the brain, including the nucleus accumbens (NAc). The GG genotype of a common single nucleotide polymorphism (SNP) within <i>CD38</i>, rs3796863, is associated with increased social reward.<i>Objective</i>: Examine whether <i>CD38</i> rs3796863 and <i>Cd38</i> knockout (KO) are associated with reward-related neural and behavioral phenotypes.<i>Methods</i>: Data from four independent human studies were used to test whether rs3796863 genotype is associated with: (1) intravenous alcohol self-administration (n = 64, 30 females), (2) alcohol-stimulated dopamine (DA) release measured using <sup>11</sup>C-raclopride positron emission tomography (n = 22 men), (3) ventral striatum (VS) response to positive feedback measured using a card guessing functional magnetic resonance imaging (fMRI) paradigm (n = 531, 276 females), and (4) resting state functional connectivity (rsfc) of the VS (n = 51, 26 females). In a fifth study, we used a mouse model to examine whether <i>cd38</i> knockout influences stimulated DA release in the NAc core and dorsal striatum using fast-scanning cyclic voltammetry.<i>Results</i>: Relative to T allele carriers, G homozygotes at rs3796863 within <i>CD38</i> were characterized by greater alcohol self-administration, alcohol-stimulated dopamine release, VS response to positive feedback, and rsfc between the VS and anterior cingulate cortex. High-frequency stimulation reduced DA release among <i>Cd38</i> KO mice had reduced dopamine release in the NAc.<i>Conclusion</i>: Converging evidence suggests that <i>CD38</i> rs3796863 genotype may increase DA-related reward response and alcohol consumption.}, Doi = {10.1080/00952990.2019.1638928}, Key = {fds364134} } @article{fds346711, Author = {Farber, MJ and Kim, MJ and Knodt, AR and Hariri, AR}, Title = {Maternal overprotection in childhood is associated with amygdala reactivity and structural connectivity in adulthood.}, Journal = {Developmental cognitive neuroscience}, Volume = {40}, Pages = {100711}, Year = {2019}, Month = {December}, url = {http://dx.doi.org/10.1016/j.dcn.2019.100711}, Abstract = {Recently, we reported that variability in early-life caregiving experiences maps onto individual differences in threat-related brain function. Here, we extend this work to provide further evidence that subtle variability in specific features of early caregiving shapes structural and functional connectivity between the amygdala and medial prefrontal cortex (mPFC) in a cohort of 312 young adult volunteers. Multiple regression analyses revealed that participants who reported higher maternal overprotection exhibited increased amygdala reactivity to explicit signals of interpersonal threat but not implicit signals of broad environmental threat. While amygdala functional connectivity with regulatory regions of the mPFC was not significantly associated with maternal overprotection, participants who reported higher maternal overprotection exhibited relatively decreased structural integrity of the uncinate fasciculus (UF), a white matter tract connecting these same brain regions. There were no significant associations between structural or functional brain measures and either maternal or paternal care ratings. These findings suggest that an overprotective maternal parenting style during childhood is associated with later functional and structural alterations of brain regions involved in generating and regulating responses to threat.}, Doi = {10.1016/j.dcn.2019.100711}, Key = {fds346711} } @article{fds346872, Author = {Wetherill, L and Lai, D and Johnson, EC and Anokhin, A and Bauer, L and Bucholz, KK and Dick, DM and Hariri, AR and Hesselbrock, V and Kamarajan, C and Kramer, J and Kuperman, S and Meyers, JL and Nurnberger, JI and Schuckit, M and Scott, DM and Taylor, RE and Tischfield, J and Porjesz, B and Goate, AM and Edenberg, HJ and Foroud, T and Bogdan, R and Agrawal, A}, Title = {ERRATUM: Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.}, Journal = {Genes, brain, and behavior}, Volume = {18}, Number = {8}, Pages = {e12608}, Year = {2019}, Month = {November}, url = {http://dx.doi.org/10.1111/gbb.12608}, Doi = {10.1111/gbb.12608}, Key = {fds346872} } @article{fds364148, Author = {Avinun, R and Hariri, AR}, Title = {A polygenic score for body mass index is associated with depressive symptoms via early life stress: Evidence for gene-environment correlation.}, Journal = {Journal of psychiatric research}, Volume = {118}, Pages = {9-13}, Year = {2019}, Month = {November}, url = {http://dx.doi.org/10.1016/j.jpsychires.2019.08.008}, Abstract = {Increasing childhood obesity rates are associated with not only adverse physical, but also mental health outcomes, including depression. These negative outcomes may be caused and/or exacerbated by the bullying and shaming overweight individuals experience. As body mass index (BMI) can be highly heritable, we hypothesized that a genetic risk for higher BMI, will predict higher early life stress (ELS), which in turn will predict higher depressive symptoms in adulthood. Such a process will reflect an evocative gene-environment correlation (rGE) wherein an individual's genetically influenced phenotype evokes a reaction from the environment that subsequently shapes the individual's health. We modeled genetic risk using a polygenic score of BMI derived from a recent large GWAS meta-analysis. Self-reports were used for the assessment of ELS and depressive symptoms in adulthood. The discovery sample consisted of 524 non-Hispanic Caucasian university students from the Duke Neurogenetics Study (DNS; 278 women, mean age 19.78 ± 1.23 years) and the independent replication sample consisted of 5930 white British individuals from the UK biobank (UKB; 3128 women, mean age 62.66 ± 7.38 years). A significant mediation effect was found in the DNS (indirect effect = 0.207, bootstrapped SE = .10, bootstrapped 95% CI: 0.014 to 0.421), and then replicated in the UKB (indirect effect = 0.04, bootstrapped SE = .01, bootstrapped 95% CI: 0.018 to 0.066). Higher BMI polygenic scores predicted higher ELS, which in turn predicted higher depressive symptoms. Our findings suggest that evocative rGE may contribute to weight-related mental health problems and stress the need for interventions that aim to reduce weight bias, specifically during childhood.}, Doi = {10.1016/j.jpsychires.2019.08.008}, Key = {fds364148} } @article{fds364973, Author = {Rasmussen, LJH and Caspi, A and Ambler, A and Broadbent, JM and Cohen, HJ and d'Arbeloff, T and Elliott, M and Hancox, RJ and Harrington, H and Hogan, S and Houts, R and Ireland, D and Knodt, AR and Meredith-Jones, K and Morey, MC and Morrison, L and Poulton, R and Ramrakha, S and Richmond-Rakerd, L and Sison, ML and Sneddon, K and Thomson, WM and Hariri, AR and Moffitt, TE}, Title = {Association of Neurocognitive and Physical Function With Gait Speed in Midlife.}, Journal = {JAMA Netw Open}, Volume = {2}, Number = {10}, Pages = {e1913123}, Year = {2019}, Month = {October}, url = {http://dx.doi.org/10.1001/jamanetworkopen.2019.13123}, Abstract = {IMPORTANCE: Gait speed is a well-known indicator of risk of functional decline and mortality in older adults, but little is known about the factors associated with gait speed earlier in life. OBJECTIVES: To test the hypothesis that slow gait speed reflects accelerated biological aging at midlife, as well as poor neurocognitive functioning in childhood and cognitive decline from childhood to midlife. DESIGN, SETTING, AND PARTICIPANTS: This cohort study uses data from the Dunedin Multidisciplinary Health and Development Study, a population-based study of a representative 1972 to 1973 birth cohort in New Zealand that observed participants to age 45 years (until April 2019). Data analysis was performed from April to June 2019. EXPOSURES: Childhood neurocognitive functions and accelerated aging, brain structure, and concurrent physical and cognitive functions in adulthood. MAIN OUTCOMES AND MEASURES: Gait speed at age 45 years, measured under 3 walking conditions: usual, dual task, and maximum gait speeds. RESULTS: Of the 1037 original participants (91% of eligible births; 535 [51.6%] male), 997 were alive at age 45 years, of whom 904 (90.7%) had gait speed measured (455 [50.3%] male; 93% white). The mean (SD) gait speeds were 1.30 (0.17) m/s for usual gait, 1.16 (0.23) m/s for dual task gait, and 1.99 (0.29) m/s for maximum gait. Adults with more physical limitations (standardized regression coefficient [β], -0.27; 95% CI, -0.34 to -0.21; P < .001), poorer physical functions (ie, weak grip strength [β, 0.36; 95% CI, 0.25 to 0.46], poor balance [β, 0.28; 95% CI, 0.21 to 0.34], poor visual-motor coordination [β, 0.24; 95% CI, 0.17 to 0.30], and poor performance on the chair-stand [β, 0.34; 95% CI, 0.27 to 0.40] or 2-minute step tests [β, 0.33; 95% CI, 0.27 to 0.39]; all P < .001), accelerated biological aging across multiple organ systems (β, -0.33; 95% CI, -0.40 to -0.27; P < .001), older facial appearance (β, -0.25; 95% CI, -0.31 to -0.18; P < .001), smaller brain volume (β, 0.15; 95% CI, 0.06 to 0.23; P < .001), more cortical thinning (β, 0.09; 95% CI, 0.02 to 0.16; P = .01), smaller cortical surface area (β, 0.13; 95% CI, 0.04 to 0.21; P = .003), and more white matter hyperintensities (β, -0.09; 95% CI, -0.15 to -0.02; P = .01) had slower gait speed. Participants with lower IQ in midlife (β, 0.38; 95% CI, 0.32 to 0.44; P < .001) and participants who exhibited cognitive decline from childhood to adulthood (β, 0.10; 95% CI, 0.04 to 0.17; P < .001) had slower gait at age 45 years. Those with poor neurocognitive functioning as early as age 3 years had slower gait in midlife (β, 0.26; 95% CI, 0.20 to 0.32; P < .001). CONCLUSIONS AND RELEVANCE: Adults' gait speed is associated with more than geriatric functional status; it is also associated with midlife aging and lifelong brain health.}, Doi = {10.1001/jamanetworkopen.2019.13123}, Key = {fds364973} } @article{fds364149, Author = {Avinun, R and Nevo, A and Knodt, AR and Elliott, ML and Hariri, AR}, Title = {A genome-wide association study-derived polygenic score for interleukin-1β is associated with hippocampal volume in two samples.}, Journal = {Human brain mapping}, Volume = {40}, Number = {13}, Pages = {3910-3917}, Year = {2019}, Month = {September}, url = {http://dx.doi.org/10.1002/hbm.24639}, Abstract = {Accumulating research suggests that the pro-inflammatory cytokine interleukin-1β (IL-1β) has a modulatory effect on the hippocampus, a brain structure important for learning and memory as well as linked with both psychiatric and neurodegenerative disorders. Here, we used an imaging genetics strategy to test an association between an IL-1β polygenic score and hippocampal volume in two independent samples. Our polygenic score was derived using summary statistics from a recent genome-wide association study of circulating cytokines that included IL-1β (N = 3,309). In the first sample of 512 non-Hispanic Caucasian university students (274 women, mean age 19.78 ± 1.24 years) from the Duke Neurogenetics Study, we identified a significant positive correlation between IL-1β polygenic scores and hippocampal volume. This positive association was successfully replicated in a second sample of 7,960 white British volunteers (4,158 women, mean age 62.63 ± 7.45 years) from the UK Biobank. Our results lend further support in humans, to the link between IL-1β and the structure of the hippocampus.}, Doi = {10.1002/hbm.24639}, Key = {fds364149} } @article{fds345489, Author = {Lam, M and Hill, WD and Trampush, JW and Yu, J and Knowles, E and Davies, G and Stahl, E and Huckins, L and Liewald, DC and Djurovic, S and Melle, I and Sundet, K and Christoforou, A and Reinvang, I and DeRosse, P and Lundervold, AJ and Steen, VM and Espeseth, T and Räikkönen, K and Widen, E and Palotie, A and Eriksson, JG and Giegling, I and Konte, B and Hartmann, AM and Roussos, P and Giakoumaki, S and Burdick, KE and Payton, A and Ollier, W and Chiba-Falek, O and Attix, DK and Need, AC and Cirulli, ET and Voineskos, AN and Stefanis, NC and Avramopoulos, D and Hatzimanolis, A and Arking, DE and Smyrnis, N and Bilder, RM and Freimer, NA and Cannon, TD and London, E and Poldrack, RA and Sabb, FW and Congdon, E and Conley, ED and Scult, MA and Dickinson, D and Straub, RE and Donohoe, G and Morris, D and Corvin, A and Gill, M and Hariri, AR and Weinberger, DR and Pendleton, N and Bitsios, P and Rujescu, D and Lahti, J and Le Hellard and S and Keller, MC and Andreassen, OA and Deary, IJ and Glahn, DC and Malhotra, AK and Lencz, T}, Title = {Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.}, Journal = {Am J Hum Genet}, Volume = {105}, Number = {2}, Pages = {334-350}, Year = {2019}, Month = {August}, url = {http://dx.doi.org/10.1016/j.ajhg.2019.06.012}, Abstract = {Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.}, Doi = {10.1016/j.ajhg.2019.06.012}, Key = {fds345489} } @article{fds343721, Author = {Lai, D and Wetherill, L and Bertelsen, S and Carey, CE and Kamarajan, C and Kapoor, M and Meyers, JL and Anokhin, AP and Bennett, DA and Bucholz, KK and Chang, KK and De Jager and PL and Dick, DM and Hesselbrock, V and Kramer, J and Kuperman, S and Nurnberger, JI and Raj, T and Schuckit, M and Scott, DM and Taylor, RE and Tischfield, J and Hariri, AR and Edenberg, HJ and Agrawal, A and Bogdan, R and Porjesz, B and Goate, AM and Foroud, T}, Title = {Genome-wide association studies of alcohol dependence, DSM-IV criterion count and individual criteria.}, Journal = {Genes, brain, and behavior}, Volume = {18}, Number = {6}, Pages = {e12579}, Year = {2019}, Month = {July}, url = {http://dx.doi.org/10.1111/gbb.12579}, Abstract = {Genome-wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (eg, ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWAS of DSM-IV AD (primary analysis), DSM-IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans-ancestral meta-analyses combined these results with data from 3175 (585 families) African-American (AA) individuals from COGA. In the EA GWAS, three loci were genome-wide significant: rs1229984 in ADH1B for AD criterion count (P = 4.16E-11) and Desire to cut drinking (P = 1.21E-11); rs188227250 (chromosome 8, Drinking more than intended, P = 6.72E-09); rs1912461 (chromosome 15, Time spent drinking, P = 1.77E-08). In the trans-ancestral meta-analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome-wide significant: rs61826952 (chromosome 1, DSM-IV AD, P = 8.42E-11); rs7597960 (chromosome 2, Time spent drinking, P = 1.22E-08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (P < .01; 0.61%-1.82% of variance). Identified novel variants (ie, rs1912461, rs61826952) were associated with differential central evoked theta power (loss - gain; P = .0037) and reward-related ventral striatum reactivity (P = .008), respectively. This study suggests that studying individual criteria may unveil new insights into the genetic etiology of AD liability.}, Doi = {10.1111/gbb.12579}, Key = {fds343721} } @article{fds348913, Author = {Elliott, ML and Belsky, DW and Anderson, K and Corcoran, DL and Ge, T and Knodt, A and Prinz, JA and Sugden, K and Williams, B and Ireland, D and Poulton, R and Caspi, A and Holmes, A and Moffitt, T and Hariri, AR}, Title = {A Polygenic Score for Higher Educational Attainment is Associated with Larger Brains.}, Journal = {Cerebral cortex (New York, N.Y. : 1991)}, Volume = {29}, Number = {8}, Pages = {3496-3504}, Year = {2019}, Month = {July}, url = {http://dx.doi.org/10.1093/cercor/bhy219}, Abstract = {People who score higher on intelligence tests tend to have larger brains. Twin studies suggest the same genetic factors influence both brain size and intelligence. This has led to the hypothesis that genetics influence intelligence partly by contributing to the development of larger brains. We tested this hypothesis using four large imaging genetics studies (combined N = 7965) with polygenic scores derived from a genome-wide association study (GWAS) of educational attainment, a correlate of intelligence. We conducted meta-analysis to test associations among participants' genetics, total brain volume (i.e., brain size), and cognitive test performance. Consistent with previous findings, participants with higher polygenic scores achieved higher scores on cognitive tests, as did participants with larger brains. Participants with higher polygenic scores also had larger brains. We found some evidence that brain size partly mediated associations between participants' education polygenic scores and their cognitive test performance. Effect sizes were larger in the population-based samples than in the convenience-based samples. Recruitment and retention of population-representative samples should be a priority for neuroscience research. Findings suggest promise for studies integrating GWAS discoveries with brain imaging to understand neurobiology linking genetics with cognitive performance.}, Doi = {10.1093/cercor/bhy219}, Key = {fds348913} } @article{fds364150, Author = {Avinun, R and Nevo, A and Hariri, AR}, Title = {Genetic Risk for Rheumatoid Arthritis is Associated with Increased Striatal Volume in Healthy Young Adults.}, Journal = {Scientific reports}, Volume = {9}, Number = {1}, Pages = {10994}, Year = {2019}, Month = {July}, url = {http://dx.doi.org/10.1038/s41598-019-47505-w}, Abstract = {Rheumatoid arthritis (RA), an autoimmune disease, has recently been associated with increased striatal volume and decreased intracranial volume (ICV) in longstanding patients. As inflammation has been shown to precede the clinical diagnosis of RA and it is a known moderator of neuro- and gliogenesis, we were interested in testing whether these brain morphological changes appear before the clinical onset of disease in healthy young adult volunteers, as a function of relative genetic risk for RA. Genetic and structural MRI data were available for 516 healthy non-Hispanic Caucasian university students (275 women, mean age 19.78 ± 1.24 years). Polygenic risk scores were computed for each individual based on a genome-wide association study of RA, so that higher scores indicated higher risk. Striatal volume (sum of caudate, putamen, and nucleus accumbens volumes) and ICV were derived for each individual from high-resolution T1-weighted images. After controlling for sex, age, genetic components of ethnicity, socioeconomic status, and depressive symptoms, we found that higher RA polygenic risk scores were associated with increased striatal volume, but not decreased ICV. Our findings suggest that increased striatal volume may be linked to processes that precede disease onset, such as inflammation, while decreased ICV may relate to disease progression.}, Doi = {10.1038/s41598-019-47505-w}, Key = {fds364150} } @article{fds364135, Author = {Wetherill, L and Lai, D and Johnson, EC and Anokhin, A and Bauer, L and Bucholz, KK and Dick, DM and Hariri, AR and Hesselbrock, V and Kamarajan, C and Kramer, J and Kuperman, S and Meyers, JL and Nurnberger, JI and Schuckit, M and Scott, DM and Taylor, RE and Tischfield, J and Porjesz, B and Goate, AM and Edenberg, HJ and Foroud, T and Bogdan, R and Agrawal, A}, Title = {Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.}, Journal = {Genes, brain, and behavior}, Volume = {18}, Number = {6}, Pages = {e12580}, Year = {2019}, Month = {July}, url = {http://dx.doi.org/10.1111/gbb.12580}, Abstract = {Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h <sup>2</sup> in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk.}, Doi = {10.1111/gbb.12580}, Key = {fds364135} } @article{fds364151, Author = {Gerin, MI and Viding, E and Pingault, J-B and Puetz, VB and Knodt, AR and Radtke, SR and Brigidi, BD and Swartz, JR and Hariri, AR and McCrory, EJ}, Title = {Heightened amygdala reactivity and increased stress generation predict internalizing symptoms in adults following childhood maltreatment.}, Journal = {Journal of child psychology and psychiatry, and allied disciplines}, Volume = {60}, Number = {7}, Pages = {752-761}, Year = {2019}, Month = {July}, url = {http://dx.doi.org/10.1111/jcpp.13041}, Abstract = {<h4>Background</h4>Childhood maltreatment is one of the most potent predictors of future psychopathology, including internalizing disorders. It remains unclear whether heightened amygdala reactivity to threat and elevated stress exposure may be implicated in the pathogenesis and maintenance of internalizing disorders among individuals with a history of childhood maltreatment.<h4>Methods</h4>Using data from a sample of 1,144 young adults, we investigated the contribution of baseline threat-related amygdala reactivity and prospective major stressful life events to internalizing symptoms severity 1 year later (on average) in individuals with a history of maltreatment (n = 100) and propensity score matched nonmaltreated peers (n = 96).<h4>Results</h4>Even after stringently matching for several potentially confounding variables - including baseline internalizing symptoms, socioeconomic status and IQ - childhood maltreatment status predicted increased amygdala reactivity at baseline, elevated post-baseline exposure to major stressful life events and internalizing symptoms at follow-up. We also showed, for the first time, that amygdala reactivity at baseline and also post-baseline exposure to major stressful life events mediated the association between a history of maltreatment and future internalizing symptoms.<h4>Conclusions</h4>These findings provide support for the view that maltreatment is a potent developmental insult leading to long-lasting neurocognitive recalibrations of the threat processing system. It is possible that such alterations, over time, may impact mental health functioning by compromising the ability to effectively negotiate everyday challenges (stress susceptibility). These alterations were not, however, found to sensitize an individual to the impact of major stressful life events. The results of this study also lend compelling support to the view that increased psychiatric risk, in the context of childhood maltreatment, follows from an increased propensity to experience major stressful life events (stress generation).}, Doi = {10.1111/jcpp.13041}, Key = {fds364151} } @article{fds364152, Author = {Farber, MJ and Romer, AL and Kim, MJ and Knodt, AR and Elsayed, NM and Williamson, DE and Hariri, AR}, Title = {Paradoxical associations between familial affective responsiveness, stress, and amygdala reactivity.}, Journal = {Emotion (Washington, D.C.)}, Volume = {19}, Number = {4}, Pages = {645-654}, Year = {2019}, Month = {June}, url = {http://dx.doi.org/10.1037/emo0000467}, Abstract = {Studies of early life extremes such as trauma, abuse, and neglect highlight the critical importance of quality caregiving in the development of brain circuits supporting emotional behavior and mental health. The impact of normative variability in caregiving on such biobehavioral processes, however, is poorly understood. Here, we provide initial evidence that even subtle variability in normative caregiving maps onto individual differences in threat-related brain function and, potentially, associated psychopathology in adolescence. Specifically, we report that greater familial affective responsiveness is associated with heightened amygdala reactivity to interpersonal threat, particularly in adolescents having experienced relatively low recent stress. These findings extend the literature on the effects of caregiving extremes on brain function to subtle, normative variability but suggest that presumably protective factors may be associated with increased risk-related amygdala reactivity. We consider these paradoxical associations with regard to studies of basic associative threat learning and further consider their relevance for understanding potential effects of caregiving on psychological development. (PsycINFO Database Record (c) 2019 APA, all rights reserved).}, Doi = {10.1037/emo0000467}, Key = {fds364152} } @article{fds364153, Author = {Kim, MJ and Elliott, ML and d'Arbeloff, TC and Knodt, AR and Radtke, SR and Brigidi, BD and Hariri, AR}, Title = {Microstructural integrity of white matter moderates an association between childhood adversity and adult trait anger.}, Journal = {Aggressive behavior}, Volume = {45}, Number = {3}, Pages = {310-318}, Year = {2019}, Month = {May}, url = {http://dx.doi.org/10.1002/ab.21820}, Abstract = {Amongst a number of negative life sequelae associated with childhood adversity is the later expression of a higher dispositional tendency to experience anger and frustration to a wide range of situations (i.e., trait anger). We recently reported that an association between childhood adversity and trait anger is moderated by individual differences in both threat-related amygdala activity and executive control-related dorsolateral prefrontal cortex (dlPFC) activity, wherein individuals with relatively low amygdala and high dlPFC activity do not express higher trait anger even when having experienced childhood adversity. Here, we examine possible structural correlates of this functional dynamic using diffusion magnetic resonance imaging data from 647 young adult men and women volunteers. Specifically, we tested whether the degree of white matter microstructural integrity as indexed by fractional anisotropy modulated the association between childhood adversity and trait anger. Our analyses revealed that higher microstructural integrity of multiple pathways was associated with an attenuated link between childhood adversity and adult trait anger. Amongst these pathways was the uncinate fasciculus (UF; ΔR <sup>2</sup> = 0.01), which not only provides a major anatomical link between the amygdala and prefrontal cortex but also is associated with individual differences in regulating negative emotion through top-down cognitive reappraisal. These findings suggest that higher microstructural integrity of distributed white matter pathways including but not limited to the UF may represent an anatomical foundation serving to buffer against the expression of childhood adversity as later trait anger, which is itself associated with multiple negative health outcomes.}, Doi = {10.1002/ab.21820}, Key = {fds364153} } @article{fds342490, Author = {Hariri, AR}, Title = {The Emerging Importance of the Cerebellum in Broad Risk for Psychopathology.}, Journal = {Neuron}, Volume = {102}, Number = {1}, Pages = {17-20}, Year = {2019}, Month = {April}, url = {http://dx.doi.org/10.1016/j.neuron.2019.02.031}, Abstract = {Recent research has identified a single factor accounting for broad risk to experience common forms of psychopathology. Structural alterations of cerebellar circuitry have emerged as a neural nexus of this broad risk, highlighting the cerebellum's importance for executive control.}, Doi = {10.1016/j.neuron.2019.02.031}, Key = {fds342490} } @article{fds364182, Author = {Elliott, ML and Knodt, AR and Cooke, M and Kim, MJ and Melzer, TR and Keenan, R and Ireland, D and Ramrakha, S and Poulton, R and Caspi, A and Moffitt, TE and Hariri, AR}, Title = {General functional connectivity: Shared features of resting-state and task fMRI drive reliable and heritable individual differences in functional brain networks.}, Journal = {NeuroImage}, Volume = {189}, Pages = {516-532}, Year = {2019}, Month = {April}, url = {http://dx.doi.org/10.1016/j.neuroimage.2019.01.068}, Abstract = {Intrinsic connectivity, measured using resting-state fMRI, has emerged as a fundamental tool in the study of the human brain. However, due to practical limitations, many studies do not collect enough resting-state data to generate reliable measures of intrinsic connectivity necessary for studying individual differences. Here we present general functional connectivity (GFC) as a method for leveraging shared features across resting-state and task fMRI and demonstrate in the Human Connectome Project and the Dunedin Study that GFC offers better test-retest reliability than intrinsic connectivity estimated from the same amount of resting-state data alone. Furthermore, at equivalent scan lengths, GFC displayed higher estimates of heritability than resting-state functional connectivity. We also found that predictions of cognitive ability from GFC generalized across datasets, performing as well or better than resting-state or task data alone. Collectively, our work suggests that GFC can improve the reliability of intrinsic connectivity estimates in existing datasets and, subsequently, the opportunity to identify meaningful correlates of individual differences in behavior. Given that task and resting-state data are often collected together, many researchers can immediately derive more reliable measures of intrinsic connectivity through the adoption of GFC rather than solely using resting-state data. Moreover, by better capturing heritable variation in intrinsic connectivity, GFC represents a novel endophenotype with broad applications in clinical neuroscience and biomarker discovery.}, Doi = {10.1016/j.neuroimage.2019.01.068}, Key = {fds364182} } @article{fds364154, Author = {Romer, AL and Su Kang and M and Nikolova, YS and Gearhardt, AN and Hariri, AR}, Title = {Dopamine genetic risk is related to food addiction and body mass through reduced reward-related ventral striatum activity.}, Journal = {Appetite}, Volume = {133}, Pages = {24-31}, Year = {2019}, Month = {February}, url = {http://dx.doi.org/10.1016/j.appet.2018.09.010}, Abstract = {The prevalence rate of obesity continues to rise in the U.S., but effective treatment options remain elusive resulting in increased emphasis on prevention. One such area of prevention research capitalizes on the relatively novel behavioral construct of food addiction, which has been implicated in obesity. Food addiction reflects an individual's propensity for compulsive eating despite negative consequences, and shares not only symptoms with both eating and substance use disorders but also genetic and neural correlates within neural reward-circuitry modulated by dopamine. Here, we examined associations between food addiction scores, body mass index (BMI), reward-related ventral striatum activity, and a polygenic score approximating dopamine signaling in 115 non-Hispanic Caucasian young adult university students. As predicted, polygenic dopamine scores were related to ventral striatum activity, which in turn was associated with higher food addiction scores. In addition, food addiction was related to BMI. An exploratory post-hoc path analysis further indicated that polygenic scores were indirectly related to both food addiction and BMI, in part, through ventral striatum activity. Collectively, our results provide evidence supporting the utility of food addiction in weight gain prevention research by establishing links with known risk-related neural and genetic biomarkers.}, Doi = {10.1016/j.appet.2018.09.010}, Key = {fds364154} } @article{fds346873, Author = {Kim, MJ and Farber, MJ and Knodt, AR and Hariri, AR}, Title = {Corticolimbic circuit structure moderates an association between early life stress and later trait anxiety.}, Journal = {NeuroImage. Clinical}, Volume = {24}, Pages = {102050}, Year = {2019}, Month = {January}, url = {http://dx.doi.org/10.1016/j.nicl.2019.102050}, Abstract = {Childhood adversity is associated with a wide range of negative behavioral and neurodevelopmental consequences. However, individuals vary substantially in their sensitivity to such adversity. Here, we examined how individual variability in structural features of the corticolimbic circuit, which plays a key role in emotional reactivity, moderates the association between childhood adversity and later trait anxiety in 798 young adult university students. Consistent with prior research, higher self-reported childhood adversity was significantly associated with higher self-reported trait anxiety. However, this association was attenuated in participants with higher microstructural integrity of the uncinate fasciculus and greater thickness of the orbitofrontal cortex. These structural properties of the corticolimbic circuit may capture a neural profile of relative resiliency to early life stress, especially against the negative effects of childhood adversity on later trait anxiety.}, Doi = {10.1016/j.nicl.2019.102050}, Key = {fds346873} } @article{fds366148, Author = {d'Arbeloff, T and Elliott, ML and Knodt, AR and Melzer, TR and Keenan, R and Ireland, D and Ramrakha, S and Poulton, R and Anderson, T and Caspi, A and Moffitt, TE and Hariri, AR}, Title = {White matter hyperintensities are common in midlife and already associated with cognitive decline.}, Journal = {Brain communications}, Volume = {1}, Number = {1}, Pages = {fcz041}, Year = {2019}, Month = {January}, url = {http://dx.doi.org/10.1093/braincomms/fcz041}, Abstract = {White matter hyperintensities proliferate as the brain ages and are associated with increased risk for cognitive decline as well as Alzheimer's disease and related dementias. As such, white matter hyperintensities have been targeted as a surrogate biomarker in intervention trials with older adults. However, it is unclear at what stage of aging white matter hyperintensities begin to relate to cognition and if they may be a viable target for early prevention. In the Dunedin Study, a population-representative cohort followed since birth, we measured white matter hyperintensities in 843 45-year-old participants using T<sub>2</sub>-weighted magnetic resonance imaging and we assessed cognitive decline from childhood to midlife. We found that white matter hyperintensities were common at age 45 and that white matter hyperintensity volume was modestly associated with both lower childhood (<i>ß</i> = -0.08, <i>P </i>=<i> </i>0.013) and adult IQ (<i>ß</i>=-0.15, <i>P </i><<i> </i>0.001). Moreover, white matter hyperintensity volume was associated with greater cognitive decline from childhood to midlife (<i>ß</i>=-0.09, <i>P </i><<i> </i>0.001). Our results demonstrate that a link between white matter hyperintensities and early signs of cognitive decline is detectable decades before clinical symptoms of dementia emerge. Thus, white matter hyperintensities may be a useful surrogate biomarker for identifying individuals in midlife at risk for future accelerated cognitive decline and selecting participants for dementia prevention trials.}, Doi = {10.1093/braincomms/fcz041}, Key = {fds366148} } @article{fds364132, Author = {Knodt, AR and Burke, JR and Welsh-Bohmer, KA and Plassman, BL and Burns, DK and Brannan, SK and Kukulka, M and Wu, J and Hariri, AR}, Title = {Effects of pioglitazone on mnemonic hippocampal function: A blood oxygen level-dependent functional magnetic resonance imaging study in elderly adults.}, Journal = {Alzheimers Dement (N Y)}, Volume = {5}, Pages = {254-263}, Year = {2019}, url = {http://dx.doi.org/10.1016/j.trci.2019.05.004}, Abstract = {INTRODUCTION: Mitochondrial dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD). Accordingly, drugs that positively influence mitochondrial function are being evaluated in delay-of-onset clinical trials with at-risk individuals. Such ongoing clinical research can be advanced by developing a better understanding of how these drugs affect intermediate brain phenotypes associated with both AD risk and pathophysiology. METHODS: Using a randomized, parallel-group, placebo-controlled design in 55 healthy elderly volunteers, we explored the effects of oral, low-dose pioglitazone, a thiazolidinedione with promitochondrial effects, on hippocampal activity measured with functional magnetic resonance imaging during the encoding of novel face-name pairs. RESULTS: Compared with placebo, 0.6 mg of pioglitazone (but not 2.1 mg, 3.9 mg, or 6.0 mg) administered daily for 14 days was associated with significant increases in right hippocampal activation during encoding of novel face-name pairs at day 7 and day 14, relative to baseline. DISCUSSION: Our exploratory analyses suggest that low-dose pioglitazone has measurable effects on mnemonic brain function associated with AD risk and pathophysiology.}, Doi = {10.1016/j.trci.2019.05.004}, Key = {fds364132} } @article{fds335689, Author = {Sethi, A and McCrory, E and Puetz, V and Hoffmann, F and Knodt, AR and Radtke, SR and Brigidi, BD and Hariri, AR and Viding, E}, Title = {Primary and Secondary Variants of Psychopathy in a Volunteer Sample Are Associated With Different Neurocognitive Mechanisms.}, Journal = {Biological psychiatry. Cognitive neuroscience and neuroimaging}, Volume = {3}, Number = {12}, Pages = {1013-1021}, Publisher = {Elsevier BV}, Year = {2018}, Month = {December}, url = {http://dx.doi.org/10.1016/j.bpsc.2018.04.002}, Abstract = {<h4>Background</h4>Recent work has indicated that there at least two distinct subtypes of psychopathy. Primary psychopathy is characterized by low anxiety and thought to result from a genetic predisposition, whereas secondary psychopathy is characterized by high anxiety and thought to develop in response to environmental adversity. Primary psychopathy is robustly associated with reduced neural activation to others' emotions and, in particular, distress. However, it has been proposed that the secondary presentation has different neurocognitive correlates.<h4>Methods</h4>Primary (n = 50), secondary (n = 100), and comparison (n = 82) groups were drawn from a large volunteer sample (N = 1444) using a quartile-split approach across psychopathic trait (affective-interpersonal) and anxiety measures. Participants performed a widely utilized emotional face processing task during functional magnetic resonance imaging.<h4>Results</h4>The primary group showed reduced amygdala and insula activity in response to fear. The secondary group did not differ from the comparison group in these regions. Instead, the secondary group showed reduced activity compared with the comparison group in other areas, including the superior temporal sulcus/inferior parietal lobe, thalamus, pallidum, and substantia nigra. Both psychopathy groups also showed reduced activity in response to fear in the anterior cingulate cortex. During anger processing, the secondary group exhibited reduced activity in the anterior cingulate cortex compared with the primary group.<h4>Conclusions</h4>Distinct neural correlates of fear processing characterize individuals with primary and secondary psychopathy. The reduced neural response to fear that characterizes individuals with the primary variant of psychopathic traits is not observed in individuals with the secondary presentation. The neurocognitive mechanisms underpinning secondary psychopathy warrant further systematic investigation.}, Doi = {10.1016/j.bpsc.2018.04.002}, Key = {fds335689} } @article{fds335682, Author = {Lam, M and Trampush, JW and Yu, J and Knowles, E and Djurovic, S and Melle, I and Sundet, K and Christoforou, A and Reinvang, I and DeRosse, P and Lundervold, AJ and Steen, VM and Espeseth, T and Räikkönen, K and Widen, E and Palotie, A and Eriksson, JG and Giegling, I and Konte, B and Roussos, P and Giakoumaki, S and Burdick, KE and Payton, A and Ollier, W and Chiba-Falek, O and Attix, DK and Need, AC and Cirulli, ET and Voineskos, AN and Stefanis, NC and Avramopoulos, D and Hatzimanolis, A and Arking, DE and Smyrnis, N and Bilder, RM and Freimer, NA and Cannon, TD and London, E and Poldrack, RA and Sabb, FW and Congdon, E and Conley, ED and Scult, MA and Dickinson, D and Straub, RE and Donohoe, G and Morris, D and Corvin, A and Gill, M and Hariri, AR and Weinberger, DR and Pendleton, N and Bitsios, P and Rujescu, D and Lahti, J and Hellard, SL and Keller, MC and Andreassen, OA and Glahn, DC and Malhotra, AK and Lencz, T}, Title = {Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018).}, Journal = {Twin Res Hum Genet}, Volume = {21}, Number = {5}, Pages = {394-397}, Year = {2018}, Month = {October}, url = {http://dx.doi.org/10.1017/thg.2018.46}, Abstract = {Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.}, Doi = {10.1017/thg.2018.46}, Key = {fds335682} } @article{fds335686, Author = {d'Arbeloff, TC and Kim, MJ and Knodt, AR and Radtke, SR and Brigidi, BD and Hariri, AR}, Title = {Microstructural integrity of a pathway connecting the prefrontal cortex and amygdala moderates the association between cognitive reappraisal and negative emotions.}, Journal = {Emotion (Washington, D.C.)}, Volume = {18}, Number = {6}, Pages = {912-915}, Year = {2018}, Month = {September}, url = {http://dx.doi.org/10.1037/emo0000447}, Abstract = {Cognitive reappraisal is a commonly used form of emotion regulation that utilizes frontal-executive control to reframe an approaching emotional event to moderate its potential psychological impact. Use of cognitive reappraisal has been associated with diminished experience of anxiety and depressive symptoms, as well as greater overall well-being. Using data from a study of 647 healthy young adults, we provide initial evidence that an association between typical use of cognitive reappraisal in daily life and the experience of anxiety and depressive symptoms is moderated by the microstructural integrity of the uncinate fasciculus, which provides a major anatomical link between the amygdala and prefrontal cortex. Our findings are consistent with the nature of top-down regulation of bottom-up negative emotions and suggest the uncinate fasciculus may be a useful target in the search for biomarkers predicting not only disorder risk but also response to psychotherapy utilizing cognitive reappraisal. (PsycINFO Database Record}, Doi = {10.1037/emo0000447}, Key = {fds335686} } @article{fds332980, Author = {Hanson, JL and Knodt, AR and Brigidi, BD and Hariri, AR}, Title = {Heightened connectivity between the ventral striatum and medial prefrontal cortex as a biomarker for stress-related psychopathology: understanding interactive effects of early and more recent stress.}, Journal = {Psychological medicine}, Volume = {48}, Number = {11}, Pages = {1835-1843}, Year = {2018}, Month = {August}, url = {http://dx.doi.org/10.1017/s0033291717003348}, Abstract = {<h4>Background</h4>The experience of childhood maltreatment is a significant risk factor for the development of depression. This risk is particularly heightened after exposure to additional, more contemporaneous stress. While behavioral evidence exists for this relation, little is known about biological correlates of these stress interactions. Identifying such correlates may provide biomarkers of risk for later depression.<h4>Methods</h4>Here, we leverage behavioral, experiential, and neuroimaging data from the Duke Neurogenetics Study to identify potential biomarkers of stress exposure. Based on the past research, we were specifically interested in reward-related connectivity and the interaction of early and more recent stress. We examined psychophysiological interactions between the ventral striatum and other brain regions in relation to these stress variables, as well as measures of internalizing symptomatology (n = 926, participant age range = 18-22 years of age).<h4>Results</h4>We found relatively increased reward-related functional connectivity between the left ventral striatum and the medial prefrontal cortex in individuals exposed to greater levels of childhood maltreatment who also experienced greater levels of recent life stress (β = 0.199, p < 0.005). This pattern of functional connectivity was further associated with elevated symptoms of depression (β = 0.089, p = 0.006). Furthermore, using a moderated mediation framework, we demonstrate that this functional connectivity provides a biological link between cumulative stress exposure and internalizing symptomatology.<h4>Conclusions</h4>These findings suggest a novel biomarker linking cumulative stress exposure with the later experience of depressive symptoms. Our results are discussed in the context of past research examining stress exposure in relation to depression.}, Doi = {10.1017/s0033291717003348}, Key = {fds332980} } @article{fds364155, Author = {Elsayed, NM and Kim, MJ and Fields, KM and Olvera, RL and Hariri, AR and Williamson, DE}, Title = {Trajectories of Alcohol Initiation and Use During Adolescence: The Role of Stress and Amygdala Reactivity.}, Journal = {Journal of the American Academy of Child and Adolescent Psychiatry}, Volume = {57}, Number = {8}, Pages = {550-560}, Year = {2018}, Month = {August}, url = {http://dx.doi.org/10.1016/j.jaac.2018.05.011}, Abstract = {<h4>Objective</h4>Early alcohol use initiation predicts onset of alcohol use disorders in adulthood. However, little is known about developmental trajectories of alcohol use initiation and their putative biological and environmental correlates.<h4>Method</h4>Adolescents (N = 330) with high or low familial loading for depression were assessed annually for up to 6 years. Data were collected assessing affective symptoms, alcohol use, and stress at each assessment. Adolescents also participated in a functional magnetic resonance imaging protocol that included measurement of threat-related amygdala and reward-related ventral striatum activity.<h4>Results</h4>Latent class analyses identified 2 trajectories of alcohol use initiation. Early initiators (n = 32) reported greater baseline alcohol use and rate of change of use compared with late initiators and/or current abstainers (n = 298). Early initiators reported higher baseline levels of stressful life events (p = .001) and exhibited higher amygdala (p = .001) but not ventral striatum activity compared with late initiators. Early initiators were 15.3 times more likely to have a full drink (p < .0001), 9.1 times more likely to experience intoxication (p < .0001), and 6.7 times more likely to develop an alcohol use disorder by 19 years of age compared with late initiators (p = .003).<h4>Conclusion</h4>Adolescents on a trajectory of early alcohol use initiation have higher levels of stress, have increased threat-related amygdala activity, are more likely to consume a full standard alcoholic drink, are more likely to experience early intoxication, and are at a heightened risk for the onset of an alcohol use disorder.}, Doi = {10.1016/j.jaac.2018.05.011}, Key = {fds364155} } @article{fds335683, Author = {Kim, MJ and Scult, MA and Knodt, AR and Radtke, SR and d'Arbeloff, TC and Brigidi, BD and Hariri, AR}, Title = {A Link Between Childhood Adversity and Trait Anger Reflects Relative Activity of the Amygdala and Dorsolateral Prefrontal Cortex.}, Journal = {Biological psychiatry. Cognitive neuroscience and neuroimaging}, Volume = {3}, Number = {7}, Pages = {644-649}, Year = {2018}, Month = {July}, url = {http://dx.doi.org/10.1016/j.bpsc.2018.03.006}, Abstract = {<h4>Background</h4>Trait anger, or the dispositional tendency to experience a wide range of situations as annoying or frustrating, is associated with negative mental and physical health outcomes. The experience of adversity during childhood is one risk factor for the later emergence of high trait anger. This association has been hypothesized to reflect alterations in neural circuits supporting bottom-up threat processing and top-down executive control.<h4>Methods</h4>Here, using functional magnetic resonance imaging and self-report questionnaire data from 220 volunteers, we examined how individual differences in top-down prefrontal executive control and bottom-up amygdala threat activity modulate the association between childhood adversity and trait anger during young adulthood.<h4>Results</h4>We report that the association between childhood adversity and trait anger is attenuated specifically in young adults who have both relatively low threat-related amygdala activity and high executive control-related dorsolateral prefrontal cortex activity.<h4>Conclusions</h4>These brain activity patterns suggest that simultaneous consideration of their underlying cognitive processes-namely, threat processing and executive control-may be useful in strategies designed to mitigate the negative mental health consequences of childhood adversity.}, Doi = {10.1016/j.bpsc.2018.03.006}, Key = {fds335683} } @article{fds335684, Author = {Savage, JE and Jansen, PR and Stringer, S and Watanabe, K and Bryois, J and de Leeuw, CA and Nagel, M and Awasthi, S and Barr, PB and Coleman, JRI and Grasby, KL and Hammerschlag, AR and Kaminski, JA and Karlsson, R and Krapohl, E and Lam, M and Nygaard, M and Reynolds, CA and Trampush, JW and Young, H and Zabaneh, D and Hägg, S and Hansell, NK and Karlsson, IK and Linnarsson, S and Montgomery, GW and Muñoz-Manchado, AB and Quinlan, EB and Schumann, G and Skene, NG and Webb, BT and White, T and Arking, DE and Avramopoulos, D and Bilder, RM and Bitsios, P and Burdick, KE and Cannon, TD and Chiba-Falek, O and Christoforou, A and Cirulli, ET and Congdon, E and Corvin, A and Davies, G and Deary, IJ and DeRosse, P and Dickinson, D and Djurovic, S and Donohoe, G and Conley, ED and Eriksson, JG and Espeseth, T and Freimer, NA and Giakoumaki, S and Giegling, I and Gill, M and Glahn, DC and Hariri, AR and Hatzimanolis, A and Keller, MC and Knowles, E and Koltai, D and Konte, B and Lahti, J and Le Hellard and S and Lencz, T and Liewald, DC and London, E and Lundervold, AJ and Malhotra, AK and Melle, I and Morris, D and Need, AC and Ollier, W and Palotie, A and Payton, A and Pendleton, N and Poldrack, RA and Räikkönen, K and Reinvang, I and Roussos, P and Rujescu, D and Sabb, FW and Scult, MA and Smeland, OB and Smyrnis, N and Starr, JM and Steen, VM and Stefanis, NC and Straub, RE and Sundet, K and Tiemeier, H and Voineskos, AN and Weinberger, DR and Widen, E and Yu, J and Abecasis, G and Andreassen, OA and Breen, G and Christiansen, L and Debrabant, B and Dick, DM and Heinz, A and Hjerling-Leffler, J and Ikram, MA and Kendler, KS and Martin, NG and Medland, SE and Pedersen, NL and Plomin, R and Polderman, TJC and Ripke, S and van der Sluis, S and Sullivan, PF and Vrieze, SI and Wright, MJ and Posthuma, D}, Title = {Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.}, Journal = {Nat Genet}, Volume = {50}, Number = {7}, Pages = {912-919}, Year = {2018}, Month = {July}, url = {http://dx.doi.org/10.1038/s41588-018-0152-6}, Abstract = {Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.}, Doi = {10.1038/s41588-018-0152-6}, Key = {fds335684} } @article{fds331566, Author = {Avinun, R and Nevo, A and Knodt, AR and Elliott, ML and Hariri, AR}, Title = {Replication in Imaging Genetics: The Case of Threat-Related Amygdala Reactivity.