Dorfman HM, Meyer-Lindenberg A, Buckholtz JW. Neurobiological Mechanisms for Impulsive-Aggression: The Role of MAOA. Curr Top Behav Neurosci. 2014.Abstract
Aggression may be present across a large part of the spectrum of psychopathology, and underlies costly criminal antisocial behaviors. Human aggression is a complex and underspecified construct, confounding scientific discovery. Nevertheless, some biologically tractable subtypes are apparent, and one in particular-impulsive (reactive) aggression-appears to account for many facets of aggression-related dysfunction in psychiatric illness. Impulsive-aggression is significantly heritable, suggesting genetic transmission. However, the specific neurobiological mechanisms that mediate genetic risk for impulsive-aggression remain unclear. Here, we review extant data on the genetics and neurobiology of individual differences in impulsive-aggression, with particular attention to the role of genetic variation in Monoamine Oxidase A (MAOA) and its impact on serotonergic signaling within corticolimbic circuitry.
Samanez-Larkin GR, Buckholtz JW, Cowan RL, Woodward ND, Li R, Ansari M, Arrington CM, Baldwin RM, Smith CE, Treadway MT, et al. A thalamocorticostriatal dopamine network for psychostimulant-enhanced human cognitive flexibility. Biological psychiatry. 2013;74 :99–105.
Treadway MT, Buckholtz JW, Zald DH. Perceived stress predicts altered reward and loss feedback processing in medial prefrontal cortex. Front Hum Neurosci. 2013;7 :180.Abstract
Stress is a significant risk factor for the development of psychopathology, particularly symptoms related to reward processing. Importantly, individuals display marked variation in how they perceive and cope with stressful events, and such differences are strongly linked to risk for developing psychiatric symptoms following stress exposure. However, many questions remain regarding the neural architecture that underlies inter-subject variability in perceptions of stressors. Using functional magnetic resonance imaging (fMRI) during a Monetary Incentive Delay (MID) paradigm, we examined the effects of self-reported perceived stress levels on neural activity during reward anticipation and feedback in a sample of healthy individuals. We found that subjects reporting more uncontrollable and overwhelming stressors displayed blunted neural responses in medial prefrontal cortex (mPFC) following feedback related to monetary gains as well monetary losses. This is consistent with preclinical models that implicate the mPFC as a key site of vulnerability to the noxious effects of uncontrollable stressors. Our data help translate these findings to humans, and elucidate some of the neural mechanisms that may underlie stress-linked risk for developing reward-related psychiatric symptoms.
Treadway MT, Buckholtz JW, Cowan RL, Woodward ND, Li R, Ansari SM, Baldwin RM, Schwartzman AN, Kessler RM, Zald DH. Dopaminergic mechanisms of individual differences in human effort-based decision-making. J Neurosci. 2012;32 (18) :6170-6.Abstract
Preferences for different combinations of costs and benefits are a key source of variability in economic decision-making. However, the neurochemical basis of individual differences in these preferences is poorly understood. Studies in both animals and humans have demonstrated that direct manipulation of the neurotransmitter dopamine (DA) significantly impacts cost/benefit decision-making, but less is known about how naturally occurring variation in DA systems may relate to individual differences in economic behavior. In the present study, 25 healthy volunteers completed a dual-scan PET imaging protocol with [(18)F]fallypride and d-amphetamine to measure DA responsivity and separately completed the effort expenditure for rewards task, a behavioral measure of cost/benefit decision-making in humans. We found that individual differences in DA function in the left striatum and ventromedial prefrontal cortex were correlated with a willingness to expend greater effort for larger rewards, particularly when probability of reward receipt was low. Additionally, variability in DA responses in the bilateral insula was negatively correlated with willingness to expend effort for rewards, consistent with evidence implicating this region in the processing of response costs. These findings highlight the role of DA signaling in striatal, prefrontal, and insular regions as key neurochemical mechanisms underlying individual differences in cost/benefit decision-making.
Buckholtz JW, Meyer-Lindenberg A. Psychopathology and the human connectome: toward a transdiagnostic model of risk for mental illness. Neuron. 2012;74 (6) :990-1004.Abstract
The panoply of cognitive, affective, motivational, and social functions that underpin everyday human experience requires precisely choreographed patterns of interaction between networked brain regions. Perhaps not surprisingly, diverse forms of psychopathology are characterized by breakdowns in these interregional relationships. Here, we discuss how functional brain imaging has provided insights into the nature of brain dysconnectivity in mental illness. Synthesizing work to date, we propose that genetic and environmental risk factors impinge upon systems-level circuits for several core dimensions of cognition, producing transdiagnostic symptoms. We argue that risk-associated disruption of these circuits mediates susceptibility to broad domains of psychopathology rather than discrete disorders.
