Influence of COMT Gene Polymorphism on fMRI-assessed Sustained and Transient Activity during a Working Memory Task

The catechol O-methyltransferase (COMT) gene—encoding an enzyme that is essential for the degradation of dopamine (DA) in prefrontal cortex (PFC)—contains a single nucleotide polymorphism (val/met) important for cognition. According to the tonic–phasic hypothesis, individuals carrying the low-enzyme-activity allele (met) are characterized by enhanced tonic DA activity in PFC, promoting sustained cognitive representations in working memory. Val carriers have reduced tonic but enhanced phasic dopaminergic activity in subcortical regions, enhancing cognitive flexibility. We tested the tonic–phasic DA hypothesis by dissociating sustained and transient brain activity during performance on a 2-back working memory test using mixed blocked/event-related functional magnetic resonance imaging. Participants were men recruited from a random sample of the population (the Betula study) and consisted of 11 met/met and 11 val/val carriers aged 50 to 65 years, matched on age, education, and cognitive performance. There were no differences in 2-back performance between genotype groups. Met carriers displayed a greater transient medial temporal lobe response in the updating phase of working memory, whereas val carriers showed a greater sustained PFC activation in the maintenance phase. These results support the tonic–phasic theory of DA function in elucidating the specific phenotypic influence of the COMT val158met polymorphism on different components of working memory.

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

[2]  James R. MacFall,et al.  The COMT Val158Met polymorphism and temporal lobe morphometry in healthy adults , 2007, Psychiatry Research: Neuroimaging.

[3]  R. Dixon,et al.  Age-related cognitive deficits mediated by changes in the striatal dopamine system. , 2000, The American journal of psychiatry.

[4]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[5]  P. Dash,et al.  Traumatic brain injury stimulates hippocampal catechol-O-methyl transferase expression in microglia , 2007, Neuroscience Letters.

[6]  M. Egan,et al.  NEUROBIOLOGY OF SCHIZOPHRENIA AND THE ROLE OF ATYPICAL ANTIPSYCHOTICS Prefrontal Neurons and the Genetics of Schizophrenia , 2001 .

[7]  T. Braver,et al.  Vive les differences! Individual variation in neural mechanisms of executive control , 2010, Current Opinion in Neurobiology.

[8]  Guillén Fernández,et al.  The right hippocampus participates in short-term memory maintenance of object–location associations , 2006, NeuroImage.

[9]  P. Goldman-Rakic,et al.  Enhancement of Working Memory in Aged Monkeys by a Sensitizing Regimen of Dopamine D1 Receptor Stimulation , 2004, The Journal of Neuroscience.

[10]  Matti Laine,et al.  Frontal and Temporal Dopamine Release during Working Memory and Attention Tasks in Healthy Humans: a Positron Emission Tomography Study Using the High-Affinity Dopamine D2 Receptor Ligand [11C]FLB 457 , 2005, The Journal of Neuroscience.

[11]  N. Volkow,et al.  Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. , 1998, The American journal of psychiatry.

[12]  L. Nyberg,et al.  Temporal dynamics of basal ganglia under-recruitment in Parkinson's disease: transient caudate abnormalities during updating of working memory. , 2008, Brain : a journal of neurology.

[13]  Vinod Menon,et al.  Temporal dynamics of basal ganglia response and connectivity during verbal working memory , 2007, NeuroImage.

[14]  Peter Fransson,et al.  Unity and diversity of tonic and phasic executive control components in episodic and working memory , 2007, NeuroImage.

[15]  Leslie G. Ungerleider,et al.  Transient and sustained activity in a distributed neural system for human working memory , 1997, Nature.

[16]  Mark G. Packard,et al.  The dopaminergic mesencephalic projections to the hippocampal formation in the rat , 1997, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[17]  I. Ulmanen,et al.  Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. , 1995, Biochemistry.

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

[19]  J. Ghajar.  Traumatic brain injury , 2000, The Lancet.

[20]  P. Goldman-Rakic,et al.  Selective D2 Receptor Actions on the Functional Circuitry of Working Memory , 2004, Science.