}, Journal = {Biological psychiatry}, Volume = {84}, Number = {2}, Pages = {148-159}, Year = {2018}, Month = {July}, url = {http://dx.doi.org/10.1016/j.biopsych.2017.11.010}, Abstract = {<h4>Background</h4>Low replication rates are a concern in most, if not all, scientific disciplines. In psychiatric genetics specifically, targeting intermediate brain phenotypes, which are more closely associated with putative genetic effects, was touted as a strategy leading to increased power and replicability. In the current study, we attempted to replicate previously published associations between single nucleotide polymorphisms and threat-related amygdala reactivity, which represents a robust brain phenotype not only implicated in the pathophysiology of multiple disorders, but also used as a biomarker of future risk.<h4>Methods</h4>We conducted a literature search for published associations between single nucleotide polymorphisms and threat-related amygdala reactivity and found 37 unique findings. Our replication sample consisted of 1117 young adult volunteers (629 women, mean age 19.72 ± 1.25 years) for whom both genetic and functional magnetic resonance imaging data were available.<h4>Results</h4>Of the 37 unique associations identified, only three replicated as previously reported. When exploratory analyses were conducted with different model parameters compared to the original findings, significant associations were identified for 28 additional studies: eight of these were for a different contrast/laterality; five for a different gender and/or race/ethnicity; and 15 in the opposite direction and for a different contrast, laterality, gender, and/or race/ethnicity. No significant associations, regardless of model parameters, were detected for six studies. Notably, none of the significant associations survived correction for multiple comparisons.<h4>Conclusions</h4>We discuss these patterns of poor replication with regard to the general strategy of targeting intermediate brain phenotypes in genetic association studies and the growing importance of advancing the replicability of imaging genetics findings.}, Doi = {10.1016/j.biopsych.2017.11.010}, Key = {fds331566} } @article{fds335691, Author = {Miller, JA and Scult, MA and Conley, ED and Chen, Q and Weinberger, DR and Hariri, AR}, Title = {Effects of Schizophrenia Polygenic Risk Scores on Brain Activity and Performance During Working Memory Subprocesses in Healthy Young Adults.}, Journal = {Schizophrenia bulletin}, Volume = {44}, Number = {4}, Pages = {844-853}, Year = {2018}, Month = {June}, url = {http://dx.doi.org/10.1093/schbul/sbx140}, Abstract = {Recent work has begun to shed light on the neural correlates and possible mechanisms of polygenic risk for schizophrenia. Here, we map a schizophrenia polygenic risk profile score (PRS) based on genome-wide association study significant loci onto variability in the activity and functional connectivity of a frontoparietal network supporting the manipulation versus maintenance of information during a numerical working memory (WM) task in healthy young adults (n = 99, mean age = 19.8). Our analyses revealed that higher PRS was associated with hypoactivity of the dorsolateral prefrontal cortex (dlPFC) during the manipulation but not maintenance of information in WM (r2 = .0576, P = .018). Post hoc analyses revealed that PRS-modulated dlPFC hypoactivity correlated with faster reaction times during WM manipulation (r2 = .0967, P = .002), and faster processing speed (r2 = .0967, P = .003) on a separate behavioral task. These PRS-associated patterns recapitulate dlPFC hypoactivity observed in patients with schizophrenia during central executive manipulation of information in WM on this task.}, Doi = {10.1093/schbul/sbx140}, Key = {fds335691} } @article{fds335685, Author = {Davies, G and Lam, M and Harris, SE and Trampush, JW and Luciano, M and Hill, WD and Hagenaars, SP and Ritchie, SJ and Marioni, RE and Fawns-Ritchie, C and Liewald, DCM and Okely, JA and Ahola-Olli, AV and Barnes, CLK and Bertram, L and Bis, JC and Burdick, KE and Christoforou, A and DeRosse, P and Djurovic, S and Espeseth, T and Giakoumaki, S and Giddaluru, S and Gustavson, DE and Hayward, C and Hofer, E and Ikram, MA and Karlsson, R and Knowles, E and Lahti, J and Leber, M and Li, S and Mather, KA and Melle, I and Morris, D and Oldmeadow, C and Palviainen, T and Payton, A and Pazoki, R and Petrovic, K and Reynolds, CA and Sargurupremraj, M and Scholz, M and Smith, JA and Smith, AV and Terzikhan, N and Thalamuthu, A and Trompet, S and van der Lee, SJ and Ware, EB and Windham, BG and Wright, MJ and Yang, J and Yu, J and Ames, D and Amin, N and Amouyel, P and Andreassen, OA and Armstrong, NJ and Assareh, AA and Attia, JR and Attix, D and Avramopoulos, D and Bennett, DA and Böhmer, AC and Boyle, PA and Brodaty, H and Campbell, H and Cannon, TD and Cirulli, ET and Congdon, E and Conley, ED and Corley, J and Cox, SR and Dale, AM and Dehghan, A and Dick, D and Dickinson, D and Eriksson, JG and Evangelou, E and Faul, JD and Ford, I and Freimer, NA and Gao, H and Giegling, I and Gillespie, NA and Gordon, SD and Gottesman, RF and Griswold, ME and Gudnason, V and Harris, TB and Hartmann, AM and Hatzimanolis, A and Heiss, G and Holliday, EG and Joshi, PK and Kähönen, M and Kardia, SLR and Karlsson, I and Kleineidam, L and Knopman, DS and Kochan, NA and Konte, B and Kwok, JB and Le Hellard and S and Lee, T and Lehtimäki, T and Li, S-C and Lill, CM and Liu, T and Koini, M and London, E and Longstreth, WT and Lopez, OL and Loukola, A and Luck, T and Lundervold, AJ and Lundquist, A and Lyytikäinen, L-P and Martin, NG and Montgomery, GW and Murray, AD and Need, AC and Noordam, R and Nyberg, L and Ollier, W and Papenberg, G and Pattie, A and Polasek, O and Poldrack, RA and Psaty, BM and Reppermund, S and Riedel-Heller, SG and Rose, RJ and Rotter, JI and Roussos, P and Rovio, SP and Saba, Y and Sabb, FW and Sachdev, PS and Satizabal, CL and Schmid, M and Scott, RJ and Scult, MA and Simino, J and Slagboom, PE and Smyrnis, N and Soumaré, A and Stefanis, NC and Stott, DJ and Straub, RE and Sundet, K and Taylor, AM and Taylor, KD and Tzoulaki, I and Tzourio, C and Uitterlinden, A and Vitart, V and Voineskos, AN and Kaprio, J and Wagner, M and Wagner, H and Weinhold, L and Wen, KH and Widen, E and Yang, Q and Zhao, W and Adams, HHH and Arking, DE and Bilder, RM and Bitsios, P and Boerwinkle, E and Chiba-Falek, O and Corvin, A and De Jager and PL and Debette, S and Donohoe, G and Elliott, P and Fitzpatrick, AL and Gill, M and Glahn, DC and Hägg, S and Hansell, NK and Hariri, AR and Ikram, MK and Jukema, JW and Vuoksimaa, E and Keller, MC and Kremen, WS and Launer, L and Lindenberger, U and Palotie, A and Pedersen, NL and Pendleton, N and Porteous, DJ and Räikkönen, K and Raitakari, OT and Ramirez, A and Reinvang, I and Rudan, I and Dan Rujescu, and Schmidt, R and Schmidt, H and Schofield, PW and Schofield, PR and Starr, JM and Steen, VM and Trollor, JN and Turner, ST and Van Duijn, CM and Villringer, A and Weinberger, DR and Weir, DR and Wilson, JF and Malhotra, A and McIntosh, AM and Gale, CR and Seshadri, S and Mosley, TH and Bressler, J and Lencz, T and Deary, IJ}, Title = {Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.}, Journal = {Nat Commun}, Volume = {9}, Number = {1}, Pages = {2098}, Year = {2018}, Month = {May}, url = {http://dx.doi.org/10.1038/s41467-018-04362-x}, Abstract = {General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.}, Doi = {10.1038/s41467-018-04362-x}, Key = {fds335685} } @article{fds335687, Author = {Agrawal, A and Chou, Y-L and Carey, CE and Baranger, DAA and Zhang, B and Sherva, R and Wetherill, L and Kapoor, M and Wang, J-C and Bertelsen, S and Anokhin, AP and Hesselbrock, V and Kramer, J and Lynskey, MT and Meyers, JL and Nurnberger, JI and Rice, JP and Tischfield, J and Bierut, LJ and Degenhardt, L and Farrer, LA and Gelernter, J and Hariri, AR and Heath, AC and Kranzler, HR and Madden, PAF and Martin, NG and Montgomery, GW and Porjesz, B and Wang, T and Whitfield, JB and Edenberg, HJ and Foroud, T and Goate, AM and Bogdan, R and Nelson, EC}, Title = {Genome-wide association study identifies a novel locus for cannabis dependence.}, Journal = {Molecular psychiatry}, Volume = {23}, Number = {5}, Pages = {1293-1302}, Year = {2018}, Month = {May}, url = {http://dx.doi.org/10.1038/mp.2017.200}, Abstract = {Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.}, Doi = {10.1038/mp.2017.200}, Key = {fds335687} } @article{fds335690, Author = {Elliott, ML and Romer, A and Knodt, AR and Hariri, AR}, Title = {A Connectome Wide Functional Signature of Transdiagnostic Risk for Mental Illness}, Journal = {Biological Psychiatry}, Volume = {84}, Number = {6}, Pages = {452-459}, Year = {2018}, Month = {April}, url = {http://dx.doi.org/10.1016/j.biopsych.2018.03.012}, Abstract = {Background High rates of comorbidity, shared risk, and overlapping therapeutic mechanisms have led psychopathology research towards transdiagnostic dimensional investigations of clustered symptoms. One influential framework accounts for these transdiagnostic phenomena through a single general factor, sometimes referred to as the ‘p’ factor, associated with risk for all common forms of mental illness. Methods Here we build on past research identifying unique structural neural correlates of the p factor by conducting a data-driven analysis of connectome wide intrinsic functional connectivity (n = 605). Results We demonstrate that higher p factor scores and associated risk for common mental illness maps onto hyper-connectivity between visual association cortex and both frontoparietal and default mode networks. Conclusions These results provide initial evidence that the transdiagnostic risk for common forms of mental illness is associated with patterns of inefficient connectome wide intrinsic connectivity between visual association cortex and networks supporting executive control and self-referential processes, networks which are often impaired across categorical disorders.}, Doi = {10.1016/j.biopsych.2018.03.012}, Key = {fds335690} } @article{fds335688, Author = {Chen, Q and Ursini, G and Romer, AL and Knodt, AR and Mezeivtch, K and Xiao, E and Pergola, G and Blasi, G and Straub, RE and Callicott, JH and Berman, KF and Hariri, AR and Bertolino, A and Mattay, VS and Weinberger, DR}, Title = {Schizophrenia polygenic risk score predicts mnemonic hippocampal activity.}, Journal = {Brain : a journal of neurology}, Volume = {141}, Number = {4}, Pages = {1218-1228}, Year = {2018}, Month = {April}, url = {http://dx.doi.org/10.1093/brain/awy004}, Abstract = {The use of polygenic risk scores has become a practical translational approach to investigating the complex genetic architecture of schizophrenia, but the link between polygenic risk scores and pathophysiological components of this disorder has been the subject of limited research. We investigated in healthy volunteers whether schizophrenia polygenic risk score predicts hippocampal activity during simple memory encoding, which has been proposed as a risk-associated intermediate phenotype of schizophrenia. We analysed the relationship between polygenic risk scores and hippocampal activity in a discovery sample of 191 unrelated healthy volunteers from the USA and in two independent replication samples of 76 and 137 healthy unrelated participants from Europe and the USA, respectively. Polygenic risk scores for each individual were calculated as the sum of the imputation probability of reference alleles weighted by the natural log of odds ratio from the recent schizophrenia genome-wide association study. We examined hippocampal activity during simple memory encoding of novel visual stimuli assessed using blood oxygen level-dependent functional MRI. Polygenic risk scores were significantly associated with hippocampal activity in the discovery sample [P = 0.016, family-wise error (FWE) corrected within Anatomical Automatic Labeling (AAL) bilateral hippocampal-parahippocampal mask] and in both replication samples (P = 0.033, FWE corrected within AAL right posterior hippocampal-parahippocampal mask in Bari sample, and P = 0.002 uncorrected in the Duke Neurogenetics Study sample). The relationship between polygenic risk scores and hippocampal activity was consistently negative, i.e. lower hippocampal activity in individuals with higher polygenic risk scores, consistent with previous studies reporting decreased hippocampal-parahippocampal activity during declarative memory tasks in patients with schizophrenia and in their healthy siblings. Polygenic risk scores accounted for more than 8% of variance in hippocampal activity during memory encoding in discovery sample. We conclude that polygenic risk scores derived from the most recent schizophrenia genome-wide association study predict significant variability in hippocampal activity during memory encoding in healthy participants. Our findings validate mnemonic hippocampal activity as a genetic risk associated intermediate phenotype of schizophrenia, indicating that the aggregate neurobiological effect of schizophrenia risk alleles converges on this pattern of neural activity.awy004media15749593779001.}, Doi = {10.1093/brain/awy004}, Key = {fds335688} } @article{fds326208, Author = {Romer, AL and Knodt, AR and Houts, R and Brigidi, BD and Moffitt, TE and Caspi, A and Hariri, AR}, Title = {Structural alterations within cerebellar circuitry are associated with general liability for common mental disorders.}, Journal = {Molecular psychiatry}, Volume = {23}, Number = {4}, Pages = {1084-1090}, Year = {2018}, Month = {April}, url = {http://dx.doi.org/10.1038/mp.2017.57}, Abstract = {Accumulating mental-health research encourages a shift in focus toward transdiagnostic dimensional features that are shared across categorical disorders. In support of this shift, recent studies have identified a general liability factor for psychopathology-sometimes called the 'p factor'- that underlies shared risk for a wide range of mental disorders. Identifying neural correlates of this general liability would substantiate its importance in characterizing the shared origins of mental disorders and help us begin to understand the mechanisms through which the 'p factor' contributes to risk. Here we believe we first replicate the 'p factor' using cross-sectional data from a volunteer sample of 1246 university students, and then using high-resolution multimodal structural neuroimaging, we demonstrate that individuals with higher 'p factor' scores show reduced structural integrity of white matter pathways, as indexed by lower fractional anisotropy values, uniquely within the pons. Whole-brain analyses further revealed that higher 'p factor' scores are associated with reduced gray matter volume in the occipital lobe and left cerebellar lobule VIIb, which is functionally connected with prefrontal regions supporting cognitive control. Consistent with the preponderance of cerebellar afferents within the pons, we observed a significant positive correlation between the white matter integrity of the pons and cerebellar gray matter volume associated with higher 'p factor' scores. The results of our analyses provide initial evidence that structural alterations in corticocerebellar circuitry supporting core functions related to the basic integration, coordination and monitoring of information may contribute to a general liability for common mental disorders.}, Doi = {10.1038/mp.2017.57}, Key = {fds326208} } @article{fds332044, Author = {Scult, MA and Hariri, AR}, Title = {A BRIEF INTRODUCTION TO THE NEUROGENETICS OF COGNITION-EMOTION INTERACTIONS.}, Journal = {Current opinion in behavioral sciences}, Volume = {19}, Pages = {50-54}, Year = {2018}, Month = {February}, url = {http://dx.doi.org/10.1016/j.cobeha.2017.09.014}, Abstract = {Neuroscience research has demonstrated that cognition, emotion, and their dynamic interactions emerge from complex and flexible patterns of activity across distributed neural circuits. A parallel branch of research in genetics has begun to identify common variation in the human DNA sequence (i.e., genome) that may shape individual differences in cognition-emotion interactions by altering molecular and cellular pathways that modulate the activity of these neural circuits. Here we provide a brief introduction to such neurogenetics research and how it may usefully inform our understanding of the biological mechanisms through which dynamic cognition-emotion interactions emerge and, subsequently, help shape normal and abnormal behavior.}, Doi = {10.1016/j.cobeha.2017.09.014}, Key = {fds332044} } @article{fds331564, Author = {Swartz, JR and Knodt, AR and Radtke, SR and Hariri, AR}, Title = {Post-secondary maternal education buffers against neural risk for psychological vulnerability to future life stress.}, Journal = {Neuropsychologia}, Volume = {109}, Pages = {134-139}, Publisher = {Elsevier BV}, Year = {2018}, Month = {January}, url = {http://dx.doi.org/10.1016/j.neuropsychologia.2017.12.019}, Abstract = {We have previously reported that threat-related amygdala activity measured during a baseline fMRI scan predicts the experience of depression and anxiety associated with stressful life events years later. Here, we examine whether two broad measures of childhood environmental enrichment, namely parental educational achievement and subjective parental socioeconomic status, buffer against the effects of amygdala activity on future vulnerability to stress. Analyses of data available from 579 young adults revealed that maternal, but not paternal, educational achievement moderates the association between amygdala activity, recent life stress, and changes in mood and anxiety symptoms, even when controlling for participants' current subjective socioeconomic status. Specifically, only participants reporting lower maternal educational achievement exhibited our previously observed interaction between amygdala activity and future life stress predicting increases in depression and anxiety. These results suggest that higher maternal educational achievement may help buffer stress sensitivity associated with heightened threat-related amygdala activity.}, Doi = {10.1016/j.neuropsychologia.2017.12.019}, Key = {fds331564} } @article{fds332756, Author = {Nikolova, YS and Misquitta, KA and Rocco, BR and Prevot, TD and Knodt, AR and Ellegood, J and Voineskos, AN and Lerch, JP and Hariri, AR and Sibille, E and Banasr, M}, Title = {Shifting priorities: highly conserved behavioral and brain network adaptations to chronic stress across species.}, Journal = {Translational psychiatry}, Volume = {8}, Number = {1}, Pages = {26}, Year = {2018}, Month = {January}, url = {http://dx.doi.org/10.1038/s41398-017-0083-5}, Abstract = {Parallel clinical and preclinical research have begun to illuminate the biological basis of stress-related disorders, including major depression, but translational bridges informing discrete mechanistic targets for intervention are missing. To address this critical need, we used structural MRI in a mouse model and in a large human sample to examine stress effects on brain structure that may be conserved across species. Specifically, we focused on a previously unexplored approach, whole-brain structural covariance, as it reflects synchronized changes in neuroanatomy, potentially due to mutual trophic influences or shared plasticity across regions. Using the unpredictable chronic mild stress (UCMS) paradigm in mouse we first demonstrate that UCMS-induced elevated behavioral emotionality correlates with increased size of the amygdala and other corticolimbic regions. We further identify focal increases in the amygdala's 'hubness' (degree and strength) set against the background of a global stress-related loss of network clustering and modularity. These macroscopic changes are supported on the molecular level by increased postsynaptic density-95 protein in the amygdala, consistent with stress-induced plastic changes and synaptic strengthening. Finally, we provide clinical evidence that strikingly similar structural network reorganization patterns exist in young adults reporting high childhood trauma and increased mood symptoms. Collectively, we provide initial translational evidence for a conserved stress-related increase in amygdala-centered structural synchrony, as measured by enhanced structural covariance, which is paralleled by a decrease in global structural synchrony. This putative trade-off reflected in increased amygdala-centered plastic changes at the expense of global structural dedifferentiation may represent a mechanistic pathway for depression and related psychopathology.}, Doi = {10.1038/s41398-017-0083-5}, Key = {fds332756} } @article{fds364156, Author = {d'Arbeloff, TC and Freedy, KR and Knodt, AR and Radtke, SR and Brigidi, BD and Hariri, AR}, Title = {Emotion Regulation and the Experience of Future Negative Mood: The Importance of Assessing Social Support.}, Journal = {Frontiers in psychology}, Volume = {9}, Pages = {2287}, Year = {2018}, Month = {January}, url = {http://dx.doi.org/10.3389/fpsyg.2018.02287}, Abstract = {Emotion regulation refers to the use of various strategies, such as cognitive reappraisal and expressive suppression, to help manage our negative experiences, emotions, and thoughts. Although such emotion regulation often occurs within broader social dynamics and interactions, little is known about how social contexts interact with specific regulation strategies to shape the experience of negative emotions. Using data from 544 young adult university students, we provide initial evidence that habitual use of cognitive reappraisal is associated with lower future experience of depression and anxiety primarily through higher perceived social support (PSS). In contrast, expressive suppression is associated with higher future depression and anxiety primarily through lower PSS. These patterns are consistent with the importance of interpersonal influences on emotion regulation and suggest that assessment of social support can help elucidate the mechanisms of successfully regulating negative mood.}, Doi = {10.3389/fpsyg.2018.02287}, Key = {fds364156} } @article{fds329769, Author = {Dotterer, HL and Waller, R and Neumann, CS and Shaw, DS and Forbes, EE and Hariri, AR and Hyde, LW}, Title = {Examining the Factor Structure of the Self-Report of Psychopathy Short-Form Across Four Young Adult Samples.}, Journal = {Assessment}, Volume = {24}, Number = {8}, Pages = {1062-1079}, Year = {2017}, Month = {December}, url = {http://dx.doi.org/10.1177/1073191116640355}, Abstract = {Psychopathy refers to a range of complex behaviors and personality traits, including callousness and antisocial behavior, typically studied in criminal populations. Recent studies have used self-reports to examine psychopathic traits among noncriminal samples. The goal of the current study was to examine the underlying factor structure of the Self-Report of Psychopathy Scale-Short Form (SRP-SF) across complementary samples and examine the impact of gender on factor structure. We examined the structure of the SRP-SF among 2,554 young adults from three undergraduate samples and a high-risk young adult sample. Using confirmatory factor analysis, a four-correlated factor model and a four-bifactor model showed good fit to the data. Evidence of weak invariance was found for both models across gender. These findings highlight that the SRP-SF is a useful measure of low-level psychopathic traits in noncriminal samples, although the underlying factor structure may not fully translate across men and women.}, Doi = {10.1177/1073191116640355}, Key = {fds329769} } @article{fds330405, Author = {Lam, M and Trampush, JW and Yu, J and Knowles, E and Davies, G and Liewald, DC and Starr, JM and Djurovic, S and Melle, I and Sundet, K and Christoforou, A and Reinvang, I and DeRosse, P and Lundervold, AJ and Steen, VM and Espeseth, T and Räikkönen, K and Widen, E and Palotie, A and Eriksson, JG and Giegling, I and Konte, B and Roussos, P and Giakoumaki, S and Burdick, KE and Payton, A and Ollier, W and Chiba-Falek, O and Attix, DK and Need, AC and Cirulli, ET and Voineskos, AN and Stefanis, NC and Avramopoulos, D and Hatzimanolis, A and Arking, DE and Smyrnis, N and Bilder, RM and Freimer, NA and Cannon, TD and London, E and Poldrack, RA and Sabb, FW and Congdon, E and Conley, ED and Scult, MA and Dickinson, D and Straub, RE and Donohoe, G and Morris, D and Corvin, A and Gill, M and Hariri, AR and Weinberger, DR and Pendleton, N and Bitsios, P and Rujescu, D and Lahti, J and Le Hellard and S and Keller, MC and Andreassen, OA and Deary, IJ and Glahn, DC and Malhotra, AK and Lencz, T}, Title = {Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.}, Journal = {Cell Rep}, Volume = {21}, Number = {9}, Pages = {2597-2613}, Year = {2017}, Month = {November}, url = {http://dx.doi.org/10.1016/j.celrep.2017.11.028}, Abstract = {Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.}, Doi = {10.1016/j.celrep.2017.11.028}, Key = {fds330405} } @article{fds343723, Author = {Scult, MA and Knodt, AR and Radtke, SR and Brigidi, BD and Hariri, AR}, Title = {Prefrontal Executive Control Rescues Risk for Anxiety Associated with High Threat and Low Reward Brain Function}, Journal = {Cerebral Cortex}, Volume = {29}, Number = {1}, Pages = {70-76}, Year = {2017}, Month = {November}, url = {http://dx.doi.org/10.1093/cercor/bhx304}, Abstract = {Compared with neural biomarkers of risk for mental illness, little is known about biomarkers of resilience. We explore if greater executive control-related prefrontal activity may function as a resilience biomarker by “rescuing” risk associated with higher threat-related amygdala and lower reward-related ventral striatum activity. Functional MRI was used to assay baseline threat-related amygdala, reward-related ventral striatum, and executive control-related prefrontal activity in 120 young adult volunteers. Participants provided self-reported mood and anxiety ratings at baseline and follow-up. A moderation model revealed a significant three-way interaction wherein higher amygdala and lower ventral striatum activity predicted increases in anxiety in those with average or low but not high prefrontal activity. This effect was specific to anxiety, with the neural biomarkers explaining ~10% of the variance in change over time, above and beyond baseline symptoms, sex, age, IQ, presence or absence of DMS-IV diagnosis, and both early and recent stress. Our findings are consistent with the importance of top-down executive control in adaptive regulation of negative emotions, and highlight a unique combination of neural biomarkers that may identify at-risk individuals for whom the adoption of strategies to improve executive control of negative emotions may prove particularly beneficial.}, Doi = {10.1093/cercor/bhx304}, Key = {fds343723} } @article{fds332981, Author = {Lissek, T and Adams, M and Adelman, J and Ahissar, E and Akaaboune, M and Akil, H and al'Absi, M and Arain, F and Arango-Lasprilla, JC and Atasoy, D and Avila, J and Badawi, A and Bading, H and Baig, AM and Baleriola, J and Belmonte, C and Bertocchi, I and Betz, H and Blakemore, C and Blanke, O and Boehm-Sturm, P and Bonhoeffer, T and Bonifazi, P and Brose, N and Campolongo, P and Celikel, T and Chang, CC and Chang, T-Y and Citri, A and Cline, HT and Cortes, JM and Cullen, K and Dean, K and Delgado-Garcia, JM and Desroches, M and Disterhoft, JF and Dowling, JE and Draguhn, A and El-Khamisy, SF and El Manira and A and Enam, SA and Encinas, JM and Erramuzpe, A and Esteban, JA and Fariñas, I and Fischer, E and Fukunaga, I and Gabilondo, I and Ganten, D and Gidon, A and Gomez-Esteban, JC and Greengard, P and Grinevich, V and Gruart, A and Guillemin, R and Hariri, AR and Hassan, B and Häusser, M and Hayashi, Y and Hussain, NK and Jabbar, AA and Jaber, M and Jahn, R and Janahi, EM and Kabbaj, M and Kettenmann, H and Kindt, M and Knafo, S and Köhr, G and Komai, S and Krugers, H and Kuhn, B and Ghazal, NL and Larkum, ME and London, M and Lutz, B and Matute, C and Martinez-Millan, L and Maroun, M and McGaugh, J and Moustafa, AA and Nasim, A and Nave, K-A and Neher, E and Nikolich, K and Outeiro, T and Palmer, LM and Penagarikano, O and Perez-Otano, I and Pfaff, DW and Poucet, B and Rahman, A-U and Ramos-Cabrer, P and Rashidy-Pour, A and Roberts, RJ and Rodrigues, S and Sanes, JR and Schaefer, AT and Segal, M and Segev, I and Shafqat, S and Siddiqui, NA and Soreq, H and Soriano-García, E and Spanagel, R and Sprengel, R and Stuart, G and Südhof, TC and Tønnesen, J and Treviño, M and Uthman, BM and Venter, JC and Verkhratsky, A and Weiss, C and Wiesel, TN and Yaksi, E and Yizhar, O and Young, LJ and Young, P and Zawia, NH and Zugaza, JL and Hasan, MT}, Title = {Building Bridges through Science.}, Journal = {Neuron}, Volume = {96}, Number = {4}, Pages = {730-735}, Year = {2017}, Month = {November}, url = {http://dx.doi.org/10.1016/j.neuron.2017.09.028}, Abstract = {Science is ideally suited to connect people from different cultures and thereby foster mutual understanding. To promote international life science collaboration, we have launched "The Science Bridge" initiative. Our current project focuses on partnership between Western and Middle Eastern neuroscience communities.}, Doi = {10.1016/j.neuron.2017.09.028}, Key = {fds332981} } @article{fds330404, Author = {Schaefer, JD and Scult, MA and Caspi, A and Arseneault, L and Belsky, DW and Hariri, AR and Harrington, H and Houts, R and Ramrakha, S and Poulton, R and Moffitt, TE}, Title = {Is low cognitive functioning a predictor or consequence of major depressive disorder? A test in two longitudinal birth cohorts.}, Journal = {Development and psychopathology}, Pages = {1-15}, Year = {2017}, Month = {November}, url = {http://dx.doi.org/10.1017/s095457941700164x}, Abstract = {Cognitive impairment has been identified as an important aspect of major depressive disorder (MDD). We tested two theories regarding the association between MDD and cognitive functioning using data from longitudinal cohort studies. One theory, the cognitive reserve hypothesis, suggests that higher cognitive ability in childhood decreases risk of later MDD. The second, the scarring hypothesis, instead suggests that MDD leads to persistent cognitive deficits following disorder onset. We tested both theories in the Dunedin Study, a population-representative cohort followed from birth to midlife and assessed repeatedly for both cognitive functioning and psychopathology. We also used data from the Environmental Risk Longitudinal Twin Study to test whether childhood cognitive functioning predicts future MDD risk independent of family-wide and genetic risk using a discordant twin design. Contrary to both hypotheses, we found that childhood cognitive functioning did not predict future risk of MDD, nor did study members with a past history of MDD show evidence of greater cognitive decline unless MDD was accompanied by other comorbid psychiatric conditions. Our results thus suggest that low cognitive functioning is related to comorbidity, but is neither an antecedent nor an enduring consequence of MDD. Future research may benefit from considering cognitive deficits that occur during depressive episodes from a transdiagnostic perspective.}, Doi = {10.1017/s095457941700164x}, Key = {fds330404} } @article{fds328846, Author = {Gard, AM and Waller, R and Shaw, DS and Forbes, EE and Hariri, AR and Hyde, LW}, Title = {The long reach of early adversity: Parenting, stress, and neural pathways to antisocial behavior in adulthood.}, Journal = {Biological psychiatry. Cognitive neuroscience and neuroimaging}, Volume = {2}, Number = {7}, Pages = {582-590}, Publisher = {Elsevier BV}, Year = {2017}, Month = {October}, url = {http://dx.doi.org/10.1016/j.bpsc.2017.06.005}, Abstract = {<h4>Background</h4>Early life adversities including harsh parenting, maternal depression, neighborhood deprivation, and low family economic resources are more prevalent in low-income urban environments and are potent predictors of psychopathology, including, for boys, antisocial behavior (AB). However, little research has examined how these stressful experiences alter later neural function. Moreover, identifying genetic markers of greater susceptibility to adversity is critical to understanding biopsychosocial pathways from early adversity to later psychopathology.<h4>Methods</h4>Within a sample of 310 low-income boys followed from age 1.5 to 20, multimethod assessments of adversities were examined at age 2 and age 12. At age 20, amygdala reactivity to emotional facial expressions was assessed using fMRI, and symptoms of Antisocial Personality Disorder were assessed via structured clinical interview. Genetic variability in cortisol signaling (<i>CRHR1</i>) was examined as a moderator of pathways to amygdala reactivity.<h4>Results</h4>Observed parenting and neighborhood deprivation at age 2 each uniquely predicted amygdala reactivity to emotional faces at age 20 over and above other adversities measured at multiple developmental periods. Harsher parenting and greater neighborhood deprivation in toddlerhood predicted clinically-significant symptoms of AB via less amygdala reactivity to fearful facial expressions and this pathway was moderated by genetic variation in <i>CRHR1</i>.<h4>Conclusions</h4>These results elucidate a pathway linking early adversity to less amygdala reactivity to social signals of interpersonal distress 18 years later, which in turn increased risk for serious AB. Moreover, these findings suggest a genetic marker of youth more susceptible to adversity.}, Doi = {10.1016/j.bpsc.2017.06.005}, Key = {fds328846} } @article{fds329468, Author = {Avinun, R and Nevo, A and Knodt, AR and Elliott, ML and Radtke, SR and Brigidi, BD and Hariri, AR}, Title = {Reward-Related Ventral Striatum Activity Buffers against the Experience of Depressive Symptoms Associated with Sleep Disturbances.}, Journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, Volume = {37}, Number = {40}, Pages = {9724-9729}, Year = {2017}, Month = {October}, url = {http://dx.doi.org/10.1523/jneurosci.1734-17.2017}, Abstract = {Sleep disturbances represent one risk factor for depression. Reward-related brain function, particularly the activity of the ventral striatum (VS), has been identified as a potential buffer against stress-related depression. We were therefore interested in testing whether reward-related VS activity would moderate the effect of sleep disturbances on depression in a large cohort of young adults. Data were available from 1129 university students (mean age 19.71 ± 1.25 years; 637 women) who completed a reward-related functional MRI task to assay VS activity and provided self-reports of sleep using the Pittsburgh Sleep Quality Index and symptoms of depression using a summation of the General Distress/Depression and Anhedonic Depression subscales of the Mood and Anxiety Symptoms Questionnaire-short form. Analyses revealed that as VS activity increased the association between sleep disturbances and depressive symptoms decreased. The interaction between sleep disturbances and VS activity was robust to the inclusion of sex, age, race/ethnicity, past or present clinical disorder, early and recent life stress, and anxiety symptoms, as well as the interactions between VS activity and early or recent life stress as covariates. We provide initial evidence that high reward-related VS activity may buffer against depressive symptoms associated with poor sleep. Our analyses help advance an emerging literature supporting the importance of individual differences in reward-related brain function as a potential biomarker of relative risk for depression.<b>SIGNIFICANCE STATEMENT</b> Sleep disturbances are a common risk factor for depression. An emerging literature suggests that reward-related activity of the ventral striatum (VS), a brain region critical for motivation and goal-directed behavior, may buffer against the effect of negative experiences on the development of depression. Using data from a large sample of 1129 university students we demonstrate that as reward-related VS activity increases, the link between sleep disturbances and depression decreases. This finding contributes to accumulating research demonstrating that reward-related brain function may be a useful biomarker of relative risk for depression in the context of negative experiences.}, Doi = {10.1523/jneurosci.1734-17.2017}, Key = {fds329468} } @article{fds329035, Author = {Kim, MJ and Avinun, R and Knodt, AR and Radtke, SR and Hariri, AR}, Title = {Neurogenetic plasticity and sex influence the link between corticolimbic structural connectivity and trait anxiety.}, Journal = {Scientific reports}, Volume = {7}, Number = {1}, Pages = {10959}, Year = {2017}, Month = {September}, url = {http://dx.doi.org/10.1038/s41598-017-11497-2}, Abstract = {Corticolimbic pathways connecting the amygdala and ventral prefrontal cortex (vPFC) are linked with trait anxiety, but it remains unclear what potential genetic moderators contribute to this association. We sought to address this by examining the inter-individual variability in neuroplasticity as modeled by a functional polymorphism (rs6265) in the human gene for brain derived neurotrophic factor (BDNF). Amygdala-vPFC pathway fractional anisotropy (FA) from 669 diffusion magnetic resonance images was used to examine associations with trait anxiety as a function of rs6265 genotype. We first replicated the inverse correlation between trait anxiety and amygdala-vPFC pathway FA in women. Furthermore, we found a moderating influence of rs6265 genotype such that the association between trait anxiety and right amygdala-vPFC pathway FA was strongest in women carrying the Met allele, which is linked with decreased activity-dependent neuroplasticity. Results indicate that the microstructural integrity of pathways supporting communication between the amygdala and vPFC help shape the expression of trait anxiety in women, and that this association is further modulated by genetically driven variability in neuroplasticity.}, Doi = {10.1038/s41598-017-11497-2}, Key = {fds329035} } @article{fds331565, Author = {Baranger, DAA and Margolis, S and Hariri, AR and Bogdan, R}, Title = {An earlier time of scan is associated with greater threat-related amygdala reactivity.}, Journal = {Social cognitive and affective neuroscience}, Volume = {12}, Number = {8}, Pages = {1272-1283}, Year = {2017}, Month = {August}, url = {http://dx.doi.org/10.1093/scan/nsx057}, Abstract = {Time-dependent variability in mood and anxiety suggest that related neural phenotypes, such as threat-related amygdala reactivity, may also follow a diurnal pattern. Here, using data from 1,043 young adult volunteers, we found that threat-related amygdala reactivity was negatively coupled with time of day, an effect which was stronger in the left hemisphere (β = -0.1083, p-fdr = 0.0012). This effect was moderated by subjective sleep quality (β = -0.0715, p-fdr = 0.0387); participants who reported average and poor sleep quality had relatively increased left amygdala reactivity in the morning. Bootstrapped simulations suggest that similar cross-sectional samples with at least 300 participants would be able to detect associations between amygdala reactivity and time of scan. In control analyses, we found no associations between time and V1 activation. Our results provide initial evidence that threat-related amygdala reactivity may vary diurnally, and that this effect is potentiated among individuals with average to low sleep quality. More broadly, our results suggest that considering time of scan in study design or modeling time of scan in analyses, as well as collecting additional measures of circadian variation, may be useful for understanding threat-related neural phenotypes and their associations with behavior, such as fear conditioning, mood and anxiety symptoms, and related phenotypes.}, Doi = {10.1093/scan/nsx057}, Key = {fds331565} } @article{fds325037, Author = {Bogdan, R and Salmeron, BJ and Carey, CE and Agrawal, A and Calhoun, VD and Garavan, H and Hariri, AR and Heinz, A and Hill, MN and Holmes, A and Kalin, NH and Goldman, D}, Title = {Imaging Genetics and Genomics in Psychiatry: A Critical Review of Progress and Potential.}, Journal = {Biological psychiatry}, Volume = {82}, Number = {3}, Pages = {165-175}, Year = {2017}, Month = {August}, url = {http://dx.doi.org/10.1016/j.biopsych.2016.12.030}, Abstract = {Imaging genetics and genomics research has begun to provide insight into the molecular and genetic architecture of neural phenotypes and the neural mechanisms through which genetic risk for psychopathology may emerge. As it approaches its third decade, imaging genetics is confronted by many challenges, including the proliferation of studies using small sample sizes and diverse designs, limited replication, problems with harmonization of neural phenotypes for meta-analysis, unclear mechanisms, and evidence that effect sizes may be more modest than originally posited, with increasing evidence of polygenicity. These concerns have encouraged the field to grow in many new directions, including the development of consortia and large-scale data collection projects and the use of novel methods (e.g., polygenic approaches, machine learning) that enhance the quality of imaging genetic studies but also introduce new challenges. We critically review progress in imaging genetics and offer suggestions and highlight potential pitfalls of novel approaches. Ultimately, the strength of imaging genetics and genomics lies in their translational and integrative potential with other research approaches (e.g., nonhuman animal models, psychiatric genetics, pharmacologic challenge) to elucidate brain-based pathways that give rise to the vast individual differences in behavior as well as risk for psychopathology.}, Doi = {10.1016/j.biopsych.2016.12.030}, Key = {fds325037} } @article{fds315805, Author = {Scult, MA and Knodt, AR and Hanson, JL and Ryoo, M and Adcock, RA and Hariri, AR and Strauman, TJ}, Title = {Individual differences in regulatory focus predict neural response to reward.}, Journal = {Soc Neurosci}, Volume = {12}, Number = {4}, Pages = {419-429}, Year = {2017}, Month = {August}, ISSN = {1747-0919}, url = {http://dx.doi.org/10.1080/17470919.2016.1178170}, Abstract = {Although goal pursuit is related to both functioning of the brain's reward circuits and psychological factors, the literatures surrounding these concepts have often been separate. Here, we use the psychological construct of regulatory focus to investigate individual differences in neural response to reward. Regulatory focus theory proposes two motivational orientations for personal goal pursuit: (1) promotion, associated with sensitivity to potential gain, and (2) prevention, associated with sensitivity to potential loss. The monetary incentive delay task was used to manipulate reward circuit function, along with instructional framing corresponding to promotion and prevention in a within-subject design. We observed that the more promotion oriented an individual was, the lower their ventral striatum response to gain cues. Follow-up analyses revealed that greater promotion orientation was associated with decreased ventral striatum response even to no-value cues, suggesting that promotion orientation may be associated with relatively hypoactive reward system function. The findings are also likely to represent an interaction between the cognitive and motivational characteristics of the promotion system with the task demands. Prevention orientation did not correlate with ventral striatum response to gain cues, supporting the discriminant validity of regulatory focus theory. The results highlight a dynamic association between individual differences in self-regulation and reward system function.}, Doi = {10.1080/17470919.2016.1178170}, Key = {fds315805} } @article{fds325971, Author = {Di Iorio and CR and Carey, CE and Michalski, LJ and Corral-Frias, NS and Conley, ED and Hariri, AR and Bogdan, R}, Title = {Hypothalamic-pituitary-adrenal axis genetic variation and early stress moderates amygdala function.}, Journal = {Psychoneuroendocrinology}, Volume = {80}, Pages = {170-178}, Year = {2017}, Month = {June}, url = {http://dx.doi.org/10.1016/j.psyneuen.2017.03.016}, Abstract = {Early life stress may precipitate psychopathology, at least in part, by influencing amygdala function. Converging evidence across species suggests that links between childhood stress and amygdala function may be dependent upon hypothalamic-pituitary-adrenal (HPA) axis function. Using data from college-attending non-Hispanic European-Americans (n=308) who completed the Duke Neurogenetics Study, we examined whether early life stress (ELS) and HPA axis genetic variation interact to predict threat-related amygdala function as well as psychopathology symptoms. A biologically-informed multilocus profile score (BIMPS) captured HPA axis genetic variation (FKBP5 rs1360780, CRHR1 rs110402; NR3C2 rs5522/rs4635799) previously associated with its function (higher BIMPS are reflective of higher HPA axis activity). BOLD fMRI data were acquired while participants completed an emotional face matching task. ELS and depression and anxiety symptoms were measured using the childhood trauma questionnaire and the mood and anxiety symptom questionnaire, respectively. The interaction between HPA axis BIMPS and ELS was associated with right amygdala reactivity to threat-related stimuli, after accounting for multiple testing (empirical-p=0.016). Among individuals with higher BIMPS (i.e., the upper 21.4%), ELS was positively coupled with threat-related amygdala reactivity, which was absent among those with average or low BIMPS. Further, higher BIMPS were associated with greater self-reported anxious arousal, though there was no evidence that amygdala function mediated this relationship. Polygenic variation linked to HPA axis function may moderate the effects of early life stress on threat-related amygdala function and confer risk for anxiety symptomatology. However, what, if any, neural mechanisms may mediate the relationship between HPA axis BIMPS and anxiety symptomatology remains unclear.}, Doi = {10.1016/j.psyneuen.2017.03.016}, Key = {fds325971} } @article{fds325036, Author = {Dotterer, HL and Hyde, LW and Swartz, JR and Hariri, AR and Williamson, DE}, Title = {Amygdala reactivity predicts adolescent antisocial behavior but not callous-unemotional traits.}, Journal = {Developmental cognitive neuroscience}, Volume = {24}, Pages = {84-92}, Year = {2017}, Month = {April}, url = {http://dx.doi.org/10.1016/j.dcn.2017.02.008}, Abstract = {Recent neuroimaging studies have suggested divergent relationships between antisocial behavior (AB) and callous-unemotional (CU) traits and amygdala reactivity to fearful and angry facial expressions in adolescents. However, little work has examined if these findings extend to dimensional measures of behavior in ethnically diverse, non-clinical samples, or if participant sex, ethnicity, pubertal stage, and age moderate associations. We examined links between amygdala reactivity and dimensions of AB and CU traits in 220 Hispanic and non-Hispanic Caucasian adolescents (age 11-15; 49.5% female; 38.2% Hispanic), half of whom had a family history for depression and thus were at relatively elevated risk for late starting, emotionally dysregulated AB. We found that AB was significantly related to increased right amygdala reactivity to angry facial expressions independent of sex, ethnicity, pubertal stage, age, and familial risk status for depression. CU traits were not related to fear- or anger-related amygdala reactivity. The present study further demonstrates that AB is related to increased amygdala reactivity to interpersonal threat cues in adolescents, and that this relationship generalizes across sex, ethnicity, pubertal stage, age, and familial risk status for depression.}, Doi = {10.1016/j.dcn.2017.02.008}, Key = {fds325036} } @article{fds325035, Author = {Swartz, JR and Prather, AA and Hariri, AR}, Title = {Threat-related amygdala activity is associated with peripheral CRP concentrations in men but not women.}, Journal = {Psychoneuroendocrinology}, Volume = {78}, Pages = {93-96}, Year = {2017}, Month = {April}, url = {http://dx.doi.org/10.1016/j.psyneuen.2017.01.024}, Abstract = {Increased levels of peripheral inflammatory markers, including C-Reactive Protein (CRP), are associated with increased risk for depression, anxiety, and suicidality. The brain mechanisms that may underlie the association between peripheral inflammation and internalizing problems remain to be determined. The present study examines associations between peripheral CRP concentrations and threat-related amygdala activity, a neural biomarker of depression and anxiety risk, in a sample of 172 young adult undergraduate students. Participants underwent functional MRI scanning while performing an emotional face matching task to obtain a measure of threat-related amygdala activity to angry and fearful faces; CRP concentrations were assayed from dried blood spots. Results indicated a significant interaction between CRP and sex: in men, but not women, higher CRP was associated with higher threat-related amygdala activity. These results add to the literature finding associations between systemic levels of inflammation and brain function and suggest that threat-related amygdala activity may serve as a potential pathway through which heightened chronic inflammation may increase risk for mood and anxiety problems.}, Doi = {10.1016/j.psyneuen.2017.01.024}, Key = {fds325035} } @article{fds323253, Author = {Carey, CE and Knodt, AR and Conley, ED and Hariri, AR and Bogdan, R}, Title = {Reward-related ventral striatum activity links polygenic risk for attention-deficit/hyperactivity disorder to problematic alcohol use in young adulthood.}, Journal = {Biological psychiatry. Cognitive neuroscience and neuroimaging}, Volume = {2}, Number = {2}, Pages = {180-187}, Publisher = {Elsevier BV}, Year = {2017}, Month = {March}, url = {http://dx.doi.org/10.1016/j.bpsc.2016.10.003}, Abstract = {<h4>Background</h4>Problematic alcohol use in adolescence and adulthood is a common and often debilitating correlate of childhood attention-deficit/hyperactivity disorder (ADHD). Converging evidence suggests that ADHD and problematic alcohol use share a common additive genetic basis, which may be mechanistically related to reward-related brain function. In the current study, we examined whether polygenic risk for childhood ADHD is linked to problematic alcohol use in young adulthood through alterations in reward-related activity of the ventral striatum, a neural hub supporting appetitive behaviors and reinforcement learning.