title: Altered DLPFC-Hippocampus Connectivity During Working Memory: Independent Replication and Disorder Specificity of a Putative Genetic Risk Phenotype for Schizophrenia.
abstract: Altered connectivity of dorsolateral prefrontal cortex (DLPFC) and hippocampus during working memory is considered an intermediate phenotype for schizophrenia (SCZ), but the relevance for other mental disorders with shared genetic background remains unknown. Here we investigated its presence in unaffected first-degree relatives of patients with bipolar disorder (BD) or major depressive disorder (MDD). Furthermore, we aimed to provide an independent replication of this phenotype in first-degree relatives of SCZ patients. We acquired functional magnetic resonance imaging (fMRI) data from 309 healthy controls and 218 healthy first-degree relatives of index patients with SCZ (n = 62), BD (n = 66) and MDD (n = 90), who completed the n-back working memory paradigm. We observed a significant group effect on DLPFC-hippocampus coupling (PFWE = .031, all P-values region of interest [ROI] corrected). Post hoc comparisons revealed that this effect was driven by the SCZ relatives, who showed a significant increase in the negative functional connectivity of the DLPFC and right hippocampus compared to controls (PFWE = .001), BD relatives (PFWE = .015) and trend-wise also MDD relatives (PFWE = .082). Comparison of BD and MDD relatives to the controls revealed no difference (PFWE-values > .451). Supplementary analyses suggested that the SCZ relatives finding is robust to a range of potential confounds, including structural differences. Our data further support altered DLPFC-hippocampus connectivity during working memory as an intermediate phenotype for SCZ. This suggests that this phenotype is relatively specific to SCZ and does not translate to other genetically related disorders in the mood-psychosis spectrum.
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/ Heidelberg University, Mannheim, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: Walter
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/ Heidelberg University, Mannheim, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Moessnang
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/ Heidelberg University, Mannheim, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Schäfer
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Erk
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mohnke
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Romund
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Garbusow
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/ Heidelberg University, Mannheim, Germany.
authors.forename: Luanna
authors.initials: L
authors.lastname: Dixson
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinz
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Romanczuk-Seiferth
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/ Heidelberg University, Mannheim, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/ Heidelberg University, Mannheim, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Tost
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000000981:diagnostic imaging / Q000503:physiopathology*; D063132:Connectome / Q000379:methods*; D003865:Major Depressive Disorder / Q000000981:diagnostic imaging / Q000503:physiopathology*; D005190:Family; D005260:Female; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000503:physiopathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008875:Middle Aged; D010641:Phenotype; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000503:physiopathology*; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000503:physiopathology*; D055815:Young Adult
keywords: fMRI; imaging genetics; intermediate phenotype; schizophrenia; working memory