[21]  Marcus R. Munafò,et al.  Meta-Analysis of the Cognitive Effects of the Catechol-O-Methyltransferase Gene Val158/108Met Polymorphism , 2008, Biological Psychiatry.

[22]  Mark D'Esposito,et al.  A subsequent-memory effect in dorsolateral prefrontal cortex. , 2003, Brain research. Cognitive brain research.

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

[24]  Pekka T. Männistö,et al.  Catechol-O-Methyltransferase , 1996, Encyclopedia of Molecular Pharmacology.

[25]  P. Arner,et al.  Large‐scale genotyping of single nucleotide polymorphisms by Pyrosequencing™ and validation against the 5′nuclease (Taqman®) assay , 2002 .

[26]  M. Egan,et al.  Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications , 2004, Biological Psychiatry.

[27]  A. Malhotra,et al.  A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. , 2002, The American journal of psychiatry.

[28]  L. Nyberg,et al.  The betula prospective cohort study: Memory, health, and aging , 1997 .

[29]  Kathryn M. McMillan,et al.  N‐back working memory paradigm: A meta‐analysis of normative functional neuroimaging studies , 2005, Human brain mapping.

[30]  Lars Bäckman,et al.  Transfer of Learning After Updating Training Mediated by the Striatum , 2008, Science.

[31]  Fumitoshi Kodaka,et al.  Differential Contributions of Prefrontal and Hippocampal Dopamine D1 and D2 Receptors in Human Cognitive Functions , 2008, The Journal of Neuroscience.

[32]  T. Robbins,et al.  Effects of two dopamine-modulating genes (DAT1 9/10 and COMT Val/Met) on n-back working memory performance in healthy volunteers , 2010, Psychological Medicine.

[33]  A. Grace,et al.  Dopamine modulation of hippocampal-prefrontal cortical interaction drives memory-guided behavior. , 2008, Cerebral cortex.

[34]  J. Seamans,et al.  The principal features and mechanisms of dopamine modulation in the prefrontal cortex , 2004, Progress in Neurobiology.

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

[36]  M. D’Esposito,et al.  Functional connectivity during working memory maintenance , 2004, Cognitive, affective & behavioral neuroscience.

[37]  Yoshiro Okubo,et al.  Memory and frontal lobe functions; possible relations with dopamine D2 receptors in the hippocampus , 2007, NeuroImage.

[38]  T. Rao,et al.  Pharmacological characterization of nicotine‐induced acetylcholine release in the rat hippocampus in vivo: evidence for a permissive dopamine synapse , 1999, British journal of pharmacology.

[39]  Peter Fransson,et al.  Sustained and Transient Neural Modulations in Prefrontal Cortex Related to Declarative Long-Term Memory, Working Memory, and Attention , 2007, Cortex.

[40]  A. Grace,et al.  Regulation of firing of dopaminergic neurons and control of goal-directed behaviors , 2007, Trends in Neurosciences.

[41]  Randy L. Buckner,et al.  Mixed blocked/event-related designs separate transient and sustained activity in fMRI , 2003, NeuroImage.

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

[43]  Lars-Göran Nilsson,et al.  Catechol O-Methyltransferase Val158Met Polymorphism is Associated with Cognitive Performance in Nondemented Adults , 2005, Journal of Cognitive Neuroscience.

[44]  Nicole M. Dudukovic,et al.  Goal-dependent modulation of declarative memory: Neural correlates of temporal recency decisions and novelty detection , 2007, Neuropsychologia.

[46]  R. Henson,et al.  State-related and item-related neural correlates of successful memory encoding , 2002, Nature Neuroscience.

[47]  Karl J. Friston,et al.  Generalisability, Random Effects & Population Inference , 1998, NeuroImage.

[48]  N. J. Herrod,et al.  Redefining the functional organization of working memory processes within human lateral prefrontal cortex , 1999, The European journal of neuroscience.

