Catechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation.

CONTEXT Catechol O-methyltransferase (COMT), the major enzyme determining cortical dopamine flux, has a common functional polymorphism (val(158)met) that affects prefrontal function and working memory capacity and has also been associated with anxiety and emotional dysregulation. OBJECTIVES To examine COMT val(158)met effects on corticolimbic circuitry reactivity and functional connectivity during processing of biologically salient stimuli, as well as the relationship to the temperamental trait of novelty seeking. DESIGN Within-subject functional magnetic resonance imaging study. SETTING National Institute of Mental Health, Genes, Cognition, and Psychosis Program, Bethesda, Md. Patients One hundred one healthy subjects of both sexes. RESULTS We found that the met allele was associated with a dose-dependent increase in hippocampal formation and ventrolateral prefrontal cortex activation during viewing of faces displaying negative emotion. In met/met homozygotes, limbic and prefrontal regions showed increased functional coupling. Moreover, in these same subjects, the magnitude of amygdala-orbitofrontal coupling was inversely correlated with novelty seeking, an index of temperamental inflexibility. CONCLUSIONS Our results indicate that heritable variation in dopamine neurotransmission associated with the met allele of the COMT polymorphism results in heightened reactivity and connectivity in corticolimbic circuits. This may reflect a genetic predisposition for inflexible processing of affective stimuli, a mechanism possibly accounting for aspects of arousal and behavioral control that contribute to emotional dysregulation previously reported in met/met individuals.

[1]  R. Weinshilboum,et al.  Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. , 1999, Annual review of pharmacology and toxicology.

[2]  Richard J Davidson,et al.  Hippocampal morphometry in depressed patients and control subjects: relations to anxiety symptoms , 2001, Biological Psychiatry.

[3]  Kevin N. Ochsner,et al.  For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion , 2004, NeuroImage.

[4]  P. Donnelly,et al.  Case-control studies of association in structured or admixed populations. , 2001, Theoretical population biology.

[5]  G. Schoenbaum,et al.  Changes in Functional Connectivity in Orbitofrontal Cortex and Basolateral Amygdala during Learning and Reversal Training , 2000, The Journal of Neuroscience.

[6]  M L Phillips,et al.  Understanding the neurobiology of emotion perception: implications for psychiatry , 2003, British Journal of Psychiatry.

[7]  C. R. Cloninger,et al.  A psychobiological model of temperament and character. , 1993, Archives of general psychiatry.

[8]  R. Plomin,et al.  Hippocampal gene expression profiling across eight mouse inbred strains: towards understanding the molecular basis for behaviour , 2004, The European journal of neuroscience.

[9]  Mats Fredrikson,et al.  Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia , 2004, Neuroscience Letters.

[10]  Francesco Fera,et al.  Dextroamphetamine Modulates the Response of the Human Amygdala , 2002, Neuropsychopharmacology.

[11]  D. Shields,et al.  Preliminary evidence of an association between bipolar disorder in females and the catechol‐O‐methyltransferase gene , 1998, Psychiatric genetics.

[12]  K. Livak,et al.  Allelic discrimination using fluorogenic probes and the 5' nuclease assay. , 1999, Genetic analysis : biomolecular engineering.

[13]  Christian Büchel,et al.  Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter , 2005, Nature Neuroscience.

[14]  Katharina Domschke,et al.  Association of the functional V158M catechol-O-methyl-transferase polymorphism with panic disorder in women. , 2004, The international journal of neuropsychopharmacology.

[15]  Timothy Edward John Behrens,et al.  New approaches for exploring anatomical and functional connectivity in the human brain , 2004, Biological Psychiatry.

[16]  C. Mervis,et al.  Neural Basis of Genetically Determined Visuospatial Construction Deficit in Williams Syndrome , 2004, Neuron.

[17]  P. Ekman.  Pictures of Facial Affect , 1976 .

[18]  J. Hewitt,et al.  Investigating Age Differences in the Genetic and Environmental Structure of the Tridimensional Personality Questionnaire in Later Adulthood , 2003, Behavior genetics.

[19]  L. Peltonen,et al.  Association Between the Type 4 Dopamine Receptor Gene Polymorphism and Novelty Seeking , 2003, Psychosomatic medicine.

[20]  R. Nussbaum,et al.  Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype , 2005, Nature Neuroscience.

[21]  Francesco Fera,et al.  Dopamine Modulates the Response of the Human Amygdala: A Study in Parkinson's Disease , 2002, The Journal of Neuroscience.

[22]  M. Egan,et al.  Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. , 2004, American journal of human genetics.

[23]  J. Gabrieli,et al.  Rethinking Feelings: An fMRI Study of the Cognitive Regulation of Emotion , 2002, Journal of Cognitive Neuroscience.

[24]  H. Heinze,et al.  Reward-Related fMRI Activation of Dopaminergic Midbrain Is Associated with Enhanced Hippocampus- Dependent Long-Term Memory Formation , 2005, Neuron.

