Hostname: page-component-cd9895bd7-lnqnp Total loading time: 0 Render date: 2024-12-18T21:51:49.391Z Has data issue: false hasContentIssue false
  • English
  • Français

Catechol-O-methyltransferase Val(108/158)Met polymorphism affects fronto-limbic connectivity during emotional processing in bipolar disorder

Published online by Cambridge University Press:  03 February 2017

B. Vai ,
M. Riberto ,
S. Poletti ,
I. Bollettini ,
C. Lorenzi ,
C. Colombo  and
F. Benedetti
B. Vai*
Affiliation:
IRCCS Ospedale San Raffaele, Department of Clinical Neurosciences, Milan, Italy CERMAC (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milan, Italy Department of Human Studies, Libera Università Maria Ss. Assunta, Roma, Italy
M. Riberto
Affiliation:
IRCCS Ospedale San Raffaele, Department of Clinical Neurosciences, Milan, Italy
S. Poletti
Affiliation:
IRCCS Ospedale San Raffaele, Department of Clinical Neurosciences, Milan, Italy CERMAC (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milan, Italy
I. Bollettini
Affiliation:
IRCCS Ospedale San Raffaele, Department of Clinical Neurosciences, Milan, Italy CERMAC (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milan, Italy
C. Lorenzi
Affiliation:
IRCCS Ospedale San Raffaele, Department of Clinical Neurosciences, Milan, Italy
C. Colombo
Affiliation:
IRCCS Ospedale San Raffaele, Department of Clinical Neurosciences, Milan, Italy
F. Benedetti
Affiliation:
IRCCS Ospedale San Raffaele, Department of Clinical Neurosciences, Milan, Italy CERMAC (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milan, Italy
*
⁎Corresponding author. Department of Clinical Neurosciences, Istituto Scientifico Ospedale San Raffaele, San Raffaele Turro, Via Stamira d’Ancona 20, Milano, Italy. Tel.: +39 02 264 331 56; fax: +39 02 264 332 65. E-mail address: b.vai@hotmail.it (B. Vai).
Get access

Abstract

Catechol-O-methyltransferase (COMT) inactivates catecholamines, Val/Val genotype was associated to an increased amygdala (Amy) response to negative stimuli and can influence the symptoms severity and the outcome of bipolar disorder, probably mediated by the COMT polymorphism (rs4680) interaction between cortical and subcortical dopaminergic neurotransmission. The aim of this study is to explore how rs4680 and implicit emotional processing of negative emotional stimuli could interact in affecting the Amy connectivity in bipolar depression. Forty-five BD patients (34 Met carriers vs. 11 Val/Val) underwent fMRI scanning during implicit processing of fearful and angry faces. We explore the effect of rs4680 on the strength of functional connectivity from the amygdalae to whole brain. Val/Val and Met carriers significantly differed for the connectivity between Amy and dorsolateral prefrontal cortex (DLPFC) and supramarginal gyrus. Val/Val patients showed a significant positive connectivity for all of these areas, where Met carriers presented a significant negative one for the connection between DLPFC and Amy. Our findings reveal a COMT genotype-dependent difference in corticolimbic connectivity during affective regulation, possibly identifying a neurobiological underpinning of clinical and prognostic outcome of BD. Specifically, a worse antidepressant recovery and clinical outcome previously detected in Val/Val patients could be associated to a specific increased sensitivity to negative emotional stimuli.