[49]  Patrick R Hof,et al.  Mice Lacking Dopamine D2 and D3 Receptors Have Spatial Working Memory Deficits , 2002, The Journal of Neuroscience.

[50]  Fabio Sambataro,et al.  Selective updating of working memory content modulates meso-cortico-striatal activity , 2011, NeuroImage.

[51]  Seth A. Herd,et al.  From an Executive Network to Executive Control: A Computational Model of the n-back Task , 2011, Journal of Cognitive Neuroscience.

[52]  R. Turner,et al.  Event-Related fMRI: Characterizing Differential Responses , 1998, NeuroImage.

[53]  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.

[54]  L. Nyberg,et al.  The correlative triad among aging, dopamine, and cognition: Current status and future prospects , 2006, Neuroscience & Biobehavioral Reviews.

[55]  David I Donaldson,et al.  Parsing brain activity with fMRI and mixed designs: what kind of a state is neuroimaging in? , 2004, Trends in Neurosciences.

[56]  James B. Rowe,et al.  Parahippocampal Reactivation Signal at Retrieval after Interruption of Rehearsal , 2002, The Journal of Neuroscience.

[57]  N. Volkow,et al.  Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals. , 1998, The American journal of psychiatry.

[58]  E. Levin,et al.  Ventral hippocampal dopamine D1 and D2 systems and spatial working memory in rats , 1999, Neuroscience.

[59]  R. O’Reilly.  Biologically Based Computational Models of High-Level Cognition , 2006, Science.

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

[61]  Anderson M. Winkler,et al.  Genetic influence on the working memory circuitry: Behavior, structure, function and extensions to illness , 2011, Behavioural Brain Research.

[62]  Hans-Jochen Heinze,et al.  Human Hippocampal and Parahippocampal Activity during Visual Associative Recognition Memory for Spatial and Nonspatial Stimulus Configurations , 2003, The Journal of Neuroscience.

[63]  P. Grasby,et al.  The Effects of The COMT val108/158met Polymorphism on BOLD Activation During Working Memory, Planning, and Response Inhibition: A Role for The Posterior Cingulate Cortex? , 2011, Neuropsychopharmacology.

[64]  R. Coppola,et al.  Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. , 2003, Archives of general psychiatry.

[65]  J. Yesavage,et al.  The Roles of COMT val158met Status and Aviation Expertise in Flight Simulator Performance and Cognitive Ability , 2011, Behavior genetics.

[66]  W. Jagust,et al.  Striatal dopamine and working memory. , 2009, Cerebral cortex.

[67]  M. D’Esposito,et al.  Isolating the neural mechanisms of age-related changes in human working memory , 2000, Nature Neuroscience.

[68]  A. Grace.  Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: A hypothesis for the etiology of schizophrenia , 1991, Neuroscience.

[69]  Shih-Jen Tsai,et al.  The effects of catechol-O-methyl-transferase polymorphism Val158Met on functional connectivity in healthy young females: A resting EEG study , 2011, Brain Research.

[70]  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.

[71]  Lars-Göran Nilsson,et al.  COMT Gene Polymorphism Is Associated with Declarative Memory in Adulthood and Old Age , 2004, Behavior genetics.

[72]  Florin Dolcos,et al.  Similarities and Differences in the Neural Correlates of Episodic Memory Retrieval and Working Memory , 2002, NeuroImage.

[73]  Michael F Egan,et al.  Tolcapone Improves Cognition and Cortical Information Processing in Normal Human Subjects , 2007, Neuropsychopharmacology.

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

[75]  L. Nyberg,et al.  Betula: A Prospective Cohort Study on Memory, Health and Aging , 2004 .

[76]  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.

[77]  J. Lisman,et al.  The Hippocampal-VTA Loop: Controlling the Entry of Information into Long-Term Memory , 2005, Neuron.

[78]  N C Andreasen,et al.  Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow , 2005, Molecular Psychiatry.

[79]  M. Torrens.  Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268 , 1990 .

[80]  Paul J. Laurienti,et al.  An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets , 2003, NeuroImage.