Buckholtz JW, Marois RE. The roots of modern justice: cognitive and neural foundations of social norms and their enforcement. Nature Neuroscience. 2012;15 :655–661.Abstract
Treadway MT, Buckholtz JW. On the use and misuse of genomic and neuroimaging science in forensic psychiatry: current roles and future directions. Child and Adolescent Psychiatry Clinics of NA. 2011;20 :533–546.Abstract
Buckholtz JW, Treadway MT, Cowan RL, Woodward ND, Li R, Ansari SM, Baldwin RM, Schwartzman AN, Shelby ES, Smith CE, et al. Dopaminergic network differences in human impulsivity. Science. 2010;329 :532.
Buckholtz JW, Treadway MT, Cowan RL, Woodward ND, Benning SD, Li R, Ansari SM, Baldwin RM, Schwartzman AN, Shelby ES, et al. Mesolimbic dopamine reward system hypersensitivity in individuals with psychopathic traits. Nature Neuroscience. 2010;13 :419–421.
Blackford JU, Buckholtz JW, Avery SN, Zald DH. A unique role for the human amygdala in novelty detection. NeuroImage. 2010;50 :1188–1193.Abstract
Treadway MT, Buckholtz JW, Schwartzman AN, Lambert WE, Zald DH. Worth the 'EEfRT'? The effort expenditure for rewards task as an objective measure of motivation and anhedonia. PLoS ONE. 2009;4 :e6598.Abstract
Buckholtz JW, Meyer-Lindenberg A. {MAOA and the neurogenetic architecture of human aggression.}. Trends in neurosciences. 2008;31 :120–129.Abstract
Montag C, Buckholtz JW, Hartmann P, Merz M, Burk C, Hennig J, Reuter M. {COMT genetic variation affects fear processing: psychophysiological evidence.}. Behavioral neuroscience. 2008;122 :901–909.Abstract
Buckholtz JW, Asplund CL, Dux PE, Zald DH, Gore JC, Jones OD, Marois RE. {The neural correlates of third-party punishment.}. Neuron. 2008;60 :930–940.Abstract
Buckholtz JW, Callicott JH, Kolachana B, Hariri AR, Goldberg TE, Genderson M, Egan MF, Mattay VS, Weinberger DR, Meyer-Lindenberg A. Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personality. Molecular Psychiatry. 2008;13 :313–324.
Buckholtz JW, Meyer-Lindenberg A, Honea RA, Straub RE, Pezawas L, Egan MF, Vakkalanka R, Kolachana B, Verchinski BA, Sust S, et al. {Allelic variation in RGS4 impacts functional and structural connectivity in the human brain.}. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2007;27 :1584–1593.Abstract
Tan H-Y, Chen Q, Sust S, Buckholtz JW, Meyers JD, Egan MF, Mattay VS, Meyer-Lindenberg A, Weinberger DR, Callicott JH. {Epistasis between catechol-O-methyltransferase and type II metabotropic glutamate receptor 3 genes on working memory brain function.}. Proceedings of the National Academy of Sciences of the United States of America. 2007;104 :12536–12541.Abstract
Buckholtz JW, Sust S, Tan HY, Mattay VS, Straub RE, Meyer-Lindenberg A, Weinberger DR, Callicott JH. {fMRI evidence for functional epistasis between COMT and RGS4.}. Molecular Psychiatry. 2007;12 :893–5– 885.Abstract
Meyer-Lindenberg A, Buckholtz JW, Kolachana B, R Hariri A, Pezawas L, Blasi G, Wabnitz A, Honea R, Verchinski B, Callicott JH, et al. {Neural mechanisms of genetic risk for impulsivity and violence in humans.}. Proceedings of the National Academy of Sciences of the United States of America. 2006;103 :6269–6274.Abstract
Tan H-Y, Sust S, Buckholtz JW, Mattay VS, Meyer-Lindenberg A, Egan MF, Weinberger DR, Callicott JH. {Dysfunctional prefrontal regional specialization and compensation in schizophrenia.}. The American journal of psychiatry. 2006;163 :1969–1977.Abstract