Keywords

Functional connectivityCOMTDepressionBipolarEmotion
Type
Original article
Information
European Psychiatry , Volume 41 , Issue 1 , March 2017 , pp. 53 - 59
Copyright
Copyright © European Psychiatric Association 2017

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Vai, B.Bollettini, I.Benedetti, F.Corticolimbic connectivity as a possible biomarker for bipolar disorder. Expert Rev Neurother 2014;14:631–650.CrossRefGoogle ScholarPubMed
Amaral, D.G.Price, J.L.Amygdalo-cortical projections in the monkey (Macaca fascicularis). J Comp Neurol 1984;230:465–496.CrossRefGoogle Scholar
LeDoux, J.E.Emotion circuits in the brain. Annu Rev Neurosci 2000;23:155–184.CrossRefGoogle Scholar
Ochsner, K.N.Ray, R.D.Cooper, J.C.Robertson, E.R.Chopra, S.Gabrieli, J.D.et al.For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. Neuroimage 2004;23:483–499.CrossRefGoogle ScholarPubMed
Beauregard, M.Levesque, J.Bourgouin, P.Neural correlates of conscious self-regulation of emotion. J Neurosci 2001;21:RC165.CrossRefGoogle ScholarPubMed
Schaefer, S.M.Jackson, D.C.Davidson, R.J.Aguirre, G.K.Kimberg, D.Y.Thompson-Schill, S.L.Modulation of amygdalar activity by the conscious regulation of negative emotion. J Cogn Neurosci 2002;14:913–921.CrossRefGoogle ScholarPubMed
Phan, K.L.Fitzgerald, D.A.Nathan, P.J.Moore, G.J.Uhde, T.W.Tancer, M.E.Neural substrates for voluntary suppression of negative affect: a functional magnetic resonance imaging study. Biol Psychiatry 2005;57:210–219.CrossRefGoogle ScholarPubMed
Urry, H.L.van Reekum, C.M.Johnstone, T.Kalin, N.H.Thurow, M.E.Schaefer, H.S.et al.Amygdala and ventromedial prefrontal cortex are inversely coupled during regulation of negative affect and predict the diurnal pattern of cortisol secretion among older adults. J Neurosci 2006;26:4415–4425.CrossRefGoogle ScholarPubMed
Phillips, M.L.Drevets, W.C.Rauch, S.L.Lane, R.Neurobiology of emotion perception I: the neural basis of normal emotion perception. Biol Psychiatry 2003;54:504–514.CrossRefGoogle ScholarPubMed
Fusar-Poli, P.Placentino, A.Carletti, F.Landi, P.Allen, P.Surguladze, S.et al.Functional atlas of emotional faces processing: a voxel-based meta-analysis of 105 functional magnetic resonance imaging studies. J Psychiatry Neurosci 2009;34:418–432.Google ScholarPubMed
Ochsner, K.N.Gross, J.J.The cognitive control of emotion. Trends Cogn Sci 2005;9:242–249.CrossRefGoogle ScholarPubMed
Morawetz, C.Bode, S.Baudewig, J.Kirilina, E.Heekeren, H.R.Changes in effective connectivity between dorsal and ventral prefrontal regions moderate emotion regulation. Cereb Cortex 2015;26:1923-37.Google Scholar
Ochsner, K.N.Silvers, J.A.Buhle, J.T.Functional imaging studies of emotion regulation: a synthetic review and evolving model of the cognitive control of emotion. Ann N Y Acad Sci 2012;1251:E1–E24.CrossRefGoogle ScholarPubMed
Liu, H.Tang, Y.Womer, F.Fan, G.Lu, T.Driesen, N.et al.Differentiating patterns of amygdala-frontal functional connectivity in schizophrenia and bipolar disorder. Schizophr Bull 2014;40:469–77.CrossRefGoogle ScholarPubMed
Anticevic, A.Brumbaugh, M.S.Winkler, A.M.Lombardo, L.E.Barrett, J.Corlett, P.R.et al.Global prefrontal and fronto-amygdala dysconnectivity in bipolar I disorder with psychosis history. Biol Psychiatry 2012;73:565–573.CrossRefGoogle ScholarPubMed