<h4>Methods</h4>Genomic, neuroimaging, and self-report data were available for 404 non-Hispanic European-American participants who completed the ongoing Duke Neurogenetics Study. Polygenic risk scores for childhood ADHD were calculated based on a genome-wide association study meta-analysis conducted by the Psychiatric Genomics Consortium and tested for association with reward-related ventral striatum activity, measured using a number-guessing functional magnetic resonance imaging paradigm, and self-reported problematic alcohol use. A mediational model tested whether ventral striatum activity indirectly links polygenic risk for ADHD to problematic alcohol use.<h4>Results</h4>Despite having no main effect on problematic alcohol use, polygenic risk for childhood ADHD was indirectly associated with problematic alcohol use through increased reward-related ventral striatum activity.<h4>Conclusions</h4>Individual differences in reward-related brain function may, at least in part, mechanistically link polygenic risk for childhood ADHD to problematic alcohol use.}, Doi = {10.1016/j.bpsc.2016.10.003}, Key = {fds323253} } @article{fds323689, Author = {Trampush, JW and Yang, MLZ and Yu, J and Knowles, E and Davies, G and Liewald, DC and Starr, JM and Djurovic, S and Melle, I and Sundet, K and Christoforou, A and Reinvang, I and DeRosse, P and Lundervold, AJ and Steen, VM and Espeseth, T and Räikkönen, K and Widen, E and Palotie, A and Eriksson, JG and Giegling, I and Konte, B and Roussos, P and Giakoumaki, S and Burdick, KE and Payton, A and Ollier, W and Horan, M and Chiba-Falek, O and Attix, DK and Need, AC and Cirulli, ET and Voineskos, AN and Stefanis, NC and Avramopoulos, D and Hatzimanolis, A and Arking, DE and Smyrnis, N and Bilder, RM and Freimer, NA and Cannon, TD and London, E and Poldrack, RA and Sabb, FW and Congdon, E and Conley, ED and Scult, MA and Dickinson, D and Straub, RE and Donohoe, G and Morris, D and Corvin, A and Gill, M and Hariri, AR and Weinberger, DR and Pendleton, N and Bitsios, P and Rujescu, D and Lahti, J and Le Hellard and S and Keller, MC and Andreassen, OA and Deary, IJ and Glahn, DC and Malhotra, AK and Lencz, T}, Title = {GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.}, Journal = {Mol Psychiatry}, Volume = {22}, Number = {3}, Pages = {336-345}, Year = {2017}, Month = {March}, url = {http://dx.doi.org/10.1038/mp.2016.244}, Abstract = {The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.}, Doi = {10.1038/mp.2016.244}, Key = {fds323689} } @article{fds330406, Author = {Swartz, JR and Waller, R and Bogdan, R and Knodt, AR and Sabhlok, A and Hyde, LW and Hariri, AR}, Title = {A Common Polymorphism in a Williams Syndrome Gene Predicts Amygdala Reactivity and Extraversion in Healthy Adults.}, Journal = {Biological psychiatry}, Volume = {81}, Number = {3}, Pages = {203-210}, Year = {2017}, Month = {February}, url = {http://dx.doi.org/10.1016/j.biopsych.2015.12.007}, Abstract = {<h4>Background</h4>Williams syndrome (WS), a genetic disorder resulting from hemizygous microdeletion of chromosome 7q11.23, has emerged as a model for identifying the genetic architecture of socioemotional behavior. Common polymorphisms in GTF2I, which is found within the WS microdeletion, have been associated with reduced social anxiety in the general population. Identifying neural phenotypes affected by these polymorphisms would help advance our understanding not only of this specific genetic association but also of the broader neurogenetic mechanisms of variability in socioemotional behavior.<h4>Methods</h4>Through an ongoing parent protocol, the Duke Neurogenetics Study, we measured threat-related amygdala reactivity to fearful and angry facial expressions using functional magnetic resonance imaging, assessed trait personality using the Revised NEO Personality Inventory, and imputed GTF2I rs13227433 from saliva-derived DNA using custom Illumina arrays. Participants included 808 non-Hispanic Caucasian, African American, and Asian university students.<h4>Results</h4>The GTF2I rs13227433 AA genotype, previously associated with lower social anxiety, predicted decreased threat-related amygdala reactivity. An indirect effect of GTF2I genotype on the warmth facet of extraversion was mediated by decreased threat-related amygdala reactivity in women but not men.<h4>Conclusions</h4>A common polymorphism in the WS gene GTF2I associated with reduced social anxiety predicts decreased threat-related amygdala reactivity, which mediates an association between genotype and increased warmth in women. These results are consistent with reduced threat-related amygdala reactivity in WS and suggest that common variation in GTF2I contributes to broader variability in socioemotional brain function and behavior, with implications for understanding the neurogenetic bases of WS as well as social anxiety.}, Doi = {10.1016/j.biopsych.2015.12.007}, Key = {fds330406} } @article{fds322497, Author = {Swartz, JR and Knodt, AR and Radtke, SR and Hariri, AR}, Title = {Peering into the brain to predict behavior: Peer-reported, but not self-reported, conscientiousness links threat-related amygdala activity to future problem drinking.}, Journal = {NeuroImage}, Volume = {146}, Pages = {894-903}, Year = {2017}, Month = {February}, url = {http://dx.doi.org/10.1016/j.neuroimage.2016.10.003}, Abstract = {Personality traits such as conscientiousness as self-reported by individuals can help predict a range of outcomes, from job performance to longevity. Asking others to rate the personality of their acquaintances often provides even better predictive power than using self-report. Here, we examine whether peer-reported personality can provide a better link between brain function, namely threat-related amygdala activity, and future health-related behavior, namely problem drinking, than self-reported personality. Using data from a sample of 377 young adult university students who were rated on five personality traits by peers, we find that higher threat-related amygdala activity to fearful facial expressions is associated with higher peer-reported, but not self-reported, conscientiousness. Moreover, higher peer-reported, but not self-reported, conscientiousness predicts lower future problem drinking more than one year later, an effect specific to men. Remarkably, relatively higher amygdala activity has an indirect effect on future drinking behavior in men, linked by peer-reported conscientiousness to lower future problem drinking. Our results provide initial evidence that the perceived conscientiousness of an individual by their peers uniquely reflects variability in a core neural mechanism supporting threat responsiveness. These novel patterns further suggest that incorporating peer-reported measures of personality into individual differences research can reveal novel predictive pathways of risk and protection for problem behaviors.}, Doi = {10.1016/j.neuroimage.2016.10.003}, Key = {fds322497} } @article{fds316880, Author = {Swartz, JR and Hariri, AR and Williamson, DE}, Title = {An epigenetic mechanism links socioeconomic status to changes in depression-related brain function in high-risk adolescents.}, Journal = {Molecular psychiatry}, Volume = {22}, Number = {2}, Pages = {209-214}, Year = {2017}, Month = {February}, ISSN = {1359-4184}, url = {http://dx.doi.org/10.1038/mp.2016.82}, Abstract = {Identifying biological mechanisms through which the experience of adversity emerges as individual risk for mental illness is an important step toward developing strategies for personalized treatment and, ultimately, prevention. Preclinical studies have identified epigenetic modification of gene expression as one such mechanism. Recent clinical studies have suggested that epigenetic modification, particularly methylation of gene regulatory regions, also acts to shape human brain function associated with risk for mental illness. However, it is not yet clear whether differential gene methylation as a function of adversity contributes to the emergence of individual risk for mental illness. Using prospective longitudinal epigenetic, neuroimaging and behavioral data from 132 adolescents, we demonstrate that changes in gene methylation associated with lower socioeconomic status (SES) predict changes in risk-related brain function. Specifically, we find that lower SES during adolescence is associated with an increase in methylation of the proximal promoter of the serotonin transporter gene, which predicts greater increases in threat-related amygdala reactivity. We subsequently demonstrate that greater increases in amygdala reactivity moderate the association between a positive family history for depression and the later manifestation of depressive symptoms. These initial results suggest a specific biological mechanism through which adversity contributes to altered brain function, which in turn moderates the emergence of general liability as individual risk for mental illness. If replicated, this prospective pathway may represent a novel target biomarker for intervention and prevention among high-risk individuals.}, Doi = {10.1038/mp.2016.82}, Key = {fds316880} } @article{fds318715, Author = {Swartz, JR and Prather, AA and Di Iorio and CR and Bogdan, R and Hariri, AR}, Title = {A Functional Interleukin-18 Haplotype Predicts Depression and Anxiety through Increased Threat-Related Amygdala Reactivity in Women but Not Men.}, Journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, Volume = {42}, Number = {2}, Pages = {419-426}, Year = {2017}, Month = {January}, url = {http://dx.doi.org/10.1038/npp.2016.129}, Abstract = {Common functional polymorphisms in the gene encoding interleukin-18 (IL18), a cytokine belonging to the IL-1 superfamily that can induce synthesis of several other cytokines, have been associated with major depressive episodes following the experience of stressful life events. The neural mechanisms underlying these associations remain unexamined. Here we use an imaging genetics strategy to examine the effects of risk-related IL18 haplotypes comprising rs187238 and rs1946518 on threat-related amygdala reactivity and, through an indirect effect, stress-related symptoms of depression and anxiety in 448 non-Hispanic Caucasian university students. Analyses indicated that women but not men possessing an IL18 haplotype comprising both risk-related alleles evidenced increased threat-related left centromedial amygdala reactivity relative to other haplotype groups. Moreover, in women only, increased threat-related left centromedial amygdala reactivity predicted increased symptoms of depression and anxiety in individuals also reporting higher levels of life stress. Path analyses revealed a significant indirect effect of IL18 risk haplotype on symptoms of depression and anxiety through increased threat-related amygdala reactivity. These results suggest that a common functional IL18 haplotype associated with heightened proinflammatory responses confers susceptibility to stress-related depression and anxiety through effects on threat-related amygdala function, a risk pathway specific to women. If replicated, these patterns can inform the search for personalized interventions targeting neurobiological pathways of risk associated with inflammation.}, Doi = {10.1038/npp.2016.129}, Key = {fds318715} } @article{fds323776, Author = {Scult, MA and Knodt, AR and Swartz, JR and Brigidi, BD and Hariri, AR}, Title = {Thinking and Feeling: Individual Differences in Habitual Emotion Regulation and Stress-Related Mood are Associated with Prefrontal Executive Control.}, Journal = {Clinical psychological science : a journal of the Association for Psychological Science}, Volume = {5}, Number = {1}, Pages = {150-157}, Year = {2017}, Month = {January}, url = {http://dx.doi.org/10.1177/2167702616654688}, Abstract = {Calculating math problems from memory may seem unrelated to everyday processing of emotions, but they have more in common than one might think. Prior research highlights the importance of the dorsolateral prefrontal cortex (dlPFC) in executive control, intentional emotion regulation, and experience of dysfunctional mood and anxiety. While it has been hypothesized that emotion regulation may be related to 'cold' (ie. not emotion-related) executive control, this assertion has not been tested. We address this gap by providing evidence that greater dlPFC activity during 'cold' executive control is associated with increased use of cognitive reappraisal to regulate emotions in everyday life. We then demonstrate that in the presence of increased life stress, increased dlPFC activity is associated with lower mood and anxiety symptoms and clinical diagnoses. Collectively, our results encourage ongoing efforts to understand prefrontal executive control as a possible intervention target for improving emotion regulation in mood and anxiety disorders.}, Doi = {10.1177/2167702616654688}, Key = {fds323776} } @article{fds318712, Author = {Scult, MA and Paulli, AR and Mazure, ES and Moffitt, TE and Hariri, AR and Strauman, TJ}, Title = {The association between cognitive function and subsequent depression: a systematic review and meta-analysis.}, Journal = {Psychol Med}, Volume = {47}, Number = {1}, Pages = {1-17}, Year = {2017}, Month = {January}, url = {http://dx.doi.org/10.1017/S0033291716002075}, Abstract = {Despite a growing interest in understanding the cognitive deficits associated with major depressive disorder (MDD), it is largely unknown whether such deficits exist before disorder onset or how they might influence the severity of subsequent illness. The purpose of the present study was to conduct a systematic review and meta-analysis of longitudinal datasets to determine whether cognitive function acts as a predictor of later MDD diagnosis or change in depression symptoms. Eligible studies included longitudinal designs with baseline measures of cognitive functioning, and later unipolar MDD diagnosis or symptom assessment. The systematic review identified 29 publications, representing 34 unique samples, and 121 749 participants, that met the inclusion/exclusion criteria. Quantitative meta-analysis demonstrated that higher cognitive function was associated with decreased levels of subsequent depression (r = -0.088, 95% confidence interval. -0.121 to -0.054, p < 0.001). However, sensitivity analyses revealed that this association is likely driven by concurrent depression symptoms at the time of cognitive assessment. Our review and meta-analysis indicate that the association between lower cognitive function and later depression is confounded by the presence of contemporaneous depression symptoms at the time of cognitive assessment. Thus, cognitive deficits predicting MDD likely represent deleterious effects of subclinical depression symptoms on performance rather than premorbid risk factors for disorder.}, Doi = {10.1017/S0033291716002075}, Key = {fds318712} } @article{fds318709, Author = {Pornpattananangkul, N and Hariri, AR and Harada, T and Mano, Y and Komeda, H and Parrish, TB and Sadato, N and Iidaka, T and Chiao, JY}, Title = {Cultural influences on neural basis of inhibitory control.}, Journal = {NeuroImage}, Volume = {139}, Pages = {114-126}, Year = {2016}, Month = {October}, url = {http://dx.doi.org/10.1016/j.neuroimage.2016.05.061}, Abstract = {Research on neural basis of inhibitory control has been extensively conducted in various parts of the world. It is often implicitly assumed that neural basis of inhibitory control is universally similar across cultures. Here, we investigated the extent to which culture modulated inhibitory-control brain activity at both cultural-group and cultural-value levels of analysis. During fMRI scanning, participants from different cultural groups (including Caucasian-Americans and Japanese-Americans living in the United States and native Japanese living in Japan) performed a Go/No-Go task. They also completed behavioral surveys assessing cultural values of behavioral consistency, or the extent to which one's behaviors in daily life are consistent across situations. Across participants, the Go/No-Go task elicited stronger neural activity in several inhibitory-control areas, such as the inferior frontal gyrus (IFG) and anterior cingulate cortex (ACC). Importantly, at the cultural-group level, we found variation in left IFG (L-IFG) activity that was explained by a cultural region where participants lived in (as opposed to race). Specifically, L-IFG activity was stronger for native Japanese compared to Caucasian- and Japanese-Americans, while there was no systematic difference in L-IFG activity between Japanese- and Caucasian-Americans. At the cultural-value level, we found that participants who valued being "themselves" across situations (i.e., having high endorsement of behavioral consistency) elicited stronger rostral ACC activity during the Go/No-Go task. Altogether, our findings provide novel insight into how culture modulates the neural basis of inhibitory control.}, Doi = {10.1016/j.neuroimage.2016.05.061}, Key = {fds318709} } @article{fds318710, Author = {Nikolova, YS and Swartz, JR and Hariri, AR}, Title = {Can we identify meaningful epigenetic effects on human brain function and related risk for mental illness?}, Journal = {Epigenomics}, Volume = {8}, Number = {10}, Pages = {1307-1310}, Year = {2016}, Month = {October}, url = {http://dx.doi.org/10.2217/epi-2016-0099}, Doi = {10.2217/epi-2016-0099}, Key = {fds318710} } @article{fds318711, Author = {Kragel, PA and Knodt, AR and Hariri, AR and LaBar, KS}, Title = {Decoding Spontaneous Emotional States in the Human Brain}, Journal = {PLoS Biol}, Volume = {14}, Number = {9}, Pages = {e2000106}, Publisher = {Public Library of Science}, Year = {2016}, Month = {September}, url = {http://dx.doi.org/10.1371/journal.pbio.2000106}, Abstract = {<title>Author Summary</title> <p>Functional brain imaging techniques provide a window into neural activity underpinning diverse cognitive processes, including visual perception, decision-making, and memory, among many others. By treating functional imaging data as a pattern-recognition problem, similar to face- or character-recognition, researchers have successfully identified patterns of brain activity that predict specific mental states; for example, the kind of an object being viewed. Moreover, these methods are capable of predicting mental states in the absence of external stimulation. For example, pattern-classifiers trained on brain responses to visual stimuli can successfully predict the contents of imagery during sleep. This research shows that internally mediated brain activity can be used to infer subjective mental states; however, it is not known whether more complex emotional mental states can be decoded from neuroimaging data in the absence of experimental manipulations. Here we show that brain-based models of specific emotions can detect individual differences in mood and emotional traits and are consistent with self-reports of emotional experience during intermittent periods of wakeful rest. These findings show that the brain dynamically fluctuates among multiple distinct emotional states at rest. More practically, the results suggest that brain-based models of emotion may help assess emotional status in clinical settings, particularly in individuals incapable of providing self-report of their own emotional experience.</p>}, Doi = {10.1371/journal.pbio.2000106}, Key = {fds318711} } @article{fds318713, Author = {Demers, CH and Drabant Conley and E and Bogdan, R and Hariri, AR}, Title = {Interactions Between Anandamide and Corticotropin-Releasing Factor Signaling Modulate Human Amygdala Function and Risk for Anxiety Disorders: An Imaging Genetics Strategy for Modeling Molecular Interactions.}, Journal = {Biological psychiatry}, Volume = {80}, Number = {5}, Pages = {356-362}, Year = {2016}, Month = {September}, url = {http://dx.doi.org/10.1016/j.biopsych.2015.12.021}, Abstract = {<h4>Background</h4>Preclinical models reveal that stress-induced amygdala activity and impairment in fear extinction reflect reductions in anandamide driven by corticotropin-releasing factor receptor type 1 (CRF1) potentiation of the anandamide catabolic enzyme fatty acid amide hydrolase.<h4>Methods</h4>Here, we provide clinical translation for the importance of these molecular interactions using an imaging genetics strategy to examine whether interactions between genetic polymorphisms associated with differential anandamide (FAAH rs324420) and CRF1 (CRHR1 rs110402) signaling modulate amygdala function and anxiety disorder diagnosis.<h4>Results</h4>Analyses revealed that individuals with a genetic background predicting relatively high anandamide and CRF1 signaling exhibited blunted basolateral amygdala habituation, which further mediated increased risk for anxiety disorders among these same individuals.<h4>Conclusions</h4>The convergence of preclinical and clinical data suggests that interactions between anandamide and CRF1 represent a fundamental molecular mechanism regulating amygdala function and anxiety. Our results further highlight the potential of imaging genetics to powerfully translate complex preclinical findings to clinically meaningful human phenotypes.}, Doi = {10.1016/j.biopsych.2015.12.021}, Key = {fds318713} } @article{fds318714, Author = {Waller, R and Corral-Frías, NS and Vannucci, B and Bogdan, R and Knodt, AR and Hariri, AR and Hyde, LW}, Title = {An oxytocin receptor polymorphism predicts amygdala reactivity and antisocial behavior in men.}, Journal = {Social cognitive and affective neuroscience}, Volume = {11}, Number = {8}, Pages = {1218-1226}, Year = {2016}, Month = {August}, url = {http://dx.doi.org/10.1093/scan/nsw042}, Abstract = {Variability in oxytocin (OXT) signaling is associated with individual differences in sex-specific social behavior across species. The effects of OXT signaling on social behavior are, in part, mediated through its modulation of amygdala function. Here, we use imaging genetics to examine sex-specific effects of three single-nucleotide polymorphisms in the human oxytocin receptor gene (OXTR; rs1042778, rs53576 and rs2254298) on threat-related amygdala reactivity and social behavior in 406 Caucasians. Analyses revealed that among men but not women, OXTR rs1042778 TT genotype was associated with increased right amygdala reactivity to angry facial expressions, which was uniquely related to higher levels of antisocial behavior among men. Moderated meditation analysis suggested a trending indirect effect of OXTR rs1042778 TT genotype on higher antisocial behavior via increased right amygdala reactivity to angry facial expressions in men. Our results provide evidence linking genetic variation in OXT signaling to individual differences in amygdala function. The results further suggest that these pathways may be uniquely important in shaping antisocial behavior in men.}, Doi = {10.1093/scan/nsw042}, Key = {fds318714} } @article{fds318716, Author = {Krystal, JH and Abi-Dargham, A and Akbarian, S and Arnsten, AFT and Barch, DM and Bearden, CE and Braff, DL and Brown, ES and Bullmore, ET and Carlezon, WA and Carter, CS and Cook, EH and Daskalakis, ZJ and DiLeone, RJ and Duman, RS and Grace, AA and Hariri, AR and Harrison, PJ and Hiroi, N and Kenny, PJ and Kleinman, JE and Krystal, AD and Lewis, DA and Lipska, BK and Marder, SR and Mason, GF and Mathalon, DH and McClung, CA and McDougle, CJ and McIntosh, AM and McMahon, FJ and Mirnics, K and Monteggia, LM and Narendran, R and Nestler, EJ and Neumeister, A and O'Donovan, MC and Öngür, D and Pariante, CM and Paulus, MP and Pearlson, G and Phillips, ML and Pine, DS and Pizzagalli, DA and Pletnikov, MV and Ragland, JD and Rapoport, JL and Ressler, KJ and Russo, SJ and Sanacora, G and Sawa, A and Schatzberg, AF and Shaham, Y and Shamay-Tsoory, SG and Sklar, P and State, MW and Stein, MB and Strakowski, SM and Taylor, SF and Turecki, G and Turetsky, BI and Weissman, MM and Zachariou, V and Zarate, CA and Zubieta, J-K}, Title = {Constance E. Lieber, Theodore R. Stanley, and the Enduring Impact of Philanthropy on Psychiatry Research.}, Journal = {Biol Psychiatry}, Volume = {80}, Number = {2}, Pages = {84-86}, Year = {2016}, Month = {July}, url = {http://dx.doi.org/10.1016/j.biopsych.2016.05.004}, Doi = {10.1016/j.biopsych.2016.05.004}, Key = {fds318716} } @article{fds316881, Author = {Corral-Frías, NS and Pizzagalli, DA and Carré, JM and Michalski, LJ and Nikolova, YS and Perlis, RH and Fagerness, J and Lee, MR and Conley, ED and Lancaster, TM and Haddad, S and Wolf, A and Smoller, JW and Hariri, AR and Bogdan, R}, Title = {COMT Val(158) Met genotype is associated with reward learning: a replication study and meta-analysis.}, Journal = {Genes, brain, and behavior}, Volume = {15}, Number = {5}, Pages = {503-513}, Year = {2016}, Month = {June}, ISSN = {1601-1848}, url = {http://dx.doi.org/10.1111/gbb.12296}, Abstract = {Identifying mechanisms through which individual differences in reward learning emerge offers an opportunity to understand both a fundamental form of adaptive responding as well as etiological pathways through which aberrant reward learning may contribute to maladaptive behaviors and psychopathology. One candidate mechanism through which individual differences in reward learning may emerge is variability in dopaminergic reinforcement signaling. A common functional polymorphism within the catechol-O-methyl transferase gene (COMT; rs4680, Val(158) Met) has been linked to reward learning, where homozygosity for the Met allele (linked to heightened prefrontal dopamine function and decreased dopamine synthesis in the midbrain) has been associated with relatively increased reward learning. Here, we used a probabilistic reward learning task to asses response bias, a behavioral form of reward learning, across three separate samples that were combined for analyses (age: 21.80 ± 3.95; n = 392; 268 female; European-American: n = 208). We replicate prior reports that COMT rs4680 Met allele homozygosity is associated with increased reward learning in European-American participants (β = 0.20, t = 2.75, P < 0.01; ΔR(2) = 0.04). Moreover, a meta-analysis of 4 studies, including the current one, confirmed the association between COMT rs4680 genotype and reward learning (95% CI -0.11 to -0.03; z = 3.2; P < 0.01). These results suggest that variability in dopamine signaling associated with COMT rs4680 influences individual differences in reward which may potentially contribute to psychopathology characterized by reward dysfunction.}, Doi = {10.1111/gbb.12296}, Key = {fds316881} } @article{fds251943, Author = {Nelson, EC and Agrawal, A and Heath, AC and Bogdan, R and Sherva, R and Zhang, B and Al-Hasani, R and Bruchas, MR and Chou, Y-L and Demers, CH and Carey, CE and Conley, ED and Fakira, AK and Farrer, LA and Goate, A and Gordon, S and Henders, AK and Hesselbrock, V and Kapoor, M and Lynskey, MT and Madden, PAF and Moron, JA and Rice, JP and Saccone, NL and Schwab, SG and Shand, FL and Todorov, AA and Wallace, L and Wang, T and Wray, NR and Zhou, X and Degenhardt, L and Martin, NG and Hariri, AR and Kranzler, HR and Gelernter, J and Bierut, LJ and Clark, DJ and Montgomery, GW}, Title = {Evidence of CNIH3 involvement in opioid dependence.}, Journal = {Molecular psychiatry}, Volume = {21}, Number = {5}, Pages = {608-614}, Year = {2016}, Month = {May}, ISSN = {1359-4184}, url = {http://dx.doi.org/10.1038/mp.2015.102}, Abstract = {Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid-dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 single-nucleotide polymorphisms (SNPs), were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid-dependent individuals. Meta-analyses found five genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective (P=4.30E-9; odds ratio 0.64 (95% confidence interval 0.55-0.74)). Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP's in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence, complementing prior studies implicating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate system.}, Doi = {10.1038/mp.2015.102}, Key = {fds251943} } @article{fds330407, Author = {Victor, EC and Hariri, AR}, Title = {A neuroscience perspective on sexual risk behavior in adolescence and emerging adulthood.}, Journal = {Development and psychopathology}, Volume = {28}, Number = {2}, Pages = {471-487}, Year = {2016}, Month = {May}, url = {http://dx.doi.org/10.1017/s0954579415001042}, Abstract = {Late adolescence and emerging adulthood (specifically ages 15-24) represent a period of heightened sexual risk taking resulting in the greatest annual rates of sexually transmitted infections and unplanned pregnancies in the US population. Ongoing efforts to prevent such negative consequences are likely to benefit from a deepening of our understanding of biological mechanisms through which sexual risk taking emerges and biases decision making during this critical window. Here we present a neuroscience framework from which a mechanistic examination of sexual risk taking can be advanced. Specifically, we adapt the neurodevelopmental triadic model, which outlines how motivated behavior is governed by three systems: approach, avoidance, and regulation, to sexual decision making and subsequent risk behavior. We further propose a testable hypothesis of the triadic model, wherein relatively decreased threat-related amygdala reactivity and increased reward-related ventral striatum reactivity leads to sexual risk taking, which is particularly exaggerated during adolescence and young adulthood when there is an overexpression of dopaminergic neurons coupled with immature top-down prefrontal cortex regulation. We conclude by discussing how future research based on our adapted triadic model can inform ongoing efforts to improve intervention and prevention efforts.}, Doi = {10.1017/s0954579415001042}, Key = {fds330407} } @article{fds313398, Author = {Gorka, AX and LaBar, KS and Hariri, AR}, Title = {Variability in emotional responsiveness and coping style during active avoidance as a window onto psychological vulnerability to stress.}, Journal = {Physiology & behavior}, Volume = {158}, Pages = {90-99}, Year = {2016}, Month = {May}, ISSN = {0031-9384}, url = {http://dx.doi.org/10.1016/j.physbeh.2016.02.036}, Abstract = {Individual differences in coping styles are associated with psychological vulnerability to stress. Recent animal research suggests that coping styles reflect trade-offs between proactive and reactive threat responses during active avoidance paradigms, with proactive responses associated with better stress tolerance. Based on these preclinical findings, we developed a novel instructed active avoidance paradigm to characterize patterns of proactive and reactive responses using behavioral, motoric, and autonomic measures in humans. Analyses revealed significant inter-individual variability not only in the magnitude of general emotional responsiveness but also the likelihood to specifically express proactive or reactive responses. In men but not women, individual differences in general emotional responsiveness were linked to increased trait anxiety while proactive coping style was linked to increased trait aggression. These patterns are consistent with preclinical findings and suggest that instructed active avoidance paradigms may be useful in assessing psychological vulnerability to stress using objective behavioral measures.}, Doi = {10.1016/j.physbeh.2016.02.036}, Key = {fds313398} } @article{fds251941, Author = {Nikolova, YS and Knodt, AR and Radtke, SR and Hariri, AR}, Title = {Divergent responses of the amygdala and ventral striatum predict stress-related problem drinking in young adults: possible differential markers of affective and impulsive pathways of risk for alcohol use disorder.}, Journal = {Molecular psychiatry}, Volume = {21}, Number = {3}, Pages = {348-356}, Year = {2016}, Month = {March}, ISSN = {1359-4184}, url = {http://dx.doi.org/10.1038/mp.2015.85}, Abstract = {Prior work suggests that there may be two distinct pathways of alcohol use disorder (AUD) risk: one associated with positive emotion enhancement and behavioral impulsivity, and another associated with negative emotion relief and coping. We sought to map these two pathways onto individual differences in neural reward and threat processing assessed using blood-oxygen-level-dependent functional magnetic resonance imaging in a sample of 759 undergraduate students (426 women, mean age 19.65±1.24 years) participating in the Duke Neurogenetics Study. We demonstrate that problem drinking is highest in the context of stress and in those with one of two distinct neural phenotypes: (1) a combination of relatively low reward-related activity of the ventral striatum (VS) and high threat-related reactivity of the amygdala; or (2) a combination of relatively high VS activity and low amygdala reactivity. In addition, we demonstrate that the relationship between stress and problem alcohol use is mediated by impulsivity, as reflected in monetary delay discounting rates, for those with high VS-low amygdala reactivity, and by anxious/depressive symptomatology for those with the opposite neural risk phenotype. Across both neural phenotypes, we found that greater divergence between VS and amygdala reactivity predicted greater risk for problem drinking. Finally, for those individuals with the low VS-high amygdala risk phenotype we found that stress not only predicted the presence of AUD diagnosis at the time of neuroimaging but also subsequent problem drinking reported 3 months following study completion. These results offer new insight into the neural basis of AUD risk and suggest novel biological targets for early individualized treatment or prevention.}, Doi = {10.1038/mp.2015.85}, Key = {fds251941} } @article{fds314439, Author = {Baranger, DAA and Ifrah, C and Prather, AA and Carey, CE and Corral-Frías, NS and Drabant Conley and E and Hariri, AR and Bogdan, R}, Title = {PER1 rs3027172 Genotype Interacts with Early Life Stress to Predict Problematic Alcohol Use, but Not Reward-Related Ventral Striatum Activity.}, Journal = {Frontiers in psychology}, Volume = {7}, Pages = {464}, Year = {2016}, Month = {January}, url = {http://dx.doi.org/10.3389/fpsyg.2016.00464}, Abstract = {Increasing evidence suggests that the circadian and stress regulatory systems contribute to alcohol use disorder (AUD) risk, which may partially arise through effects on reward-related neural function. The C allele of the PER1 rs3027172 single nucleotide polymorphism (SNP) reduces PER1 expression in cells incubated with cortisol and has been associated with increased risk for adult AUD and problematic drinking among adolescents exposed to high levels of familial psychosocial adversity. Using data from undergraduate students who completed the ongoing Duke Neurogenetics Study (DNS) (n = 665), we tested whether exposure to early life stress (ELS; Childhood Trauma Questionnaire) moderates the association between rs3027172 genotype and later problematic alcohol use (Alcohol Use Disorders Identification Test) as well as ventral striatum (VS) reactivity to reward (card-guessing task while functional magnetic resonance imaging data were acquired). Initial analyses found that PER1 rs3027172 genotype interacted with ELS to predict both problematic drinking and VS reactivity; minor C allele carriers, who were also exposed to elevated ELS reported greater problematic drinking and exhibited greater ventral striatum reactivity to reward-related stimuli. When gene × covariate and environment × covariate interactions were controlled for, the interaction predicting problematic alcohol use remained significant (p < 0.05, corrected) while the interaction predicting VS reactivity was no longer significant. These results extend our understanding of relationships between PER1 genotype, ELS, and problematic alcohol use, and serve as a cautionary tale on the importance of controlling for potential confounders in studies of moderation including gene × environment interactions.}, Doi = {10.3389/fpsyg.2016.00464}, Key = {fds314439} } @article{fds330408, Author = {Bogdan, R and Pagliaccio, D and Baranger, DA and Hariri, AR}, Title = {Genetic Moderation of Stress Effects on Corticolimbic Circuitry.}, Journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, Volume = {41}, Number = {1}, Pages = {275-296}, Year = {2016}, Month = {January}, url = {http://dx.doi.org/10.1038/npp.2015.216}, Abstract = {Stress exposure is associated with individual differences in corticolimbic structure and function that often mirror patterns observed in psychopathology. Gene x environment interaction research suggests that genetic variation moderates the impact of stress on risk for psychopathology. On the basis of these findings, imaging genetics, which attempts to link variability in DNA sequence and structure to neural phenotypes, has begun to incorporate measures of the environment. This research paradigm, known as imaging gene x environment interaction (iGxE), is beginning to contribute to our understanding of the neural mechanisms through which genetic variation and stress increase psychopathology risk. Although awaiting replication, evidence suggests that genetic variation within the canonical neuroendocrine stress hormone system, the hypothalamic-pituitary-adrenal axis, contributes to variability in stress-related corticolimbic structure and function, which, in turn, confers risk for psychopathology. For iGxE research to reach its full potential it will have to address many challenges, of which we discuss: (i) small effects, (ii) measuring the environment and neural phenotypes, (iii) the absence of detailed mechanisms, and (iv) incorporating development. By actively addressing these challenges, iGxE research is poised to help identify the neural mechanisms underlying genetic and environmental associations with psychopathology.}, Doi = {10.1038/npp.2015.216}, Key = {fds330408} } @article{fds365877, Author = {Hyde, LW and Shaw, DS and Murray, L and Gard, A and Hariri, AR and Forbes, EE}, Title = {Dissecting the Role of Amygdala Reactivity in Antisocial Behavior in a Sample of Young, Low-Income, Urban Men}, Journal = {Clinical Psychological Science}, Volume = {4}, Number = {3}, Pages = {527-544}, Year = {2016}, Month = {January}, url = {http://dx.doi.org/10.1177/2167702615614511}, Abstract = {Neuroimaging has suggested that amygdala reactivity to emotional facial expressions is associated with antisocial behavior (AB), particularly among those high on callous–unemotional (CU) traits. To investigate this association and potential moderators of this relationship, including task/stimuli effects, subregional anatomy of the amygdala, and participant race, we used fMRI in a sample of 167 racially diverse 20-year-old men from low-income families. We found that AB, but not CU traits, was negatively related to amygdala reactivity to fearful faces. This result was specific to fearful faces and strongest in the centromedial subregion of the amygdala. Arrest record was positively related to basolateral amygdala reactivity to fearful and angry faces. Results were strongest among those identified as African American and not present in those identified as European American. Our findings suggest substantial complexity in the relationship between amygdala function and AB reflecting moderating effects of task stimulus, subregional anatomy, and race.}, Doi = {10.1177/2167702615614511}, Key = {fds365877} } @article{fds318717, Author = {Carey, CE and Agrawal, A and Zhang, B and Conley, ED and Degenhardt, L and Heath, AC and Li, D and Lynskey, MT and Martin, NG and Montgomery, GW and Wang, T and Bierut, LJ and Hariri, AR and Nelson, EC and Bogdan, R}, Title = {Monoacylglycerol lipase (MGLL) polymorphism rs604300 interacts with childhood adversity to predict cannabis dependence symptoms and amygdala habituation: Evidence from an endocannabinoid system-level analysis.}, Journal = {Journal of abnormal psychology}, Volume = {124}, Number = {4}, Pages = {860-877}, Year = {2015}, Month = {November}, url = {http://dx.doi.org/10.1037/abn0000079}, Abstract = {Despite evidence for heritable variation in cannabis involvement and the discovery of cannabinoid receptors and their endogenous ligands, no consistent patterns have emerged from candidate endocannabinoid (eCB) genetic association studies of cannabis involvement. Given interactions between eCB and stress systems and associations between childhood stress and cannabis involvement, it may be important to consider childhood adversity in the context of eCB-related genetic variation. We employed a system-level gene-based analysis of data from the Comorbidity and Trauma Study (N = 1,558) to examine whether genetic variation in six eCB genes (anabolism: DAGLA, DAGLB, NAPEPLD; catabolism: MGLL, FAAH; binding: CNR1; SNPs N = 65) and childhood sexual abuse (CSA) predict cannabis dependence symptoms. Significant interactions with CSA emerged for MGLL at the gene level (p = .009), and for rs604300 within MGLL (ΔR2 = .007, p < .001), the latter of which survived SNP-level Bonferroni correction and was significant in an additional sample with similar directional effects (N = 859; ΔR2 = .005, p = .026). Furthermore, in a third sample (N = 312), there was evidence that rs604300 genotype interacts with early life adversity to predict threat-related basolateral amygdala habituation, a neural phenotype linked to the eCB system and addiction (ΔR2 = .013, p = .047). Rs604300 may be related to epigenetic modulation of MGLL expression. These results are consistent with rodent models implicating 2-arachidonoylglycerol (2-AG), an endogenous cannabinoid metabolized by the enzyme encoded by MGLL, in the etiology of stress adaptation related to cannabis dependence, but require further replication.}, Doi = {10.1037/abn0000079}, Key = {fds318717} } @article{fds251944, Author = {Hanson, JL and Hariri, AR and Williamson, DE}, Title = {Blunted Ventral Striatum Development in Adolescence Reflects Emotional Neglect and Predicts Depressive Symptoms.}, Journal = {Biological psychiatry}, Volume = {78}, Number = {9}, Pages = {598-605}, Year = {2015}, Month = {November}, ISSN = {0006-3223}, url = {http://dx.doi.org/10.1016/j.biopsych.2015.05.010}, Abstract = {<h4>Background</h4>Emotional neglect is associated with multiple negative outcomes, particularly increased risk for depression. Motivated by increasing evidence of reward-related ventral striatum (VS) dysfunction in depression, we investigated the role of developmental changes in VS activity on the emergence of depressive symptomatology as a function of emotional neglect.<h4>Methods</h4>We examined relationships between longitudinal neuroimaging of reward-related VS activity, assessments of mood, and measures of emotional neglect in 106 participants first scanned between ages 11 to 15 and then 2 years later.<h4>Results</h4>We found that greater levels of emotional neglect were associated with blunted development of reward-related VS activity between the first and second assessments (as indexed by lower residualized change scores). Additionally, we found that decreases in this reward-related VS activity were related to greater depressive symptomatology and partially mediated the association between emotional neglect and subsequent depressive symptomatology.<h4>Conclusions</h4>Our results provide an important demonstration that blunted development of reward-related VS activity as a function of emotional neglect predicts the emergence of depressive symptoms in adolescents. Further, our results are consistent with emerging evidence for the importance of reward-related VS dysfunction in the etiology and pathophysiology of depression. These results are a first step toward developing the ability to predict, prevent, and treat stress-related psychopathology through the targeting of specific neural phenotypes.}, Doi = {10.1016/j.biopsych.2015.05.010}, Key = {fds251944} } @article{fds330409, Author = {Hanson, JL and Knodt, AR and Brigidi, BD and Hariri, AR}, Title = {Lower structural integrity of the uncinate fasciculus is associated with a history of child maltreatment and future psychological vulnerability to stress.}, Journal = {Development and psychopathology}, Volume = {27}, Number = {4 Pt 2}, Pages = {1611-1619}, Year = {2015}, Month = {November}, url = {http://dx.doi.org/10.1017/s0954579415000978}, Abstract = {The experience of child maltreatment is a significant risk factor for the development of later internalizing disorders such as depression and anxiety. This risk is particularly heightened after exposure to additional, more contemporaneous stress. While behavioral evidence exists for such "stress sensitization," little is known about the mechanisms mediating such relationships, particularly within the brain. Here we report that the experience of child maltreatment independent of recent life stress, gender, and age is associated with reduced structural integrity of the uncinate fasciculus, a major white matter pathway between the amygdala and ventromedial prefrontal cortex, in young adults. We further demonstrate that individuals with lower uncinate fasciculus integrity at baseline who subsequently experience stressful life events report higher levels of internalizing symptomatology at follow-up. Our findings suggest a novel neurobiological mechanism linking child maltreatment with later internalizing symptoms, specifically altered structural connectivity within the brain's threat-detection and emotion-regulation circuitry.}, Doi = {10.1017/s0954579415000978}, Key = {fds330409} } @article{fds315132, Author = {Hanson, JL and Albert, WD and Iselin, AR and Carré, JM and Dodge, KA and Hariri, AR}, Title = {Cumulative Stress In Childhood is Associated with Blunted Reward-Related Brain Activity In Adulthood}, Journal = {Social Cognitive and Affective Neuroscience}, Volume = {11}, Number = {3}, Pages = {405-412}, Year = {2015}, Month = {October}, ISSN = {1749-5016}, url = {http://hdl.handle.net/10161/10777 Duke open access}, Abstract = {Early life stress (ELS) is strongly associated with negative outcomes in adulthood, including reduced motivation and increased negative mood. The mechanisms mediating these relations, however, are poorly understood. We examined the relation between exposure to ELS and reward-related brain activity, which is known to predict motivation and mood, at age 26, in a sample followed since kindergarten with annual assessments. Using functional neuroimaging, we assayed individual differences in the activity of the ventral striatum (VS) during the processing of monetary rewards associated with a simple card-guessing task, in a sample of 72 male participants. We examined associations between a cumulative measure of ELS exposure and VS activity in adulthood. We found that greater levels of cumulative stress during childhood and adolescence predicted lower reward-related VS activity in adulthood. Extending this general developmental pattern, we found that exposure to stress early in development (between kindergarten and grade 3) was significantly associated with variability in adult VS activity. Our results provide an important demonstration that cumulative life stress, especially during this childhood period, is associated with blunted reward-related VS activity in adulthood. These differences suggest neurobiological pathways through which a history of ELS may contribute to reduced motivation and increased negative mood.}, Doi = {10.1093/scan/nsv124}, Key = {fds315132} } @article{fds251937, Author = {Hariri, AR and Holmes, A}, Title = {Finding translation in stress research.}, Journal = {Nature neuroscience}, Volume = {18}, Number = {10}, Pages = {1347-1352}, Year = {2015}, Month = {October}, ISSN = {1097-6256}, url = {http://dx.doi.org/10.1038/nn.4111}, Abstract = {In our ongoing efforts to advance understanding of human diseases, translational research across rodents and humans on stress-related mental disorders stands out as a field that is producing discoveries that illuminate mechanisms of risk and pathophysiology at a brisk rate. Here we offer a Perspective on how a productive translational research dialog between preclinical models and clinical studies of these disorders is being powered by an ever-developing appreciation of the shared neural circuits and genetic architecture that moderate the response to stress across species. Working from these deep foundations, we discuss the approaches, both traditional and innovative, that have the potential to deliver a new generation of risk biomarkers and therapeutic strategies for stress-related disorders.}, Doi = {10.1038/nn.4111}, Key = {fds251937} } @article{fds291135, Author = {Scult, MA and Trampush, JW and Zheng, F and Conley, ED and Lencz, T and Malhotra, AK and Dickinson, D and Weinberger, DR and Hariri, AR}, Title = {A Common Polymorphism in SCN2A Predicts General Cognitive Ability through Effects on PFC Physiology.}, Journal = {Journal of cognitive neuroscience}, Volume = {27}, Number = {9}, Pages = {1766-1774}, Year = {2015}, Month = {September}, ISSN = {0898-929X}, url = {http://dx.doi.org/10.1162/jocn_a_00826}, Abstract = {Here we provide novel convergent evidence across three independent cohorts of healthy adults (n = 531), demonstrating that a common polymorphism in the gene encoding the α2 subunit of neuronal voltage-gated type II sodium channels (SCN2A) predicts human general cognitive ability or "g." Using meta-analysis, we demonstrate that the minor T allele of a common polymorphism (rs10174400) in SCN2A is associated with significantly higher "g" independent of gender and age. We further demonstrate using resting-state fMRI data from our discovery cohort (n = 236) that this genetic advantage may be mediated by increased capacity for information processing between the dorsolateral PFC and dorsal ACC, which support higher cognitive functions. Collectively, these findings fill a gap in our understanding of the genetics of general cognitive ability and highlight a specific neural mechanism through which a common polymorphism shapes interindividual variation in "g."