title: Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults.
abstract: Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents and adults in prefrontal brain networks at rest. Resting state functional connectivity data were collected from cross-sectional and multicenter study sites involving 106 healthy young adults (mean age 24 ± 2.6 years), gender matched to 106 randomly chosen 14-year-olds. We selected the anterior medial prefrontal cortex (amPFC) as seed due to its important role as nexus of the executive control and default mode network. We observed a significant age-dependent reversal of COMT Val158Met effects on resting state functional connectivity between amPFC and ventrolateral as well as dorsolateral prefrontal cortex, and parahippocampal gyrus. Val homozygous adults exhibited increased and adolescents decreased connectivity compared to Met homozygotes for all reported regions. Network analyses underscored the importance of the parahippocampal gyrus as mediator of observed effects. Results of this study demonstrate that adolescent and adult resting state networks are dose-dependently and diametrically affected by COMT genotypes following a hypothetical model of dopamine function that follows an inverted U-shaped curve. This study might provide cues for the understanding of disease onset or dopaminergic treatment mechanisms in major neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder.
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Bernhard M
authors.initials: BM
authors.lastname: Meyer
authors.affiliation: Department of Child and Adolescent Psychiatry, Medical University of Vienna, Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Huemer
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Rabl
authors.affiliation: MR Centre of Excellence, Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria.
authors.forename: Roland N
authors.initials: RN
authors.lastname: Boubela
authors.affiliation: MR Centre of Excellence, Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria.
authors.forename: Klaudius
authors.initials: K
authors.lastname: Kalcher
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Berger
authors.affiliation: Central Institute of Mental Health, Faculty of Clinical Medicine Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Banaschewski
authors.affiliation: Institute of Psychiatry, King's College, London, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Barker
authors.affiliation: Institute of Neuroscience, Trinity College, Dublin, Ireland.
authors.forename: Arun
authors.initials: A
authors.lastname: Bokde
authors.affiliation: University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Büchel
authors.affiliation: Department of Psychiatry, Université de Montreal, CHU St. Justine Hospital, Montreal, Canada.
authors.forename: Patricia
authors.initials: P
authors.lastname: Conrod
authors.affiliation: Institute of Psychiatry, King's College, London, UK.
authors.forename: Sylvane
authors.initials: S
authors.lastname: Desrivières
authors.affiliation: Central Institute of Mental Health, Faculty of Clinical Medicine Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Herta
authors.initials: H
authors.lastname: Flor
authors.affiliation: Neurospin, Commissariat à l'Energie Atomique, CEA-Saclay Center, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Frouin
authors.affiliation: Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Berlin, Germany.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Gallinat
authors.affiliation: Department of Psychiatry and Psychology, University of Vermont, Burlington, USA.
authors.forename: Hugh
authors.initials: H
authors.lastname: Garavan
authors.affiliation: Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinz
authors.affiliation: Physikalisch-Technische Bundesanstalt, Berlin, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Ittermann
authors.affiliation: Institute of Psychiatry, King's College, London, UK.
authors.forename: Tianye
authors.initials: T
authors.lastname: Jia
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montreal, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, INSERM CEA Unit 1000 "Imaging and Psychiatry", Orsay, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Martinot
authors.affiliation: Central Institute of Mental Health, Faculty of Clinical Medicine Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Nees
authors.affiliation: Central Institute of Mental Health, Faculty of Clinical Medicine Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Smolka
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Lucie
authors.initials: L
authors.lastname: Bartova
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Ana
authors.initials: A
authors.lastname: Popovic
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Scharinger
authors.affiliation: Center for Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Harald H
authors.initials: HH
authors.lastname: Sitte
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Division of Child and Adolescent Psychiatry and Child Development, Stanford University School of Medicine, Stanford, USA.
authors.forename: Hans
authors.initials: H
authors.lastname: Steiner
authors.affiliation: Department of Child and Adolescent Psychiatry, Medical University of Vienna, Vienna, Austria.
authors.forename: Max H
authors.initials: MH
authors.lastname: Friedrich
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Kasper
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Perkmann
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Nicole
authors.initials: N
authors.lastname: Praschak-Rieder
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Helmuth
authors.initials: H
authors.lastname: Haslacher
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Esterbauer
authors.affiliation: MR Centre of Excellence, Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria.
authors.forename: Ewald
authors.initials: E
authors.lastname: Moser
authors.affiliation: Institute of Psychiatry, King's College, London, UK.
authors.forename: Gunter
authors.initials: G
authors.lastname: Schumann
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria. lukas.pezawas@meduniwien.ac.at.
authors.forename: Lukas
authors.initials: L
authors.lastname: Pezawas
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000502:physiology; D001931:Brain Mapping; D002394:Catechol O-Methyltransferase / Q000235:genetics* / Q000502:physiology*; D003430:Cross-Sectional Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000502:physiology*; D055815:Young Adult
chemical_list: C588010:COMT protein, human; D002394:Catechol O-Methyltransferase
keywords: Adolescents; Catechol-O-methyltransferase; Cognition; Dopamine; Functional neuroimaging; Magnetic resonance imaging