Vizueta, N.Rudie, J.D.Townsend, J.D.Torrisi, S.Moody, T.D.Bookheimer, S.Y.et al.Regional fMRI hypoactivation and altered functional connectivity during emotion processing in non-medicated depressed patients with bipolar II disorder. Am J Psychiatry 2012;169:831–840.CrossRefGoogle Scholar
Townsend, J.D.Torrisi, S.J.Lieberman, M.D.Sugar, C.A.Bookheimer, S.Y.Altshuler, L.L.Frontal-amygdala connectivity alterations during emotion downregulation in bipolar I disorder. Biol Psychiatry 2013;73:127–135.CrossRefGoogle ScholarPubMed
Rich, B.A.Fromm, S.J.Berghorst, L.H.Dickstein, D.P.Brotman, M.A.Pine, D.S.et al.Neural connectivity in children with bipolar disorder: impairment in the face emotion processing circuit. J Child Psychol Psychiatry 2008;49:88–96.CrossRefGoogle ScholarPubMed
Dickstein, D.P.Gorrostieta, C.Ombao, H.Goldberg, L.D.Brazel, A.C.Gable, C.J.et al.Fronto-temporal spontaneous resting state functional connectivity in pediatric bipolar disorder. Biol Psychiatry 2010;68:839–846.CrossRefGoogle ScholarPubMed
Almeida, J.R.Versace, A.Mechelli, A.Hassel, S.Quevedo, K.Kupfer, D.J.et al.Abnormal amygdala-prefrontal effective connectivity to happy faces differentiates bipolar from major depression. Biol Psychiatry 2009;66:451–459.CrossRefGoogle ScholarPubMed
Almeida, J.R.Mechelli, A.Hassel, S.Versace, A.Kupfer, D.J.Phillips, M.L.Abnormally increased effective connectivity between parahippocampal gyrus and ventromedial prefrontal regions during emotion labeling in bipolar disorder. Psychiatry Res 2009;174:195–201.CrossRefGoogle ScholarPubMed
Radaelli, D.Sferrazza Papa, G.Vai, B.Poletti, S.Smeraldi, E.Colombo, C.et al.Fronto-limbic disconnection in bipolar disorder. Eur Psychiatry 2015;30:82-8.CrossRefGoogle Scholar
Strakowski, S.M.Adler, C.M.Almeida, J.Altshuler, L.L.Blumberg, H.P.Chang, K.D.et al.The functional neuroanatomy of bipolar disorder: a consensus model. Bipolar Disord 2012;14:313–325.CrossRefGoogle ScholarPubMed
Frey, B.N.Andreazza, A.C.Houenou, J.Jamain, S.Goldstein, B.I.Frye, M.A.et al.Biomarkers in bipolar disorder: a positional paper from the International Society for Bipolar Disorders Biomarkers Task Force. Aust N Z J Psychiatry 2013;47:321–332.CrossRefGoogle ScholarPubMed
Bilder, R.M.Volavka, J.Lachman, H.M.Grace, A.A.The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes. Neuropsychopharmacology 2004;29:1943–1961.CrossRefGoogle ScholarPubMed
Chen, J.Lipska, B.K.Halim, N.Ma, Q.D.Matsumoto, M.Melhem, S.et al.Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 2004;75:807–821.CrossRefGoogle ScholarPubMed
Egan, M.F.Goldberg, T.E.Kolachana, B.S.Callicott, J.H.Mazzanti, C.M.Straub, R.E.et al.Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A 2001;98:6917–6922.CrossRefGoogle ScholarPubMed
Lachman, H.M.Papolos, D.F.Saito, T.Yu, Y.M.Szumlanski, C.L.Weinshilboum, R.M.Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996;6:243–250.CrossRefGoogle ScholarPubMed
Dickinson, D.Elvevag, B.Genes, cognition and brain through a COMT lens. Neuroscience 2009;164:72–87.CrossRefGoogle ScholarPubMed
Williams, L.M.Gatt, J.M.Grieve, S.M.Dobson-Stone, C.Paul, R.H.Gordon, E.et al.COMT Val(108/158)Met polymorphism effects on emotional brain function and negativity bias. Neuroimage 2010;53:918–925.CrossRefGoogle Scholar
Heinz, A.Smolka, M.N.The effects of catechol O-methyltransferase genotype on brain activation elicited by affective stimuli and cognitive tasks. Rev Neurosci 2006;17:359–367.CrossRefGoogle ScholarPubMed