}, Doi = {10.1162/jocn_a_00826}, Key = {fds291135} } @article{fds251948, Author = {Nikolova, YS and Hariri, AR}, Title = {Can we observe epigenetic effects on human brain function?}, Journal = {Trends in cognitive sciences}, Volume = {19}, Number = {7}, Pages = {366-373}, Year = {2015}, Month = {July}, ISSN = {1364-6613}, url = {http://dx.doi.org/10.1016/j.tics.2015.05.003}, Abstract = {Imaging genetics has identified many contributions of DNA sequence variation to individual differences in brain function, behavior, and risk for psychopathology. Recent studies have extended this work beyond the genome by mapping epigenetic differences, specifically gene methylation in peripherally assessed DNA, onto variability in behaviorally and clinically relevant brain function. These data have generated understandable enthusiasm for the potential of such research to illuminate biological mechanisms of risk. We use our research on the effects of genetic and epigenetic variation in the human serotonin transporter on brain function to generate a guardedly optimistic opinion that the available data encourage continued research in this direction, and suggest strategies to promote faster progress.}, Doi = {10.1016/j.tics.2015.05.003}, Key = {fds251948} } @article{fds251949, Author = {Trampush, JW and Lencz, T and Knowles, E and Davies, G and Guha, S and Pe'er, I and Liewald, DC and Starr, JM and Djurovic, S and Melle, I and Sundet, K and Christoforou, A and Reinvang, I and Mukherjee, S and DeRosse, P and Lundervold, A and Steen, VM and John, M and Espeseth, T and Räikkönen, K and Widen, E and Palotie, A and Eriksson, JG and Giegling, I and Konte, B and Ikeda, M and Roussos, P and Giakoumaki, S and Burdick, KE and Payton, A and Ollier, W and Horan, M and Scult, M and Dickinson, D and Straub, RE and Donohoe, G and Morris, D and Corvin, A and Gill, M and Hariri, A and Weinberger, DR and Pendleton, N and Iwata, N and Darvasi, A and Bitsios, P and Rujescu, D and Lahti, J and Le Hellard and S and Keller, MC and Andreassen, OA and Deary, IJ and Glahn, DC and Malhotra, AK}, Title = {Independent evidence for an association between general cognitive ability and a genetic locus for educational attainment.}, Journal = {American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics}, Volume = {168B}, Number = {5}, Pages = {363-373}, Year = {2015}, Month = {July}, ISSN = {1552-4841}, url = {http://dx.doi.org/10.1002/ajmg.b.32319}, Abstract = {Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genome-wide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability ("g") in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals from a recent GWAS of cognition. A SNP (rs1906252) located at chromosome 6q16.1, previously associated with years of schooling, was significantly associated with g (P = 1.47 × 10(-4) ) in COGENT. The first joint analysis of 43,381 non-overlapping individuals for this a priori-designated locus was strongly significant (P = 4.94 × 10(-7) ), and the second joint analysis of 68,159 non-overlapping individuals was even more robust (P = 1.65 × 10(-9) ). These results provide independent replication, in a large-scale dataset, of a genetic locus associated with cognitive function and education. As sample sizes grow, cognitive GWAS will identify increasing numbers of associated loci, as has been accomplished in other polygenic quantitative traits, which may be relevant to psychiatric illness.}, Doi = {10.1002/ajmg.b.32319}, Key = {fds251949} } @article{fds251938, Author = {Telch, MJ and Beevers, CG and Rosenfield, D and Lee, H-J and Reijntjes, A and Ferrell, RE and Hariri, AR}, Title = {5-HTTLPR genotype potentiates the effects of war zone stressors on the emergence of PTSD, depressive and anxiety symptoms in soldiers deployed to iraq.}, Journal = {World psychiatry : official journal of the World Psychiatric Association (WPA)}, Volume = {14}, Number = {2}, Pages = {198-206}, Year = {2015}, Month = {June}, ISSN = {1723-8617}, url = {http://dx.doi.org/10.1002/wps.20215}, Abstract = {Exposure to war zone stressors is common, yet only a minority of soldiers experience clinically meaningful disturbance in psychological function. Identification of biomarkers that predict vulnerability to war zone stressors is critical for developing more effective treatment and prevention strategies not only in soldiers but also in civilians who are exposed to trauma. We investigated the role of the serotonin transporter linked polymorphic region (5-HTTLPR) genotype in predicting the emergence of post-traumatic stress disorder (PTSD), depressive and anxiety symptoms as a function of war zone stressors. A prospective cohort of 133 U.S. Army soldiers with no prior history of deployment to a war zone, who were scheduled to deploy to Iraq, was recruited. Multilevel regression models were used to investigate associations between 5-HTTLPR genotype, level of war zone stressors, and reported symptoms of PTSD, depression and anxiety while deployed to Iraq. Level of war zone stressors was associated with symptoms of PTSD, depression and anxiety. Consistent with its effects on stress responsiveness, 5-HTTLPR genotype moderated the relationship between level of war zone stressors and symptoms of emotional disturbance. Specifically, soldiers carrying one or two low functioning alleles (S or LG ) reported heightened symptoms of PTSD, depression and anxiety in response to increased levels of exposure to war zone stressors, relative to soldiers homozygous for the high functioning allele (LA ). These data suggest that 5-HTTLPR genotype moderates individual sensitivity to war zone stressors and the expression of emotional disturbance including PTSD symptoms. Replication of this association along with identification of other genetic moderators of risk can inform the development of biomarkers that can predict relative resilience vs. vulnerability to stress.}, Doi = {10.1002/wps.20215}, Key = {fds251938} } @article{fds251939, Author = {Arloth, J and Bogdan, R and Weber, P and Frishman, G and Menke, A and Wagner, KV and Balsevich, G and Schmidt, MV and Karbalai, N and Czamara, D and Altmann, A and Trümbach, D and Wurst, W and Mehta, D and Uhr, M and Klengel, T and Erhardt, A and Carey, CE and Conley, ED and Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (PGC), and Ruepp, A and Müller-Myhsok, B and Hariri, AR and Binder, EB and Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium PGC}, Title = {Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders.}, Journal = {Neuron}, Volume = {86}, Number = {5}, Pages = {1189-1202}, Year = {2015}, Month = {June}, ISSN = {0896-6273}, url = {http://dx.doi.org/10.1016/j.neuron.2015.05.034}, Abstract = {Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain.}, Doi = {10.1016/j.neuron.2015.05.034}, Key = {fds251939} } @article{fds251940, Author = {Victor, EC and Sansosti, AA and Bowman, HC and Hariri, AR}, Title = {Differential patterns of amygdala and ventral striatum activation predict gender-specific changes in sexual risk behavior.}, Journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, Volume = {35}, Number = {23}, Pages = {8896-8900}, Year = {2015}, Month = {June}, ISSN = {0270-6474}, url = {http://dx.doi.org/10.1523/jneurosci.0737-15.2015}, Abstract = {Although the initiation of sexual behavior is common among adolescents and young adults, some individuals express this behavior in a manner that significantly increases their risk for negative outcomes including sexually transmitted infections. Based on accumulating evidence, we have hypothesized that increased sexual risk behavior reflects, in part, an imbalance between neural circuits mediating approach and avoidance in particular as manifest by relatively increased ventral striatum (VS) activity and relatively decreased amygdala activity. Here, we test our hypothesis using data from seventy 18- to 22-year-old university students participating in the Duke Neurogenetics Study. We found a significant three-way interaction between amygdala activation, VS activation, and gender predicting changes in the number of sexual partners over time. Although relatively increased VS activation predicted greater increases in sexual partners for both men and women, the effect in men was contingent on the presence of relatively decreased amygdala activation and the effect in women was contingent on the presence of relatively increased amygdala activation. These findings suggest unique gender differences in how complex interactions between neural circuit function contributing to approach and avoidance may be expressed as sexual risk behavior in young adults. As such, our findings have the potential to inform the development of novel, gender-specific strategies that may be more effective at curtailing sexual risk behavior.}, Doi = {10.1523/jneurosci.0737-15.2015}, Key = {fds251940} } @article{fds251946, Author = {Gorka, AX and Norman, RE and Radtke, SR and Carré, JM and Hariri, AR}, Title = {Anterior cingulate cortex gray matter volume mediates an association between 2D:4D ratio and trait aggression in women but not men.}, Journal = {Psychoneuroendocrinology}, Volume = {56}, Pages = {148-156}, Year = {2015}, Month = {June}, ISSN = {0306-4530}, url = {http://dx.doi.org/10.1016/j.psyneuen.2015.03.004}, Abstract = {Previous research demonstrates that prenatal testosterone exposure increases aggression, possibly through its effects on the structure and function of neural circuits supporting threat detection and emotion regulation. Here we examined associations between regional gray matter volume, trait aggression, and the ratio of the second and fourth digit of the hand (2D:4D ratio) as a putative index of prenatal testosterone exposure in 464 healthy young adult volunteers. Our analyses revealed a significant positive correlation between 2D:4D ratio and gray matter volume of the dorsal anterior cingulate cortex (dACC), a brain region supporting emotion regulation, conflict monitoring, and behavioral inhibition. Subsequent analyses demonstrated that reduced (i.e., masculinized) gray matter volume in the dACC mediated the relationship between 2D:4D ratio and aggression in women, but not men. Expanding on this gender-specific mediation, additional analyses demonstrated that the shared variance between 2D:4D ratio, dACC gray matter volume, and aggression in women reflected the tendency to engage in cognitive reappraisal of emotionally provocative stimuli. Our results provide novel evidence that 2D:4D ratio is associated with masculinization of dACC gray matter volume, and that this neural phenotype mediates, in part, the expression of trait aggression in women.}, Doi = {10.1016/j.psyneuen.2015.03.004}, Key = {fds251946} } @article{fds251953, Author = {Kochunov, P and Jahanshad, N and Marcus, D and Winkler, A and Sprooten, E and Nichols, TE and Wright, SN and Hong, LE and Patel, B and Behrens, T and Jbabdi, S and Andersson, J and Lenglet, C and Yacoub, E and Moeller, S and Auerbach, E and Ugurbil, K and Sotiropoulos, SN and Brouwer, RM and Landman, B and Lemaitre, H and den Braber, A and Zwiers, MP and Ritchie, S and van Hulzen, K and Almasy, L and Curran, J and deZubicaray, GI and Duggirala, R and Fox, P and Martin, NG and McMahon, KL and Mitchell, B and Olvera, RL and Peterson, C and Starr, J and Sussmann, J and Wardlaw, J and Wright, M and Boomsma, DI and Kahn, R and de Geus, EJC and Williamson, DE and Hariri, A and van 't Ent, D and Bastin, ME and McIntosh, A and Deary, IJ and Hulshoff Pol and HE and Blangero, J and Thompson, PM and Glahn, DC and Van Essen and DC}, Title = {Heritability of fractional anisotropy in human white matter: a comparison of Human Connectome Project and ENIGMA-DTI data.}, Journal = {NeuroImage}, Volume = {111}, Pages = {300-311}, Year = {2015}, Month = {May}, ISSN = {1053-8119}, url = {http://dx.doi.org/10.1016/j.neuroimage.2015.02.050}, Abstract = {The degree to which genetic factors influence brain connectivity is beginning to be understood. Large-scale efforts are underway to map the profile of genetic effects in various brain regions. The NIH-funded Human Connectome Project (HCP) is providing data valuable for analyzing the degree of genetic influence underlying brain connectivity revealed by state-of-the-art neuroimaging methods. We calculated the heritability of the fractional anisotropy (FA) measure derived from diffusion tensor imaging (DTI) reconstruction in 481 HCP subjects (194/287 M/F) consisting of 57/60 pairs of mono- and dizygotic twins, and 246 siblings. FA measurements were derived using (Enhancing NeuroImaging Genetics through Meta-Analysis) ENIGMA DTI protocols and heritability estimates were calculated using the SOLAR-Eclipse imaging genetic analysis package. We compared heritability estimates derived from HCP data to those publicly available through the ENIGMA-DTI consortium, which were pooled together from five-family based studies across the US, Europe, and Australia. FA measurements from the HCP cohort for eleven major white matter tracts were highly heritable (h(2)=0.53-0.90, p<10(-5)), and were significantly correlated with the joint-analytical estimates from the ENIGMA cohort on the tract and voxel-wise levels. The similarity in regional heritability suggests that the additive genetic contribution to white matter microstructure is consistent across populations and imaging acquisition parameters. It also suggests that the overarching genetic influence provides an opportunity to define a common genetic search space for future gene-discovery studies. Uniquely, the measurements of additive genetic contribution performed in this study can be repeated using online genetic analysis tools provided by the HCP ConnectomeDB web application.}, Doi = {10.1016/j.neuroimage.2015.02.050}, Key = {fds251953} } @article{fds251950, Author = {Gorka, AX and Knodt, AR and Hariri, AR}, Title = {Basal forebrain moderates the magnitude of task-dependent amygdala functional connectivity.}, Journal = {Social cognitive and affective neuroscience}, Volume = {10}, Number = {4}, Pages = {501-507}, Year = {2015}, Month = {April}, ISSN = {1749-5016}, url = {http://dx.doi.org/10.1093/scan/nsu080}, Abstract = {Animal studies reveal that the amygdala promotes attention and emotional memory, in part, by driving activity in downstream target regions including the prefrontal cortex (PFC) and hippocampus. Prior work has demonstrated that the amygdala influences these regions directly through monosynaptic glutamatergic signaling, and indirectly by driving activity of the cholinergic basal forebrain and subsequent downstream acetylcholine release. Yet to date, no work has addressed the functional relevance of the cholinergic basal forebrain in facilitating signaling from the amygdala in humans. We set out to determine how blood oxygen level-dependent signal within the amygdala and cholinergic basal forebrain interact to predict neural responses within downstream targets. Here, we use functional connectivity analyses to demonstrate that the cholinergic basal forebrain moderates increased amygdala connectivity with both the PFC and the hippocampus during the processing of biologically salient stimuli in humans. We further demonstrate that functional variation within the choline transporter gene predicts the magnitude of this modulatory effect. Collectively, our results provide novel evidence for the importance of cholinergic signaling in modulating neural pathways supporting arousal, attention and memory in humans. Further, our results may shed light on prior association studies linking functional variation within the choline transporter gene and diagnoses of major depression and attention-deficit hyperactivity disorder.}, Doi = {10.1093/scan/nsu080}, Key = {fds251950} } @article{fds251952, Author = {Swartz, JR and Williamson, DE and Hariri, AR}, Title = {Developmental change in amygdala reactivity during adolescence: effects of family history of depression and stressful life events.}, Journal = {The American journal of psychiatry}, Volume = {172}, Number = {3}, Pages = {276-283}, Year = {2015}, Month = {March}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/appi.ajp.2014.14020195}, Abstract = {<h4>Objective</h4>Although heightened amygdala reactivity is observed in patients with major depression, two critical gaps in our knowledge remain. First, it is unclear whether heightened amygdala reactivity is a premorbid vulnerability or a consequence of the disorder. Second, it is unknown how and when this neural phenotype develops. The authors sought to address these gaps by evaluating developmental change in threat-related amygdala reactivity in adolescents at high or low risk for depression based on family history, before onset of disorder.<h4>Method</h4>At baseline and again 2 years later, adolescents (initially 11-15 years of age) participated in a functional MRI paradigm that elicited threat-related amygdala reactivity. After quality control, data were available for 232 adolescents at wave 1 and 197 adolescents at wave 2; longitudinal data meeting quality control at both waves were available for 157 of these participants. Change in amygdala reactivity was assessed as a function of family history of depression and severity of stressful life events.<h4>Results</h4>Threat-related amygdala reactivity increased with age in participants with a positive family history regardless of the severity of life stress reported, and it increased in adolescents with a negative family history who reported relatively severe life stress. These changes in amygdala reactivity with age occurred in the absence of clinical disorder or increases in depressive symptoms.<h4>Conclusions</h4>These results suggest that heightened amygdala reactivity emerges during adolescence, prior to the development of depression, as a function of familial risk or, in the absence of familial risk, stressful life events.}, Doi = {10.1176/appi.ajp.2014.14020195}, Key = {fds251952} } @article{fds251955, Author = {Swartz, J and Knodt, A and Radtke, S and Hariri, A}, Title = {A Neural Biomarker of Psychological Vulnerability to Future Life Stress}, Journal = {Neuron}, Volume = {85}, Number = {3}, Pages = {505-511}, Publisher = {Elsevier}, Year = {2015}, Month = {February}, ISSN = {0896-6273}, url = {http://hdl.handle.net/10161/9483 Duke open access}, Abstract = {We all experience a host of common life stressors such as the death of a family member, medical illness, and financial uncertainty. While most of us are resilient to such stressors, continuing to function normally, for a subset of individuals, experiencing these stressors increases the likelihood of developing treatment-resistant, chronic psychological problems, including depression and anxiety. It is thus paramount to identify predictive markers of risk, particularly those reflecting fundamental biological processes that can be targets for intervention and prevention. Using data from a longitudinal study of 340 healthy young adults, we demonstrate that individual differences in threat-related amygdala reactivity predict psychological vulnerability to life stress occurring as much as 1 to 4 years later. These results highlight a readily assayed biomarker, threat-related amygdala reactivity, which predicts psychological vulnerability to commonly experienced stressors and represents a discrete target for intervention and prevention.}, Doi = {10.1016/j.neuron.2014.12.055}, Key = {fds251955} } @article{fds251951, Author = {Corral-Frías, NS and Nikolova, YS and Michalski, LJ and Baranger, DAA and Hariri, AR and Bogdan, R}, Title = {Stress-related anhedonia is associated with ventral striatum reactivity to reward and transdiagnostic psychiatric symptomatology.}, Journal = {Psychological medicine}, Volume = {45}, Number = {12}, Pages = {2605-2617}, Year = {2015}, Month = {January}, ISSN = {0033-2917}, url = {http://dx.doi.org/10.1017/s0033291715000525}, Abstract = {<h4>Background</h4>Early life stress (ELS) is consistently associated with increased risk for subsequent psychopathology. Individual differences in neural response to reward may confer vulnerability to stress-related psychopathology. Using data from the ongoing Duke Neurogenetics Study, the present study examined whether reward-related ventral striatum (VS) reactivity moderates the relationship between retrospectively reported ELS and anhedonic symptomatology. We further assessed whether individual differences in reward-related VS reactivity were associated with other depressive symptoms and problematic alcohol use via stress-related anhedonic symptoms and substance use-associated coping.<h4>Method</h4>Blood oxygen level-dependent functional magnetic resonance imaging (fMRI) was collected while participants (n = 906) completed a card-guessing task, which robustly elicits VS reactivity. ELS, anhedonic symptoms, other depressive symptoms, coping behavior, and alcohol use behavior were assessed with self-report questionnaires. Linear regressions were run to examine whether VS reactivity moderated the relationship between ELS and anhedonic symptoms. Structural equation models examined whether this moderation was indirectly associated with other depression symptoms and problematic alcohol use through its association with anhedonia.<h4>Results</h4>Analyses of data from 820 participants passing quality control procedures revealed that the VS × ELS interaction was associated with anhedonic symptoms (p = 0.011). Moreover, structural equation models indirectly linked this interaction to non-anhedonic depression symptoms and problematic alcohol use through anhedonic symptoms and substance-related coping.<h4>Conclusions</h4>These findings suggest that reduced VS reactivity to reward is associated with increased risk for anhedonia in individuals exposed to ELS. Such stress-related anhedonia is further associated with other depressive symptoms and problematic alcohol use through substance-related coping.}, Doi = {10.1017/s0033291715000525}, Key = {fds251951} } @article{fds364221, Author = {Nikolova, YS and Iruku, SP and Lin, C-W and Conley, ED and Puralewski, R and French, B and Hariri, AR and Sibille, E}, Title = {FRAS1-related extracellular matrix 3 (FREM3) single-nucleotide polymorphism effects on gene expression, amygdala reactivity and perceptual processing speed: An accelerated aging pathway of depression risk.}, Journal = {Frontiers in psychology}, Volume = {6}, Pages = {1377}, Year = {2015}, Month = {January}, url = {http://dx.doi.org/10.3389/fpsyg.2015.01377}, Abstract = {The A allele of the FRAS1-related extracellular matrix protein 3 (FREM3) rs7676614 single nucleotide polymorphism (SNP) was linked to major depressive disorder (MDD) in an early genome-wide association study (GWAS), and to symptoms of psychomotor retardation in a follow-up investigation. In line with significant overlap between age- and depression-related molecular pathways, parallel work has shown that FREM3 expression in postmortem human brain decreases with age. Here, we probe the effect of rs7676614 on amygdala reactivity and perceptual processing speed, both of which are altered in depression and aging. Amygdala reactivity was assessed using a face-matching BOLD fMRI paradigm in 365 Caucasian participants in the Duke Neurogenetics Study (DNS) (192 women, mean age 19.7 ± 1.2). Perceptual processing speed was indexed by reaction times in the same task and the Trail Making Test (TMT). The effect of rs7676614 on FREM3 mRNA brain expression levels was probed in a postmortem cohort of 169 Caucasian individuals (44 women, mean age 50.8 ± 14.9). The A allele of rs7676614 was associated with blunted amygdala reactivity to faces, slower reaction times in the face-matching condition (p < 0.04), as well as marginally slower performance on TMT Part B (p = 0.056). In the postmortem cohort, the T allele of rs6537170 (proxy for the rs7676614 A allele), was associated with trend-level reductions in gene expression in Brodmann areas 11 and 47 (p = 0.066), reminiscent of patterns characteristic of older age. The low-expressing allele of another FREM3 SNP (rs1391187) was similarly associated with reduced amygdala reactivity and slower TMT Part B speed, in addition to reduced BA47 activity and extraversion (p < 0.05). Together, these results suggest common genetic variation associated with reduced FREM3 expression may confer risk for a subtype of depression characterized by reduced reactivity to environmental stimuli and slower perceptual processing speed, possibly suggestive of accelerated aging.}, Doi = {10.3389/fpsyg.2015.01377}, Key = {fds364221} } @article{fds251954, Author = {Carré, JM and Baird-Rowe, CD and Hariri, AR}, Title = {Testosterone responses to competition predict decreased trust ratings of emotionally neutral faces.}, Journal = {Psychoneuroendocrinology}, Volume = {49}, Pages = {79-83}, Year = {2014}, Month = {November}, ISSN = {0306-4530}, url = {http://dx.doi.org/10.1016/j.psyneuen.2014.06.011}, Abstract = {A wealth of evidence has linked individual differences in testosterone (T) to social, cognitive, and behavioral processes related to human dominance. Moreover, recent evidence indicates that a single administration of T reduces interpersonal trust in healthy young women. Here, in a sample of men and women (n=96), we investigated the extent to which endogenous fluctuations in T during a competitive interaction would predict subsequent ratings of trust from emotionally neutral faces. Results indicated that a rise in T predicted a decrease in trust ratings in men, but not women. These findings provide further support for the idea that competition-induced fluctuations in T may serve to modulate ongoing and/or future social behavior.}, Doi = {10.1016/j.psyneuen.2014.06.011}, Key = {fds251954} } @article{Ahs2013, Author = {Ahs, F and Davis, CF and Gorka, AX and Hariri, AR}, Title = {Feature-based representations of emotional facial expressions in the human amygdala.}, Journal = {Social cognitive and affective neuroscience}, Volume = {9}, Number = {9}, Pages = {1372-1378}, Address = {Center for Cognitive Neuroscience, Duke University Box 90999, Durham, NC 27708, USA. fredrik.ahs@duke.edu.}, Year = {2014}, Month = {September}, ISSN = {1749-5016}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23887817}, Abstract = {The amygdala plays a central role in processing facial affect, responding to diverse expressions and features shared between expressions. Although speculation exists regarding the nature of relationships between expression- and feature-specific amygdala reactivity, this matter has not been fully explored. We used functional magnetic resonance imaging and principal component analysis (PCA) in a sample of 300 young adults, to investigate patterns related to expression- and feature-specific amygdala reactivity to faces displaying neutral, fearful, angry or surprised expressions. The PCA revealed a two-dimensional correlation structure that distinguished emotional categories. The first principal component separated neutral and surprised from fearful and angry expressions, whereas the second principal component separated neutral and angry from fearful and surprised expressions. This two-dimensional correlation structure of amygdala reactivity may represent specific feature-based cues conserved across discrete expressions. To delineate which feature-based cues characterized this pattern, face stimuli were averaged and then subtracted according to their principal component loadings. The first principal component corresponded to displacement of the eyebrows, whereas the second principal component corresponded to increased exposure of eye whites together with movement of the brow. Our results suggest a convergent representation of facial affect in the amygdala reflecting feature-based processing of discrete expressions.}, Language = {Eng}, Doi = {10.1093/scan/nst112}, Key = {Ahs2013} } @article{fds251958, Author = {Nikolova, YS and Koenen, KC and Galea, S and Wang, C-M and Seney, ML and Sibille, E and Williamson, DE and Hariri, AR}, Title = {Beyond genotype: serotonin transporter epigenetic modification predicts human brain function.}, Journal = {Nature neuroscience}, Volume = {17}, Number = {9}, Pages = {1153-1155}, Year = {2014}, Month = {September}, ISSN = {1097-6256}, url = {http://dx.doi.org/10.1038/nn.3778}, Abstract = {We examined epigenetic regulation in regards to behaviorally and clinically relevant human brain function. Specifically, we found that increased promoter methylation of the serotonin transporter gene predicted increased threat-related amygdala reactivity and decreased mRNA expression in postmortem amygdala tissue. These patterns were independent of functional genetic variation in the same region. Furthermore, the association with amygdala reactivity was replicated in a second cohort and was robust to both sampling methods and age.}, Doi = {10.1038/nn.3778}, Key = {fds251958} } @article{fds251956, Author = {Bergman, O and Åhs, F and Furmark, T and Appel, L and Linnman, C and Faria, V and Bani, M and Pich, EM and Bettica, P and Henningsson, S and Manuck, SB and Ferrell, RE and Nikolova, YS and Hariri, AR and Fredrikson, M and Westberg, L and Eriksson, E}, Title = {Association between amygdala reactivity and a dopamine transporter gene polymorphism.}, Journal = {Translational psychiatry}, Volume = {4}, Pages = {e420}, Year = {2014}, Month = {August}, url = {http://dx.doi.org/10.1038/tp.2014.50}, Abstract = {Essential for detection of relevant external stimuli and for fear processing, the amygdala is under modulatory influence of dopamine (DA). The DA transporter (DAT) is of fundamental importance for the regulation of DA transmission by mediating reuptake inactivation of extracellular DA. This study examined if a common functional variable number tandem repeat polymorphism in the 3' untranslated region of the DAT gene (SLC6A3) influences amygdala function during the processing of aversive emotional stimuli. Amygdala reactivity was examined by comparing regional cerebral blood flow, measured with positron emission tomography and [(15)O]water, during exposure to angry and neutral faces, respectively, in a Swedish sample comprising 32 patients with social anxiety disorder and 17 healthy volunteers. In a separate US sample, comprising 85 healthy volunteers studied with blood oxygen level-dependent functional magnetic resonance imaging, amygdala reactivity was assessed by comparing the activity during exposure to threatening faces and neutral geometric shapes, respectively. In both the Swedish and the US sample, 9-repeat carriers displayed higher amygdala reactivity than 10-repeat homozygotes. The results suggest that this polymorphism contributes to individual variability in amygdala reactivity.}, Doi = {10.1038/tp.2014.50}, Key = {fds251956} } @article{fds251957, Author = {Goetz, SMM and Tang, L and Thomason, ME and Diamond, MP and Hariri, AR and Carré, JM}, Title = {Testosterone rapidly increases neural reactivity to threat in healthy men: a novel two-step pharmacological challenge paradigm.}, Journal = {Biological psychiatry}, Volume = {76}, Number = {4}, Pages = {324-331}, Year = {2014}, Month = {August}, ISSN = {0006-3223}, url = {http://dx.doi.org/10.1016/j.biopsych.2014.01.016}, Abstract = {<h4>Background</h4>Previous research suggests that testosterone (T) plays a key role in shaping competitive and aggressive behavior in humans, possibly by modulating threat-related neural circuitry. However, this research has been limited by the use of T augmentation that fails to account for baseline differences and has been conducted exclusively in women. Thus, the extent to which normal physiologic concentrations of T affect threat-related brain function in men remains unknown.<h4>Methods</h4>In the current study, we use a novel two-step pharmacologic challenge protocol to overcome these limitations and to evaluate causal modulation of threat- and aggression-related neural circuits by T in healthy young men (n = 16). First, we controlled for baseline differences in T through administration of a gonadotropin releasing hormone antagonist. Once a common baseline was established across participants, we then administered T to within the normal physiologic range. During this second step of the protocol we acquired functional neuroimaging data to examine the impact of T augmentation on neural circuitry supporting threat and aggression.<h4>Results</h4>Gonadotropin releasing hormone antagonism successfully reduced circulating concentrations of T and brought subjects to a common baseline. Administration of T rapidly increased circulating T concentrations and was associated with heightened reactivity of the amygdala, hypothalamus, and periaqueductal grey to angry facial expressions.<h4>Conclusions</h4>These findings provide novel causal evidence that T rapidly potentiates the response of neural circuits mediating threat processing and aggressive behavior in men.}, Doi = {10.1016/j.biopsych.2014.01.016}, Key = {fds251957} } @article{fds251959, Author = {Carré, JM and Iselin, A-MR and Welker, KM and Hariri, AR and Dodge, KA}, Title = {Testosterone reactivity to provocation mediates the effect of early intervention on aggressive behavior.}, Journal = {Psychological science}, Volume = {25}, Number = {5}, Pages = {1140-1146}, Year = {2014}, Month = {May}, ISSN = {0956-7976}, url = {http://dx.doi.org/10.1177/0956797614525642}, Abstract = {We tested the hypotheses that the Fast Track intervention program for high-risk children would reduce adult aggressive behavior and that this effect would be mediated by decreased testosterone responses to social provocation. Participants were a subsample of males from the full trial sample, who during kindergarten had been randomly assigned to the 10-year Fast Track intervention or to a control group. The Fast Track program attempted to develop children's social competencies through child social-cognitive and emotional-coping skills training, peer-relations coaching, academic tutoring, and classroom management, as well as training for parents to manage their child's behavior. At a mean age of 26 years, participants responded to laboratory provocations. Results indicated that, relative to control participants, men assigned to the intervention demonstrated reduced aggression and testosterone reactivity to social provocations. Moreover, reduced testosterone reactivity mediated the effect of intervention on aggressive behavior, which provides evidence for an enduring biological mechanism underlying the effect of early psychosocial intervention on aggressive behavior in adulthood.}, Doi = {10.1177/0956797614525642}, Key = {fds251959} } @article{fds303796, Author = {Gianaros, PJ and Marsland, AL and Kuan, DC-H and Schirda, BL and Jennings, JR and Sheu, LK and Hariri, AR and Gross, JJ and Manuck, SB}, Title = {An inflammatory pathway links atherosclerotic cardiovascular disease risk to neural activity evoked by the cognitive regulation of emotion.}, Journal = {Biological psychiatry}, Volume = {75}, Number = {9}, Pages = {738-745}, Year = {2014}, Month = {May}, ISSN = {0006-3223}, url = {http://dx.doi.org/10.1016/j.biopsych.2013.10.012}, Abstract = {<h4>Background</h4>Cognitive reappraisal is a form of emotion regulation that alters emotional responding by changing the meaning of emotional stimuli. Reappraisal engages regions of the prefrontal cortex that support multiple functions, including visceral control functions implicated in regulating the immune system. Immune activity plays a role in the preclinical pathophysiology of atherosclerotic cardiovascular disease (CVD), an inflammatory condition that is highly comorbid with affective disorders characterized by problems with emotion regulation. Here, we tested whether prefrontal engagement by reappraisal would be associated with atherosclerotic CVD risk and whether this association would be mediated by inflammatory activity.<h4>Methods</h4>Community volunteers (n = 157; 30-54 years of age; 80 women) without DSM-IV Axis-1 psychiatric diagnoses or cardiovascular or immune disorders performed a functional neuroimaging task involving the reappraisal of negative emotional stimuli. Carotid artery intima-media thickness and inter-adventitial diameter were measured by ultrasonography and used as markers of preclinical atherosclerosis. Also measured were circulating levels of interleukin-6 (IL-6), an inflammatory cytokine linked to CVD risk and prefrontal neural activity.<h4>Results</h4>Greater reappraisal-related engagement of the dorsal anterior cingulate cortex was associated with greater preclinical atherosclerosis and IL-6. Moreover, IL-6 mediated the association of dorsal anterior cingulate cortex engagement with preclinical atherosclerosis. These results were independent of age, sex, race, smoking status, and other known CVD risk factors.<h4>Conclusions</h4>The cognitive regulation of emotion might relate to CVD risk through a pathway involving the functional interplay between the anterior cingulate region of the prefrontal cortex and inflammatory activity.}, Doi = {10.1016/j.biopsych.2013.10.012}, Key = {fds303796} } @article{fds251963, Author = {McCarty, CA and Huggins, W and Aiello, AE and Bilder, RM and Hariri, A and Jernigan, TL and Newman, E and Sanghera, DK and Strauman, TJ and Zeng, Y and Ramos, EM and Junkins, HA and PhenX RISING network}, Title = {PhenX RISING: real world implementation and sharing of PhenX measures.}, Journal = {BMC Med Genomics}, Volume = {7}, Pages = {16}, Year = {2014}, Month = {March}, url = {http://dx.doi.org/10.1186/1755-8794-7-16}, Abstract = {BACKGROUND: The purpose of this manuscript is to describe the PhenX RISING network and the site experiences in the implementation of PhenX measures into ongoing population-based genomic studies. METHODS: Eighty PhenX measures were implemented across the seven PhenX RISING groups, thirty-three of which were used at more than two sites, allowing for cross-site collaboration. Each site used between four and 37 individual measures and five of the sites are validating the PhenX measures through comparison with other study measures. Self-administered and computer-based administration modes are being evaluated at several sites which required changes to the original PhenX Toolkit protocols. A network-wide data use agreement was developed to facilitate data sharing and collaboration. RESULTS: PhenX Toolkit measures have been collected for more than 17,000 participants across the PhenX RISING network. The process of implementation provided information that was used to improve the PhenX Toolkit. The Toolkit was revised to allow researchers to select self- or interviewer administration when creating the data collection worksheets and ranges of specimens necessary to run biological assays has been added to the Toolkit. CONCLUSIONS: The PhenX RISING network has demonstrated that the PhenX Toolkit measures can be implemented successfully in ongoing genomic studies. The next step will be to conduct gene/environment studies.}, Doi = {10.1186/1755-8794-7-16}, Key = {fds251963} } @article{fds251961, Author = {Hyde, LW and Byrd, AL and Votruba-Drzal, E and Hariri, AR and Manuck, SB}, Title = {Amygdala reactivity and negative emotionality: divergent correlates of antisocial personality and psychopathy traits in a community sample.}, Journal = {Journal of abnormal psychology}, Volume = {123}, Number = {1}, Pages = {214-224}, Year = {2014}, Month = {February}, ISSN = {0021-843X}, url = {http://dx.doi.org/10.1037/a0035467}, Abstract = {Previous studies have emphasized that antisocial personality disorder (APD) and psychopathy overlap highly but differ critically in several features, notably negative emotionality (NEM) and possibly amygdala reactivity to social signals of threat and distress. Here we examined whether dimensions of psychopathy and APD correlate differentially with NEM and amygdala reactivity to emotional faces. Testing these relationships among healthy individuals, dimensions of psychopathy and APD were generated by the profile matching technique of Lynam and Widiger (2001), using facet scales of the NEO Personality Inventory-Revised, and amygdala reactivity was measured using a well-established emotional faces task, in a community sample of 103 men and women. Higher psychopathy scores were associated with lower NEM and lower amygdala reactivity, whereas higher APD scores were related to greater NEM and greater amygdala reactivity, but only after overlapping variance in APD and psychopathy was adjusted for in the statistical model. Amygdala reactivity did not mediate the relationship of APD and psychopathy scores to NEM. Supplemental analyses also compared other measures of factors within psychopathy in predicting NEM and amygdala reactivity and found that Factor 2 psychopathy was positively related to NEM and amygdala reactivity across measures of psychopathy. The overall findings replicate seminal observations on NEM in psychopathy by Hicks and Patrick (2006) and extend this work to neuroimaging in a normative population. They also suggest that one critical way in which APD and psychopathy dimensions may differ in their etiology is through their opposing levels of NEM and amygdala reactivity to threat.}, Doi = {10.1037/a0035467}, Key = {fds251961} } @article{fds251965, Author = {Roses, AD and Saunders, AM and Lutz, MW and Zhang, N and Hariri, AR and Asin, KE and Crenshaw, DG and Budur, K and Burns, DK and Brannan, SK}, Title = {New applications of disease genetics and pharmacogenetics to drug development.}, Journal = {Curr Opin Pharmacol}, Volume = {14}, Pages = {81-89}, Year = {2014}, Month = {February}, ISSN = {1471-4892}, url = {http://dx.doi.org/10.1016/j.coph.2013.12.002}, Abstract = {TOMMORROW is a Phase III delay of onset clinical trial to determine whether low doses of pioglitazone, a molecule that induces mitochondrial doubling, delays the onset of MCI-AD in normal subjects treated with low dose compared to placebo. BOLD imaging studies in rodents and man were used to find the dose that increases oxygen consumption at central regions of the brain in higher proportion than activation of large corticol regions. The trial is made practical by the use of a pharmacogenetic algorithm based on TOMM40 and APOE genotypes and age to identify normal subjects at high risk of MCI-AD between the ages of 65-83 years within a five year follow-up period.}, Doi = {10.1016/j.coph.2013.12.002}, Key = {fds251965} } @article{fds251967, Author = {Wellman, CL and Camp, M and Jones, VM and MacPherson, KP and Ihne, J and Fitzgerald, P and Maroun, M and Drabant, E and Bogdan, R and Hariri, AR and Holmes, A}, Title = {Corrigendum to "Convergent effects of mouse Pet-1 deletion and human PET-1 variation on amygdala fear and threat processing" [Exp. Neurol. 250 (2013) 260-269]}, Journal = {Experimental Neurology}, Volume = {252}, Pages = {104}, Publisher = {Elsevier BV}, Year = {2014}, Month = {February}, ISSN = {0014-4886}, url = {http://dx.doi.org/10.1016/j.expneurol.2013.11.002}, Doi = {10.1016/j.expneurol.2013.11.002}, Key = {fds251967} } @article{fds251942, Author = {Gorka, AX and Hanson, JL and Radtke, SR and Hariri, AR}, Title = {Reduced hippocampal and medial prefrontal gray matter mediate the association between reported childhood maltreatment and trait anxiety in adulthood and predict sensitivity to future life stress}, Journal = {Biology of Mood and Anxiety Disorders}, Volume = {4}, Number = {1}, Pages = {12-12}, Publisher = {Springer Nature}, Year = {2014}, Month = {January}, ISSN = {2045-5380}, url = {http://dx.doi.org/10.1186/2045-5380-4-12}, Abstract = {Background: The experience of early life stress is a consistently identified risk factor for the development of mood and anxiety disorders. Preclinical research employing animal models of early life stress has made inroads in understanding this association and suggests that the negative sequelae of early life stress may be mediated by developmental disruption of corticolimbic structures supporting stress responsiveness. Work in humans has corroborated this idea, as childhood adversity has been associated with alterations in gray matter volumes of the hippocampus, amygdala, and medial prefrontal cortex. Yet, missing from this body of research is a full understanding of how these neurobiological vulnerabilities may mechanistically contribute to the reported link between adverse childhood experiences and later affective psychopathology.Results: Analyses revealed that self-reported childhood maltreatment was associated with reduced gray matter volumes within the medial prefrontal cortex and left hippocampus. Furthermore, reduced left hippocampal and medial prefrontal gray matter volume mediated the relationship between childhood maltreatment and trait anxiety. Additionally, individual differences in corticolimbic gray matter volume within these same structures predicted the anxious symptoms as a function of life stress 1 year after initial assessment.Conclusions: Collectively, these findings provide novel evidence that reductions in corticolimbic gray matter, particularly within the hippocampus and medial prefrontal cortex, are associated with reported childhood maltreatment and individual differences in adult trait anxiety. Furthermore, our results suggest that these structural alterations contribute to increased affective sensitivity to stress later in life in those that have experienced early adversity. More broadly, the findings contribute to an emerging literature highlighting the critical importance of early stress on the development of corticolimbic structures supporting adaptive functioning later in life.}, Doi = {10.1186/2045-5380-4-12}, Key = {fds251942} } @article{Lohoff2013, Author = {Lohoff, FW and Hodge, R and Narasimhan, S and Nall, A and Ferraro, TN and Mickey, BJ and Heitzeg, MM and Langenecker, SA and Zubieta, J-K and Bogdan, R and Nikolova, YS and Drabant, E and Hariri, AR and Bevilacqua, L and Goldman, D and Doyle, GA}, Title = {Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing.}, Journal = {Molecular psychiatry}, Volume = {19}, Number = {1}, Pages = {129-139}, Address = {Translational Research Laboratories, Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.}, Year = {2014}, Month = {January}, ISSN = {1359-4184}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23337945}, Abstract = {Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology.}, Language = {Eng}, Doi = {10.1038/mp.2012.193}, Key = {Lohoff2013} } @article{fds251964, Author = {Goetz, SMM and Tang, L and Thomason, ME and Diamond, MP and Hariri, AR and Carré, JM}, Title = {Testosterone Rapidly Increases Neural Reactivity to Threat in Healthy Men: A Novel Two-Step Pharmacological Challenge Paradigm}, Journal = {Biological Psychiatry}, Volume = {76}, Number = {4}, Pages = {324-331}, Publisher = {Elsevier BV}, Year = {2014}, ISSN = {0006-3223}, url = {http://dx.doi.org/10.1016/j.biopsych.2014.01.016}, Doi = {10.1016/j.biopsych.2014.01.016}, Key = {fds251964} } @article{Wellman2013, Author = {Wellman, CL and Camp, M and Jones, VM and MacPherson, KP and Ihne, J and Fitzgerald, P and Maroun, M and Drabant, E and Bogdan, R and Hariri, AR and Holmes, A}, Title = {Convergent effects of mouse Pet-1 deletion and human PET-1 variation on amygdala fear and threat processing.}, Journal = {Experimental neurology}, Volume = {250}, Pages = {260-269}, Address = {Department of Psychological and Brain Sciences, Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, IN, USA. Electronic address: wellmanc@indiana.edu.}, Year = {2013}, Month = {December}, ISSN = {0014-4886}, url = {http://www.ncbi.nlm.nih.gov/pubmed/24100022}, Abstract = {Serotonin is critical for shaping the development of neural circuits regulating emotion. Pet-1 (FEV-1) is an ETS-domain transcription factor essential for differentiation and forebrain targeting of serotonin neurons. Constitutive Pet-1 knockout (KO) causes major loss of serotonin neurons and forebrain serotonin availability, and behavioral abnormalities. We phenotyped Pet-1 KO mice for fear conditioning and extinction, and on a battery of assays for anxiety- and depression-related behaviors. Morphology of Golgi-stained neurons in basolateral amygdala (BLA) and prelimbic cortex was examined. Using human imaging genetics, a common variant (rs860573) in the PET-1 (FEV) gene was tested for effects on threat-related amygdala reactivity and psychopathology in 88 Asian-ancestry subjects. Pet-1 KO mice exhibited increased acquisition and expression of fear, and elevated fear recovery following extinction, relative to wild-type (WT). BLA dendrites of Pet-1 KO mice were significantly longer than in WT. Human PET-1 variation associated with differences in amygdala threat processing and psychopathology. This novel evidence for the role of Pet-1 in fear processing and dendritic organization of amygdala neurons and in human amygdala threat processing extends a growing literature demonstrating the influence of genetic variation in the serotonin system on emotional regulation via effects on structure and function of underlying corticolimbic circuitry.}, Language = {eng}, Doi = {10.1016/j.expneurol.2013.09.025}, Key = {Wellman2013} } @article{fds251968, Author = {Disner, SG and Beevers, CG and Lee, HJ and Ferrell, RE and Hariri, AR and Telch, MJ}, Title = {War zone stress interacts with the 5-HTTLPR polymorphism to predict the development of sustained attention for negative emotion stimuli in soldiers returning from Iraq}, Journal = {Clinical Psychological Science}, Volume = {1}, Number = {4}, Pages = {413-425}, Publisher = {SAGE Publications}, Year = {2013}, Month = {October}, ISSN = {2167-7026}, url = {http://dx.doi.org/10.1177/2167702613485564}, Abstract = {Biased attention toward negative stimuli is a known vulnerability for affective psychopathology. However, factors that contribute to the development of this cognitive bias are largely unknown. Variation within the serotonin transporter gene (i.e., 5-HTTLPR) is associated with increased susceptibility to environmental influence and biased processing of negative stimuli. Using a passive viewing eye-tracking paradigm, this study examined gaze fixation for emotion stimuli in 91 U.S. Army soldiers before and after deployment to Iraq. In addition, participants underwent genetic assay and provided in situ measures of war zone stress exposure. 