[25]  T Foitzi,et al.  Allelic discrimination using fluorogenic probes and the 5' nuclease assay , 1999 .

[26]  Young-Hee Choi,et al.  The association between panic disorder and the L/L genotype of catechol-O-methyltransferase. , 2004, Journal of psychiatric research.

[27]  Simon J Graham,et al.  An fMRI study investigating cognitive modulation of brain regions associated with emotional processing of visual stimuli , 2003, Neuropsychologia.

[28]  Shih-Jen Tsai,et al.  Association Study of Catechol- O-Methyltransferase Gene and Dopamine D4 Receptor Gene Polymorphisms and Personality Traits in Healthy Young Chinese Females , 2004, Neuropsychobiology.

[29]  Joseph E LeDoux.  The Emotional Brain, Fear, and the Amygdala , 2003, Cellular and Molecular Neurobiology.

[30]  J. Gray,et al.  Anxiolytic action on the behavioural inhibition system implies multiple types of arousal contribute to anxiety. , 2000, Journal of affective disorders.

[31]  Michael F Egan,et al.  A susceptibility gene for affective disorders and the response of the human amygdala. , 2005, Archives of general psychiatry.

[32]  C. R. Cloninger,et al.  Mood states and personality traits. , 1992, Journal of affective disorders.

[33]  M. First,et al.  The Structured Clinical Interview for DSM-III-R (SCID). I: History, rationale, and description. , 1992, Archives of general psychiatry.

[34]  E. Rolls,et al.  Emotion-related learning in patients with social and emotional changes associated with frontal lobe damage. , 1994, Journal of neurology, neurosurgery, and psychiatry.

[35]  Hans-Jürgen Möller,et al.  A functional single nucleotide polymorphism (V158M) in the COMT gene is associated with aggressive personality traits , 2003, Biological Psychiatry.

[36]  R. Straub,et al.  Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[37]  J. Lisman,et al.  Dopamine Selectively Inhibits the Direct Cortical Pathway to the CA1 Hippocampal Region , 1999, The Journal of Neuroscience.

[38]  P. Kuo,et al.  Assessing personality features and their relations with behavioral problems in adolescents: Tridimensional Personality Questionnaire and Junior Eysenck Personality Questionnaire. , 2004, Comprehensive psychiatry.

[39]  D. Zald,et al.  Anatomy and function of the orbital frontal cortex, II: Function and relevance to obsessive-compulsive disorder. , 1996, The Journal of neuropsychiatry and clinical neurosciences.

[40]  Makoto Tsunoda,et al.  High-performance liquid chromatography-fluorescent assay of catechol-O-methyltransferase activity in rat brain , 2003, Analytical and bioanalytical chemistry.

[41]  Brian Sheitman,et al.  COMT158 polymorphism and hostility , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[42]  T. Sejnowski,et al.  Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[43]  R. Blair,et al.  The roles of orbital frontal cortex in the modulation of antisocial behavior , 2004, Brain and Cognition.

[44]  R. Dolan,et al.  Distinct spatial frequency sensitivities for processing faces and emotional expressions , 2003, Nature Neuroscience.

[45]  D. Weinberger,et al.  Neocortical modulation of the amygdala response to fearful stimuli , 2003, Biological Psychiatry.

[46]  Robert M Bilder,et al.  Catechol O-methyltransferase Val158Met polymorphism in schizophrenia: differential effects of Val and Met alleles on cognitive stability and flexibility. , 2004, The American journal of psychiatry.

[47]  M. Koulu,et al.  Association between the functional variant of the catechol-O-methyltransferase (COMT) gene and type 1 alcoholism , 1999, Molecular Psychiatry.

[48]  P. Matthews,et al.  Exacerbation of Pain by Anxiety Is Associated with Activity in a Hippocampal Network , 2001, The Journal of Neuroscience.

[49]  P. Männistö,et al.  Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. , 1999, Pharmacological reviews.

[50]  B. Moghaddam,et al.  The Prefrontal Cortex Regulates the Basal Release of Dopamine in the Limbic Striatum: An Effect Mediated by Ventral Tegmental Area , 1996, Journal of neurochemistry.

[51]  T. Robbins,et al.  Dissociation in prefrontal cortex of affective and attentional shifts , 1996, Nature.

[52]  E. Stip,et al.  The functional neuroanatomy of major depression: an fMRI study using an emotional activation paradigm , 1998, Neuroreport.

[53]  M. Egan,et al.  Prefrontal neurons and the genetics of schizophrenia , 2001, Biological Psychiatry.

[54]  J. Ott,et al.  Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[55]  K. Ohara,et al.  Low activity allele of catechol‐o‐methyltransferase gene and Japanese unipolar depression , 1998, Neuroreport.

[56]  J. Rawlins,et al.  Regional dissociations within the hippocampus—memory and anxiety , 2004, Neuroscience & Biobehavioral Reviews.

[57]  P. M. Wall,et al.  The hippocampal formation — orbitomedial prefrontal cortex circuit in the attentional control of active memory , 2001, Behavioural Brain Research.