Klucken, T.Kruse, O.Wehrum-Osinsky, S.Hennig, J.Schweckendiek, J.Stark, R.Impact of COMT Val158Met-polymorphism on appetitive conditioning and amygdala/prefrontal effective connectivity. Hum Brain Mapp 2015;36:1093–1101.CrossRefGoogle ScholarPubMed
Rasch, B.Spalek, K.Buholzer, S.Luechinger, R.Boesiger, P.de Quervain, D.J.et al.Aversive stimuli lead to differential amygdala activation and connectivity patterns depending on catechol-O-methyltransferase Val158Met genotype. Neuroimage 2010;52:1712–1719.CrossRefGoogle ScholarPubMed
Smolka, M.N.Buhler, M.Schumann, G.Klein, S.Hu, X.Z.Moayer, M.et al.Gene–gene effects on central processing of aversive stimuli. Mol Psychiatry 2007;12:307–317.CrossRefGoogle ScholarPubMed
Lonsdorf, T.B.Golkar, A.Lindstom, K.M.Fransson, P.Schalling, M.Ohman, A.et al.5-HTTLPR and COMTval158met genotype gate amygdala reactivity and habituation. Biol Psychol 2011;87:106–112.CrossRefGoogle ScholarPubMed
Gao, X.Gong, P.Liu, J.Hu, J.Li, Y.Yu, H.et al.COMT Val158Met polymorphism influences the susceptibility to framing in decision-making: OFC-amygdala functional connectivity as a mediator. Hum Brain Mapp 2016;37:1880–92.CrossRefGoogle ScholarPubMed
Mier, D.Kirsch, P.Meyer-Lindenberg, A.Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis. Mol Psychiatry 2010;15:918–927.CrossRefGoogle ScholarPubMed
Lelli-Chiesa, G.Kempton, M.J.Jogia, J.Tatarelli, R.Girardi, P.Powell, J.et al.The impact of the Val158Met catechol-O-methyltransferase genotype on neural correlates of sad facial affect processing in patients with bipolar disorder and their relatives. Psychol Med 2011;41:779–788.CrossRefGoogle ScholarPubMed
Gutierrez, B.Bertranpetit, J.Guillamat, R.Valles, V.Arranz, M.J.Kerwin, R.et al.Association analysis of the catechol O-methyltransferase gene and bipolar affective disorder. Am J Psychiatry 1997;154:113–115.Google ScholarPubMed
Benedetti, F.Colombo, C.Pirovano, A.Marino, E.Smeraldi, E.The catechol-O-methyltransferase Val(108/158)Met polymorphism affects antidepressant response to paroxetine in a naturalistic setting. Psychopharmacology (Berl) 2009;203:155–160.CrossRefGoogle Scholar
Benedetti, F.Dallaspezia, S.Colombo, C.Lorenzi, C.Pirovano, A.Smeraldi, E.Effect of catechol-O-methyltransferase Val(108/158)Met polymorphism on antidepressant efficacy of fluvoxamine. Eur Psychiatry 2010;25:476–478.CrossRefGoogle Scholar
Benedetti, F.Barbini, B.Bernasconi, A.Fulgosi, M.C.Dallaspezia, S.Gavinelli, C.et al.Acute antidepressant response to sleep deprivation combined with light therapy is influenced by the catechol-O-methyltransferase Val(108/158)Met polymorphism. J Affect Disord 2010;121:68–72.CrossRefGoogle Scholar
Benedetti, F.Dallaspezia, S.Locatelli, C.Radaelli, D.Poletti, S.Lorenzi, C.et al.Recurrence of bipolar mania is associated with catechol-O-methyltransferase Val(108/158)Met polymorphism. J Affect Disord 2011;132:293–296.CrossRefGoogle Scholar
Benedetti, F.Dallaspezia, S.Colombo, C.Lorenzi, C.Pirovano, A.Smeraldi, E.Association between catechol-O-methyltransferase Val(108/158)Met polymorphism and psychotic features of bipolar disorder. J Affect Disord 2010;125:341–344.CrossRefGoogle Scholar
Kirov, G.Murphy, K.C.Arranz, M.J.Jones, I.McCandles, F.Kunugi, H.et al.Low activity allele of catechol-O-methyltransferase gene associated with rapid cycling bipolar disorder. Mol Psychiatry 1998;3:342–345.CrossRefGoogle ScholarPubMed