5-HTTLPR short allele homozygotes were more likely than other genotype groups to develop a gaze bias toward negative stimuli as a function of increasing war zone stress, even when controlling for postdeployment posttraumatic stress disorder and depression severity. Short allele homozygotes appear especially sensitive to environmental influence, which likely contributes to the development of cognitive vulnerability to anxiety and mood disorders. © The Author(s) 2013.}, Doi = {10.1177/2167702613485564}, Key = {fds251968} } @article{Hyde2013, Author = {Hyde, LW and Shaw, DS and Hariri, AR}, Title = {Understanding Youth Antisocial Behavior Using Neuroscience through a Developmental Psychopathology Lens: Review, Integration, and Directions for Research.}, Journal = {Developmental review : DR}, Volume = {33}, Number = {3}, Pages = {168-223}, Publisher = {Elsevier BV}, Address = {University of Michigan.}, Year = {2013}, Month = {September}, ISSN = {0273-2297}, url = {http://www.ncbi.nlm.nih.gov/pubmed/24273368}, Abstract = {Youth antisocial behavior (AB) is an important public health concern impacting perpetrators, victims, and society. Functional neuroimaging is becoming a more common and useful modality for understanding neural correlates of youth AB. Although there has been a recent increase in neuroimaging studies of youth AB and corresponding theoretical articles on the neurobiology of AB, there has been little work critically examining the strengths and weaknesses of individual studies and using this knowledge to inform the design of future studies. Additionally, research on neuroimaging and youth AB has not been integrated within the broader framework of developmental psychopathology. Thus, this paper provides an in-depth review of the youth AB functional neuroimaging literature with the following goals: 1. to evaluate how this literature has informed our understanding of youth AB, 2. to evaluate current neuroimaging studies of youth AB from a developmental psychopathology perspective with a focus on integrating research from neuroscience and developmental psychopathology, as well as placing this research in the context of other related areas (e.g., psychopathy, molecular genetics), and 3. to examine strengths and weaknesses of neuroimaging and behavioral studies of youth AB to suggest how future studies can develop a more informed and integrated understanding of youth AB.}, Language = {Eng}, Doi = {10.1016/j.dr.2013.06.001}, Key = {Hyde2013} } @article{Nikolova2013, Author = {Nikolova, YS and Singhi, EK and Drabant, EM and Hariri, AR}, Title = {Reward-related ventral striatum reactivity mediates gender-specific effects of a galanin remote enhancer haplotype on problem drinking.}, Journal = {Genes, brain, and behavior}, Volume = {12}, Number = {5}, Pages = {516-524}, Address = {Laboratory of NeuroGenetics, Department of Psychology and Neuroscience; Institute for Genome Sciences \& Policy, Duke University, Durham, NC 27705, USA. yuliya.nikolova@duke.edu}, Year = {2013}, Month = {July}, ISSN = {1601-1848}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23489876}, Abstract = {The neuropeptide galanin has been implicated in the regulation of appetitive and consummatory behaviors. Prior studies have shown that direct injection of galanin into the hypothalamus results in increased release of dopamine (DA) in the nucleus accumbens (NAcc), and parallel increases in food and alcohol consumption. These studies are consistent with a role of hypothalamic galanin in regulating reward system reactivity. In humans, a common functional haplotype (GAL5.1) within a remote enhancer region upstream of the galanin gene (GAL) affects promoter activity and galanin expression in hypothalamic neurons in vitro. Given the effects of hypothalamic galanin on NAcc DA release and the effects of the GAL5.1 haplotype on GAL expression, we examined the impact of this functional genetic variation on human reward-related ventral striatum (VS) reactivity. Using an imaging genetics strategy in Caucasian individuals (N = 138, 72 women) participating in the ongoing Duke Neurogenetics Study, we report a significant gender-by-genotype interaction (right hemisphere: F1,134 = 8.08, P = 0.005; left hemisphere: F1,134 = 5.39, P = 0.022), such that homozygosity for the GG haplotype, which predicts greater GAL expression, is associated with relatively increased VS reactivity in women (n = 50, right hemisphere: P = 0.015; left hemisphere: P = 0.060), but not in men (N = 49, P-values > 0.10). Furthermore, these differences in VS reactivity correlated positively with differences in alcohol use, such that VS reactivity mediated a gender-specific association between GAL5.1 haplotype and problem drinking. Our current results support those in animal models implicating galanin signaling in neural pathways associated with appetitive and consummatory behaviors of relevance for understanding risk for substance use and abuse.}, Language = {eng}, Doi = {10.1111/gbb.12035}, Key = {Nikolova2013} } @article{Zuurbier2013, Author = {Zuurbier, LA and Nikolova, YS and Åhs, F and Hariri, AR}, Title = {Uncinate fasciculus fractional anisotropy correlates with typical use of reappraisal in women but not men.}, Journal = {Emotion (Washington, D.C.)}, Volume = {13}, Number = {3}, Pages = {385-390}, Address = {Laboratory of NeuroGenetics, Department of Psychology \& Neuroscience, Institute for Genome Sciences \& Policy, Duke University, Durham, NC, USA.}, Year = {2013}, Month = {June}, ISSN = {1528-3542}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23398586}, Abstract = {Emotion regulation refers to strategies through which individuals influence their experience and expression of emotions. Two typical strategies are reappraisal, a cognitive strategy for reframing the context of an emotional experience, and suppression, a behavioral strategy for inhibiting emotional responses. Functional neuroimaging studies have revealed that regions of the prefrontal cortex modulate amygdala reactivity during both strategies, but relatively greater downregulation of the amygdala occurs during reappraisal. Moreover, these studies demonstrated that engagement of this modulatory circuitry varies as a function of gender. The uncinate fasciculus is a major structural pathway connecting regions of the anterior temporal lobe, including the amygdala to inferior frontal regions, especially the orbitofrontal cortex. The objective of the current study was to map variability in the structural integrity of the uncinate fasciculus onto individual differences in self-reported typical use of reappraisal and suppression. Diffusion tensor imaging was used in 194 young adults to derive regional fractional anisotropy values for the right and left uncinate fasciculus. All participants also completed the Emotion Regulation Questionnaire. In women but not men, self-reported typical reappraisal use was positively correlated with fractional anisotropy values in a region of the left uncinate fasciculus within the orbitofrontal cortex. In contrast, typical use of suppression was not significantly correlated with fractional anisotropy in any region of the uncinate fasciculus in either men or women. Our data suggest that in women typical reappraisal use is specifically related to the integrity of white matter pathways linking the amygdala and prefrontal cortex.}, Language = {eng}, Doi = {10.1037/a0031163}, Key = {Zuurbier2013} } @article{Kienast2013, Author = {Kienast, T and Schlagenhauf, F and Rapp, MA and Wrase, J and Daig, I and Buchholz, H-G and Smolka, MN and Gründer, G and Kumakura, Y and Cumming, P and Charlet, K and Bartenstein, P and Hariri, AR and Heinz, A}, Title = {Dopamine-modulated aversive emotion processing fails in alcohol-dependent patients.}, Journal = {Pharmacopsychiatry}, Volume = {46}, Number = {4}, Pages = {130-136}, Address = {Department of Psychiatry and Psychotherapy, Campus Charite Mitte, -Charite - Universitatsmedizin Berlin, Berlin, Germany.}, Year = {2013}, Month = {June}, ISSN = {0176-3679}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23364872}, Abstract = {Negative mood states after alcohol detoxification may enhance the relapse risk. As recently shown in healthy volunteers, dopamine storage capacity (V d) in the left amygdala was positively correlated with functional activation in the left amygdala and anterior cingulate cortex (ACC) during an emotional task; high functional connectivity between the amygdala and the ACC, a region important for emotion regulation, was associated with low trait anxiety. Based on these findings, we now tested whether detoxified alcohol-dependent patients have a disrupted modulation of the anterior cingulate cortex activation in response to aversive stimuli by amygdala dopamine. Furthermore, we asked whether disrupted functional coupling between amygdala and ACC during aversive processing is related to trait anxiety.We used combined 6-[18F]-fluoro-l-DOPA positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and Spielberger's state-trait anxiety questionnaire (STAI) in 11 male detoxified alcohol-dependent patients compared to 13 matched healthy controls.Unlike healthy controls, patients showed no significant correlation between our PET metric for dopamine storage capacity (FDOPA V d), in left amygdala and activation in left ACC. Moreover, the functional connectivity between amygdala and ACC during processing of aversive emotional stimuli was reduced in patients. Voxel-based morphometry did not reveal any discernible group differences in amygdala volume.These results suggest that dopamine-modulated corticolimbic circuit function is important for responding to emotional information such that apparent functional deficits in this neuromodulatory circuitry may contribute to trait anxiety in alcohol-dependent patients.}, Language = {eng}, Doi = {10.1055/s-0032-1331747}, Key = {Kienast2013} } @article{Prather2013, Author = {Prather, AA and Bogdan, R and Hariri, AR}, Title = {Impact of sleep quality on amygdala reactivity, negative affect, and perceived stress.}, Journal = {Psychosomatic medicine}, Volume = {75}, Number = {4}, Pages = {350-358}, Address = {Department of Psychiatry, University of California, San Francisco, CA, USA. prathera@chc.ucsf.edu}, Year = {2013}, Month = {May}, ISSN = {0033-3174}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23592753}, Keywords = {Adolescent • Adult • Affect/*physiology • Amygdala/*physiopathology • Anger • Anxiety/physiopathology/psychology • Depression/physiopathology/psychology • Facial Expression • Fear • Female • Humans • *Magnetic Resonance Imaging • Male • Self Report • Severity of Illness Index • Sex Factors • Sleep/*physiology • Sleep Disorders/*physiopathology/psychology • Stress, Psychological/etiology/*physiopathology • Visual Cortex/physiopathology • Young Adult}, Abstract = {<h4>Objective</h4>Research demonstrates a negative impact of sleep disturbance on mood and affect; however, the biological mechanisms mediating these links are poorly understood. Amygdala reactivity to negative stimuli has emerged as one potential pathway. Here, we investigate the influence of self-reported sleep quality on associations between threat-related amygdala reactivity and measures of negative affect and perceived stress.<h4>Methods</h4>Analyses on data from 299 participants (125 men, 50.5% white, mean [standard deviation] age = 19.6 [1.3] years) who completed the Duke Neurogenetics Study were conducted. Participants completed several self-report measures of negative affect and perceived stress. Threat-related (i.e., angry and fearful facial expressions) amygdala reactivity was assayed using blood oxygen level-dependent functional magnetic resonance imaging. Global sleep quality was assessed using the Pittsburgh Sleep Quality Index.<h4>Results</h4>Amygdala reactivity to fearful facial expressions predicted greater depressive symptoms and higher perceived stress in poor (β values = 0.18-1.86, p values < .05) but not good sleepers (β values = -0.13 to -0.01, p values > .05). In sex-specific analyses, men reporting poorer global sleep quality showed a significant association between amygdala reactivity and levels of depression and perceived stress (β values = 0.29-0.44, p values < .05). In contrast, no significant associations were observed in men reporting good global sleep quality or in women, irrespective of sleep quality.<h4>Conclusions</h4>This study provides novel evidence that self-reported sleep quality moderates the relationships between amygdala reactivity, negative affect, and perceived stress, particularly among men.}, Language = {eng}, Doi = {10.1097/psy.0b013e31828ef15b}, Key = {Prather2013} } @article{Bogdan2013, Author = {Bogdan, R and Hyde, LW and Hariri, AR}, Title = {A neurogenetics approach to understanding individual differences in brain, behavior, and risk for psychopathology.}, Journal = {Molecular psychiatry}, Volume = {18}, Number = {3}, Pages = {288-299}, Address = {Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, NC 27705, USA. ryan.bogdan@duke.edu}, Year = {2013}, Month = {March}, ISSN = {1359-4184}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22614291}, Abstract = {Neurogenetics research has begun to advance our understanding of how genetic variation gives rise to individual differences in brain function, which, in turn, shapes behavior and risk for psychopathology. Despite these advancements, neurogenetics research is currently confronted by three major challenges: (1) conducting research on individual variables with small effects, (2) absence of detailed mechanisms, and (3) a need to translate findings toward greater clinical relevance. In this review, we showcase techniques and developments that address these challenges and highlight the benefits of a neurogenetics approach to understanding brain, behavior and psychopathology. To address the challenge of small effects, we explore approaches including incorporating the environment, modeling epistatic relationships and using multilocus profiles. To address the challenge of mechanism, we explore how non-human animal research, epigenetics research and genome-wide association studies can inform our mechanistic understanding of behaviorally relevant brain function. Finally, to address the challenge of clinical relevance, we examine how neurogenetics research can identify novel therapeutic targets and for whom treatments work best. By addressing these challenges, neurogenetics research is poised to exponentially increase our understanding of how genetic variation interacts with the environment to shape the brain, behavior and risk for psychopathology.}, Language = {eng}, Doi = {10.1038/mp.2012.35}, Key = {Bogdan2013} } @article{fds251962, Author = {Salazar, E and Bogdan, R and Gorka, A and Hariri, AR and Carin, L}, Title = {Exploring the mind: Integrating questionnaires and fMRI}, Journal = {30th International Conference on Machine Learning, ICML 2013}, Number = {PART 2}, Pages = {921-929}, Year = {2013}, Month = {January}, Abstract = {A new model is developed for joint analysis of ordered, categorical, real and count data. The ordered and categorical data are answers to questionnaires, the (word) count data correspond to the text questions from the questionnaires, and the real data correspond to fMRI responses for each subject. The Bayesian model employs the von Mises distribution in a novel manner to infer sparse graphical models jointly across people, questions, fMRI stimuli and brain region, with this integrated within a new matrix factorization based on latent binary features. The model is compared with simpler alternatives on two real datasets. We also demonstrate the ability to predict the response of the brain to visual stimuli (as measured by fMRI), based on knowledge of how the associated person answered classical questionnaires. Copyright 2013 by the author(s).}, Key = {fds251962} } @article{Fisher2013, Author = {Fisher, PM and Hariri, AR}, Title = {Identifying serotonergic mechanisms underlying the corticolimbic response to threat in humans.}, Journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, Volume = {368}, Number = {1615}, Pages = {20120192}, Address = {Center for Integrated Molecular Brain Imaging, University of Copenhagen, Copenhagen 2100, Denmark. patrick.fisher@nru.dk}, Year = {2013}, Month = {January}, ISSN = {0962-8436}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23440464}, Keywords = {Amygdala/drug effects/*metabolism/physiology • Antidepressive Agents/pharmacology • Depression/drug therapy/physiopathology • Fear/*physiology • Humans • Neural Pathways/metabolism/physiology • Neuroimaging • Personality/physiology • Prefrontal Cortex/*metabolism/physiology • Protein Binding • Receptor, Serotonin, 5-HT1A/metabolism • Serotonin/*metabolism • Serotonin Uptake Inhibitors/pharmacology}, Abstract = {A corticolimbic circuit including the amygdala and medial prefrontal cortex (mPFC) plays an important role in regulating sensitivity to threat, which is heightened in mood and anxiety disorders. Serotonin is a potent neuromodulator of this circuit; however, specific serotonergic mechanisms mediating these effects are not fully understood. Recent studies have evaluated molecular mechanisms mediating the effects of serotonin signalling on corticolimbic circuit function using a multi-modal neuroimaging strategy incorporating positron emission tomography and blood oxygen level-dependent functional magnetic resonance imaging. This multi-modal neuroimaging strategy can be integrated with additional techniques including imaging genetics and pharmacological challenge paradigms to more clearly understand how serotonin signalling modulates neural pathways underlying sensitivity to threat. Integrating these methodological approaches offers novel opportunities to identify mechanisms through which serotonin signalling contributes to differences in brain function and behaviour, which in turn can illuminate factors that confer risk for illness and inform the development of more effective treatment strategies.}, Language = {eng}, Doi = {10.1098/rstb.2012.0192}, Key = {Fisher2013} } @article{Goetz2013, Author = {Goetz, E. L. and Hariri, A. R. and Pizzagalli, D. A. and Strauman, T. J.}, Title = {Genetic moderation of the association between regulatory focus and reward responsiveness: a proof-of-concept study}, Journal = {Biology of mood \& anxiety disorders}, Volume = {3}, Number = {1}, Pages = {3}, Address = {Department of Psychology \& Neuroscience, Duke University, Durham, NC, USA. elena.goetz@duke.edu.}, Year = {2013}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23369671}, Abstract = {BACKGROUND: Recent studies implicate individual differences in regulatory focus as contributing to self-regulatory dysfunction, particularly not responding to positive outcomes. How such individual differences emerge, however, is unclear. We conducted a proof-of-concept study to examine the moderating effects of genetically driven variation in dopamine signaling, a key modulator of neural reward circuits, on the association between regulatory focus and reward cue responsiveness. METHOD: Healthy Caucasians (N=59) completed a measure of chronic regulatory focus and a probabilistic reward task. A common functional genetic polymorphism impacting prefrontal dopamine signaling (COMT rs4680) was evaluated. RESULTS: Response bias, the participants' propensity to modulate behavior as a function of reward, was predicted by an interaction of regulatory focus and COMT genotype. Specifically, self-perceived success at achieving promotion goals predicted total response bias, but only for individuals with the COMT genotype (Val/Val) associated with relatively increased phasic dopamine signaling and cognitive flexibility. CONCLUSIONS: The combination of success in promotion goal pursuit and Val/Val genotype appears to facilitate responding to reward opportunities in the environment. This study is among the first to integrate an assessment of self-regulatory style with an examination of genetic variability that underlies responsiveness to positive outcomes in goal pursuit.}, Language = {eng}, Doi = {10.1186/2045-5380-3-3}, Key = {Goetz2013} } @article{Carre2013a, Author = {Carre, J. M. and Murphy, K. R. and Hariri, A. R.}, Title = {What lies beneath the face of aggression?}, Journal = {Social cognitive and affective neuroscience}, Volume = {8}, Number = {2}, Pages = {224--9}, Address = {Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, NC, USA. justin@carrelab.com}, Year = {2013}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22198969}, Keywords = {Adult • Aggression/*physiology • Amygdala/*physiology • Anger/physiology • Anthropometry • *Face/anatomy \& histology/physiology • *Facial Expression • Fear/physiology • Female • Humans • Magnetic Resonance Imaging/instrumentation/*methods • Male • Neuroimaging/methods/psychology • Neuropsychological Tests • Sex Characteristics • Young Adult}, Abstract = {Recent evidence indicates that a sexually dimorphic feature of humans, the facial width-to-height ratio (FWHR), is positively correlated with reactive aggression, particularly in men. Also, predictions about the aggressive tendencies of others faithfully map onto FWHR in the absence of explicit awareness of this metric. Here, we provide the first evidence that amygdala reactivity to social signals of interpersonal challenge may underlie the link between aggression and the FWHR. Specifically, amygdala reactivity to angry faces was positively correlated with aggression, but only among men with relatively large FWHRs. The patterns of association were specific to angry facial expressions and unique to men. These links may reflect the common influence of pubertal testosterone on craniofacial growth and development of neural circuitry underlying aggression. Amygdala reactivity may also represent a plausible pathway through which FWHR may have evolved to represent an honest indicator of conspecific threat, namely by reflecting the responsiveness of neural circuitry mediating aggressive behavior.}, Language = {eng}, Doi = {10.1093/scan/nsr096}, Key = {Carre2013a} } @article{Gianaros2013, Author = {Gianaros, PJ and Marsland, AL and Kuan, DC-H and Schirda, BL and Jennings, JR and Sheu, LK and Hariri, AR and Gross, JJ and Manuck, SB}, Title = {An Inflammatory Pathway Links Atherosclerotic Cardiovascular Disease Risk to Neural Activity Evoked by the Cognitive Regulation of Emotion}, Journal = {Biological Psychiatry}, Volume = {75}, Number = {9}, Pages = {738-745}, Publisher = {Elsevier BV}, Address = {Department of Psychology (PJG, ALM, DC-HK, LKS, SBM). Electronic address: gianaros@pitt.edu.}, Year = {2013}, ISSN = {0006-3223}, url = {http://www.ncbi.nlm.nih.gov/pubmed/24267410}, Abstract = {BACKGROUND: Cognitive reappraisal is a form of emotion regulation that alters emotional responding by changing the meaning of emotional stimuli. Reappraisal engages regions of the prefrontal cortex that support multiple functions, including visceral control functions implicated in regulating the immune system. Immune activity plays a role in the preclinical pathophysiology of atherosclerotic cardiovascular disease (CVD), an inflammatory condition that is highly comorbid with affective disorders characterized by problems with emotion regulation. Here, we tested whether prefrontal engagement by reappraisal would be associated with atherosclerotic CVD risk and whether this association would be mediated by inflammatory activity. METHODS: Community volunteers (n = 157; 30-54 years of age; 80 women) without DSM-IV Axis-1 psychiatric diagnoses or cardiovascular or immune disorders performed a functional neuroimaging task involving the reappraisal of negative emotional stimuli. Carotid artery intima-media thickness and inter-adventitial diameter were measured by ultrasonography and used as markers of preclinical atherosclerosis. Also measured were circulating levels of interleukin-6 (IL-6), an inflammatory cytokine linked to CVD risk and prefrontal neural activity. RESULTS: Greater reappraisal-related engagement of the dorsal anterior cingulate cortex was associated with greater preclinical atherosclerosis and IL-6. Moreover, IL-6 mediated the association of dorsal anterior cingulate cortex engagement with preclinical atherosclerosis. These results were independent of age, sex, race, smoking status, and other known CVD risk factors. CONCLUSIONS: The cognitive regulation of emotion might relate to CVD risk through a pathway involving the functional interplay between the anterior cingulate region of the prefrontal cortex and inflammatory activity.}, Language = {Eng}, Doi = {10.1016/j.biopsych.2013.10.012}, Key = {Gianaros2013} } @article{Bogdan2012b, Author = {Bogdan, R and Hariri, AR}, Title = {Neural embedding of stress reactivity.}, Journal = {Nature neuroscience}, Volume = {15}, Number = {12}, Pages = {1605-1607}, Year = {2012}, Month = {December}, ISSN = {1097-6256}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23187689}, Keywords = {Adolescent Behavior/*physiology • Amygdala/*growth \& development • Anxiety/*metabolism • Depression/*metabolism • Female • Humans • Hydrocortisone/*metabolism • Male • Prefrontal Cortex/*growth \& development}, Language = {eng}, Doi = {10.1038/nn.3270}, Key = {Bogdan2012b} } @article{White2012, Author = {White, MG and Bogdan, R and Fisher, PM and Muñoz, KE and Williamson, DE and Hariri, AR}, Title = {FKBP5 and emotional neglect interact to predict individual differences in amygdala reactivity.}, Journal = {Genes, brain, and behavior}, Volume = {11}, Number = {7}, Pages = {869-878}, Address = {Laboratory of NeuroGenetics, Department of Psychology \& Neuroscience, Duke University, Durham, NC, USA.}, Year = {2012}, Month = {October}, ISSN = {1601-1848}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22979952}, Keywords = {Adolescent • Alleles • Amygdala/pathology/*physiopathology • *Child Abuse • Female • Gene-Environment Interaction • Haplotypes • Humans • Magnetic Resonance Imaging • Polymorphism, Single Nucleotide • Risk Factors • Stress, Psychological/pathology • Tacrolimus Binding Proteins/*genetics}, Abstract = {Individual variation in physiological responsiveness to stress mediates risk for mental illness and is influenced by both experiential and genetic factors. Common polymorphisms in the human gene for FK506 binding protein 5 (FKBP5), which is involved in transcriptional regulation of the hypothalamic-pituitary-adrenal (HPA) axis, have been shown to interact with childhood abuse and trauma to predict stress-related psychopathology. In the current study, we examined if such gene-environment interaction effects may be related to variability in the threat-related reactivity of the amygdala, which plays a critical role in mediating physiological and behavioral adaptations to stress including modulation of the HPA axis. To this end, 139 healthy Caucasian youth completed a blood oxygen level-dependent functional magnetic resonance imaging probe of amygdala reactivity and self-report assessments of emotional neglect (EN) and other forms of maltreatment. These individuals were genotyped for 6 FKBP5 polymorphisms (rs7748266, rs1360780, rs9296158, rs3800373, rs9470080 and rs9394309) previously associated with psychopathology and/or HPA axis function. Interactions between each SNP and EN emerged such that risk alleles predicted relatively increased dorsal amygdala reactivity in the context of higher EN, even after correcting for multiple testing. Two different haplotype analyses confirmed this relationship as haplotypes with risk alleles also exhibited increased amygdala reactivity in the context of higher EN. Our results suggest that increased threat-related amygdala reactivity may represent a mechanism linking psychopathology to interactions between common genetic variants affecting HPA axis function and childhood trauma.}, Language = {eng}, Doi = {10.1111/j.1601-183x.2012.00837.x}, Key = {White2012} } @article{Fisher2012, Author = {Fisher, PM and Hariri, AR}, Title = {Linking variability in brain chemistry and circuit function through multimodal human neuroimaging.}, Journal = {Genes, brain, and behavior}, Volume = {11}, Number = {6}, Pages = {633-642}, Address = {Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. patrick.fisher@gmail.com}, Year = {2012}, Month = {August}, ISSN = {1601-1848}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22443230}, Keywords = {Brain/physiology/radionuclide imaging • Brain Chemistry/genetics/*physiology • Brain Diseases/genetics/*physiopathology/*radionuclide imaging • Humans • Magnetic Resonance Imaging/methods • Neuroimaging/*methods • Positron-Emission Tomography/*methods}, Abstract = {Identifying neurobiological mechanisms mediating the emergence of individual differences in behavior is critical for advancing our understanding of relative risk for psychopathology. Neuroreceptor positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) can be used to assay in vivo regional brain chemistry and function, respectively. Typically, these neuroimaging modalities are implemented independently despite the capacity for integrated data sets to offer unique insight into molecular mechanisms associated with brain function. Through examples from the serotonin and dopamine system and its effects on threat- and reward-related brain function, we review evidence for how such a multimodal neuroimaging strategy can be successfully implemented. Furthermore, we discuss how multimodal PET-fMRI can be integrated with techniques such as imaging genetics, pharmacological challenge paradigms and gene-environment interaction models to more completely map biological pathways mediating individual differences in behavior and related risk for psychopathology and inform the development of novel therapeutic targets.}, Language = {eng}, Doi = {10.1111/j.1601-183x.2012.00786.x}, Key = {Fisher2012} } @article{Hariri2012, Author = {Hariri, AR}, Title = {The highs and lows of amygdala reactivity in bipolar disorders.}, Journal = {The American journal of psychiatry}, Volume = {169}, Number = {8}, Pages = {780-783}, Year = {2012}, Month = {August}, ISSN = {0002-953X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22854927}, Keywords = {Bipolar Disorder/*physiopathology • Brain/*physiopathology • Emotions/*physiology • Female • Humans • *Magnetic Resonance Imaging • Male}, Language = {eng}, Doi = {10.1176/appi.ajp.2012.12050639}, Key = {Hariri2012} } @article{Brown2012, Author = {Brown, AA and Jensen, J and Nikolova, YS and Djurovic, S and Agartz, I and Server, A and Ferrell, RE and Manuck, SB and Mattingsdal, M and Melle, I and Hariri, AR and Frigessi, A and Andreassen, OA}, Title = {Genetic variants affecting the neural processing of human facial expressions: evidence using a genome-wide functional imaging approach.}, Journal = {Translational psychiatry}, Volume = {2}, Pages = {e143}, Address = {Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. andrew.brown@medisin.uio.no}, Year = {2012}, Month = {July}, ISSN = {2158-3188}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22828495}, Keywords = {Adult • Brain Mapping • *Facial Expression • Female • Genetic Variation • Genome-Wide Association Study • Humans • Magnetic Resonance Imaging/methods • Male • Polymorphism, Single Nucleotide • Reproducibility of Results • Temporal Lobe/*physiopathology • Visual Perception/*genetics}, Abstract = {Human faces present crucial visual information for social interaction. Specialized brain regions are involved in the perception of faces, with the fusiform face area (FFA) a key neuronal substrate. Face processing is genetically controlled, but by which specific genes is unknown. A genome-wide approach identified common single nucleotide polymorphisms (SNPs) associated with areas of increased brain activity in response to affective facial expressions, measured with functional magnetic resonance imaging. SNPs in 20 genetic regions were linked with neural responses to negative facial expressions in a Norwegian sample (n=246), which included patients with mental illness. Three genetic regions were linked with FFA activation in a further discovery experiment using positive facial expressions and involving many of the same individuals (n=284). Two of these three regions showed significant association with right FFA activation to negative facial expressions in an independent North American replication sample of healthy Caucasians (n=85, 3q26.31, P=0.004; 20p12.3, P=0.045). The activation patterns were particularly striking for the SNP in 3q26.31, which lies in a gene TMEM212; only the FFA was activated. The specialized function of this brain region suggests that TMEM212 could contribute to the innate architecture of face processing.}, Language = {eng}, Doi = {10.1038/tp.2012.67}, Key = {Brown2012} } @article{Nikolova2012b, Author = {Nikolova, YS and Bogdan, R and Brigidi, BD and Hariri, AR}, Title = {Ventral striatum reactivity to reward and recent life stress interact to predict positive affect.}, Journal = {Biological psychiatry}, Volume = {72}, Number = {2}, Pages = {157-163}, Address = {Department of Psychology and Neuroscience and Institute for Genome Sciences and Policy, Duke University, Durham, NC 27705, USA. yuliya.nikolova@duke.edu}, Year = {2012}, Month = {July}, ISSN = {0006-3223}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22534456}, Keywords = {Adult • Affect/*physiology • Brain Mapping/methods/*psychology • Corpus Striatum/blood supply/*physiology • Depressive Disorder, Major/*physiopathology • Ethnic Groups/psychology • Female • Humans • Life Change Events • Magnetic Resonance Imaging/methods/psychology • Male • *Reward • Self Report • Stress, Psychological/*physiopathology}, Abstract = {<h4>Background</h4>Stressful life events are among the most reliable precipitants of major depressive disorder; yet, not everyone exposed to stress develops depression. It has been hypothesized that robust neural reactivity to reward and associated stable levels of positive affect (PA) may protect against major depressive disorder in the context of environmental adversity. However, little empirical data exist to confirm this postulation. Here, we test the hypothesis that individuals with relatively low ventral striatum (VS) reactivity to reward will show low PA levels in the context of recent life stress, while those with relatively high VS reactivity will be protected against these potentially depressogenic effects.<h4>Methods</h4>Differential VS reactivity to positive feedback was assessed using blood oxygen level-dependent functional magnetic resonance imaging in a sample of 200 nonpatient young adults. Recent life stress, current depressive symptoms, and PA were assessed via self-report. Linear regression models were used to investigate the moderating effects of VS reactivity on the relationship between recent stress and state PA across participants.<h4>Results</h4>Recent life stress interacted with VS reactivity to predict self-reported state PA, such that higher levels of life stress were associated with lower PA for participants with relatively low, but not for those with high, VS reactivity. These effects were independent of age, gender, race/ethnicity, trait PA, and early childhood trauma.<h4>Conclusions</h4>The current results provide empirical evidence for the potentially protective role of robust reward-related neural responsiveness against reductions in PA that may occur in the wake of life stress and possibly vulnerability to depression precipitated by stressful life events.}, Language = {eng}, Doi = {10.1016/j.biopsych.2012.03.014}, Key = {Nikolova2012b} } @article{Sweitzer2012, Author = {Sweitzer, MM and Donny, EC and Hariri, AR}, Title = {Imaging genetics and the neurobiological basis of individual differences in vulnerability to addiction.}, Journal = {Drug Alcohol Depend}, Volume = {123 Suppl 1}, Number = {SUPPL.1}, Pages = {S59-S71}, Address = {Department of Psychology, University of Pittsburgh, Pittsburgh, PA 15260, USA. mms74@pitt.edu}, Year = {2012}, Month = {June}, ISSN = {0376-8716}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22342427}, Keywords = {Adult • Basal Ganglia/drug effects • Behavior, Addictive/*genetics/physiopathology • Genetic Variation/*physiology • Humans • Impulsive Behavior/*genetics/psychology • Individuality • Male • Neural Pathways/*physiopathology • *Neuroimaging • Phenotype • Polymorphism, Genetic/physiology • Receptors, Dopamine D2/*genetics/physiology • Tobacco Use Disorder/*genetics/physiopathology}, Abstract = {BACKGROUND: Addictive disorders are heritable, but the search for candidate functional polymorphisms playing an etiological role in addiction is hindered by complexity of the phenotype and the variety of factors interacting to impact behavior. Advances in human genome sequencing and neuroimaging technology provide an unprecedented opportunity to explore the impact of functional genetic variants on variability in behaviorally relevant neural circuitry. Here, we present a model for merging these technologies to trace the links between genes, brain, and addictive behavior. METHODS: We describe imaging genetics and discuss the utility of its application to addiction. We then review data pertaining to impulsivity and reward circuitry as an example of how genetic variation may lead to variation in behavioral phenotype. Finally, we present preliminary data relating the neural basis of reward processing to individual differences in nicotine dependence. RESULTS: Complex human behaviors such as addiction can be traced to their basic genetic building blocks by identifying intermediate behavioral phenotypes, associated neural circuitry, and underlying molecular signaling pathways. Impulsivity has been linked with variation in reward-related activation in the ventral striatum (VS), altered dopamine signaling, and functional polymorphisms of DRD2 and DAT1 genes. In smokers, changes in reward-related VS activation induced by smoking abstinence may be associated with severity of nicotine dependence. CONCLUSIONS: Variation in genes related to dopamine signaling may contribute to heterogeneity in VS sensitivity to reward and, ultimately, to addiction. These findings illustrate the utility of the imaging genetics approach for investigating the neurobiological basis for vulnerability to addiction.}, Language = {eng}, Doi = {10.1016/j.drugalcdep.2012.01.017}, Key = {Sweitzer2012} } @article{Ousdal2012, Author = {Ousdal, OT and Anand Brown and A and Jensen, J and Nakstad, PH and Melle, I and Agartz, I and Djurovic, S and Bogdan, R and Hariri, AR and Andreassen, OA}, Title = {Associations between variants near a monoaminergic pathways gene (PHOX2B) and amygdala reactivity: a genome-wide functional imaging study.}, Journal = {Twin research and human genetics : the official journal of the International Society for Twin Studies}, Volume = {15}, Number = {3}, Pages = {273-285}, Address = {Oslo University Hospital, Oslo, Norway. o.t.ousdal@medisin.uio.no}, Year = {2012}, Month = {June}, ISSN = {1832-4274}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22856363}, Keywords = {Adult • Amygdala/*physiology • Bipolar Disorder/genetics/physiopathology • Catecholamines/biosynthesis • Female • *Genome-Wide Association Study • Genotype • Homeodomain Proteins/*genetics/metabolism • Humans • Linkage Disequilibrium • *Magnetic Resonance Imaging • Male • *Polymorphism, Single Nucleotide • Schizophrenia/genetics/physiopathology • Serotonin/biosynthesis • Signal Transduction/*genetics • Transcription Factors/*genetics/metabolism}, Abstract = {As the amygdala is part of the phylogenetic old brain, and its anatomical and functional properties are conserved across species, it is reasonable to assume genetic influence on its activity. A large corpus of candidate gene studies indicate that individual differences in amygdala activity may be caused by genetic variants within monoaminergic signaling pathways such as dopamine, serotonin, and norepinephrine. However, to our knowledge, the use of genome-wide data to discover genetic variants underlying individual differences in adult amygdala activity is novel. In the present study, the combination of genome-wide data and functional imaging phenotypes from an emotional faces task yielded a significant association between rs10014254 and the amygdala using a region of interest approach. This single nucleotide polymorphism is located in a regulatory region upstream of the Paired-like homeobox 2b (PHOX2B) gene; therefore it could affect the expression of this gene. PHOX2B regulates the expression of enzymes necessary for the synthesis of several monoamines and is essential for the development of the autonomic nervous system. However, an attempt to replicate the finding in an independent sample from North America did not succeed. The synthesis of functional magnetic resonance imaging (fMRI) and genome-wide data takes a hypothesis-free approach as to which genetic variants are of interest. Therefore, we believe that an undirected finding within such a plausible region is of interest, and that our results add further support to the hypothesis that monoaminergic signaling pathways play a central role in regulating amygdala activity.}, Language = {eng}, Doi = {10.1017/thg.2012.5}, Key = {Ousdal2012} } @article{Josephs2012, Author = {Josephs, RA and Telch, MJ and Hixon, JG and Evans, JJ and Lee, H and Knopik, VS and McGeary, JE and Hariri, AR and Beevers, CG}, Title = {Genetic and hormonal sensitivity to threat: testing a serotonin transporter genotype × testosterone interaction.}, Journal = {Psychoneuroendocrinology}, Volume = {37}, Number = {6}, Pages = {752-761}, Address = {Department of Psychology, The University of Texas at Austin, Austin, TX 78756, USA. josephs@mail.psy.utexas.edu}, Year = {2012}, Month = {June}, ISSN = {0306-4530}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21978869}, Keywords = {Carbon Dioxide/diagnostic use • DNA/genetics • Depression/genetics/psychology • Ethnic Groups • Female • Genotype • Heterozygote • Humans • Hydrocortisone/blood • Male • Military Personnel • Psychiatric Status Rating Scales • Psychomotor Performance/physiology • Questionnaires • Saliva/chemistry • Serotonin Plasma Membrane Transport Proteins/*genetics/*metabolism • Social Environment • Stress, Psychological/*genetics/*metabolism • Testosterone/*blood • Young Adult}, Abstract = {<h4>Background</h4>Striking parallels are observed when comparing the literature on the 5-HTTLPR of the serotonin transporter gene (SLC6A4) to the testosterone (T) literature on measures of stress reactivity and neural activity. Short (S) allele carriers and individuals higher in testosterone levels show exaggerated stress responses, amygdala hyperactivity, and reduction of amygdala-prefrontal cortex coupling when exposed to threat.<h4>Methods</h4>Three studies tested the hypothesis that higher T, S carriers would show increased cortisol responses to threat.<h4>Results</h4>Supporting the hypothesis, a T × 5-HTTLPR interaction was obtained across all studies. Threats to status via social exclusion (Study 1), cognitive/perceptual failure (Study 2), and physical competence (Study 3) all produced elevated cortisol levels in S carriers with higher T levels. An unexpected result was that 5-HTTLPR long (L) allele homozygotes with higher T showed lower cortisol levels in response to threat-a pattern of response that closely parallels that reported for psychopathic individuals. Finally, combining effect sizes across studies showed that the likelihood that these effects were due to Type 1 errors was quite low.<h4>Conclusions</h4>What emerges from these studies is a novel yet reliable, and synergistic relationship between 5-HTTLPR genotype and testosterone on stress reactivity, possibly conferring vulnerability for multiple neuropsychiatric disorders.}, Language = {eng}, Doi = {10.1016/j.psyneuen.2011.09.006}, Key = {Josephs2012} } @article{Bogdan2012a, Author = {Bogdan, R and Williamson, DE and Hariri, AR}, Title = {Mineralocorticoid receptor Iso/Val (rs5522) genotype moderates the association between previous childhood emotional neglect and amygdala reactivity.}, Journal = {The American journal of psychiatry}, Volume = {169}, Number = {5}, Pages = {515-522}, Address = {Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, and Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA. bogdan.ryan@gmail.com}, Year = {2012}, Month = {May}, ISSN = {0002-953X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22407082}, Keywords = {Adolescent • Alleles • Amygdala/*physiopathology • Child • *Child Abuse/psychology • Female • Functional Neuroimaging • Genotype • Homozygote • Humans • Magnetic Resonance Imaging • Male • Mutation, Missense/*genetics/physiology • Receptors, Mineralocorticoid/*genetics/physiology}, Abstract = {<h4>Objective</h4>The amygdala is especially reactive to threatening stimuli, and the degree of reactivity predicts individual differences in the expression of depression and anxiety. Emerging research suggests that emotional neglect during childhood as well as hypercortisolemia may lead to heightened threat-related amygdala reactivity. This raises the possibility that genetic variation affecting hypothalamic-pituitary-adrenal (HPA) axis function contributes to individual differences in amygdala reactivity, both independently and as a function of childhood emotional neglect.<h4>Method</h4>This study assessed whether the mineralocorticoid receptor iso/val polymorphism (rs5522), a functional genetic variant affecting HPA axis function, influenced threat-related amygdala reactivity in 279 individuals in late childhood and early adolescence. The study also explored the extent to which any effects of the genotype on amygdala reactivity were contingent upon previous childhood emotional neglect.<h4>Results</h4>Prior childhood emotional neglect and the val allele were associated with greater amygdala reactivity. Moreover, a significant genotype-by-emotional neglect interaction was observed whereby greater amygdala reactivity in val allele carriers was independent of previous childhood emotional neglect, while greater reactivity in iso homozygotes was revealed only in the context of a history of elevated emotional neglect. At relatively low levels of previous emotional neglect, val carriers had heightened amygdala reactivity relative to iso homozygotes.<h4>Conclusions</h4>These results suggest that relatively greater amygdala reactivity may represent a biological mechanism through which childhood adversity and functional genetic variation in HPA axis responsiveness to stress may mediate risk for psychopathology.}, Language = {eng}, Doi = {10.1176/appi.ajp.2011.11060855}, Key = {Bogdan2012a} } @article{Lahey2012a, Author = {Lahey, BB and McNealy, K and Knodt, A and Zald, DH and Sporns, O and Manuck, SB and Flory, JD and Applegate, B and Rathouz, PJ and Hariri, AR}, Title = {Using confirmatory factor analysis to measure contemporaneous activation of defined neuronal networks in functional magnetic resonance imaging.}, Journal = {NeuroImage}, Volume = {60}, Number = {4}, Pages = {1982-1991}, Address = {Department of Health Studies, University of Chicago, Chicago, IL 60637, United States. blahey@health.bsd.uchicago.edu}, Year = {2012}, Month = {May}, ISSN = {1053-8119}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22348884}, Keywords = {Adolescent • Adult • Brain/physiology • Brain Mapping/*methods • *Factor Analysis, Statistical • Female • Humans • Image Interpretation, Computer-Assisted/*methods • *Magnetic Resonance Imaging • Male • *Models, Theoretical • Young Adult}, Abstract = {Functional neuroimaging often generates large amounts of data on regions of interest. Such data can be addressed effectively with a widely-used statistical technique based on measurement theory that has not yet been applied to neuroimaging. Confirmatory factor analysis is a convenient hypothesis-driven modeling environment that can be used to conduct formal statistical tests comparing alternative hypotheses regarding the elements of putative neuronal networks. In such models, measures of each activated region of interest are treated as indicators of an underlying latent construct that represents the contemporaneous activation of the elements in the network. As such, confirmatory factor analysis focuses analyses on the activation of hypothesized networks as a whole, improves statistical power by modeling measurement error, and provides a theory-based approach to data reduction with a robust statistical basis. This approach is illustrated using data on seven regions of interest in a hypothesized mesocorticostriatal reward system in a sample of 262 adult volunteers assessed during a card-guessing reward task. A latent construct reflecting contemporaneous activation of the reward system was found to be significantly associated with a latent construct measuring impulsivity, particularly in males.}, Language = {eng}, Doi = {10.1016/j.neuroimage.2012.02.002}, Key = {Lahey2012a} } @article{Terburg2012, Author = {Terburg, D and Morgan, BE and Montoya, ER and Hooge, IT and Thornton, HB and Hariri, AR and Panksepp, J and Stein, DJ and van Honk, J}, Title = {Hypervigilance for fear after basolateral amygdala damage in humans.