title: The interaction between 5-HTTLPR and stress exposure influences connectivity of the executive control and default mode brain networks.
abstract: We recently reported that the serotonin transporter polymorphism 5-HTTLPR moderates the relation between stress exposure and attention-deficit/hyperactivity disorder (ADHD) severity. This gene-environment interaction (GxE) has been previously tied to the processing of emotional stimuli, which is increasingly recognized to be a key factor in ADHD-related impairment. The executive control and default mode brain networks play an important role in the regulation of emotion processing, and altered connectivity of these networks has also been associated with ADHD. We therefore investigated whether resting-state connectivity of either of these networks mediates the relation of 5-HTTLPR and stress exposure with ADHD severity. Resting-state functional magnetic resonance imaging, genetic, and stress exposure questionnaire data was available for 425 adolescents and young adults (average age 17.2 years). We found that 5-HTTLPR S-allele carriers showed a more negative relation between stress exposure and connectivity of the executive control network than L-allele homozygotes, specifically in the pre/postcentral gyrus, striatum, and frontal pole. In the default mode network, we found a positive association between the GxE and supramarginal gyrus connectivity. Connectivity of either network did not significantly mediate the effect of this GxE on ADHD. Opposite effects of stress exposure on connectivity in the executive and default mode networks may contribute to findings that stress exposure is associated with lowered cognitive control and heightened levels of rumination and worrying, for S-allele carriers but not L-allele homozygotes. When combined, these effects on connectivity of both networks may relate to the emotional problems seen in individuals with ADHD.
authors.affiliation: Department of Psychiatry, University Medical Center Groningen, University of Groningen, P.O. Box 30001, 9700 RB, Groningen, The Netherlands. dvdm09@gmail.com.
authors.forename: Dennis
authors.initials: D
authors.lastname: van der Meer
authors.affiliation: Department of Psychiatry, University Medical Center Groningen, University of Groningen, P.O. Box 30001, 9700 RB, Groningen, The Netherlands.
authors.forename: Catharina A
authors.initials: CA
authors.lastname: Hartman
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands.|Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Raimon H R
authors.initials: RHR
authors.lastname: Pruim
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands.|Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Mennes
authors.affiliation: Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, the Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Heslenfeld
authors.affiliation: Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Oosterlaan
authors.affiliation: Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, USA.|K.G. Jebsen Centre for Psychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.affiliation: Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands.|Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands.|Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, The Netherlands.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
authors.affiliation: Department of Psychiatry, University Medical Center Groningen, University of Groningen, P.O. Box 30001, 9700 RB, Groningen, The Netherlands.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Hoekstra
mesh_terms: D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology; D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology*; D001931:Brain Mapping; D003430:Cross-Sectional Studies; D056344:Executive Function / Q000502:physiology*; D005500:Follow-Up Studies; D059647:Gene-Environment Interaction; D060005:Genotyping Techniques; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D009434:Neural Pathways / Q000000981:diagnostic imaging / Q000503:physiopathology; D012044:Regression Analysis; D012146:Rest; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D012720:Severity of Illness Index; D013315:Stress, Psychological / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology*; D011795:Surveys and Questionnaires
chemical_list: C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins
keywords: Attention-deficit/hyperactivity disorder; Functional magnetic resonance imaging; Gene-environment interaction; Psychological stress; Serotonin transporter