Lachman, H.M.Morrow, B.Shprintzen, R.Veit, S.Parsia, S.S.Faedda, G.et al.Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome. Am J Med Genet 1996;67:468–472.3.0.CO;2-G>CrossRefGoogle ScholarPubMed
Papolos, D.F.Veit, S.Faedda, G.L.Saito, T.Lachman, H.M.Ultra-ultra rapid cycling bipolar disorder is associated with the low activity catecholamine-O-methyltransferase allele. Mol Psychiatry 1998;3:346–349.CrossRefGoogle ScholarPubMed
Hamilton, M.A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62.CrossRefGoogle ScholarPubMed
Hariri, A.R.Mattay, V.S.Tessitore, A.Kolachana, B.Fera, F.Goldman, D.et al.Serotonin transporter genetic variation and the response of the human amygdala. Science 2002;297:400–403.CrossRefGoogle ScholarPubMed
Sladky, R.Hoflich, A.Kublbock, M.Kraus, C.Baldinger, P.Moser, E.et al.Disrupted effective connectivity between the amygdala and orbitofrontal cortex in social anxiety disorder during emotion discrimination revealed by dynamic causal modeling for fMRI. Cereb Cortex 2015;25:895–903.CrossRefGoogle ScholarPubMed
Vai, B.Sferrazza Papa, G.Poletti, S.Radaelli, D.Donnici, E.Bollettini, I.et al.Abnormal cortico-limbic connectivity during emotional processing correlates with symptom severity in schizophrenia. Eur Psychiatry 2015;30:590–597.CrossRefGoogle Scholar
Benkert, O.Grunder, G.Wetzel, H.Hackett, D.A randomized, double-blind comparison of a rapidly escalating dose of venlafaxine and imipramine in inpatients with major depression and melancholia. J Psychiatr Res 1996;30:441–451.CrossRefGoogle ScholarPubMed
Chumbley, J.R.Friston, K.J.False discovery rate revisited: FDR and topological inference using Gaussian random fields. Neuroimage 2009;44:62–70.CrossRefGoogle ScholarPubMed
Stein, J.L.Wiedholz, L.M.Bassett, D.S.Weinberger, D.R.Zink, C.F.Mattay, V.S.et al.A validated network of effective amygdala connectivity. Neuroimage 2007;36:736–745.CrossRefGoogle ScholarPubMed
Dima, D.Stephan, K.E.Roiser, J.P.Friston, K.J.Frangou, S.Effective connectivity during processing of facial affect: evidence for multiple parallel pathways. J Neurosci 2011;31:14378–14385.CrossRefGoogle ScholarPubMed
Fairhall, S.L.Ishai, A.Effective connectivity within the distributed cortical network for face perception. Cereb Cortex 2007;17:2400–2406.CrossRefGoogle ScholarPubMed
Behzadi, Y.Restom, K.Liau, J.Liu, T.T.A component based noise correction method (CompCor) for BOLD and perfusion based fMRI. Neuroimage 2007;37:90–101.CrossRefGoogle ScholarPubMed
Liu, T.Y.Chen, Y.S.Hsieh, J.C.Chen, L.F.Asymmetric engagement of amygdala and its gamma connectivity in early emotional face processing. PLoS One 2015;10:e0115677.CrossRefGoogle ScholarPubMed
Wang, F.Kalmar, J.H.He, Y.Jackowski, M.Chepenik, L.G.Edmiston, E.E.et al.Functional and structural connectivity between the perigenual anterior cingulate and amygdala in bipolar disorder. Biol Psychiatry 2009;66:516–521.CrossRefGoogle ScholarPubMed
Kunugi, H.Nanko, S.Ueki, A.Otsuka, E.Hattori, M.Hoda, F.et al.High and low activity alleles of catechol-O-methyltransferase gene: ethnic difference and possible association with Parkinson's disease. Neurosci Lett 1997;221:202–204.CrossRefGoogle ScholarPubMed
Davidson, R.J.Anxiety and affective style: role of prefrontal cortex and amygdala. Biol Psychiatry 2002;51:68–80.CrossRefGoogle ScholarPubMed