}, Journal = {Translational psychiatry}, Volume = {2}, Pages = {e115}, Address = {Department of Psychology, Utrecht University, Utrecht, The Netherlands. d.terburg@uu.nl}, Year = {2012}, Month = {May}, ISSN = {2158-3188}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22832959}, Keywords = {Adult • Amygdala/*physiopathology • Anxiety/genetics/pathology/*physiopathology • Attention • Brain Damage, Chronic/genetics/pathology/*physiopathology • Brain Mapping • Calcinosis/genetics/pathology/physiopathology • Discrimination (Psychology)/physiology • Dominance, Cerebral/physiology • Emotions/physiology • Facial Expression • Fear/*physiology • Female • Humans • Image Interpretation, Computer-Assisted • Lipoid Proteinosis of Urbach and Wiethe/genetics/pathology/*physiopathology • Magnetic Resonance Imaging • Male • Middle Aged • Nerve Growth Factors • Neural Inhibition/*physiology • Pattern Recognition, Visual/physiology • Recognition (Psychology)/physiology • Reference Values • Stroop Test • Subliminal Stimulation}, Abstract = {Recent rodent research has shown that the basolateral amygdala (BLA) inhibits unconditioned, or innate, fear. It is, however, unknown whether the BLA acts in similar ways in humans. In a group of five subjects with a rare genetic syndrome, that is, Urbach-Wiethe disease (UWD), we used a combination of structural and functional neuroimaging, and established focal, bilateral BLA damage, while other amygdala sub-regions are functionally intact. We tested the translational hypothesis that these BLA-damaged UWD-subjects are hypervigilant to facial expressions of fear, which are prototypical innate threat cues in humans. Our data indeed repeatedly confirm fear hypervigilance in these UWD subjects. They show hypervigilant responses to unconsciously presented fearful faces in a modified Stroop task. They attend longer to the eyes of dynamically displayed fearful faces in an eye-tracked emotion recognition task, and in that task recognize facial fear significantly better than control subjects. These findings provide the first direct evidence in humans in support of an inhibitory function of the BLA on the brain's threat vigilance system, which has important implications for the understanding of the amygdala's role in the disorders of fear and anxiety.}, Language = {eng}, Doi = {10.1038/tp.2012.46}, Key = {Terburg2012} } @article{Joeyen-Waldorf2012, Author = {Joeyen-Waldorf, J and Nikolova, YS and Edgar, N and Walsh, C and Kota, R and Lewis, DA and Ferrell, R and Manuck, SB and Hariri, AR and Sibille, E}, Title = {Adenylate cyclase 7 is implicated in the biology of depression and modulation of affective neural circuitry.}, Journal = {Biological psychiatry}, Volume = {71}, Number = {7}, Pages = {627-632}, Address = {Department of Psychiatry, University of Pittsburgh, Pennsylvania 15219, USA.}, Year = {2012}, Month = {April}, ISSN = {0006-3223}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22264442}, Keywords = {Adenylate Cyclase/genetics/metabolism/*physiology • Adult • Amygdala/metabolism/*physiopathology • Animals • Depressive Disorder/genetics/metabolism/*physiopathology • Disease Models, Animal • Emotions/*physiology • Female • Functional Neuroimaging/methods/*psychology • Gene Expression/genetics/physiology • Genetic Predisposition to Disease • Genotype • Gyrus Cinguli/physiopathology • Humans • Magnetic Resonance Imaging/methods/psychology • Male • Mice • Mice, Inbred C57BL • Mice, Knockout • Polymorphism, Single Nucleotide • Serotonin Plasma Membrane Transport Proteins/genetics}, Abstract = {<h4>Background</h4>Evolutionarily conserved genes and their associated molecular pathways can serve as a translational bridge between human and mouse research, extending our understanding of biological pathways mediating individual differences in behavior and risk for psychopathology.<h4>Methods</h4>Comparative gene array analysis in the amygdala and cingulate cortex between the serotonin transporter knockout mouse, a genetic animal model replicating features of human depression, and existing brain transcriptome data from postmortem tissue derived from clinically depressed humans was conducted to identify genes with similar changes across species (i.e., conserved) that may help explain risk of depressive-like phenotypes. Human neuroimaging analysis was then used to investigate the impact of a common single-nucleotide polymorphism (rs1064448) in a gene with identified conserved human-mouse changes, adenylate cyclase 7 (ADCY7), on threat-associated amygdala reactivity in two large independent samples.<h4>Results</h4>Comparative analysis identified genes with conserved transcript changes in amygdala (n = 29) and cingulate cortex (n = 19), both critically involved in the generation and regulation of emotion. Selected results were confirmed by real-time quantitative polymerase chain reaction, including upregulation in the amygdala of transcripts for ADCY7, a gene previously implicated in human depression and associated with altered emotional responsiveness in mouse models. Translating these results back to living healthy human subjects, we show that genetic variation (rs1064448) in ADCY7 biases threat-related amygdala reactivity.<h4>Conclusions</h4>This converging cross-species evidence implicates ADCY7 in the modulation of mood regulatory neural mechanisms and, possibly, risk for and pathophysiology of depression, together supporting a continuous dimensional approach to major depressive disorder and other affective disorders.}, Language = {eng}, Doi = {10.1016/j.biopsych.2011.11.029}, Key = {Joeyen-Waldorf2012} } @article{Drabant2012, Author = {Drabant, EM and Ramel, W and Edge, MD and Hyde, LW and Kuo, JR and Goldin, PR and Hariri, AR and Gross, JJ}, Title = {Neural mechanisms underlying 5-HTTLPR-related sensitivity to acute stress.}, Journal = {The American journal of psychiatry}, Volume = {169}, Number = {4}, Pages = {397-405}, Address = {Department of Psychology, Stanford University, Stanford, California, USA.}, Year = {2012}, Month = {April}, ISSN = {0002-953X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22362395}, Keywords = {Adult • Alleles • Brain/*physiopathology • Female • Functional Neuroimaging/methods/*psychology • Genotype • Humans • Magnetic Resonance Imaging/methods/*psychology • Neural Pathways/physiopathology • Polymorphism, Single Nucleotide • Serotonin Plasma Membrane Transport Proteins/genetics/*physiology • Stress, Psychological/genetics/*physiopathology}, Abstract = {<h4>Objective</h4>Many studies have shown that 5-HTTLPR genotype interacts with exposure to stress in conferring risk for psychopathology. However, the specific neural mechanisms through which this gene-by-environment interaction confers risk remain largely unknown, and no study to date has directly examined the modulatory effects of 5-HTTLPR on corticolimbic circuit responses during exposure to acute stress.<h4>Method</h4>An acute laboratory stressor was administered to 51 healthy women during blood-oxygen-level-dependent functional magnetic resonance imaging. In this task, participants were threatened with electric shocks of uncertain intensity, which were unpredictably delivered to the wrist after a long anticipatory cue period of unpredictable duration.<h4>Results</h4>Relative to women carrying the L allele, those with the SS genotype showed enhanced activation during threat anticipation in a network of regions, including the amygdala, hippocampus, anterior insula, thalamus, pulvinar, caudate, precuneus, anterior cingulate cortex, and medial prefrontal cortex. Individuals with the SS genotype also displayed enhanced positive coupling between medial prefrontal cortex activation and anxiety experience, whereas enhanced negative coupling between insula activation and perceived success at regulating anxiety was observed in individuals carrying the L allele.<h4>Conclusions</h4>These findings suggest that during stress exposure, neural systems that enhance fear and arousal, modulate attention toward threat, and perseverate on emotional salience of the threat may be engaged preferentially in individuals with the SS genotype. This may be one mechanism underlying the risk for psychopathology conferred by the S allele upon exposure to life stressors.}, Language = {eng}, Doi = {10.1176/appi.ajp.2011.10111699}, Key = {Drabant2012} } @article{Carre2012, Author = {Carré, JM and Fisher, PM and Manuck, SB and Hariri, AR}, Title = {Interaction between trait anxiety and trait anger predict amygdala reactivity to angry facial expressions in men but not women.}, Journal = {Social cognitive and affective neuroscience}, Volume = {7}, Number = {2}, Pages = {213-221}, Address = {Department of Psychology and Neuroscience, Duke University, Durham, NC 27708, USA. justin.carre@duke.edu}, Year = {2012}, Month = {February}, ISSN = {1749-5016}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21183456}, Keywords = {Adult • Amygdala/*physiology • Anger/*physiology • Anxiety/*psychology • Brain/physiology • Emotions/physiology • *Facial Expression • Female • Humans • Individuality • Male • Middle Aged • Neuroimaging}, Abstract = {The amygdala is critically involved in mediating physiological and behavioral responses to threat. In particular, neuroimaging research indicates that the amygdala is highly responsive to facial signals of threat such as fearful and angry expressions. However, individuals differ substantially in both their relative sensitivity to threat and the magnitude of amygdala reactivity to facial signals of threat. Here, we report the novel finding that individual differences in trait anger are positively correlated with bilateral dorsal amygdala reactivity to angry facial expressions, but only among men with elevated trait anxiety scores. These findings add to the growing body of evidence indicating that variability in personality traits contribute to individual differences in threat-related amygdala reactivity and further suggest that heightened amygdala reactivity to angry faces may be uniquely involved in the expression of reactive aggression in men.}, Language = {eng}, Doi = {10.1093/scan/nsq101}, Key = {Carre2012} } @article{Davis2013, Author = {Davis, FC and Knodt, AR and Sporns, O and Lahey, BB and Zald, DH and Brigidi, BD and Hariri, AR}, Title = {Impulsivity and the Modular Organization of Resting-State Neural Networks}, Journal = {Cerebral cortex}, Volume = {23}, Number = {6}, Pages = {1444-1452}, Address = {Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, NC 27708, USA. caroline.davis@duke.edu}, Year = {2012}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22645253}, Keywords = {Adolescent • *Brain Mapping • Female • Head Movements • Humans • Image Processing, Computer-Assisted • Impulsive Behavior/classification/*pathology • Magnetic Resonance Imaging • Male • Models, Neurological • Neural Pathways/blood supply/*pathology • Oxygen • Rest/*physiology • Self Report • Young Adult}, Abstract = {Impulsivity is a complex trait associated with a range of maladaptive behaviors, including many forms of psychopathology. Previous research has implicated multiple neural circuits and neurotransmitter systems in impulsive behavior, but the relationship between impulsivity and organization of whole-brain networks has not yet been explored. Using graph theory analyses, we characterized the relationship between impulsivity and the functional segregation (``modularity'') of the whole-brain network architecture derived from resting-state functional magnetic resonance imaging (fMRI) data. These analyses revealed remarkable differences in network organization across the impulsivity spectrum. Specifically, in highly impulsive individuals, regulatory structures including medial and lateral regions of the prefrontal cortex were isolated from subcortical structures associated with appetitive drive, whereas these brain areas clustered together within the same module in less impulsive individuals. Further exploration of the modular organization of whole-brain networks revealed novel shifts in the functional connectivity between visual, sensorimotor, cortical, and subcortical structures across the impulsivity spectrum. The current findings highlight the utility of graph theory analyses of resting-state fMRI data in furthering our understanding of the neurobiological architecture of complex behaviors.}, Language = {eng}, Doi = {10.1093/cercor/bhs126}, Key = {Davis2013} } @article{Bogdan2012c, Author = {Bogdan, R and Carre, JM and Hariri, AR}, Title = {Toward a mechanistic understanding of how variability in neurobiology shapes individual differences in behavior}, Journal = {Current topics in behavioral neurosciences}, Volume = {12}, Pages = {361-393}, Address = {Laboratory of NeuroGenetics, Department of Psychology \& Neuroscience, Institute for Genome Sciences \& Policy, Duke University, 417 Chapel Drive, Durham, NC, 27708, USA, bogdan.ryan@gmail.com.}, Year = {2012}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22437943}, Abstract = {Research has begun to identify how variability in brain function contributes to individual differences in complex behavioral traits. Examining variability in molecular signaling pathways with emerging and established methodologies such as pharmacologic fMRI, multimodal PET/fMRI, and hormonal assays are beginning to provide a mechanistic understanding of how individual differences in brain function arise. Against this background, functional genetic polymorphisms are being utilized to understand the origins of variability in signaling pathways as well as to efficiently model how such emergent variability impacts behaviorally relevant brain function and health outcomes. This chapter provides an overview of a research strategy that integrates these complimentary levels of analysis; existing empirical data is used to illustrate the effectiveness of this approach in illuminating the mechanistic neurobiology of individual differences in complex behavioral traits. This chapter also discusses how such efforts can contribute to the identification of predictive risk markers that interact with unique environmental factors to precipitate psychopathology.}, Language = {eng}, Doi = {10.1007/7854_2011_182}, Key = {Bogdan2012c} } @article{Minkel2012, Author = {Minkel, JD and McNealy, K and Gianaros, PJ and Drabant, EM and Gross, JJ and Manuck, SB and Hariri, AR}, Title = {Sleep quality and neural circuit function supporting emotion regulation}, Journal = {Biology of mood \& anxiety disorders}, Volume = {2}, Number = {1}, Pages = {22}, Publisher = {Springer Science and Business Media LLC}, Address = {Laboratory of NeuroGenetics, Department of Psychology \& Neuroscience, Duke University, 417 Chapel Dr,, Durham, NC 27708, USA. jared.minkel@duke.edu.}, Year = {2012}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23216889}, Abstract = {ABSTRACT: BACKGROUND: Recent laboratory studies employing an extended sleep deprivation model have mapped sleep-related changes in behavior onto functional alterations in specific brain regions supporting emotion, suggesting possible biological mechanisms for an association between sleep difficulties and deficits in emotion regulation. However, it is not yet known if similar behavioral and neural changes are associated with the more modest variability in sleep observed in daily life. METHODS: We examined relationships between sleep and neural circuitry of emotion using the Pittsburgh Sleep Quality Index and fMRI data from a widely used emotion regulation task focusing on cognitive reappraisal of negative emotional stimuli in an unselected sample of 97 adult volunteers (48 women; mean age 42.78+/-7.37years, range 30--54years old). RESULTS: Emotion regulation was associated with greater activation in clusters located in the dorsomedial prefrontal cortex (dmPFC), left dorsolateral prefrontal cortex (dlPFC), and inferior parietal cortex. Only one subscale from the Pittsburgh Sleep Quality Index, use of sleep medications, was related to BOLD responses in the dmPFC and dlPFC during cognitive reappraisal. Use of sleep medications predicted lesser BOLD responses during reappraisal, but other aspects of sleep, including sleep duration and subjective sleep quality, were not related to neural activation in this paradigm. CONCLUSIONS: The relatively modest variability in sleep that is common in the general community is unlikely to cause significant disruption in neural circuits supporting reactivity or regulation by cognitive reappraisal of negative emotion. Use of sleep medication however, may influence emotion regulation circuitry, but additional studies are necessary to determine if such use plays a causal role in altering emotional responses.}, Language = {eng}, Doi = {10.1186/2045-5380-2-22}, Key = {Minkel2012} } @article{Carre2013b, Author = {Carre, JM and Hyde, LW and Neumann, CS and Viding, E and Hariri, AR}, Title = {The neural signatures of distinct psychopathic traits}, Journal = {Social neuroscience}, Volume = {8}, Number = {2}, Pages = {122-135}, Address = {Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, NC, USA. justin.carre@wayne.edu}, Year = {2012}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22775289}, Keywords = {Amygdala/pathology • Antisocial Personality Disorder/pathology/psychology • Data Interpretation, Statistical • Female • Humans • Image Processing, Computer-Assisted • Impulsive Behavior/pathology/psychology • Magnetic Resonance Imaging • Male • Neostriatum/pathology • Nervous System/*pathology • Neuropsychological Tests • Oxygen/blood • Reward • Sex Characteristics • Young Adult}, Abstract = {Recent studies suggest that psychopathy may be associated with dysfunction in the neural circuitry supporting both threat- and reward-related processes. However, these studies have involved small samples and often focused on extreme groups. Thus, it is unclear to what extent current findings may generalize to psychopathic traits in the general population. Furthermore, no studies have systematically and simultaneously assessed associations between distinct psychopathy facets and both threat- and reward-related brain function in the same sample of participants. Here, we examined the relationship between threat-related amygdala reactivity and reward-related ventral striatum (VS) reactivity and variation in four facets of self-reported psychopathy in a sample of 200 young adults. Path models indicated that amygdala reactivity to fearful facial expressions is negatively associated with the interpersonal facet of psychopathy, whereas amygdala reactivity to angry facial expressions is positively associated with the lifestyle facet. Furthermore, these models revealed that differential VS reactivity to positive versus negative feedback is negatively associated with the lifestyle facet. There was suggestive evidence for gender-specific patterns of association between brain function and psychopathy facets. Our findings are the first to document differential associations between both threat- and reward-related neural processes and distinct facets of psychopathy and thus provide a more comprehensive picture of the pattern of neural vulnerabilities that may predispose to maladaptive outcomes associated with psychopathy.}, Language = {eng}, Doi = {10.1080/17470919.2012.703623}, Key = {Carre2013b} } @article{Nikolova2012a, Author = {Nikolova, YS and Hariri, AR}, Title = {Neural responses to threat and reward interact to predict stress-related problem drinking: A novel protective role of the amygdala}, Journal = {Biology of mood \& anxiety disorders}, Volume = {2}, Number = {1}, Pages = {19}, Publisher = {Springer Science and Business Media LLC}, Address = {Laboratory of NeuroGenetics, Department of Psychology \& Neuroscience and Institute for Genome Sciences \& Policy, Duke University, NC 27708, Durham, USA. yuliya.nikolova@duke.edu.}, Year = {2012}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23151390}, Abstract = {ABSTRACT: BACKGROUND: Research into neural mechanisms of drug abuse risk has focused on the role of dysfunction in neural circuits for reward. In contrast, few studies have examined the role of dysfunction in neural circuits of threat in mediating drug abuse risk. Although typically regarded as a risk factor for mood and anxiety disorders, threat-related amygdala reactivity may serve as a protective factor against substance use disorders, particularly in individuals with exaggerated responsiveness to reward. FINDINGS: We used well-established neuroimaging paradigms to probe threat-related amygdala and reward-related ventral striatum reactivity in a sample of 200 young adult students from the ongoing Duke Neurogenetics Study. Recent life stress and problem drinking were assessed using self-report. We found a significant three-way interaction between threat-related amygdala reactivity, reward-related ventral striatum reactivity, and recent stress, wherein individuals with higher reward-related ventral striatum reactivity exhibit higher levels of problem drinking in the context of stress, but only if they also have lower threat-related amygdala reactivity. This three-way interaction predicted both contemporaneous problem drinking and problem drinking reported three-months later in a subset of participants. CONCLUSIONS: These findings suggest complex interactions between stress and neural responsiveness to both threat and reward mediate problem drinking. Furthermore, they highlight a novel protective role for threat-related amygdala reactivity against drug use in individuals with high neural reactivity to reward.}, Language = {eng}, Doi = {10.1186/2045-5380-2-19}, Key = {Nikolova2012a} } @article{Gunduz-Cinar2013, Author = {Gunduz Cinar and O and Macpherson, KP and Cinar, R and Gamble George and J and Sugden, K and Williams, B and Godlewski, G and Ramikie, TS and Gorka, AX and Alapafuja, SO and Nikas, SP and Makriyannis, A and Poulton, R and Patel, S and Hariri, AR and Caspi, A and Moffitt, TE and Kunos, G and Holmes, A}, Title = {Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity}, Journal = {Molecular psychiatry}, Volume = {18}, Number = {7}, Pages = {813-823}, Address = {Laboratory of Behavioral and Genomic Neuroscience, Section on Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, Bethesda, MD, USA.}, Year = {2012}, ISSN = {1359-4184}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22688188}, Abstract = {Endocannabinoids are released 'on-demand' on the basis of physiological need, and can be pharmacologically augmented by inhibiting their catabolic degradation. The endocannabinoid anandamide is degraded by the catabolic enzyme fatty acid amide hydrolase (FAAH). Anandamide is implicated in the mediation of fear behaviors, including fear extinction, suggesting that selectively elevating brain anandamide could modulate plastic changes in fear. Here we first tested this hypothesis with preclinical experiments employing a novel, potent and selective FAAH inhibitor, AM3506 (5-(4-hydroxyphenyl)pentanesulfonyl fluoride). Systemic AM3506 administration before extinction decreased fear during a retrieval test in a mouse model of impaired extinction. AM3506 had no effects on fear in the absence of extinction training, or on various non-fear-related measures. Anandamide levels in the basolateral amygdala were increased by extinction training and augmented by systemic AM3506, whereas application of AM3506 to amygdala slices promoted long-term depression of inhibitory transmission, a form of synaptic plasticity linked to extinction. Further supporting the amygdala as effect-locus, the fear-reducing effects of systemic AM3506 were blocked by intra-amygdala infusion of a CB1 receptor antagonist and were fully recapitulated by intra-amygdala infusion of AM3506. On the basis of these preclinical findings, we hypothesized that variation in the human FAAH gene would predict individual differences in amygdala threat-processing and stress-coping traits. Consistent with this, carriers of a low-expressing FAAH variant (385A allele; rs324420) exhibited quicker habituation of amygdala reactivity to threat, and had lower scores on the personality trait of stress-reactivity. Our findings show that augmenting amygdala anandamide enables extinction-driven reductions in fear in mouse and may promote stress-coping in humans.Molecular Psychiatry advance online publication, 12 June 2012; doi:10.1038/mp.2012.72.}, Language = {eng}, Doi = {10.1038/mp.2012.72}, Key = {Gunduz-Cinar2013} } @article{Lahey2012b, Author = {Lahey, BB and Applegate, B and Hakes, JK and Zald, DH and Hariri, AR and Rathouz, PJ}, Title = {Is there a general factor of prevalent psychopathology during adulthood?}, Journal = {Journal of abnormal psychology}, Volume = {121}, Number = {4}, Pages = {971-977}, Address = {Department of Health Studies (MC 2007), University of Chicago, Chicago, IL 60637, USA. blahey@uchicago.edu}, Year = {2012}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22845652}, Keywords = {Adolescent • Adult • Comorbidity • Diagnostic and Statistical Manual of Mental Disorders • Factor Analysis, Statistical • Female • Humans • Interview, Psychological • Male • Mental Disorders/diagnosis/*epidemiology • Middle Aged • *Models, Psychological • Prevalence}, Abstract = {The patterns of comorbidity among prevalent mental disorders in adults lead them to load on ``externalizing,'' ``distress,'' and ``fears'' factors. These factors are themselves robustly correlated, but little attention has been paid to this fact. As a first step in studying the implications of these interfactor correlations, we conducted confirmatory factor analyses on diagnoses of 11 prevalent Diagnostic and Statistical Manual of Mental Disorders (4th ed.) mental disorders in a nationally representative sample. A model specifying correlated externalizing, distress, and fears factors fit well, but an alternative model was tested in which a ``general'' bifactor was added to capture what these disorders share in common. There was a modest but significant improvement in fit for the bifactor model relative to the 3-factor oblique model, with all disorders loading strongly on the bifactor. Tests of external validity revealed that the fears, distress, and externalizing factors were differentially associated with measures of functioning and potential risk factors. Nonetheless, the general bifactor accounted for significant independent variance in future psychopathology, functioning, and other criteria over and above the fears, distress, and externalizing factors. These findings support the hypothesis that these prevalent forms of psychopathology have both important common and unique features. Future studies should determine whether this is because they share elements of their etiology and neurobiological mechanisms. If so, the existence of common features across diverse forms of prevalent psychopathology could have important implications for understanding the nature, etiology, and outcomes of psychopathology. (PsycINFO Database Record (c) 2012 APA, all rights reserved).}, Language = {eng}, Doi = {10.1037/a0028355}, Key = {Lahey2012b} } @article{Hyde2011b, Author = {Hyde, LW and Bogdan, R and Hariri, AR}, Title = {Understanding risk for psychopathology through imaging gene-environment interactions.}, Journal = {Trends in cognitive sciences}, Volume = {15}, Number = {9}, Pages = {417-427}, Address = {Department of Psychology and Center for the Neural Basis of Cognition, University of Pittsburgh, 210 South Bouquet St, Pittsburgh, PA 15260, USA. LWH2@pitt.edu}, Year = {2011}, Month = {September}, ISSN = {1364-6613}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21839667}, Keywords = {Brain/*pathology/physiopathology • Epigenomics • *Gene-Environment Interaction • *Genetic Predisposition to Disease • Humans • Models, Biological • Neuroimaging • *Psychopathology}, Abstract = {Examining the interplay of genes, experience and the brain is crucial to understanding psychopathology. We review the recent gene-environment interaction (G×E) and imaging genetics literature with the goal of developing models to bridge these approaches within single imaging gene-environment interaction (IG×E) studies. We explore challenges inherent in both G×E and imaging genetics and highlight studies that address these limitations. In specifying IG×E models, we examine statistical methods for combining these approaches, and explore plausible biological mechanisms (e.g. epigenetics) through which these conditional mechanisms can be understood. Finally, we discuss the potential contribution that IG×E studies can make to understanding psychopathology and developing more personalized and effective prevention and treatment.}, Language = {eng}, Doi = {10.1016/j.tics.2011.07.001}, Key = {Hyde2011b} } @article{Nikolova2011, Author = {Nikolova, YS and Ferrell, RE and Manuck, SB and Hariri, AR}, Title = {Multilocus genetic profile for dopamine signaling predicts ventral striatum reactivity.}, Journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, Volume = {36}, Number = {9}, Pages = {1940-1947}, Address = {Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.}, Year = {2011}, Month = {August}, ISSN = {0893-133X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21593733}, Keywords = {Adult • Basal Ganglia/*metabolism/physiopathology • Cohort Studies • Dopamine/genetics/*physiology • Dopamine Plasma Membrane Transport Proteins/genetics • Female • Gene Expression Profiling/*methods • Genetic Loci/*genetics • Genetic Predisposition to Disease/genetics • Humans • Male • Middle Aged • Mood Disorders/diagnosis/*genetics/physiopathology • Polymorphism, Genetic/genetics • Predictive Value of Tests • Receptors, Dopamine D2/genetics • Receptors, Dopamine D4/genetics • Signal Transduction/*genetics}, Abstract = {Research integrating neuroimaging and molecular genetics has yielded important insights into how variability in brain chemistry predicts individual differences in brain function, behavior and related risk for psychopathology. However, existing studies have been limited by their focus on the independent effects of single polymorphisms with modest impact on brain chemistry. Here, we explored the effects of five functional polymorphisms affecting dopamine (DA) signaling on reward-related ventral striatum (VS) reactivity, measured with BOLD fMRI, in a sample of 69 Caucasians. We also compiled individual multilocus genetic profile scores reflecting the additive effects of alleles conferring relatively increased DA signaling across the five polymorphic loci: DAT1 9-repeat, DRD4 7-repeat, DRD2 -141C Del, DRD2 Taq1A C (A2), and COMT (158)Met. These multilocus DA profile scores accounted for 10.9% of the inter-individual variability in reward-related VS reactivity. In contrast, none of the individual polymorphisms accounted for significant variability. Our results show that biologically informed multilocus genetic profiles have unique promise as indices of variability in brain chemistry that may yield advances in mapping individual differences in behaviorally relevant brain function. In turn, such genetic profiles may fuel gene-environment interactions research establishing trajectories of risk for psychopathology.}, Language = {eng}, Doi = {10.1038/npp.2011.82}, Key = {Nikolova2011} } @article{Carre2011, Author = {Carré, JM and McCormick, CM and Hariri, AR}, Title = {The social neuroendocrinology of human aggression.}, Journal = {Psychoneuroendocrinology}, Volume = {36}, Number = {7}, Pages = {935-944}, Address = {Department of Psychology and Neuroscience, Duke University, Durham, NC, USA. justin.carre@duke.edu}, Year = {2011}, Month = {August}, ISSN = {0306-4530}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21367531}, Keywords = {Aggression/*physiology/psychology • Animals • Competitive Behavior/physiology • Humans • Models, Animal • Models, Biological • Neural Pathways/metabolism/physiology • Neuroendocrinology • Neurosecretory Systems/metabolism/*physiology • *Social Behavior • Testosterone/blood/physiology}, Abstract = {Testosterone concentrations fluctuate rapidly in response to competitive and aggressive interactions, suggesting that changes in testosterone rather than baseline differences shape ongoing and/or future competitive and aggressive behaviors. Although recent experiments in animal models provide compelling empirical support for this idea, studies in humans have focused largely on how competitive interactions drive changes in testosterone concentrations and not how these changes influence subsequent behavior. In this paper, we provide a review of the literature on testosterone and human aggression with a main focus on the role of testosterone dynamics in modulating reactive aggression. We also speculate on one putative neural mechanism through which testosterone may bias human aggressive behavior. Finally, we conclude by highlighting important questions that should be addressed in future research.}, Language = {eng}, Doi = {10.1016/j.psyneuen.2011.02.001}, Key = {Carre2011} } @article{Hariri2011c, Author = {Hariri, AR}, Title = {The what, where, and when of catechol-O-methyltransferase.}, Journal = {Biological psychiatry}, Volume = {70}, Number = {3}, Pages = {214-215}, Address = {Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Institute for Genome Sciences and Policy, Duke University, 417 Chapel Drive, Durham, NC 27708, USA. ahmad.hariri@duke.edu}, Year = {2011}, Month = {August}, ISSN = {0006-3223}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21745617}, Keywords = {Attention Deficit Disorder with Hyperactivity/*genetics • Brain/*physiology • Catechol O-Methyltransferase/*genetics • Central Nervous System Stimulants/*therapeutic use • Female • Humans • Male • Memory, Short-Term/*physiology • Methylphenidate/*therapeutic use • *Polymorphism, Single Nucleotide}, Language = {eng}, Doi = {10.1016/j.biopsych.2011.06.002}, Key = {Hariri2011c} } @article{Morey2011, Author = {Morey, RA and Hariri, AR and Gold, AL and Hauser, MA and Munger, HJ and Dolcos, F and McCarthy, G}, Title = {Serotonin transporter gene polymorphisms and brain function during emotional distraction from cognitive processing in posttraumatic stress disorder.}, Journal = {BMC Psychiatry}, Volume = {11}, Pages = {76}, Address = {Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC 27710, USA. morey@biac.duke.edu}, Year = {2011}, Month = {May}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21545724}, Keywords = {Amygdala/physiopathology • Case-Control Studies • Cognition/*physiology • Emotions/*physiology • Functional Neuroimaging/methods/psychology • Humans • Magnetic Resonance Imaging/psychology • Memory, Short-Term/physiology • *Polymorphism, Single Nucleotide • Prefrontal Cortex/physiopathology • Promoter Regions, Genetic/genetics/physiology • Psychomotor Performance/physiology • September 11 Terrorist Attacks/psychology • Serotonin Plasma Membrane Transport Proteins/genetics/*physiology • Stress Disorders, Post-Traumatic/*genetics/*physiopathology/psychology • Veterans/psychology • Wounds and Injuries/physiopathology/psychology}, Abstract = {BACKGROUND: Serotonergic system dysfunction has been implicated in posttraumatic stress disorder (PTSD). Genetic polymorphisms associated with serotonin signaling may predict differences in brain circuitry involved in emotion processing and deficits associated with PTSD. In healthy individuals, common functional polymorphisms in the serotonin transporter gene (SLC6A4) have been shown to modulate amygdala and prefrontal cortex (PFC) activity in response to salient emotional stimuli. Similar patterns of differential neural responses to emotional stimuli have been demonstrated in PTSD but genetic factors influencing these activations have yet to be examined. METHODS: We investigated whether SLC6A4 promoter polymorphisms (5-HTTLPR, rs25531) and several downstream single nucleotide polymorphisms (SNPs) modulated activity of brain regions involved in the cognitive control of emotion in post-9/11 veterans with PTSD. We used functional MRI to examine neural activity in a PTSD group (n = 22) and a trauma-exposed control group (n = 20) in response to trauma-related images presented as task-irrelevant distractors during the active maintenance period of a delayed-response working memory task. Regions of interest were derived by contrasting activation for the most distracting and least distracting conditions across participants. RESULTS: In patients with PTSD, when compared to trauma-exposed controls, rs16965628 (associated with serotonin transporter gene expression) modulated task-related ventrolateral PFC activation and 5-HTTLPR tended to modulate left amygdala activation. Subsequent to combat-related trauma, these SLC6A4 polymorphisms may bias serotonin signaling and the neural circuitry mediating cognitive control of emotion in patients with PTSD. CONCLUSIONS: The SLC6A4 SNP rs16965628 and 5-HTTLPR are associated with a bias in neural responses to traumatic reminders and cognitive control of emotions in patients with PTSD. Functional MRI may help identify intermediate phenotypes and dimensions of PTSD that clarify the functional link between genes and disease phenotype, and also highlight features of PTSD that show more proximal influence of susceptibility genes compared to current clinical categorizations.}, Language = {eng}, Doi = {10.1186/1471-244X-11-76}, Key = {Morey2011} } @article{Gianaros2011, Author = {Gianaros, PJ and Manuck, SB and Sheu, LK and Kuan, DCH and Votruba-Drzal, E and Craig, AE and Hariri, AR}, Title = {Parental education predicts corticostriatal functionality in adulthood.}, Journal = {Cerebral cortex (New York, N.Y. : 1991)}, Volume = {21}, Number = {4}, Pages = {896-910}, Address = {Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA. gianarospj@upmc.edu}, Year = {2011}, Month = {April}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20810623}, Keywords = {Adult • Cerebral Cortex/*physiology • *Educational Status • Female • Humans • Magnetic Resonance Imaging • Male • Middle Aged • Neural Pathways/*physiology • *Parents • Socioeconomic Factors}, Abstract = {Socioeconomic disadvantage experienced in early development predicts ill health in adulthood. However, the neurobiological pathways linking early disadvantage to adult health remain unclear. Lower parental education-a presumptive indicator of early socioeconomic disadvantage-predicts health-impairing adult behaviors, including tobacco and alcohol dependencies. These behaviors depend, in part, on the functionality of corticostriatal brain systems that 1) show developmental plasticity and early vulnerability, 2) process reward-related information, and 3) regulate impulsive decisions and actions. Hence, corticostriatal functionality in adulthood may covary directly with indicators of early socioeconomic disadvantage, particularly lower parental education. Here, we tested the covariation between parental education and corticostriatal activation and connectivity in 76 adults without confounding clinical syndromes. Corticostriatal activation and connectivity were assessed during the processing of stimuli signaling monetary gains (positive feedback [PF]) and losses (negative feedback). After accounting for participants' own education and other explanatory factors, lower parental education predicted reduced activation in anterior cingulate and dorsomedial prefrontal cortices during PF, along with reduced connectivity between these cortices and orbitofrontal and striatal areas implicated in reward processing and impulse regulation. In speculation, adult alterations in corticostriatal functionality may represent facets of a neurobiological endophenotype linked to socioeconomic conditions of early development.}, Language = {eng}, Doi = {10.1093/cercor/bhq160}, Key = {Gianaros2011} } @article{Drabant2011, Author = {Drabant, EM and Kuo, JR and Ramel, W and Blechert, J and Edge, MD and Cooper, JR and Goldin, PR and Hariri, AR and Gross, JJ}, Title = {Experiential, autonomic, and neural responses during threat anticipation vary as a function of threat intensity and neuroticism.}, Journal = {NeuroImage}, Volume = {55}, Number = {1}, Pages = {401-410}, Address = {Psychology Department, Stanford University, Stanford, CA 94305, USA. drabant@stanford.edu}, Year = {2011}, Month = {March}, ISSN = {1053-8119}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21093595}, Keywords = {Brain/*physiopathology • *Fear • Female • Humans • *Magnetic Resonance Imaging • Neurotic Disorders/*physiopathology • *Personal Autonomy • *Problem-Based Learning • Young Adult}, Abstract = {Anticipatory emotional responses play a crucial role in preparing individuals for impending challenges. They do this by triggering a coordinated set of changes in behavioral, autonomic, and neural response systems. In the present study, we examined the biobehavioral impact of varying levels of anticipatory anxiety, using a shock anticipation task in which unpredictable electric shocks were threatened and delivered to the wrist at variable intervals and intensities (safe, medium, strong). This permitted investigation of a dynamic range of anticipatory anxiety responses. In two studies, 95 and 51 healthy female participants, respectively, underwent this shock anticipation task while providing continuous ratings of anxiety experience and electrodermal responding (Study 1) and during fMRI BOLD neuroimaging (Study 2). Results indicated a step-wise pattern of responding in anxiety experience and electrodermal responses. Several brain regions showed robust responses to shock anticipation relative to safe trials, including the hypothalamus, periaqueductal gray, caudate, precentral gyrus, thalamus, insula, ventrolateral PFC, dorsomedial PFC, and ACC. A subset of these regions demonstrated a linear pattern of increased responding from safe to medium to strong trials, including the bilateral insula, ACC, and inferior frontal gyrus. These responses were modulated by individual differences in neuroticism, such that those high in neuroticism showed exaggerated anxiety experience across the entire task, and reduced brain activation from medium to strong trials in a subset of brain regions. These findings suggest that individual differences in neuroticism may influence sensitivity to anticipatory threat and provide new insights into the mechanism through which neuroticism may confer risk for developing anxiety disorders via dysregulated anticipatory responses.}, Language = {eng}, Doi = {10.1016/j.neuroimage.2010.11.040}, Key = {Drabant2011} } @article{Hyde2011a, Author = {Hyde, LW and Gorka, A and Manuck, SB and Hariri, AR}, Title = {Perceived social support moderates the link between threat-related amygdala reactivity and trait anxiety.}, Journal = {Neuropsychologia}, Volume = {49}, Number = {4}, Pages = {651-656}, Address = {Department of Psychology, University of Pittsburgh, Pittsburgh, PA 15260, USA. lwh2@pitt.edu}, Year = {2011}, Month = {March}, ISSN = {0028-3932}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20813118}, Keywords = {*Adaptation, Psychological • Adult • Aggression/*psychology • Amygdala/*physiology • Anxiety/*psychology • Brain Mapping • Female • Humans • Magnetic Resonance Imaging • Male • Middle Aged • Reference Values • *Social Support • Temperament}, Abstract = {Several lines of research have illustrated that negative environments can precipitate psychopathology, particularly in the context of relatively increased biological risk, while social resources can buffer the effects of these environments. However, little research has examined how social resources might buffer proximal biological risk for psychopathology or the neurobiological pathways through which such buffering may be mediated. Here we report that the expression of trait anxiety as a function of threat-related amygdala reactivity is moderated by perceived social support, a resource for coping with adversity. A significant positive correlation between amygdala reactivity and trait anxiety was evident in individuals reporting below average levels of support but not in those reporting average or above average levels. These results were consistent across multiple measures of trait anxiety and were specific to anxiety in that they did not extend to measures of broad negative or positive affect. Our findings illuminate a biological pathway, namely moderation of amygdala-related anxiety, through which social support may confer resilience to psychopathology. Moreover, our results indicate that links between neural reactivity and behavior are not static but rather may be contingent on social resources.}, Language = {eng}, Doi = {10.1016/j.neuropsychologia.2010.08.025}, Key = {Hyde2011a} } @article{Hariri2011a, Author = {Hariri, AR and Whalen, PJ}, Title = {The amygdala: Inside and out}, Journal = {F1000 Biology Reports}, Volume = {3}, Number = {1}, Pages = {2}, Publisher = {Faculty of 1000, Ltd.}, Year = {2011}, Month = {February}, ISSN = {1740-4118}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21399763}, Abstract = {Research at the interface of psychology, neuroscience, molecular biology, and genetics, focusing on the amygdala, has begun to reveal a rule book for emotional reactions. Variations in intrinsic and extrinsic factors tweak the sensitivity of the amygdala, giving rise to differences in behavior between individuals. At their most extreme, these variations may generate psychological disorders, and even our current rudimentary understanding of this brain region suggests novel strategies for the treatment of such disorders. © 2011 Faculty of 1000 Ltd.}, Language = {eng}, Doi = {10.3410/B3-2}, Key = {Hariri2011a} } @article{fds252004, Author = {Hariri, AR and Whalen, PJ}, Title = {Face to face with the emotional brain}, Journal = {Scientist}, Volume = {25}, Number = {2}, Pages = {30}, Year = {2011}, Month = {February}, ISSN = {0890-3670}, Key = {fds252004} } @article{Beevers2011, Author = {Beevers, CG and Marti, CN and Lee, H-J and Stote, DL and Ferrell, RE and Hariri, AR and Telch, MJ}, Title = {Associations between serotonin transporter gene promoter region (5-HTTLPR) polymorphism and gaze bias for emotional information.}, Journal = {Journal of abnormal psychology}, Volume = {120}, Number = {1}, Pages = {187-197}, Address = {Department of Psychology, University of Texas at Austin, 1 University Station, A8000, Austin, TX 78712, USA. beevers@psy.utexas.edu}, Year = {2011}, Month = {February}, ISSN = {0021-843X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21319930}, Keywords = {Adult • Alleles • Analysis of Variance • Attention/*physiology • Emotions/*physiology • Eye Movements/*genetics • Facial Expression • Female • Gene Frequency • Genotype • Humans • Male • Photic Stimulation • *Polymorphism, Single Nucleotide • Promoter Regions, Genetic • Serotonin Plasma Membrane Transport Proteins/*genetics • Time Factors}, Abstract = {The serotonin transporter promoter region polymorphism (5-HTTLPR) is associated with neural response to negative images in brain regions involved in the experience of emotion. However, the behavioral implications of this sensitivity have been studied far less extensively. The current study used eye-tracking methodology to examine how individuals genotyped for the 5-HTTLPR, including the single nucleotide polymorphism (SNP) rs25531, allocated attention during prolonged (30-s) exposure to face stimuli depicting positive and negative emotion. Short 5-HTTLPR allele carriers and carriers of the long allele with guanine at the sixth nucleotide (S/LG) displayed a stronger gaze bias (total fixation time, number of fixations, mean fixation length) for positive than for sad, threat, or neutral stimuli. In contrast, those homozygous for the long 5-HTTLPR allele with adenine at the sixth nucleotide (LA) viewed the emotion stimuli in an unbiased fashion. Time course analyses indicated no initial 5-HTTLPR group differences; however, S/LG 5-HTTLPR allele carriers were more likely than LA 5-HTTLPR homozygotes to direct gaze toward happy than toward sad stimuli over time. This bias toward positive stimuli during the later stages of information processing likely reflects a strategic effort to downregulate heightened reactivity to negative stimuli among 5-HTTLPR S/LG allele carriers.}, Language = {eng}, Doi = {10.1037/a0022125}, Key = {Beevers2011} } @article{Hariri2011b, Author = {Hariri, AR and Shin, LM}, Title = {Welcome to biology of mood \& anxiety disorders}, Journal = {Biology of mood \& anxiety disorders}, Volume = {1}, Number = {1}, Pages = {1}, Publisher = {Springer Science and Business Media LLC}, Address = {Laboratory of NeuroGenetics, Department of Psychology \& Neuroscience, Institute for Genome Sciences \& Policy, Duke University, Durham, NC USA. ahmad.hariri@duke.edu.}, Year = {2011}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22738418}, Language = {eng}, Doi = {10.1186/2045-5380-1-1}, Key = {Hariri2011b} } @article{fds252110, Author = {Carre, JM and Murphy, KR and Hariri, AR}, Title = {What lies beneath the face of aggression?}, Journal = {Social cognitive and affective neuroscience}, Volume = {8}, Number = {2}, Pages = {224-229}, Year = {2011}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22198969}, Abstract = {Recent evidence indicates that a sexually dimorphic feature of humans, the facial width-to-height ratio (FWHR), is positively correlated with reactive aggression, particularly in men. Also, predictions about the aggressive tendencies of others faithfully map onto FWHR in the absence of explicit awareness of this metric. Here, we provide the first evidence that amygdala reactivity to social signals of interpersonal challenge may underlie the link between aggression and the FWHR. Specifically, amygdala reactivity to angry faces was positively correlated with aggression, but only among men with relatively large FWHRs. The patterns of association were specific to angry facial expressions and unique to men. These links may reflect the common influence of pubertal testosterone on craniofacial growth and development of neural circuitry underlying aggression. Amygdala reactivity may also represent a plausible pathway through which FWHR may have evolved to represent an honest indicator of conspecific threat, namely by reflecting the responsiveness of neural circuitry mediating aggressive behavior.}, Doi = {10.1093/scan/nsr096}, Key = {fds252110} } @article{Fisher2011, Author = {Fisher, PM and Price, JC and Meltzer, CC and Moses Kolko and EL and Becker, C and Berga, SL and Hariri, AR}, Title = {Medial prefrontal cortex serotonin 1A and 2A receptor binding interacts to predict threat-related amygdala reactivity}, Journal = {Biology of mood \& anxiety disorders}, Volume = {1}, Number = {1}, Pages = {2}, Publisher = {Springer Science and Business Media LLC}, Address = {Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. patrick.fisher@gmail.com.