[58]  Jeffrey S. Maxwell,et al.  Human Amygdala Responsivity to Masked Fearful Eye Whites , 2004, Science.

[59]  K. Ohara,et al.  No association between anxiety disorders and catechol-O-methyltransferase polymorphism , 1998, Psychiatry Research.

[60]  Andrew L. Alexander,et al.  Contextual Modulation of Amygdala Responsivity to Surprised Faces , 2004, Journal of Cognitive Neuroscience.

[61]  A. Diamond,et al.  Genetic and neurochemical modulation of prefrontal cognitive functions in children. , 2004, The American journal of psychiatry.

[62]  Cloninger Cr.  Discussions arising from: Cloninger, CR. A. unified biosocial theory of personality and its role in the development of anxiety states. , 1987, Psychiatric developments.

[63]  C. Cavada,et al.  The anatomical connections of the macaque monkey orbitofrontal cortex. A review. , 2000, Cerebral cortex.

[64]  Discerning Disorders and Diseases , 2004, CNS Spectrums.

[65]  A. Meyer-Lindenberg,et al.  5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression , 2005, Nature Neuroscience.

[66]  Paul J. Harrison,et al.  Catechol-O-Methyltransferase Inhibition Improves Set-Shifting Performance and Elevates Stimulated Dopamine Release in the Rat Prefrontal Cortex , 2004, The Journal of Neuroscience.

[67]  D. Pfaff,et al.  Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[68]  J. Mazziotta,et al.  Modulating emotional responses: effects of a neocortical network on the limbic system , 2000, Neuroreport.

[69]  E. Zackai,et al.  Effects of a functional COMT polymorphism on prefrontal cognitive function in patients with 22q11.2 deletion syndrome. , 2004, The American journal of psychiatry.

[70]  David Goldman,et al.  Genetic origins of anxiety in women: a role for a functional catechol-O-methyltransferase polymorphism , 2003, Psychiatric genetics.

[71]  A. Young,et al.  Task instructions modulate neural responses to fearful facial expressions , 2003, Biological Psychiatry.

[72]  R. Ebstein,et al.  Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking , 1996, Nature Genetics.

[73]  J Hong,et al.  Distribution of catechol‐O‐methyltransferase expression in human central nervous system , 1998, Neuroreport.

[74]  M. Kuhar,et al.  Dopamine transporter immunohistochemistry in median eminence, amygdala, and other areas of the rat brain , 1996, Synapse.

[75]  M. Egan,et al.  Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[76]  P. Schlattmann,et al.  Association of the G1947A COMT (Val108/158Met) gene polymorphism with prefrontal P300 during information processing , 2003, Biological Psychiatry.

[77]  C. R. Cloninger,et al.  A unified biosocial theory of personality and its role in the development of anxiety states. , 1986, Psychiatric developments.

[78]  B. Lipska,et al.  Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function , 2003, Neuroscience.

[79]  Francesco Fera,et al.  The Amygdala Response to Emotional Stimuli: A Comparison of Faces and Scenes , 2002, NeuroImage.

[80]  Andreas Heinz,et al.  Catechol-O-Methyltransferase val158met Genotype Affects Processing of Emotional Stimuli in the Amygdala and Prefrontal Cortex , 2005, The Journal of Neuroscience.

[81]  Anthony A. Grace,et al.  Regulation of conditioned responses of basolateral amygdala neurons , 2002, Physiology & Behavior.

[82]  Anxiolytic effects of cytotoxic hippocampal lesions in rats. , 2002, Behavioral neuroscience.

[83]  A. Grace,et al.  The Catechol-O-Methyltransferase Polymorphism: Relations to the Tonic–Phasic Dopamine Hypothesis and Neuropsychiatric Phenotypes , 2004, Neuropsychopharmacology.

[84]  N. McNaughton.  Cognitive Dysfunction Resulting from Hippocampal Hyperactivity—A Possible Cause of Anxiety Disorder? , 1997, Pharmacology Biochemistry and Behavior.

[85]  E. Rolls.  The orbitofrontal cortex and reward. , 2000, Cerebral cortex.

[86]  Joshua A. Bueller,et al.  COMT val158met Genotype Affects µ-Opioid Neurotransmitter Responses to a Pain Stressor , 2003, Science.

[87]  D. Zald.  The human amygdala and the emotional evaluation of sensory stimuli , 2003, Brain Research Reviews.

[88]  Martin Reuter,et al.  Association of the functional catechol-O-methyltransferase VAL158MET polymorphism with the personality trait of extraversion , 2005, Neuroreport.

[89]  M Davies,et al.  The Structured Clinical Interview for DSM-III-R (SCID). II. Multisite test-retest reliability. , 1992 .

[90]  R. Hen,et al.  Genetic approaches to the study of anxiety. , 2004, Annual review of neuroscience.

[91]  R. Weinshilboum,et al.  Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. , 1996, Pharmacogenetics.