Lee, A.Qiu, A.Modulative effects of COMT haplotype on age-related associations with brain morphology. Hum Brain Mapp 2016;37:2068–82.CrossRefGoogle Scholar
Prata, D.P.Mechelli, A.Fu, C.H.Picchioni, M.Toulopoulou, T.Bramon, E.et al.Epistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia. Proc Natl Acad Sci U S A 2009;106:13600–13605.CrossRefGoogle ScholarPubMed
Vanderhasselt, M.A.Kuhn, S.De Raedt, R.‘Put on your poker face’: neural systems supporting the anticipation for expressive suppression and cognitive reappraisal. Soc Cogn Affect Neurosci 2013;8:903–910.CrossRefGoogle ScholarPubMed
Silani, G.Lamm, C.Ruff, C.C.Singer, T.Right supramarginal gyrus is crucial to overcome emotional egocentricity bias in social judgments. J Neurosci 2013;33:15466–15476.CrossRefGoogle ScholarPubMed
Beck, A.T.The evolution of the cognitive model of depression and its neurobiological correlates. Am J Psychiatry 2008;165:969–977.CrossRefGoogle ScholarPubMed
Petrides, M.Pandya, D.N.Dorsolateral prefrontal cortex: comparative cytoarchitectonic analysis in the human and the macaque brain and corticocortical connection patterns. Eur J Neurosci 1999;11:1011–1036.CrossRefGoogle ScholarPubMed
Petrides, M.Lateral prefrontal cortex: architectonic and functional organization. Philos Trans R Soc Lond B Biol Sci 2005;360:781–795.CrossRefGoogle ScholarPubMed
Lang, U.E.Bajbouj, M.Sander, T.Gallinat, J.Gender-dependent association of the functional catechol-O-methyltransferase Val158Met genotype with sensation seeking personality trait. Neuropsychopharmacology 2007;32:1950–1955.CrossRefGoogle ScholarPubMed
Reuter, M.Peters, K.Schroeter, K.Koebke, W.Lenardon, D.Bloch, B.et al.The influence of the dopaminergic system on cognitive functioning: a molecular genetic approach. Behav Brain Res 2005;164:93–99.CrossRefGoogle ScholarPubMed
Reuter, M.Schmitz, A.Corr, P.Hennig, J.Molecular genetics support Gray's personality theory: the interaction of COMT and DRD2 polymorphisms predicts the behavioural approach system. Int J Neuropsychopharmacol 2006;9:155–166.Google ScholarPubMed
Stein, M.B.Fallin, M.D.Schork, N.J.Gelernter, J.COMT polymorphisms and anxiety-related personality traits. Neuropsychopharmacology 2005;30:2092–2102.CrossRefGoogle ScholarPubMed
Diatchenko, L.Slade, G.D.Nackley, A.G.Bhalang, K.Sigurdsson, A.Belfer, I.et al.Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 2005;14:135–143.CrossRefGoogle ScholarPubMed
Scharinger, C.Rabl, U.Sitte, H.H.Pezawas, L.Imaging genetics of mood disorders. Neuroimage 2010;53:810–821.CrossRefGoogle ScholarPubMed
Surguladze, S.A.Radua, J.El-Hage, W.Gohier, B.Sato, J.R.Kronhaus, D.M.et al.Interaction of catechol O-methyltransferase and serotonin transporter genes modulates effective connectivity in a facial emotion-processing circuitry. Transl Psychiatry 2012;2:e70.CrossRefGoogle Scholar
Haldane, M.Jogia, J.Cobb, A.Kozuch, E.Kumari, V.Frangou, S.Changes in brain activation during working memory and facial recognition tasks in patients with bipolar disorder with lamotrigine monotherapy. Eur Neuropsychopharmacol 2008;18:48–54.CrossRefGoogle ScholarPubMed
Phillips, M.L.Travis, M.J.Fagiolini, A.Kupfer, D.J.Medication effects in neuroimaging studies of bipolar disorder. Am J Psychiatry 2008;165:313–320.CrossRefGoogle ScholarPubMed
Submit a response

Comments

No Comments have been published for this article.