}, Year = {2011}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22738071}, Abstract = {BACKGROUND: The amygdala and medial prefrontal cortex (mPFC) comprise a key corticolimbic circuit that helps shape individual differences in sensitivity to threat and the related risk for psychopathology. Although serotonin (5-HT) is known to be a key modulator of this circuit, the specific receptors mediating this modulation are unclear. The colocalization of 5-HT1A and 5-HT2A receptors on mPFC glutamatergic neurons suggests that their functional interactions may mediate 5-HT effects on this circuit through top-down regulation of amygdala reactivity. Using a multimodal neuroimaging strategy in 39 healthy volunteers, we determined whether threat-related amygdala reactivity, assessed with blood oxygen level-dependent functional magnetic resonance imaging, was significantly predicted by the interaction between mPFC 5-HT1A and 5-HT2A receptor levels, assessed by positron emission tomography. RESULTS: 5-HT1A binding in the mPFC significantly moderated an inverse correlation between mPFC 5-HT2A binding and threat-related amygdala reactivity. Specifically, mPFC 5-HT2A binding was significantly inversely correlated with amygdala reactivity only when mPFC 5-HT1A binding was relatively low. CONCLUSIONS: Our findings provide evidence that 5-HT1A and 5-HT2A receptors interact to shape serotonergic modulation of a functional circuit between the amygdala and mPFC. The effect of the interaction between mPFC 5-HT1A and 5-HT2A binding and amygdala reactivity is consistent with the colocalization of these receptors on glutamatergic neurons in the mPFC.}, Language = {eng}, Doi = {10.1186/2045-5380-1-2}, Key = {Fisher2011} } @article{Cornelius2010, Author = {Cornelius, JR and Aizenstein, HJ and Hariri, AR}, Title = {Amygdala reactivity is inversely related to level of cannabis use in individuals with comorbid cannabis dependence and major depression.}, Journal = {Addictive behaviors}, Volume = {35}, Number = {6}, Pages = {644-646}, Address = {Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States. corneliusjr@upmc.edu}, Year = {2010}, Month = {June}, ISSN = {0306-4603}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20189314}, Keywords = {Amygdala/*drug effects/physiopathology • Antidepressive Agents, Second-Generation/therapeutic use • Cannabis/*adverse effects • Comorbidity • Depressive Disorder/drug therapy/epidemiology • Diagnosis, Dual (Psychiatry) • Double-Blind Method • Fear/*drug effects • Female • Fluoxetine/therapeutic use • Humans • Magnetic Resonance Imaging/methods • Male • Marijuana Abuse/epidemiology/*physiopathology • Social Behavior • Young Adult}, Abstract = {Phan et al. (2008) recently reported that an acute dose of oral THC is associated with a decrease in threat-related amygdala reactivity during a social threat stimulus task. However, to date, those findings have not been replicated, and have not been extended to clinical studies involving smoked rather than oral cannabis. In this study, we hypothesized that level of cannabis smoked by participants in our treatment study would be inversely related to the level of threat-related amygdala reactivity. Subjects were recruited from among participants in our double-blind, placebo-controlled trial of fluoxetine in comorbid youth with cannabis dependence/major depression. The threat-related amygdala reactivity task used by Hariri et al. (2009) was completed during BOLD fMRI scans at study baseline and then again 12 weeks later at the end of the trial. Data are available from six subjects with pre-and post-treatment fMRI data. During the course of the study, five of the six subjects demonstrated a decrease in their level of cannabis use, with a mean decrease of 64%, and those persons all demonstrated an increase in their level of amygdala reactivity. One subject demonstrated an increase in their level of cannabis use (a 79% increase) during the treatment trial, and that person demonstrated a decrease in their level of amygdala reactivity. Thus, a higher level of cannabis use was consistently associated with a lower level of amygdala reactivity across all subjects (matched pairs t = 2.70, df = 5, p < 0.05, two-tailed). These findings are consistent with the reports by Phan et al. (2008) and Hariri et al. (2009) suggesting that cannabinoids have an inhibitory effect on threat-related amygdala reactivity.}, Language = {eng}, Doi = {10.1016/j.addbeh.2010.02.004}, Key = {Cornelius2010} } @article{Chiao2010, Author = {Chiao, JY and Hariri, AR and Harada, T and Mano, Y and Sadato, N and Parrish, TB and Iidaka, T}, Title = {Theory and methods in cultural neuroscience.}, Journal = {Social cognitive and affective neuroscience}, Volume = {5}, Number = {2-3}, Pages = {356-361}, Address = {Department of Psychology and Interdepartmental Neuroscience Program, Northwestern University, Evanston, IL 60208, USA. jchiao@northwestern.edu}, Year = {2010}, Month = {June}, ISSN = {1749-5016}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20592044}, Keywords = {Brain/physiology • Brain Mapping • Cross-Cultural Comparison • *Culture • Humans • Magnetic Resonance Imaging • Neurosciences/*methods • Polymorphism, Genetic/genetics • Research Design • Stereotyping}, Abstract = {Cultural neuroscience is an emerging research discipline that investigates cultural variation in psychological, neural and genomic processes as a means of articulating the bidirectional relationship of these processes and their emergent properties. Research in cultural neuroscience integrates theory and methods from anthropology, cultural psychology, neuroscience and neurogenetics. Here, we review a set of core theoretical and methodological challenges facing researchers when planning and conducting cultural neuroscience studies, and provide suggestions for overcoming these challenges. In particular, we focus on the problems of defining culture and culturally appropriate experimental tasks, comparing neuroimaging data acquired from different populations and scanner sites and identifying functional genetic polymorphisms relevant to culture. Implications of cultural neuroscience research for addressing current issues in population health disparities are discussed.}, Language = {eng}, Doi = {10.1093/scan/nsq063}, Key = {Chiao2010} } @article{fds252003, Author = {Jedema, HP and Gianaros, PJ and Greer, PJ and Kerr, DD and Liu, S and Higley, JD and Suomi, SJ and Olsen, AS and Porter, JN and Lopresti, BJ and Hariri, AR and Bradberry, CW}, Title = {Morphological differences associated with a serotonin transporter polymorphism (5-HTTLPR) in rhesus macaques}, Journal = {Molecular Psychiatry}, Volume = {15}, Number = {5}, Pages = {446}, Publisher = {Springer Nature}, Year = {2010}, Month = {May}, ISSN = {1359-4184}, url = {http://dx.doi.org/10.1038/mp.2010.49}, Doi = {10.1038/mp.2010.49}, Key = {fds252003} } @article{Jedema2010, Author = {Jedema, HP and Gianaros, PJ and Greer, PJ and Kerr, DD and Liu, S and Higley, JD and Suomi, SJ and Olsen, AS and Porter, JN and Lopresti, BJ and Hariri, AR and Bradberry, CW}, Title = {Cognitive impact of genetic variation of the serotonin transporter in primates is associated with differences in brain morphology rather than serotonin neurotransmission.}, Journal = {Molecular psychiatry}, Volume = {15}, Number = {5}, Pages = {512-446}, Address = {Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15261, USA.}, Year = {2010}, Month = {May}, ISSN = {1359-4184}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19721434}, Keywords = {Animals • Avoidance Learning/physiology • Behavior, Animal/physiology • Benzylamines/metabolism • Brain/drug effects/radionuclide imaging • Brain Mapping • Carbon Isotopes/metabolism • Choice Behavior/*physiology • Cognition/*physiology • Genotype • Macaca mulatta • Magnetic Resonance Imaging/methods • Male • Neuropsychological Tests • Piperazines/metabolism • Polymorphism, Genetic/*genetics • Positron-Emission Tomography/methods • Protein Binding/drug effects/genetics • Pyridines/metabolism • Receptor, Serotonin, 5-HT1A/genetics • Serotonin/genetics/*metabolism • Serotonin Plasma Membrane Transport Proteins/*genetics • Synaptic Transmission/*genetics • Time Factors • Tritium/metabolism}, Abstract = {A powerful convergence of genetics, neuroimaging and epidemiological research has identified the biological pathways mediating individual differences in complex behavioral processes and the related risk for disease. Orthologous genetic variation in non-human primates (NHPs) represents a unique opportunity to characterize the detailed molecular and cellular mechanisms that bias behaviorally and clinically relevant brain function. We report that a rhesus macaque orthologue of a common polymorphism of the serotonin transporter gene (rh5-HTTLPR) has strikingly similar effects on behavior and brain morphology to those in humans. Specifically, the rh5-HTTLPR (S)hort allele broadly affects cognitive choice behavior and brain morphology without observably affecting the 5-hydroxytryptamine (5-HT) transporter or 5-HT(1A) concentrations in vivo. Collectively, our findings indicate that 5-HTTLPR-associated behavioral effects reflect genotype-dependent biases in cortical development rather than static differences in serotonergic signaling mechanisms. Moreover, these data highlight the vast potential of NHP models in advancing our understanding of human genetic variation affecting behavior and neuropsychiatric disease liability.}, Language = {eng}, Doi = {10.1038/mp.2009.90}, Key = {Jedema2010} } @article{Caspi2010, Author = {Caspi, A and Hariri, AR and Holmes, A and Uher, R and Moffitt, TE}, Title = {Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits.}, Journal = {The American journal of psychiatry}, Volume = {167}, Number = {5}, Pages = {509-527}, Address = {Department of Psychology, and Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA. ac115@duke.edu}, Year = {2010}, Month = {May}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20231323}, Keywords = {Animals • Brain/pathology/physiopathology • Depressive Disorder/genetics • Environment • Genetic Predisposition to Disease/*genetics • Genome-Wide Association Study/methods • Genotype • Humans • Models, Psychological • Mood Disorders/genetics • Primates/genetics/psychology • Serotonin Plasma Membrane Transport Proteins/*genetics/physiology • Stress, Psychological/complications/*genetics}, Abstract = {Evidence of marked variability in response among people exposed to the same environmental risk implies that individual differences in genetic susceptibility might be at work. The study of such Gene-by-Environment (GxE) interactions has gained momentum. In this article, the authors review research about one of the most extensive areas of inquiry: variation in the promoter region of the serotonin transporter gene (SLC6A4; also known as 5-HTT) and its contribution to stress sensitivity. Research in this area has both advanced basic science and generated broader lessons for studying complex diseases and traits. The authors evaluate four lines of evidence about the 5-HTT stress-sensitivity hypothesis: 1) observational studies about the serotonin transporter linked polymorphic region (5-HTTLPR), stress sensitivity, and depression in humans; 2) experimental neuroscience studies about the 5-HTTLPR and biological phenotypes relevant to the human stress response; 3) studies of 5-HTT variation and stress sensitivity in nonhuman primates; and 4) studies of stress sensitivity and genetically engineered 5-HTT mutations in rodents. The authors then dispel some misconceptions and offer recommendations for GxE research. The authors discuss how GxE interaction hypotheses can be tested with large and small samples, how GxE research can be carried out before as well as after replicated gene discovery, the uses of GxE research as a tool for gene discovery, the importance of construct validation in evaluating GxE research, and the contribution of GxE research to the public understanding of genetic science.}, Language = {eng}, Doi = {10.1176/appi.ajp.2010.09101452}, Key = {Caspi2010} } @article{Munoz2010, Author = {Muñoz, KE and Meyer-Lindenberg, A and Hariri, AR and Mervis, CB and Mattay, VS and Morris, CA and Berman, KF}, Title = {Abnormalities in neural processing of emotional stimuli in Williams syndrome vary according to social vs. non-social content.}, Journal = {NeuroImage}, Volume = {50}, Number = {1}, Pages = {340-346}, Address = {Section on Integrative Neuroimaging, National Institute of Mental Health, NIH, DHHS, Bethesda, MD 20892, USA.}, Year = {2010}, Month = {March}, ISSN = {1053-8119}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20004252}, Keywords = {Adult • Amygdala/physiopathology • Brain/*physiopathology • Brain Mapping • Cognition/*physiology • Emotions/*physiology • Female • Humans • Intelligence • Intelligence Tests • Magnetic Resonance Imaging • Male • Neural Pathways/physiopathology • Oxygen/blood • Prefrontal Cortex/physiopathology • *Social Behavior • Visual Perception/physiology • Williams Syndrome/*physiopathology}, Abstract = {Williams syndrome (WS) is a rare genetic disorder caused by the deletion of approximately 25 genes on chromosome 7q11.23 and is characterized by both hypersociability and increases in specific phobia and anticipatory anxiety regarding non-social entities or circumstances. Alterations in amygdala reactivity and prefrontal regulation consistent with the observed behavioral pattern of social versus non-social abnormalities have been previously demonstrated in individuals with WS (Meyer-Lindenberg et al., 2005). However, in that study, the social stimulus (faces) matching task was more difficult than the non-social scene (IAPS stimuli) matching task, making it impossible to disambiguate the relative contributions of task difficulty and stimulus type (social versus non-social). In the present study, we examined the performance of the same group of participants with WS and normal IQs during a more cognitively demanding task using the same scene stimuli as in the prior study. Confirming previous findings, the results indicated (a) a differential response of prefrontal regions as a function of task difficulty and (b) a persistently increased activation of the amygdala to non-social scenes by individuals with WS regardless of cognitive load. These data provide further evidence of disruption in amygdala-prefrontal circuitry in individuals with WS.}, Language = {eng}, Doi = {10.1016/j.neuroimage.2009.11.069}, Key = {Munoz2010} } @article{Hariri2010, Author = {Hariri, AR}, Title = {Genetic polymorphisms: a cornerstone of translational biobehavioral research.}, Journal = {Science translational medicine}, Volume = {2}, Number = {18}, Pages = {18ps6}, Address = {Department of Psychology and Neuroscience, Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA. ahmad.hariri@duke.edu}, Year = {2010}, Month = {February}, ISSN = {1946-6234}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20371481}, Keywords = {Amino Acid Substitution/genetics • Animals • *Behavior • Brain-Derived Neurotrophic Factor/genetics • Humans • Mice • *Polymorphism, Genetic • *Translational Medical Research}, Abstract = {A new generation of interdisciplinary research seeks to use common functional genetic polymorphisms to model emergent variability in brain chemistry that regulates behaviorally relevant brain structure and function. This genetically mediated variability is then being mapped onto trajectories of risk for psychopathology, especially that precipitated by environmental adversity. This Perspective highlights a recent paper in Science that provides a powerful example of how a common functional genetic polymorphism can serve as a translational bridge between human and mouse research, extending our understanding of biological pathways that mediate individual differences in behavior and in risk for psychopathology.}, Language = {eng}, Doi = {10.1126/scitranslmed.3000811}, Key = {Hariri2010} } @article{Manuck2010, Author = {Manuck, SB and Marsland, AL and Flory, JD and Gorka, A and Ferrell, RE and Hariri, AR}, Title = {Salivary testosterone and a trinucleotide (CAG) length polymorphism in the androgen receptor gene predict amygdala reactivity in men.}, Journal = {Psychoneuroendocrinology}, Volume = {35}, Number = {1}, Pages = {94-104}, Address = {Department of Psychology, University of Pittsburgh, Pittsburgh, PA 15260, United States. Manuck@pitt.edu}, Year = {2010}, Month = {January}, ISSN = {0306-4530}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19493626}, Keywords = {Adult • Amygdala/*physiology • DNA/genetics • Facial Expression • Genotype • Humans • Image Processing, Computer-Assisted • Individuality • Magnetic Resonance Imaging • Male • Middle Aged • Oxygen/blood • Polymorphism, Genetic • Receptors, Androgen/*genetics/physiology • Saliva/*metabolism • Social Perception • Testosterone/*metabolism • Trinucleotide Repeats/*genetics}, Abstract = {In studies employing functional magnetic resonance imaging (fMRI), reactivity of the amygdala to threat-related sensory cues (viz., facial displays of negative emotion) has been found to correlate positively with interindividual variability in testosterone levels of women and young men and to increase on acute administration of exogenous testosterone. Many of the biological actions of testosterone are mediated by intracellular androgen receptors (ARs), which exert transcriptional control of androgen-dependent genes and are expressed in various regions of the brain, including the amygdala. Transactivation potential of the AR decreases (yielding relative androgen insensitivity) with expansion a polyglutamine stretch in the N-terminal domain of the AR protein, as encoded by a trinucleotide (CAG) repeat polymorphism in exon 1 of the X-chromosome AR gene. Here we examined whether amygdala reactivity to threat-related facial expressions (fear, anger) differs as a function of AR CAG length variation and endogenous (salivary) testosterone in a mid-life sample of 41 healthy men (mean age=45.6 years, range: 34-54 years; CAG repeats, range: 19-29). Testosterone correlated inversely with participant age (r=-0.39, p=0.012) and positively with number of CAG repeats (r=0.45, p=0.003). In partial correlations adjusted for testosterone level, reactivity in the ventral amygdala was lowest among men with largest number of CAG repeats. This inverse association was seen in both the right (r(p)=-0.34, p<0.05) and left (r(p)=-0.32, p<0.05) hemisphere. Activation of dorsal amygdala, correlated positively with individual differences in salivary testosterone, also in right (r=0.40, p<0.02) and left (r=0.32, p<0.05) hemisphere, but was not affected by number of CAG repeats. Hence, androgenic influences on threat-related reactivity in the ventral amygdala may be moderated partially by CAG length variation in the AR gene. Because individual differences in salivary testosterone also predicted dorsal amygdala reactivity and did so independently of CAG repeats, it is suggested that androgenic influences within this anatomically distinct region may be mediated, in part, by non-genomic or AR-independent mechanisms.}, Language = {eng}, Doi = {10.1016/j.psyneuen.2009.04.013}, Key = {Manuck2010} } @article{Salgado-Pineda2010, Author = {Salgado-Pineda, P and Fakra, E and Delaveau, P and Hariri, AR and Blin, O}, Title = {Differential patterns of initial and sustained responses in amygdala and cortical regions to emotional stimuli in schizophrenia patients and healthy participants.}, Journal = {Journal of psychiatry & neuroscience : JPN}, Volume = {35}, Number = {1}, Pages = {41-48}, Address = {Centre d'Investigation Clinique-Unite de Pharmacologie Clinique et d'Evaluations Therapeutiques, Hopital de la Timone, Unite Mixte de Recherche, Centre national de la recherche scientifique, 6193 Institut de Neurosciences Cognitives de la Mediterranee, Ma}, Year = {2010}, Month = {January}, ISSN = {1180-4882}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20040245}, Keywords = {Adult • Amygdala/*physiopathology • Brain Mapping • Cerebral Cortex/*physiopathology • Emotions/*physiology • Executive Function/*physiology • Facial Expression • Female • Humans • Magnetic Resonance Imaging • Male • Middle Aged • Neural Pathways/physiopathology • Neuropsychological Tests • Pattern Recognition, Visual/physiology • Psychiatric Status Rating Scales • Reaction Time • Schizophrenia/*physiopathology • Time Factors • Young Adult}, Abstract = {<h4>Background</h4>We sought to investigate the altered brain responses to emotional stimuli in patients with schizophrenia.<h4>Methods</h4>We analyzed data from 14 patients with schizophrenia and 14 healthy controls who performed an emotional face matching task. We evaluated brain activity and connectivity in the amygdala and cortical regions during the initial (first 21 seconds of each stimulation block) and sustained (last 21 seconds) stages of an emotional processing task, and we determined changes in amygdala activity across the emotional processing task.<h4>Results</h4>The patients with schizophrenia showed similar amygdala activation to the controls during the initial stage of processing, but their activation decreased during the sustained stage. The controls showed increasing amygdala activity across the emotional blocks, whereas activity progressively decreased in the schizophrenia group. The patients with schizophrenia showed increased cortical activity and interconnectivity in the medial frontal and inferior parietal cortex in the initial stage of emotional processing.There was increased activity in the superior temporal cortex and greater connectivity with the inferior parietal cortex in the sustained stage. Performance accuracy was lower in the schizophrenia group in the first part of the block, while their reaction time was longer in the latter part of the block.<h4>Limitations</h4>It was not possible to specify the moment at which the switch in amygdala response occurred.<h4>Conclusion</h4>Our findings suggest that patients with schizophrenia have an initial automatic emotional response but that they need to switch to a compensatory cognitive strategy to solve the task.}, Language = {eng}, Doi = {10.1503/jpn.090017}, Key = {Salgado-Pineda2010} } @article{fds251972, Author = {Hariri, A}, Title = {Imaging Genetics: Integration of Neuroimaging and Genetics in the Search for Predictive Markers}, Pages = {532-537}, Publisher = {Elsevier}, Year = {2009}, Month = {December}, url = {http://dx.doi.org/10.1016/B978-0-12-369420-1.00047-0}, Doi = {10.1016/B978-0-12-369420-1.00047-0}, Key = {fds251972} } @article{fds252002, Author = {Hariri, AR}, Title = {Ahmad R. Hariri: award for distinguished scientific early career contributions to psychology.}, Journal = {The American psychologist}, Volume = {64}, Number = {8}, Pages = {683-684}, Year = {2009}, Month = {November}, ISSN = {0003-066X}, url = {http://dx.doi.org/10.1037/a0016290}, Doi = {10.1037/a0016290}, Key = {fds252002} } @article{Blasi2009, Author = {Blasi, G and Hariri, AR and Alce, G and Taurisano, P and Sambataro, F and Das, S and Bertolino, A and Weinberger, DR and Mattay, VS}, Title = {Preferential amygdala reactivity to the negative assessment of neutral faces.}, Journal = {Biological psychiatry}, Volume = {66}, Number = {9}, Pages = {847-853}, Address = {Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy.}, Year = {2009}, Month = {November}, ISSN = {0006-3223}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19709644}, Keywords = {Adult • Amygdala/*physiology • Brain Mapping • Decision Making/*physiology • Emotions • *Facial Expression • Female • Gyrus Cinguli/physiology • Humans • Magnetic Resonance Imaging • Male • Neural Pathways/physiology • Prefrontal Cortex/physiology • Prejudice • Reaction Time • Social Perception}, Abstract = {<h4>Background</h4>Prior studies suggest that the amygdala shapes complex behavioral responses to socially ambiguous cues. We explored human amygdala function during explicit behavioral decision making about discrete emotional facial expressions that can represent socially unambiguous and ambiguous cues.<h4>Methods</h4>During functional magnetic resonance imaging, 43 healthy adults were required to make complex social decisions (i.e., approach or avoid) about either relatively unambiguous (i.e., angry, fearful, happy) or ambiguous (i.e., neutral) facial expressions. Amygdala activation during this task was compared with that elicited by simple, perceptual decisions (sex discrimination) about the identical facial stimuli.<h4>Results</h4>Angry and fearful expressions were more frequently judged as avoidable and happy expressions most often as approachable. Neutral expressions were equally judged as avoidable and approachable. Reaction times to neutral expressions were longer than those to angry, fearful, and happy expressions during social judgment only. Imaging data on stimuli judged to be avoided revealed a significant task by emotion interaction in the amygdala. Here, only neutral facial expressions elicited greater activity during social judgment than during sex discrimination. Furthermore, during social judgment only, neutral faces judged to be avoided were associated with greater amygdala activity relative to neutral faces that were judged as approachable. Moreover, functional coupling between the amygdala and both dorsolateral prefrontal (social judgment > sex discrimination) and cingulate (sex discrimination > social judgment) cortices was differentially modulated by task during processing of neutral faces.<h4>Conclusions</h4>Our results suggest that increased amygdala reactivity and differential functional coupling with prefrontal circuitries may shape complex decisions and behavioral responses to socially ambiguous cues.}, Language = {eng}, Doi = {10.1016/j.biopsych.2009.06.017}, Key = {Blasi2009} } @article{Fisher2009, Author = {Fisher, PM and Meltzer, CC and Price, JC and Coleman, RL and Ziolko, SK and Becker, C and Moses-Kolko, EL and Berga, SL and Hariri, AR}, Title = {Medial prefrontal cortex 5-HT(2A) density is correlated with amygdala reactivity, response habituation, and functional coupling.}, Journal = {Cerebral cortex (New York, N.Y. : 1991)}, Volume = {19}, Number = {11}, Pages = {2499-2507}, Address = {Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA.}, Year = {2009}, Month = {November}, ISSN = {1047-3211}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19321655}, Keywords = {Adult • Amygdala/*physiology • Emotions/*physiology • Female • Habituation, Psychophysiologic/*physiology • Humans • Male • Neural Inhibition/*physiology • Prefrontal Cortex/*physiology • Receptor, Serotonin, 5-HT2A/*metabolism • Tissue Distribution}, Abstract = {Feedback inhibition of the amygdala via medial prefrontal cortex (mPFC) is an important component in the regulation of complex emotional behaviors. The functional dynamics of this corticolimbic circuitry are, in part, modulated by serotonin (5-HT). Serotonin 2A (5-HT(2A)) receptors within the mPFC represent a potential molecular mechanism through which 5-HT can modulate this corticolimbic circuitry. We employed a multimodal neuroimaging strategy to explore the relationship between threat-related amygdala reactivity, assessed using blood oxygen level-dependent functional magnetic resonance imaging, and mPFC 5-HT(2A) density, assessed using [(18)F]altanserin positron emission tomography in 35 healthy adult volunteers. We observed a significant inverse relationship wherein greater mPFC 5-HT(2A) density was associated with reduced threat-related right amygdala reactivity. Remarkably, 25-37% of the variability in amygdala reactivity was explained by mPFC 5-HT(2A) density. We also observed a positive correlation between mPFC 5-HT(2A) density and the magnitude of right amygdala habituation. Furthermore, functional coupling between the amygdala and mPFC was positively correlated with 5-HT(2A) density suggesting that effective integration of emotionally salient information within this corticolimbic circuitry may be modulated, at least in part, by mPFC 5-HT(2A). Collectively, our results indicate that mPFC 5-HT(2A) is strongly associated with threat-related amygdala reactivity as well as its temporal habituation and functional coupling with prefrontal regulatory regions.}, Language = {eng}, Doi = {10.1093/cercor/bhp022}, Key = {Fisher2009} } @article{Mechelli2009, Author = {Mechelli, A and Tognin, S and McGuire, PK and Prata, D and Sartori, G and Fusar-Poli, P and De Brito and S and Hariri, AR and Viding, E}, Title = {Genetic vulnerability to affective psychopathology in childhood: a combined voxel-based morphometry and functional magnetic resonance imaging study.}, Journal = {Biological psychiatry}, Volume = {66}, Number = {3}, Pages = {231-237}, Address = {Department of Psychology, Institute of Psychiatry, PO Box 67, Division of Psychological Medicine and Psychiatry, King's College London, 103 Denmark Hill, London SE5 8AF, United Kingdom. a.mechelli@iop.kcl.ac.uk}, Year = {2009}, Month = {August}, ISSN = {0006-3223}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19278671}, Keywords = {Affective Disorders, Psychotic/*genetics/*pathology • Brain/*blood supply/*pathology • Brain Mapping • Catechol O-Methyltransferase/*genetics • Child • Genotype • Humans • Image Processing, Computer-Assisted/methods • Longitudinal Studies • Magnetic Resonance Imaging/methods • Male • Methionine/genetics • Neuropsychological Tests • Oxygen/blood • Photic Stimulation • Polymorphism, Genetic/*drug effects • Reaction Time/physiology • Twin Studies as Topic • Valine/genetics}, Abstract = {<h4>Background</h4>The majority of affective psychopathology is rooted early in life and first emerges during childhood and adolescence. However, little is known about how genetic vulnerability affects brain structure and function in childhood since the vast majority of studies published so far have been conducted on adult participants. The present investigation examined for the first time the effects of catechol-O-methyltransferase (COMT) valine (val) 158 methionine (met) (val158met) polymorphism, which has been shown to moderate predisposition to negative mood and affective disorders, on brain structure and function in children.<h4>Methods</h4>Voxel-based morphometry and functional magnetic resonance imaging were used to measure gray matter volume and emotional reactivity in 50 children aged between 10 and 12 years. We tested the hypothesis that met158 allele affects structural brain development and confers heightened reactivity within the affective frontolimbic circuit in children.<h4>Results</h4>The met158 allele was positively associated with gray matter volume in the left hippocampal head where genotype accounted for 59% of interindividual variance. In addition, the met158 allele was positively associated with neuronal responses to fearful relative to neutral facial expressions in the right parahippocampal gyrus where genotype accounted for 14% of the interindividual variance.<h4>Conclusions</h4>These results indicate that the met158 allele is associated with increased gray matter volume and heightened reactivity during emotional processing within the limbic system in children as young as 10 to 12 years of age. These findings are consistent with the notion that genetic factors affect brain function to moderate vulnerability to affective psychopathology from childhood.}, Language = {eng}, Doi = {10.1016/j.biopsych.2009.01.033}, Key = {Mechelli2009} } @article{Hariri2009a, Author = {Hariri, AR and Gorka, A and Hyde, LW and Kimak, M and Halder, I and Ducci, F and Ferrell, RE and Goldman, D and Manuck, SB}, Title = {Divergent effects of genetic variation in endocannabinoid signaling on human threat- and reward-related brain function.}, Journal = {Biological psychiatry}, Volume = {66}, Number = {1}, Pages = {9-16}, Address = {Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. haririar@upmc.edu}, Year = {2009}, Month = {July}, ISSN = {0006-3223}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19103437}, Keywords = {Adult • Amidohydrolases/*genetics • Analysis of Variance • Anxiety/*genetics • Brain/anatomy \& histology/blood supply/*physiology • Brain Mapping • Cannabinoid Receptor Modulators/genetics • Endocannabinoids • Female • Genetic Variation/*genetics • Genotype • Humans • Image Processing, Computer-Assisted/methods • Magnetic Resonance Imaging/methods • Male • Middle Aged • Oxygen/blood • Psychiatric Status Rating Scales • Regression Analysis • *Reward • *Signal Transduction/genetics}, Abstract = {<h4>Background</h4>Fatty acid amide hydrolase (FAAH) is a key enzyme in regulating endocannabinoid (eCB) signaling. A common single nucleotide polymorphism (C385A) in the human FAAH gene has been associated with increased risk for addiction and obesity.<h4>Methods</h4>Using imaging genetics in 82 healthy adult volunteers, we examined the effects of FAAH C385A on threat- and reward-related human brain function.<h4>Results</h4>Carriers of FAAH 385A, associated with reduced enzyme and possibly increased eCB signaling, had decreased threat-related amygdala reactivity but increased reward-related ventral striatal reactivity in comparison with C385 homozygotes. Similarly divergent effects of FAAH C385A genotype were manifest at the level of brain-behavior relationships. The 385A carriers showed decreased correlation between amygdala reactivity and trait anxiety but increased correlation between ventral striatal reactivity and delay discounting, an index of impulsivity.<h4>Conclusions</h4>Our results parallel pharmacologic and genetic dissection of eCB signaling, are consistent with the psychotropic effects of Delta(9)-tetrahydrocannabinol, and highlight specific neural mechanisms through which variability in eCB signaling impacts complex behavioral processes related to risk for addiction and obesity.}, Language = {eng}, Doi = {10.1016/j.biopsych.2008.10.047}, Key = {Hariri2009a} } @article{Gianaros2009, Author = {Gianaros, PJ and Hariri, AR and Sheu, LK and Muldoon, MF and Sutton-Tyrrell, K and Manuck, SB}, Title = {Preclinical atherosclerosis covaries with individual differences in reactivity and functional connectivity of the amygdala.}, Journal = {Biological psychiatry}, Volume = {65}, Number = {11}, Pages = {943-950}, Address = {Department of Psychiatry and Psychology, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, Pennsylvania 15213, USA. gianarospj@upmc.edu}, Year = {2009}, Month = {June}, ISSN = {0006-3223}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19013557}, Keywords = {Adult • Amygdala/blood supply/*physiopathology • Atherosclerosis/epidemiology/*pathology • Brain Mapping • Carotid Arteries/pathology • Female • Humans • Image Processing, Computer-Assisted/methods • *Individuality • Magnetic Resonance Imaging/methods • Male • Middle Aged • Oxygen/blood • Risk Factors • Statistics as Topic • Tunica Media/*pathology • Ultrasonography}, Abstract = {<h4>Background</h4>Cardiovascular disease (CVD) is a major source of medical comorbidity for patients with mood and anxiety disorders, and it remains the leading public health burden for the general population in industrialized nations. Indirect neurobiological evidence suggests that preclinical risk for atherosclerosis, the main contributor to CVD, may be conferred by interindividual variation in the functionality of the amygdala, a brain system jointly involved in processing behaviorally salient stimuli and regulating the cardiovascular system.<h4>Methods</h4>In a neuroimaging study of 36 middle-aged adults (18 women) who were screened for confounding clinical cardiovascular and psychiatric disorders, we examined the direct covariation between a marker of preclinical atherosclerosis, carotid artery intima-media thickness (IMT), and interindividual variation in amygdala reactivity and functional connectivity assessed during the processing of behaviorally salient stimuli (angry and fearful facial expressions).<h4>Results</h4>After accounting for traditional CVD risk factors, a thickening of carotid IMT across individuals covaried with greater amygdala reactivity and a more positive functional connectivity between the amygdala and perigenual anterior cingulate cortex, a corticolimbic area also implicated in behavioral salience processing and cardiovascular regulation.<h4>Conclusions</h4>Individual differences in amygdala reactivity and functional connectivity may reflect facets of a novel, systems-level neural phenotype conferring risk for atherosclerosis and CVD.}, Language = {eng}, Doi = {10.1016/j.biopsych.2008.10.007}, Key = {Gianaros2009} } @article{fds252001, Author = {Zhou, Z and Zhu, G and Hariri, AR and Enoch, MA and Scott, D and Sinha, R and Virkkunen, M and Mash, DC and Lipsky, RH and Hu, XZ and Hodgkinson, CA and Xu, K and Buzas, B and Yuan, Q and Shen, PH and Ferrell, RE and Manuck, SB and Brown, SM and Hauger, RL and Stohler, CS and Zubieta, JK and Goldman, D}, Title = {Zhou et al. reply}, Journal = {Nature}, Volume = {458}, Number = {7238}, Pages = {E7-E7}, Publisher = {Springer Nature}, Year = {2009}, Month = {April}, ISSN = {0028-0836}, url = {http://dx.doi.org/10.1038/nature07928}, Doi = {10.1038/nature07928}, Key = {fds252001} } @article{Munoz2009, Author = {Gerber, AJ and Peterson, BS and Muñoz, KE and Hyde, LW and Hariri, AR}, Title = {Imaging genetics.}, Journal = {Journal of the American Academy of Child and Adolescent Psychiatry}, Volume = {48}, Number = {4}, Pages = {356-361}, Address = {Department of Psychology, Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA 15213-2593, USA.}, Year = {2009}, Month = {April}, ISSN = {0890-8567}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19318879}, Keywords = {Amygdala/metabolism • Environment • Gene Expression/genetics • Genetic Predisposition to Disease • Heterozygote Detection/*instrumentation • Humans • Mental Disorders/*genetics/metabolism • Molecular Biology/*methods • Serotonin/genetics • Temperament}, Language = {eng}, Doi = {10.1097/chi.0b013e31819aad07}, Key = {Munoz2009} } @article{Drabant2009, Author = {Drabant, EM and McRae, K and Manuck, SB and Hariri, AR and Gross, JJ}, Title = {Individual differences in typical reappraisal use predict amygdala and prefrontal responses.}, Journal = {Biological psychiatry}, Volume = {65}, Number = {5}, Pages = {367-373}, Address = {Department of Psychology, Stanford University, Stanford, California 94305, USA.}, Year = {2009}, Month = {March}, ISSN = {0006-3223}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18930182}, Keywords = {Adult • Amygdala/*physiology • Emotions/*physiology • Facial Expression • Female • Humans • *Individuality • Middle Aged • Prefrontal Cortex/*physiology}, Abstract = {<h4>Background</h4>Participants who are instructed to use reappraisal to downregulate negative emotion show decreased amygdala responses and increased prefrontal responses. However, it is not known whether individual differences in the tendency to use reappraisal manifests in similar neural responses when individuals are spontaneously confronted with negative situations. Such spontaneous emotion regulation might play an important role in normal and pathological responses to the emotional challenges of everyday life.<h4>Methods</h4>Fifty-six healthy women completed a blood oxygenation-level dependent functional magnetic resonance imaging challenge paradigm involving the perceptual processing of emotionally negative facial expressions. Participants also completed measures of typical emotion regulation use, trait anxiety, and neuroticism.<h4>Results</h4>Greater use of reappraisal in everyday life was related to decreased amygdala activity and increased prefrontal and parietal activity during the processing of negative emotional facial expressions. These associations were not attributable to variation in trait anxiety, neuroticism, or the use of another common form of emotion regulation, namely suppression.<h4>Conclusions</h4>These findings suggest that, like instructed reappraisal, individual differences in reappraisal use are associated with decreased activation in ventral emotion generative regions and increased activation in prefrontal control regions in response to negative stimuli. Such individual differences in emotion regulation might predict successful coping with emotional challenges as well as the onset of affective disorders.}, Language = {eng}, Doi = {10.1016/j.biopsych.2008.09.007}, Key = {Drabant2009} } @article{Rasetti2009, Author = {Rasetti, R and Mattay, VS and Wiedholz, LM and Kolachana, BS and Hariri, AR and Callicott, JH and Meyer-Lindenberg, A and Weinberger, DR}, Title = {Evidence that altered amygdala activity in schizophrenia is related to clinical state and not genetic risk.}, Journal = {The American journal of psychiatry}, Volume = {166}, Number = {2}, Pages = {216-225}, Address = {Genes, Cognition, and Psychosis Program, IRP, NIMH, NIH, Rm. 4S-235, 10 Center Dr., Bethesda, MD 20892, USA.}, Year = {2009}, Month = {February}, ISSN = {0002-953X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19074979}, Keywords = {Adult • Amygdala/*physiopathology • Anger • Cognition Disorders/diagnosis/*genetics/*physiopathology • Dominance, Cerebral/physiology • Facial Expression • Fear/physiology • Female • Genetic Predisposition to Disease/*genetics • Gyrus Cinguli/physiopathology • Humans • *Image Processing, Computer-Assisted • Imaging, Three-Dimensional • *Magnetic Resonance Imaging • Male • Memory, Short-Term • Nerve Net/physiopathology • *Neuropsychological Tests • Oxygen/*blood • Pattern Recognition, Visual/physiology • Phenotype • Schizophrenia/diagnosis/*genetics/*physiopathology}, Abstract = {<h4>Objective</h4>Although amygdala dysfunction is reported in schizophrenia, it is unknown whether this deficit represents a heritable phenotype that is related to risk for schizophrenia or whether it is related to disease state. The purpose of the present study was to examine amygdala response to threatening faces among healthy siblings of schizophrenia patients in whom a subtler heritable deficit might be observed.<h4>Method</h4>Participants were 34 schizophrenia patients, 29 unaffected siblings, and 20 healthy comparison subjects. Blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was conducted during an implicit facial information processing task. The N-back working memory task, which has been shown to elicit prefrontal cortex abnormalities in unaffected siblings of schizophrenia patients, was employed as a positive experimental control.<h4>Results</h4>Schizophrenia patients demonstrated a deficit in amygdala reactivity to negative face stimuli and an alteration, correlated with neuroleptic drug dosage, in the functional coupling between the amygdala and subgenual cingulate. In contrast, unaffected siblings showed a pattern that was not statistically different from that of healthy comparison subjects. During the N-back working memory task, both schizophrenia patients and their unaffected siblings demonstrated a pattern of inefficient prefrontal cortex engagement, which is consistent with earlier evidence that this pattern is related to genetic risk for schizophrenia.<h4>Conclusions</h4>These data suggest that the pathophysiological mechanism underlying the inability of individuals with schizophrenia to normally engage the amygdala in processing fearful and angry facial representations is more likely a phenomenon related to the disease state, specifically to treatment.}, Language = {eng}, Doi = {10.1176/appi.ajp.2008.08020261}, Key = {Rasetti2009} } @article{fds251971, Author = {Hariri, AR and Weinberger, DR}, Title = {Genetics of Human Anxiety and Its Disorders}, Pages = {669-677}, Publisher = {Elsevier}, Year = {2009}, Month = {January}, url = {http://dx.doi.org/10.1016/B978-008045046-9.00845-7}, Abstract = {Normal variation in human emotionality, in temperament and risk for affective disorders, is explained to a large degree by genetic variation. The sequencing of the human genome has made it possible to test the role of specific genes on measures of human emotionality, on risk for affective disorders, and on the brain systems that appear to mediate emotion-related phenotypes. A novel approach, called imaging genetics, has shown that several genes that impact on brain serotonergic signaling affect the development and function of circuits of the limbic system involved in emotional experience and behavior. © 2009 Published by null.}, Doi = {10.1016/B978-008045046-9.00845-7}, Key = {fds251971} } @article{Forbes2009b, Author = {Forbes, EE and Brown, SM and Kimak, M and Ferrell, RE and Manuck, SB and Hariri, AR}, Title = {Genetic variation in components of dopamine neurotransmission impacts ventral striatal reactivity associated with impulsivity.}, Journal = {Molecular psychiatry}, Volume = {14}, Number = {1}, Pages = {60-70}, Address = {Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.}, Year = {2009}, Month = {January}, ISSN = {1359-4184}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17893706}, Keywords = {Adult • Analysis of Variance • Basal Ganglia/blood supply/*physiopathology • Case-Control Studies • Catechol O-Methyltransferase/genetics • Dopamine/*genetics/metabolism • Dopamine Plasma Membrane Transport Proteins/genetics • Female • Gene Frequency • Genetic Variation/*genetics • Genotype • Humans • Image Processing, Computer-Assisted/methods • Impulsive Behavior/*genetics/*pathology • Magnetic Resonance Imaging/methods • Male • Middle Aged • Oxygen/blood • Receptors, Dopamine D3/genetics • Receptors, Dopamine D4/genetics • Reward • Synaptic Transmission/*genetics • Young Adult}, Abstract = {Individual differences in traits such as impulsivity involve high reward sensitivity and are associated with risk for substance use disorders. The ventral striatum (VS) has been widely implicated in reward processing, and individual differences in its function are linked to these disorders. Dopamine (DA) plays a critical role in reward processing and is a potent neuromodulator of VS reactivity. Moreover, altered DA signaling has been associated with normal and pathological reward-related behaviors. Functional polymorphisms in DA-related genes represent an important source of variability in DA function that may subsequently impact VS reactivity and associated reward-related behaviors. Using an imaging genetics approach, we examined the modulatory effects of common, putatively functional DA-related polymorphisms on reward-related VS reactivity associated with self-reported impulsivity. Genetic variants associated with relatively increased striatal DA release (DRD2 -141C deletion) and availability (DAT1 9-repeat), as well as diminished inhibitory postsynaptic DA effects (DRD2 -141C deletion and DRD4 7-repeat), predicted 9-12% of the interindividual variability in reward-related VS reactivity. In contrast, genetic variation directly affecting DA signaling only in the prefrontal cortex (COMT Val158Met) was not associated with variability in VS reactivity. Our results highlight an important role for genetic polymorphisms affecting striatal DA neurotransmission in mediating interindividual differences in reward-related VS reactivity. They further suggest that altered VS reactivity may represent a key neurobiological pathway through which these polymorphisms contribute to variability in behavioral impulsivity and related risk for substance use disorders.}, Language = {eng}, Doi = {10.1038/sj.mp.4002086}, Key = {Forbes2009b} } @article{Forbes2009a, Author = {Forbes, EE and Hariri, AR and Martin, SL and Silk, JS and Moyles, DL and Fisher, PM and Brown, SM and Ryan, ND and Birmaher, B and Axelson, DA and Dahl, RE}, Title = {Altered striatal activation predicting real-world positive affect in adolescent major depressive disorder.}, Journal = {The American journal of psychiatry}, Volume = {166}, Number = {1}, Pages = {64-73}, Address = {University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O'Hara St., Loeffler 319, Pittsburgh, PA 15213, USA. forbese@upmc.edu}, Year = {2009}, Month = {January}, ISSN = {0002-953X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19047324}, Keywords = {Adolescent • Affect/*physiology • Age Factors • Caudate Nucleus/physiopathology • Child • Computers, Handheld • Corpus Striatum/*physiopathology • Depressive Disorder, Major/diagnosis/*physiopathology/psychology • Dominance, Cerebral/physiology • Female • Humans • *Image Processing, Computer-Assisted • *Magnetic Resonance Imaging • Male • Motivation • Neurons/physiology • Oxygen/*blood • Prefrontal Cortex/physiopathology • Prognosis • Reward • *Social Environment}, Abstract = {<h4>Objective</h4>Alterations in reward-related brain function and phenomenological aspects of positive affect are increasingly examined in the development of major depressive disorder. The authors tested differences in reward-related brain function in healthy and depressed adolescents, and the authors examined direct links between reward-related brain function and positive mood that occurred in real-world contexts.<h4>Method</h4>Fifteen adolescents with major depressive disorder and 28 adolescents with no history of psychiatric disorder, ages 8-17 years, completed a functional magnetic resonance imaging guessing task involving monetary reward. Participants also reported their subjective positive affect in natural environments during a 4-day cell-phone-based ecological momentary assessment.<h4>Results</h4>Adolescents with major depressive disorder exhibited less striatal response than healthy comparison adolescents during reward anticipation and reward outcome, but more response in dorsolateral and medial prefrontal cortex. Diminished activation in a caudate region associated with this depression group difference was correlated with lower subjective positive affect in natural environments, particularly within the depressed group.<h4>Conclusions</h4>Results support models of altered reward processing and related positive affect in young people with major depressive disorder and indicate that depressed adolescents' brain response to monetary reward is related to their affective experience in natural environments. Additionally, these results suggest that reward-processing paradigms capture brain function relevant to real-world positive affect.}, Language = {eng}, Doi = {10.1176/appi.ajp.2008.07081336}, Key = {Forbes2009a} } @article{Fakra2009, Author = {Fakra, E and Hyde, LW and Gorka, A and Fisher, PM and Muñoz, KE and Kimak, M and Halder, I and Ferrell, RE and Manuck, SB and Hariri, AR}, Title = {Effects of HTR1A C(-1019)G on amygdala reactivity and trait anxiety.}, Journal = {Archives of general psychiatry}, Volume = {66}, Number = {1}, Pages = {33-40}, Address = {Hopital de laTimone, ServiceHospitalo-Universitaire dePsychiatrie, Hopital SteMarguerite, Marseille, France.}, Year = {2009}, Month = {January}, ISSN = {0003-990X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19124686}, Keywords = {Adult • *Alleles • Amygdala/*physiopathology • Anger/physiology • Anxiety Disorders/*genetics/physiopathology • Arousal/*genetics/physiology • Attention/physiology • Autoreceptors/*genetics • Dominance, Cerebral/physiology • Facial Expression • Fear/physiology • Female • Genotype • Humans • *Image Processing, Computer-Assisted • *Magnetic Resonance Imaging • Male • Middle Aged • Oxygen/*blood • Pattern Recognition, Visual/physiology • Receptor, Serotonin, 5-HT1A/*genetics • Signal Transduction/genetics}, Abstract = {<h4>Context</h4>Serotonin 1A (5-hydroxytryptamine 1A [5-HT(1A)]) autoreceptors mediate negative feedback inhibition of serotonergic neurons and play a critical role in regulating serotonin signaling involved in shaping the functional response of major forebrain targets, such as the amygdala, supporting complex behavioral processes. A common functional variation (C[-1019]G) in the human 5-HT(1A) gene (HTR1A) represents 1 potential source of such interindividual variability. Both in vitro and in vivo, -1019G blocks transcriptional repression, leading to increased autoreceptor expression. Thus, -1019G may contribute to relatively decreased serotonin signaling at postsynaptic forebrain target sites via increased negative feedback.<h4>Objectives</h4>To evaluate the effects of HTR1A C(-1019)G on amygdala reactivity and to use path analyses to explore the impact of HTR1A-mediated variability in amygdala reactivity on individual differences in trait anxiety. We hypothesized that -1019G, which potentially results in decreased serotonin signaling, would be associated with relatively decreased amygdala reactivity and related trait anxiety.<h4>Design</h4>Imaging genetics in participants from an archival database.<h4>Participants</h4>Eighty-nine healthy adults.<h4>Results</h4>Consistent with prior findings, -1019G was associated with significantly decreased threat-related amygdala reactivity. Importantly, this effect was independent of that associated with another common functional polymorphism that affects serotonin signaling, 5-HTTLPR. While there were no direct genotype effects on trait anxiety, HTR1A C(-1019)G indirectly predicted 9.2% of interindividual variability in trait anxiety through its effects on amygdala reactivity.<h4>Conclusions</h4>Our findings further implicate relatively increased serotonin signaling, associated with a genetic variation that mediates increased 5-HT(1A) autoreceptors, in driving amygdala reactivity and trait anxiety. Moreover, they provide empirical documentation of the basic premise that genetic variation indirectly affects emergent behavioral processes related to psychiatric disease risk by biasing the response of underlying neural circuitries.}, Language = {eng}, Doi = {10.1001/archpsyc.66.1.33}, Key = {Fakra2009} } @article{Hariri2009b, Author = {Hariri, AR}, Title = {The neurobiology of individual differences in complex behavioral traits.}, Journal = {Annual review of neuroscience}, Volume = {32}, Pages = {225-247}, Address = {Department of Psychology and Neuroscience, Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina 27708, USA. ah154@duke.edu}, Year = {2009}, Month = {January}, ISSN = {0147-006X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19400720}, Keywords = {Animals • Behavior/*physiology • Biological Markers/analysis • Brain Mapping/*methods • Genetic Predisposition to Disease/genetics • Genetic Variation/physiology • Humans • Magnetic Resonance Imaging/*methods • Neuropsychology/*methods • Positron-Emission Tomography/*methods • *Quantitative Trait, Heritable}, Abstract = {Neuroimaging, especially BOLD fMRI, has begun to identify how variability in brain function contributes to individual differences in complex behavioral traits. In parallel, pharmacological fMRI and multimodal PET/fMRI are identifying how variability in molecular signaling pathways influences individual differences in brain function. Against this background, functional genetic polymorphisms are being utilized to understand the origins of variability in signaling pathways as well as to model efficiently how such emergent variability impacts behaviorally relevant brain function. This article provides an overview of a research strategy seeking to integrate these complementary technologies and utilizes existing empirical data to illustrate its effectiveness in illuminating the neurobiology of individual differences in complex behavioral traits. The article also discusses how such efforts can contribute to the identification of predictive markers that interact with environmental factors to precipitate disease and to develop more effective and individually tailored treatment regimes.}, Language = {eng}, Doi = {10.1146/annurev.neuro.051508.135335}, Key = {Hariri2009b} } @article{Kienast2008, Author = {Kienast, T and Hariri, AR and Schlagenhauf, F and Wrase, J and Sterzer, P and Buchholz, HG and Smolka, MN and Gründer, G and Cumming, P and Kumakura, Y and Bartenstein, P and Dolan, RJ and Heinz, A}, Title = {Dopamine in amygdala gates limbic processing of aversive stimuli in humans.}, Journal = {Nature neuroscience}, Volume = {11}, Number = {12}, Pages = {1381-1382}, Address = {Department of Psychiatry and Psychotherapy, Campus Charite Mitte, Charite-University Medicine Berlin, Chariteplatz 1, 10117 Berlin, Germany.}, Year = {2008}, Month = {December}, ISSN = {1097-6256}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18978778}, Keywords = {Adult • *Affect • Amygdala/blood supply/*metabolism/radionuclide imaging • *Brain Mapping • Dihydroxyphenylalanine/analogs \& derivatives/pharmacokinetics • Dopamine/*metabolism • Fluorine Radioisotopes/pharmacokinetics • Gyrus Cinguli/blood supply/radionuclide imaging • Humans • Image Processing, Computer-Assisted • Limbic System/*metabolism/radionuclide imaging • Magnetic Resonance Imaging/methods • Male • Middle Aged • Oxygen/blood • Positron-Emission Tomography/methods • Psychophysics}, Abstract = {Dopamine is released under stress and modulates processing of aversive stimuli. We found that dopamine storage capacity in human amygdala, measured with 6-[(18)F]fluoro-L-DOPA positron emission tomography, was positively correlated with functional magnetic resonance imaging blood oxygen level-dependent signal changes in amygdala and dorsal anterior cingulate cortex that were evoked by aversive stimuli. Furthermore, functional connectivity between these two regions was inversely related to trait anxiety. Our results suggest that individual dopamine storage capacity in amygdala subserves modulation of emotional processing in amygdala and dorsal cingulate, thereby contributing to individual differences in anxious temperament.}, Language = {eng}, Doi = {10.1038/nn.2222}, Key = {Kienast2008} } @article{Zanardi2008, Author = {Zanardi, R and Barbini, B and Rossini, D and Bernasconi, A and Fregni, F and Padberg, F and Rossi, S and Wirz-Justice, A and Terman, M and Martiny, K and Bersani, G and Hariri, AR and Pezawas, L and Roiser, JP and Bertolino, A and Calabrese, G and Magri, L and Benedetti, F and Pontiggia, A and Malaguti, A and Smeraldi, E and Colombo, C}, Title = {New perspectives on techniques for the clinical psychiatrist: Brain stimulation, chronobiology and psychiatric brain imaging.}, Journal = {Psychiatry and clinical neurosciences}, Volume = {62}, Number = {6}, Pages = {627-637}, Address = {San Raffaele Hospital Department of Psychiatry, Vita-Salute University, Milan, Italy. zanardi.raffaella@hsr.it}, Year = {2008}, Month = {December}, ISSN = {1323-1316}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19067998}, Keywords = {Brain/*pathology • Diagnostic Imaging • Humans • Magnetic Resonance Imaging • Magnetic Resonance Spectroscopy • Mental Disorders/pathology/physiopathology/*therapy • Mood Disorders/psychology • Periodicity • Psychiatry/*methods/*trends • Tomography, Emission-Computed, Single-Photon • *Transcranial Magnetic Stimulation}, Abstract = {This review summarizes a scientific dialogue between representatives in non-pharmacological treatment options of affective disorders. Among the recently introduced somatic treatments for depression those with most evidenced efficacy will be discussed. The first part of this article presents current opinions about the clinical applications of transcranial magnetic stimulation in the treatment of depression. The second part explains the most relevant uses of chronobiology in mood disorders, while the last part deals with the main perspectives on brain imaging techniques in psychiatry. The aim was to bridge gaps between the research evidence and clinical decisions, and reach an agreement on several key points of chronobiological and brain stimulation techniques, as well as on relevant objectives for future research.}, Language = {eng}, Doi = {10.1111/j.1440-1819.2008.01863.x}, Key = {Zanardi2008} } @article{Bigos2008, Author = {Bigos, KL and Pollock, BG and Aizenstein, HJ and Fisher, PM and Bies, RR and Hariri, AR}, Title = {Acute 5-HT reuptake blockade potentiates human amygdala reactivity.}, Journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, Volume = {33}, Number = {13}, Pages = {3221-3225}, Address = {Department of Pharmaceutical Sciences, University of Pittsburgh, PA, USA. bigosk@mail.nih.gov}, Year = {2008}, Month = {December}, ISSN = {0893-133X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18463627}, Keywords = {Adult • Akathisia, Drug-Induced/metabolism/physiopathology • Amygdala/*drug effects/*metabolism • Anxiety/chemically induced/metabolism/physiopathology • Brain Chemistry/*drug effects/*physiology • Citalopram/*pharmacology • Cross-Over Studies • Depressive Disorder/drug therapy/metabolism/physiopathology • Dose-Response Relationship, Drug • Double-Blind Method • Facial Expression • Humans • Male • Middle Aged • Neuropsychological Tests • Photic Stimulation • Presynaptic Terminals/drug effects/metabolism • Serotonin/*metabolism • Serotonin Uptake Inhibitors/pharmacology • Young Adult}, Abstract = {Variability in serotonin (5-HT) function is associated with individual differences in normal mood and temperament, as well as psychiatric illnesses, all of which are influenced by amygdala function. This study evaluated the acute effects of 5-HT reuptake blockade on amygdala function using pharmacological functional MRI. Eight healthy men completed a double-blind balanced crossover study with the selective 5-HT reuptake inhibitor, citalopram (20 mg infused over 30 min), and normal saline. Amygdala reactivity in response to novel facial expressions was assessed on three successive scans, once before drug/placebo infusion, once early in the infusion, and once at the end of infusion. Acute citalopram administration resulted in concentration-dependent increases in human amygdala reactivity to salient stimuli. The current pattern of 5-HT-mediated amygdala reactivity may represent an important pathway through which SSRIs achieve an antidepressant effect. Intriguingly, our data may also reveal a mechanism contributing to clinical observations of extreme agitation, restlessness, and suicidal ideation in some individuals during acute SSRI treatment. Developing a comprehensive model of how 5-HT modulates human amygdala reactivity supporting behavioral and physiological arousal will be instrumental for our understanding of basic neurobehavioral processes, their dysfunction in psychiatric illnesses, and their contribution to mechanism of treatment response.}, Language = {eng}, Doi = {10.1038/npp.2008.52}, Key = {Bigos2008} } @article{Ousdal2008, Author = {Ousdal, OT and Jensen, J and Server, A and Hariri, AR and Nakstad, PH and Andreassen, OA}, Title = {The human amygdala is involved in general behavioral relevance detection: evidence from an event-related functional magnetic resonance imaging Go-NoGo task.}, Journal = {Neuroscience}, Volume = {156}, Number = {3}, Pages = {450-455}, Address = {TOP Project, Psychosis Research Section, Division of Psychiatry, Building 49, Ulleval University Hospital, Oslo, Norway.}, Year = {2008}, Month = {October}, ISSN = {0306-4522}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18775476}, Keywords = {Adult • Amygdala/*blood supply/*physiology • Decision Making/*physiology • Female • Humans • Image Processing, Computer-Assisted • *Magnetic Resonance Imaging • Male • Neuropsychological Tests • Oxygen/blood • Pattern Recognition, Visual • Photic Stimulation/methods • Reaction Time/physiology • Signal Detection, Psychological/*physiology • Young Adult}, Abstract = {The amygdala is classically regarded as a detector of potential threat and as a critical component of the neural circuitry mediating conditioned fear responses. However, it has been reported that the human amygdala responds to multiple expressions of emotions as well as emotionally neutral stimuli of a novel, uncertain or ambiguous nature. Thus, it has been proposed that the function of the amygdala may be of a more general art, i.e. as a detector of behaviorally relevant stimuli [Sander D, Grafman J, Zalla T (2003) The human amygdala: an evolved system for relevance detection. Rev Neurosci 14:303-316]. To investigate this putative function of the amygdala, we used event related functional magnetic resonance imaging (fMRI) and a modified Go-NoGo task composed of behaviorally relevant and irrelevant letter and number stimuli. Analyses revealed bilateral amygdala activation in response to letter stimuli that were behaviorally relevant as compared with letters with less behavioral relevance. Similar results were obtained for relatively infrequent NoGo relevant stimuli as compared with more frequent Go stimuli. Our findings support a role for the human amygdala in general detection of behaviorally relevant stimuli.}, Language = {eng}, Doi = {10.1016/j.neuroscience.2008.07.066}, Key = {Ousdal2008} } @article{Marsland2008, Author = {Marsland, AL and Gianaros, PJ and Abramowitch, SM and Manuck, SB and Hariri, AR}, Title = {Interleukin-6 covaries inversely with hippocampal grey matter volume in middle-aged adults.}, Journal = {Biological psychiatry}, Volume = {64}, Number = {6}, Pages = {484-490}, Address = {Behavioral Immunology Laboratory, University of Pittsburgh, PA 15260, USA. marsland@pitt.edu}, Year = {2008}, Month = {September}, ISSN = {0006-3223}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18514163}, Keywords = {Adipose Tissue/metabolism • Adult • Cognition Disorders/diagnosis/epidemiology • Diagnostic and Statistical Manual of Mental Disorders • Female • Hippocampus/*anatomy \& histology/*metabolism • Humans • Hypertension/epidemiology/metabolism • Inflammation/epidemiology/metabolism • Interleukin-6/*metabolism • Magnetic Resonance Imaging • Male • Middle Aged • Nerve Net/metabolism • Registries • Severity of Illness Index • Wechsler Scales}, Abstract = {<h4>Background</h4>Converging animal findings suggest that higher peripheral levels of inflammation are associated with activation of central inflammatory mechanisms that result in hippocampal neurodegeneration and related impairment of memory function. We have recently shown, consistent with animal findings, an inverse association between peripheral levels of interleukin-6 (IL-6), a relatively stable marker of systemic inflammation, and memory function in mid-life adults. In the current study, we extend this work to test whether systemic inflammation is associated with reduced grey matter volume of the hippocampus.<h4>Methods</h4>For this purpose, we used a computational structural neuroimaging method (optimized voxel-based morphometry) to evaluate the relationship between plasma IL-6 levels and hippocampal grey matter volume in a sample of 76 relatively healthy community volunteers ages 30-54.<h4>Results</h4>Peripheral levels of IL-6 covaried inversely with hippocampal grey matter volume, and this relationship persisted after accounting for several possible confounders, including age, gender, race, years of education, percent body fat, blood pressure, smoking, physical activity, hours of sleep, alcohol use, and total grey matter volume.<h4>Conclusions</h4>To our knowledge, this is the first report of a relationship between a peripheral marker of IL-6 and hippocampal grey matter volume, raising the possibility that low-grade systemic inflammation could plausibly presage subclinical cognitive decline in part via structural neural pathways.}, Language = {eng}, Doi = {10.1016/j.biopsych.2008.04.016}, Key = {Marsland2008} } @article{fds252000, Author = {Pezawas, L and Meyer-Lindenberg, A and Goldman, AL and Verchinski, BA and Chen, G and Kolachana, BS and Egan, MF and Mattay, VS and Hariri, AR and Weinberger, DR}, Title = {MET BDNF protects against morphological S allele effects of 5-HTTLPR}, Journal = {Molecular Psychiatry}, Volume = {13}, Number = {7}, Pages = {654}, Publisher = {Springer Nature}, Year = {2008}, Month = {July}, ISSN = {1359-4184}, url = {http://dx.doi.org/10.1038/mp.2008.61}, Doi = {10.1038/mp.2008.61}, Key = {fds252000} } @article{Pezawas2008, Author = {Pezawas, L and Meyer-Lindenberg, A and Goldman, AL and Verchinski, BA and Chen, G and Kolachana, BS and Egan, MF and Mattay, VS and Hariri, AR and Weinberger, DR}, Title = {Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression.}, Journal = {Molecular psychiatry}, Volume = {13}, Number = {7}, Pages = {709-716}, Address = {Genes, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.}, Year = {2008}, Month = {July}, ISSN = {1359-4184}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18347599}, Keywords = {Amino Acid Substitution • Brain/pathology • Brain-Derived Neurotrophic Factor/*genetics • Depression/*genetics/pathology • Depressive Disorder/*genetics/pathology • *Epistasis, Genetic • European Continental Ancestry Group/genetics • Gyrus Cinguli/pathology • Humans • Magnetic Resonance Imaging • Polymorphism, Genetic • Reference Values • Serotonin Plasma Membrane Transport Proteins/*genetics}, Abstract = {Complex genetic disorders such as depression likely exhibit epistasis, but neural mechanisms of such gene-gene interactions are incompletely understood. 5-HTTLPR and BDNF VAL66MET, functional polymorphisms of the serotonin (5-HT) transporter (SLC6A4) and brain-derived neurotrophic factor (BDNF) gene, impact on two distinct, but interacting signaling systems, which have been related to depression and to the modulation of neurogenesis and plasticity of circuitries of emotion processing. Recent clinical studies suggest that the BDNF MET allele, which shows abnormal intracellular trafficking and regulated secretion, has a protective effect regarding the development of depression and in mice of social defeat stress. Here we show, using anatomical neuroimaging techniques in a sample of healthy subjects (n=111), that the BDNF MET allele, which is predicted to have reduced responsivity to 5-HT signaling, protects against 5-HTTLPR S allele-induced effects on a brain circuitry encompassing the amygdala and the subgenual portion of the anterior cingulate (rAC). Our analyses revealed no effect of the 5-HTTLPR S allele on rAC volume in the presence of BDNF MET alleles, whereas a significant volume reduction (P<0.001) was seen on BDNF VAL/VAL background. Interacting genotype effects were also found in structural connectivity between amygdala and rAC (P=0.002). These data provide in vivo evidence of biologic epistasis between SLC6A4 and BDNF in the human brain by identifying a neural mechanism linking serotonergic and neurotrophic signaling on the neural systems level, and have implications for personalized treatment planning in depression.}, Language = {eng}, Doi = {10.1038/mp.2008.32}, Key = {Pezawas2008} } @article{Gianaros2008b, Author = {Gianaros, PJ and Horenstein, JA and Hariri, AR and Sheu, LK and Manuck, SB and Matthews, KA and Cohen, S}, Title = {Potential neural embedding of parental social standing.}, Journal = {Social cognitive and affective neuroscience}, Volume = {3}, Number = {2}, Pages = {91-96}, Address = {Department of Psychiatry, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA 15213, USA. gianarospj@upmc.edu}, Year = {2008}, Month = {June}, ISSN = {1749-5016}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18594696}, Keywords = {Adaptation, Psychological/physiology • Aggression/*physiology/psychology • Amygdala/*physiology • Facial Expression • Hierarchy, Social • Humans • Magnetic Resonance Imaging • Male • Parents/psychology • Reference Values • Self Concept • *Social Class • *Social Perception • Stress, Psychological/*physiopathology • Young Adult}, Abstract = {Socioeconomic disadvantage during childhood and adolescence predicts poor mental and physical health and premature death by major medical diseases in adulthood. However, the neural pathways through which socioeconomic factors may exert a developmental influence on health and longevity remain largely unknown. This fMRI study provides novel evidence of a unique relationship between the perception that one's parents had a relatively low social standing--a putative indicator of early socioeconomic disadvantage--and greater amygdala reactivity to threatening facial expressions. This relationship was not explained by several possible confounders, including sex, ethnicity, dispositional emotionality, symptoms of depression and anxiety, parental education and participants' perceptions of their own social standing. The amygdala expresses marked developmental plasticity and plays instrumental roles in processing emotional information, regulating emotion-related behaviors and orchestrating biobehavioral stress responses throughout life. Thus, these findings may provide insight into the neurodevelopmental pathways impacting socioeconomic disparities in health.}, Language = {eng}, Doi = {10.1093/scan/nsn003}, Key = {Gianaros2008b} } @article{Fisher2008, Author = {Fisher, PM and Muñoz, KE and Hariri, AR}, Title = {Identification of neurogenetic pathways of risk for psychopathology.}, Journal = {American journal of medical genetics. Part C, Seminars in medical genetics}, Volume = {148C}, Number = {2}, Pages = {147-153}, Address = {University of Pittsburgh, Pittsburgh, PA 15213-2593, USA.}, Year = {2008}, Month = {May}, ISSN = {1552-4868}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18412103}, Keywords = {Brain/growth \& development/*physiopathology • Catechol O-Methyltransferase/genetics/physiology • Diagnostic Imaging • Dopamine Plasma Membrane Transport Proteins/genetics/physiology • Female • Humans • Male • Mental Disorders/diagnosis/*genetics/*physiopathology • Monoamine Oxidase/genetics/physiology • Psychopathology • Risk Factors • Serotonin Plasma Membrane Transport Proteins/genetics/physiology • Tryptophan Hydroxylase/genetics/physiology}, Abstract = {Imaging genetics has been a highly effective and increasingly applied strategy for identifying the impact of genetic polymorphisms on individual differences in neural circuitry supporting complex behaviors. The application of imaging genetics towards further elucidating neural circuitry associated with the pathophysiology of psychiatric illness is of particular interest given its potential to guide the development and improvement of current therapeutic methods. The identification of genetic variants that contribute to or predict the disruption of specific neural pathways associated with psychopathology may also serve as useful markers of risk demarcating individuals with elevated susceptibility for psychiatric illness and affording early or even preemptive treatment strategies. In the continued development of this technique, recent multimodal neuroimaging strategies and studies examining the effects of multiple genes in concert within large subject populations have shown promise in the development of a more complete understanding of the interrelationships between genes, brain function, behavior and associated risk for psychopathology.}, Language = {eng}, Doi = {10.1002/ajmg.c.30173}, Key = {Fisher2008} } @article{Munafo2008, Author = {Munafò, MR and Brown, SM and Hariri, AR}, Title = {Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis.}, Journal = {Biological psychiatry}, Volume = {63}, Number = {9}, Pages = {852-857}, Address = {Department of Experimental Psychology, University of Bristol, United Kingdom. marcus.munafo@bristol.ac.uk}, Year = {2008}, Month = {May}, ISSN = {0006-3223}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17949693}, Keywords = {Adolescent • Adult • Alleles • Amygdala/*physiopathology • Anxiety Disorders/genetics/physiopathology • Depressive Disorder/genetics/physiopathology • Female • *Genotype • Humans • Individuality • Magnetic Resonance Imaging • Male • Phenotype • Polymorphism, Genetic/*genetics • Promoter Regions, Genetic/*genetics • Serotonin Plasma Membrane Transport Proteins/*genetics • Stress, Psychological/complications}, Abstract = {<h4>Background</h4>We evaluated the magnitude of the reported associations between amygdala activation and the serotonin transporter gene linked polymorphic region (5-HTTLPR) and the likely effect size of this relationship.<h4>Methods</h4>We used meta-analytic techniques to combine data from existing published and unpublished studies. We also tested for possible publication bias and explored possible moderating influences on any association, such as sample ancestry.<h4>Results</h4>Our results provide support for the association of the 5-HTTLPR polymorphism and amygdala activation and suggest that this locus may account for up to 10% of phenotypic variance. Although we did not observe evidence for potential publication bias in our main analysis, this was due in part to efforts to obtain unpublished data pertinent to this meta-analysis, and when three unpublished data sets were excluded we did observe evidence of such bias. We also observed evidence that the first published study may provide an overestimate of the true effect size, which is consistent with findings from genetic association studies of other phenotypes.<h4>Conclusions</h4>Although our analysis provides support for the association of the 5-HTTLPR polymorphism and amygdala activation, it also suggests that most studies to date are nevertheless lacking in statistical power. Increasing the sample sizes of future imaging genetics studies will allow a more accurate characterization of any true effect size and afford adequate power to examine the impact of multiple polymorphisms that likely work in concert to affect gene function and, in turn, bias neural processes mediating dispositional traits such as temperament and personality.}, Language = {eng}, Doi = {10.1016/j.biopsych.2007.08.016}, Key = {Munafo2008} } @article{Krystal2008, Author = {Krystal, JH and Carter, CS and Geschwind, D and Manji, HK and March, JS and Nestler, EJ and Zubieta, J-K and Charney, DS and Goldman, D and Gur, RE and Lieberman, JA and Roy-Byrne, P and Rubinow, DR and Anderson, SA and Barondes, S and Berman, KF and Blair, J and Braff, DL and Brown, ES and Calabrese, JR and Carlezon, WA and Cook, EH and Davidson, RJ and Davis, M and Desimone, R and Drevets, WC and Duman, RS and Essock, SM and Faraone, SV and Freedman, R and Friston, KJ and Gelernter, J and Geller, B and Gill, M and Gould, E and Grace, AA and Grillon, C and Gueorguieva, R and Hariri, AR and Innis, RB and Jones, EG and Kleinman, JE and Koob, GF and Krystal, AD and Leibenluft, E and Levinson, DF and Levitt, PR and Lewis, DA and Liberzon, I and Lipska, BK and Marder, SR and Markou, A and Mason, GF and McDougle, CJ and McEwen, BS and McMahon, FJ and Meaney, MJ and Meltzer, HY and Merikangas, KR and Meyer-Lindenberg, A and Mirnics, K and Monteggia, LM and Neumeister, A and O'Brien, CP and Owen, MJ and Pine, DS and Rapoport, JL and Rauch, SL and Robbins, TW and Rosenbaum, JF and Rosenberg, DR and Ross, CA and Rush, AJ and Sackeim, HA and Sanacora, G and Schatzberg, AF and Shaham, Y and Siever, LJ and Sunderland, T and Tecott, LH and Thase, ME and Todd, RD and Weissman, MM and Yehuda, R and Yoshikawa, T and Young, EA and McCandless, R}, Title = {It is time to take a stand for medical research and against terrorism targeting medical scientists.}, Journal = {Biol Psychiatry}, Volume = {63}, Number = {8}, Pages = {725-727}, Address = {Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA. john.krystal@yale.edu}, Year = {2008}, Month = {April}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18371494}, Keywords = {*Animal Experimentation • Animal Rights • Animals • *Attitude of Health Personnel • *Biomedical Research • Crime/prevention \& control • Ethics, Research • Humans • Primates • *Research Personnel • Terrorism/*prevention \& control • United States}, Language = {eng}, Doi = {10.1016/j.biopsych.2008.03.005}, Key = {Krystal2008} } @article{Zhou2008, Author = {Zhou, Z and Zhu, G and Hariri, AR and Enoch, M-A and Scott, D and Sinha, R and Virkkunen, M and Mash, DC and Lipsky, RH and Hu, X-Z and Hodgkinson, CA and Xu, K and Buzas, B and Yuan, Q and Shen, P-H and Ferrell, RE and Manuck, SB and Brown, SM and Hauger, RL and Stohler, CS and Zubieta, J-K and Goldman, D}, Title = {Genetic variation in human NPY expression affects stress response and emotion.}, Journal = {Nature}, Volume = {452}, Number = {7190}, Pages = {997-1001}, Address = {Laboratory of Neurogenetics, NIAAA, NIH, Bethesda, Maryland 20892, USA.}, Year = {2008}, Month = {April}, ISSN = {0028-0836}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18385673}, Keywords = {Alleles • Anxiety/genetics • Anxiety Disorders/genetics • Brain/*metabolism/physiology/physiopathology • *Emotions • European Continental Ancestry Group/genetics • Facial Expression • Finland/ethnology • Gene Expression Regulation/*genetics • Genetic Variation/*genetics • Haplotypes/genetics • Humans • Lymphocytes/metabolism • Magnetic Resonance Imaging • Male • Neuropeptide Y/blood/*genetics • Opioid Peptides/metabolism • Pain/genetics • Polymorphism, Single Nucleotide/genetics • RNA, Messenger/genetics/metabolism • Stress, Physiological/*genetics/psychology • United States/ethnology}, Abstract = {Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic and its release is induced by stress. NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories. Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in post-mortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases.}, Language = {eng}, Doi = {10.1038/nature06858}, Key = {Zhou2008} } @article{Fakra2008, Author = {Fakra, E and Salgado-Pineda, P and Delaveau, P and Hariri, AR and Blin, O}, Title = {Neural bases of different cognitive strategies for facial affect processing in schizophrenia.}, Journal = {Schizophrenia research}, Volume = {100}, Number = {1-3}, Pages = {191-205}, Address = {CIC-UPCET, Hopital de la Timone, UMR CNRS 6193 INCM, Marseille, France. eric.fakra@ap-hm.fr}, Year = {2008}, Month = {March}, ISSN = {0920-9964}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18234477}, Keywords = {Adult • Affect/*physiology • Amygdala/physiopathology • Brain/*physiopathology • Brain Mapping • Cerebral Cortex/physiopathology • Control Groups • *Facial Expression • Female • Functional Laterality/physiology • Humans • Limbic System/physiopathology • Magnetic Resonance Imaging/*statistics \& numerical data • Male • Models, Neurological • Neural Pathways/physiopathology • Recognition (Psychology)/physiology • Schizophrenia/*diagnosis/physiopathology • *Schizophrenic Psychology • Social Perception • Task Performance and Analysis • Visual Perception/*physiology}, Abstract = {<h4>Objective</h4>To examine the neural basis and dynamics of facial affect processing in schizophrenic patients as compared to healthy controls.<h4>Method</h4>Fourteen schizophrenic patients and fourteen matched controls performed a facial affect identification task during fMRI acquisition. The emotional task included an intuitive emotional condition (matching emotional faces) and a more cognitively demanding condition (labeling emotional faces). Individual analysis for each emotional condition, and second-level t-tests examining both within-, and between-group differences, were carried out using a random effects approach. Psychophysiological interactions (PPI) were tested for variations in functional connectivity between amygdala and other brain regions as a function of changes in experimental conditions (labeling versus matching).<h4>Results</h4>During the labeling condition, both groups engaged similar networks. During the matching condition, schizophrenics failed to activate regions of the limbic system implicated in the automatic processing of emotions. PPI revealed an inverse functional connectivity between prefrontal regions and the left amygdala in healthy volunteers but there was no such change in patients. Furthermore, during the matching condition, and compared to controls, patients showed decreased activation of regions involved in holistic face processing (fusiform gyrus) and increased activation of regions associated with feature analysis (inferior parietal cortex, left middle temporal lobe, right precuneus).<h4>Conclusions</h4>Our findings suggest that schizophrenic patients invariably adopt a cognitive approach when identifying facial affect. The distributed neocortical network observed during the intuitive condition indicates that patients may resort to feature-based, rather than configuration-based, processing and may constitute a compensatory strategy for limbic dysfunction.}, Language = {eng}, Doi = {10.1016/j.schres.2007.11.040}, Key = {Fakra2008} } @article{Buckholtz2008, Author = {Buckholtz, JW and Callicott, JH and Kolachana, B and Hariri, AR and Goldberg, TE and Genderson, M and Egan, MF and Mattay, VS and Weinberger, DR and Meyer-Lindenberg, A}, Title = {Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personality.}, Journal = {Molecular psychiatry}, Volume = {13}, Number = {3}, Pages = {313-324}, Address = {Neuroimaging Core Facility, National Institute for Mental Health, NIH, DHHS, Bethesda, MD 20892-1365, USA.}, Year = {2008}, Month = {March}, ISSN = {1359-4184}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17519928}, Keywords = {Adult • Brain Mapping • Facial Expression • Female • *Genetic Variation • Humans • Image Processing, Computer-Assisted • *Individuality • Magnetic Resonance Imaging • Male • Models, Biological • Monoamine Oxidase/*genetics • Neural Pathways/blood supply/physiology • Neuropsychological Tests • Oxygen/blood • Personality/*genetics • Photic Stimulation/methods • Prefrontal Cortex/blood supply/*physiology}, Abstract = {Little is known about neural mechanisms underlying human personality and temperament, despite their considerable importance as highly heritable risk mediators for somatic and psychiatric disorders. To identify these circuits, we used a combined genetic and imaging approach focused on Monoamine Oxidase A (MAOA), encoding a key enzyme for monoamine metabolism previously associated with temperament and antisocial behavior. Male carriers of a low-expressing genetic variant exhibited dysregulated amygdala activation and increased functional coupling with ventromedial prefrontal cortex (vmPFC). Stronger coupling predicted increased harm avoidance and decreased reward dependence scores, suggesting that this circuitry mediates a part of the association of MAOA with these traits. We utilized path analysis to parse the effective connectivity within this system, and provide evidence that vmPFC regulates amygdala indirectly by influencing rostral cingulate cortex function. Our data implicate a neural circuit for variation in human personality under genetic control, provide an anatomically consistent mechanism for vmPFC-amygdala interactions underlying this variation, and suggest a role for vmPFC as a superordinate regulatory area for emotional arousal and social behavior.}, Language = {eng}, Doi = {10.1038/sj.mp.4002020}, Key = {Buckholtz2008} } @article{fds251999, Author = {Hariri, AR}, Title = {Imaging genetics offers new predictive markers of individual differences in behavior and risk for psychiatric diseases}, Journal = {Neuropsychopharmacology}, Volume = {33}, Number = {1}, Pages = {201-202}, Publisher = {Springer Nature}, Year = {2008}, Month = {January}, ISSN = {0893-133X}, url = {http://dx.doi.org/10.1038/sj.npp.1301608}, Doi = {10.1038/sj.npp.1301608}, Key = {fds251999} } @article{Gianaros2008a, Author = {Gianaros, PJ and Sheu, LK and Matthews, KA and Jennings, JR and Manuck, SB and Hariri, AR}, Title = {Individual differences in stressor-evoked blood pressure reactivity vary with activation, volume, and functional connectivity of the amygdala.}, Journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, Volume = {28}, Number = {4}, Pages = {990-999}, Address = {Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. gianarospj@upmc.edu}, Year = {2008}, Month = {January}, ISSN = {0270-6474}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18216206}, Keywords = {Adolescent • Adult • Amygdala/anatomy \& histology/*physiology • Blood Pressure/*physiology • Female • Humans • *Individuality • Male • Nerve Net/anatomy \& histology/*physiology • Organ Size/physiology • Pons/anatomy \& histology/physiology • Stress, Psychological/*physiopathology}, Abstract = {Individuals who exhibit exaggerated blood pressure reactions to psychological stressors are at risk for hypertension, ventricular hypertrophy, and premature atherosclerosis; however, the neural systems mediating exaggerated blood pressure reactivity and associated cardiovascular risk in humans remain poorly defined. Animal models indicate that the amygdala orchestrates stressor-evoked blood pressure reactions via reciprocal signaling with corticolimbic and brainstem cardiovascular-regulatory circuits. Based on these models, we used a multimodal neuroimaging approach to determine whether human individual differences in stressor-evoked blood pressure reactivity vary with amygdala activation, gray matter volume, and functional connectivity with corticolimbic and brainstem areas implicated in stressor processing and cardiovascular regulation. We monitored mean arterial pressure (MAP) and concurrent functional magnetic resonance imaging BOLD signal changes in healthy young individuals while they completed a Stroop color-word stressor task, validated previously in epidemiological studies of cardiovascular risk. Individuals exhibiting greater stressor-evoked MAP reactivity showed (1) greater amygdala activation, (2) lower amygdala gray matter volume, and (3) stronger positive functional connectivity between the amygdala and perigenual anterior cingulate cortex and brainstem pons. Individual differences in amygdala activation, gray matter volume, and functional connectivity with corticolimbic and brainstem circuits may partly underpin cardiovascular disease risk by impacting stressor-evoked blood pressure reactivity.}, Language = {eng}, Doi = {10.1523/jneurosci.3606-07.2008}, Key = {Gianaros2008a} } @article{Bigos2007, Author = {Bigos, KL and Hariri, AR}, Title = {Neuroimaging: technologies at the interface of genes, brain, and behavior.}, Journal = {Neuroimaging clinics of North America}, Volume = {17}, Number = {4}, Pages = {459-viii}, Address = {Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15213, USA.}, Year = {2007}, Month = {November}, ISSN = {1052-5149}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17983963}, Keywords = {Behavior/*physiology • Brain/*physiology • *Brain Mapping • *Gene Expression • Humans • *Polymorphism, Genetic}, Abstract = {Neuroimaging technologies provide a powerful approach to exploring the genetic basis of individual differences in complex behaviors and vulnerability to neuropsychiatric illness. Functional MRI studies have established important physiologic links between genetic polymorphisms and robust differences in information processing within distinct brain regions and circuits that have been linked to the manifestation of various disease. Neuroimaging technologies represent a critical tool in efforts to understand the neurobiology of normal and pathologic behavioral states. Research capitalizing on neuroimagingbased integration will contribute to the identification of predictive markers and biologic pathways for neuropsychiatric disease vulnerability and the generation of novel targets for therapeutic intervention.}, Language = {eng}, Doi = {10.1016/j.nic.2007.09.005}, Key = {Bigos2007} } @article{Manuck2007, Author = {Manuck, SB and Brown, SM and Forbes, EE and Hariri, AR}, Title = {Temporal stability of individual differences in amygdala reactivity.}, Journal = {The American journal of psychiatry}, Volume = {164}, Number = {10}, Pages = {1613-1614}, Year = {2007}, Month = {October}, ISSN = {0002-953X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17898358}, Keywords = {Adult • Amygdala/*physiology • Anger/physiology • Emotions/*physiology • Fear/physiology • Female • Humans • *Individuality • Magnetic Resonance Imaging/*statistics \& numerical data • Male • Middle Aged • Mood Disorders/diagnosis}, Language = {eng}, Doi = {10.1176/appi.ajp.2007.07040609}, Key = {Manuck2007} } @article{fds251998, Author = {Rubino, V and Blasi, G and Latorre, V and Fazio, L and d'Errico, I and Mazzola, V and Caforio, G and Nardini, M and Popolizio, T and Hariri, A and Arciero, G and Bertolino, A}, Title = {Activity in medial prefrontal cortex during cognitive evaluation of threatening stimuli as a function of personality style.}, Journal = {Brain research bulletin}, Volume = {74}, Number = {4}, Pages = {250-257}, Year = {2007}, Month = {September}, ISSN = {0361-9230}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17720547}, Abstract = {Cognitive evaluation of emotional stimuli involves a network of brain regions including the medial prefrontal cortex (mPFC). However, threatening stimuli may be perceived with differential salience in different individuals. The goal of our study was to evaluate how different personality styles are associated with differential modulation of brain activity during explicit recognition of fearful and angry facial expressions. Twenty-eight healthy subjects underwent fMRI. Based on a cognitivist model, subjects were categorized according to how they attribute salience to emotional stimuli and how they regulate their emotional activation. We compared 14 phobic prone (PP) subjects, whose identity is more centered on the inner experience ("inward") and around control of environmental threat, and 14 eating disorders prone (EDP) subjects, whose identity is more centered on external referential contexts ("outward") and much less around control of threatening stimuli. During fMRI subjects either matched the identity of one of two angry and fearful faces to that of a simultaneously presented target face or identified the expression of a target face by choosing one of two simultaneously presented linguistic labels. The fMRI results indicated that PP subjects had greater mPFC activation when compared with EDP subjects during cognitive labeling of threatening stimuli. Activity in the mPFC also correlated with personality style scores. These results demonstrate that PP subjects recruit greater neuronal resources in mPFC whose activity is associated with cognitive aspects that are closely intertwined with emotional processing. These findings are consistent with the contention that cognitive evaluation and salience of emotional stimuli are associated with different personality styles.}, Doi = {10.1016/j.brainresbull.2007.06.019}, Key = {fds251998} } @article{Gianaros2007, Author = {Gianaros, PJ and Horenstein, JA and Cohen, S and Matthews, KA and Brown, SM and Flory, JD and Critchley, HD and Manuck, SB and Hariri, AR}, Title = {Perigenual anterior cingulate morphology covaries with perceived social standing.}, Journal = {Social cognitive and affective neuroscience}, Volume = {2}, Number = {3}, Pages = {161-173}, Address = {Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA. gianarospj@upmc.edu}, Year = {2007}, Month = {September}, ISSN = {1749-5016}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18418472}, Keywords = {Adult • Cognition/physiology • Female • Gyrus Cinguli/*anatomy \& histology/physiology • Humans • Male • Middle Aged • *Social Class • *Social Perception}, Abstract = {Low socioeconomic status (SES) increases the risk for developing psychiatric and chronic medical disorders. A stress-related pathway by which low SES may affect mental and physical health is through the perception of holding a low social standing, termed low subjective social status. This proposal implicates overlapping brain regions mediating stress reactivity and socioemotional behaviors as neuroanatomical substrates that could plausibly link subjective social status to health-related outcomes. In a test of this proposal, we used a computational structural neuroimaging method (voxel-based morphometry) in a healthy community sample to examine the relationships between reports of subjective social status and regional gray matter volume. Results showed that after accounting for potential demographic confounds, subclinical depressive symptoms, dispositional forms of negative emotionality and conventional indicators of SES, self-reports of low subjective social status uniquely covaried with reduced gray matter volume in the perigenual area of the anterior cingulate cortex (pACC)-a brain region involved in experiencing emotions and regulating behavioral and physiological reactivity to psychosocial stress. The pACC may represent a neuroanatomical substrate by which perceived social standing relates to mental and physical health.}, Language = {eng}, Doi = {10.1093/scan/nsm013}, Key = {Gianaros2007} } @article{Conklin2007, Author = {Conklin, SM and Gianaros, PJ and Brown, SM and Yao, JK and Hariri, AR and Manuck, SB and Muldoon, MF}, Title = {Long-chain omega-3 fatty acid intake is associated positively with corticolimbic gray matter volume in healthy adults.}, Journal = {Neuroscience letters}, Volume = {421}, Number = {3}, Pages = {209-212}, Address = {Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15260, United States. conklinSM@UPMC.Edu}, Year = {2007}, Month = {June}, ISSN = {0304-3940}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17574755}, Keywords = {Adult • Brain Mapping • Cerebral Cortex/anatomy \& histology/*drug effects • Fatty Acids, Omega-3/*administration \& dosage • Female • Humans • Limbic System/*anatomy \& histology/*drug effects • Magnetic Resonance Imaging/methods • Male • Middle Aged}, Abstract = {<h4>Background</h4>In animals, dendritic arborization and levels of brain derived neurotrophic factor are positively associated with intake of the omega-3 fatty acids. Here, we test whether omega-3 fatty acid intake in humans varies with individual differences in gray matter volume, an in vivo, systems-level index of neuronal integrity.<h4>Methods</h4>Fifty-five healthy adults completed two 24h dietary recall interviews. Intake of long-chain omega-3 fatty acids was categorized by tertiles. Regional gray matter volumes in a putative emotional brain circuitry comprised of the anterior cingulate cortex (ACC), amygdala and hippocampus were calculated using optimized voxel-based morphometry on high-resolution structural magnetic resonance images.<h4>Results</h4>Region of interest analyses revealed positive associations between reported dietary omega-3 intake and gray matter volume in the subgenual ACC, the right hippocampus and the right amygdala, adjusted for total gray matter volume of brain. Unconstrained whole-brain analyses confirmed that higher intake of omega-3 fatty acids was selectively associated with increased greater gray matter volume in these and not other regions.<h4>Conclusions</h4>Higher reported consumption of the long-chain omega-3 fatty acids is associated with greater gray matter volume in nodes of a corticolimbic circuitry supporting emotional arousal and regulation. Such associations may mediate previously observed effects of omega-3 fatty acids on memory, mood and affect regulation.}, Language = {eng}, Doi = {10.1016/j.neulet.2007.04.086}, Key = {Conklin2007} } @article{Heinz2007, Author = {Heinz, A and Smolka, MN and Braus, DF and Wrase, J and Beck, A and Flor, H and Mann, K and Schumann, G and Büchel, C and Hariri, AR and Weinberger, DR}, Title = {Serotonin transporter genotype (5-HTTLPR): effects of neutral and undefined conditions on amygdala activation.}, Journal = {Biological psychiatry}, Volume = {61}, Number = {8}, Pages = {1011-1014}, Address = {Department of Psychiatry, Charite University Medicine Berlin, Campus Charite Mitte, Germany.}, Year = {2007}, Month = {April}, ISSN = {0006-3223}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17157270}, Keywords = {Adult • Amygdala/blood supply/*physiology • Emotions/*physiology • Functional Laterality • Gene Frequency • Genotype • Humans • Image Processing, Computer-Assisted/methods • Magnetic Resonance Imaging/methods • Male • Middle Aged • Oxygen/blood • Photic Stimulation • Polymorphism, Genetic • Serotonin Plasma Membrane Transport Proteins/*genetics}, Abstract = {<h4>Background</h4>A polymorphism of the human serotonin transporter gene (SCL6A4) has been associated with serotonin transporter expression and with processing of aversive stimuli in the amygdala. Functional imaging studies show that during the presentation of aversive versus neutral cues, healthy carriers of the short (s) allele showed stronger amygdala activation than long (l) carriers. However, a recent report suggested that this interaction is driven by amygdala deactivation during presentation of neutral stimuli in s carriers.<h4>Methods</h4>Functional MRI was used to assess amygdala activation during the presentation of a fixation cross or affectively aversive or neutral visual stimuli in 29 healthy men.<h4>Results</h4>Amygdala activation was increased in s carriers during undefined states such as the presentation of a fixation cross compared with emotionally neutral conditions.<h4>Conclusions</h4>This finding suggests that s carriers show stronger amygdala reactivity to stimuli and contexts that are relatively uncertain, which we propose are stressful.}, Language = {eng}, Doi = {10.1016/j.biopsych.2006.08.019}, Key = {Heinz2007} } @article{fds251997, Author = {Hariri, AR and Fisher, PM}, Title = {Regulation of corticolimbic reactivity via the 5-HT | |
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