title: Network dysfunction of emotional and cognitive processes in those at genetic risk of bipolar disorder.
abstract: The emotional and cognitive vulnerabilities that precede the development of bipolar disorder are poorly understood. The inferior frontal gyrus-a key cortical hub for the integration of cognitive and emotional processes-exhibits both structural and functional changes in bipolar disorder, and is also functionally impaired in unaffected first-degree relatives, showing diminished engagement during inhibition of threat-related emotional stimuli. We hypothesized that this functional impairment of the inferior frontal gyrus in those at genetic risk of bipolar disorder reflects the dysfunction of broader network dynamics underlying the coordination of emotion perception and cognitive control. To test this, we studied effective connectivity in functional magnetic resonance imaging data acquired from 41 first-degree relatives of patients with bipolar disorder, 45 matched healthy controls and 55 participants with established bipolar disorder. Dynamic causal modelling was used to model the neuronal interaction between key regions associated with fear perception (the anterior cingulate), inhibition (the left dorsolateral prefrontal cortex) and the region upon which these influences converge, namely the inferior frontal gyrus. Network models that embodied non-linear, hierarchical relationships were the most strongly supported by data from our healthy control and bipolar participants. We observed a marked difference in the hierarchical influence of the anterior cingulate on the effective connectivity from the dorsolateral prefrontal cortex to the inferior frontal gyrus that is unique to the at-risk cohort. Non-specific, non-hierarchical mechanisms appear to compensate for this network disturbance. We thus establish a specific network disturbance suggesting dysfunction in the processes that support hierarchical relationships between emotion and cognitive control in those at high genetic risk for bipolar disorder.
authors.affiliation: 1 QIMR Berghofer, Brisbane, Queensland, Australia 2 Metro North Mental Health Service, Brisbane, Queensland, Australia 3 School of Psychiatry, University of New South Wales, Randwick, NSW, Australia michael.breakspear@qimrberghofer.edu.au.
authors.forename: Michael
authors.initials: M
authors.lastname: Breakspear
authors.affiliation: 3 School of Psychiatry, University of New South Wales, Randwick, NSW, Australia 4 Black Dog Institute, Prince of Wales Hospital, Randwick, NSW, Australia michael.breakspear@qimrberghofer.edu.au.
authors.forename: Gloria
authors.initials: G
authors.lastname: Roberts
authors.affiliation: 3 School of Psychiatry, University of New South Wales, Randwick, NSW, Australia 4 Black Dog Institute, Prince of Wales Hospital, Randwick, NSW, Australia 5 Schizophrenia Research Institute, Sydney, NSW, Australia 6 Neuroscience Research Australia, Randwick, NSW, Australia.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Green
authors.affiliation: 1 QIMR Berghofer, Brisbane, Queensland, Australia.
authors.forename: Vinh T
authors.initials: VT
authors.lastname: Nguyen
authors.affiliation: 3 School of Psychiatry, University of New South Wales, Randwick, NSW, Australia 4 Black Dog Institute, Prince of Wales Hospital, Randwick, NSW, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Frankland
authors.affiliation: 3 School of Psychiatry, University of New South Wales, Randwick, NSW, Australia.
authors.forename: Florence
authors.initials: F
authors.lastname: Levy
authors.affiliation: 3 School of Psychiatry, University of New South Wales, Randwick, NSW, Australia 6 Neuroscience Research Australia, Randwick, NSW, Australia.
authors.forename: Rhoshel
authors.initials: R
authors.lastname: Lenroot
authors.affiliation: 3 School of Psychiatry, University of New South Wales, Randwick, NSW, Australia 4 Black Dog Institute, Prince of Wales Hospital, Randwick, NSW, Australia.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Mitchell
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics / Q000503:physiopathology*; D001921:Brain / Q000503:physiopathology; D016022:Case-Control Studies; D003071:Cognition; D004644:Emotions; D005190:Family; D005239:Fear; D005260:Female; D059907:Functional Neuroimaging; D020022:Genetic Predisposition to Disease; D006179:Gyrus Cinguli / Q000503:physiopathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000503:physiopathology; D017711:Nonlinear Dynamics; D010465:Perception; D017397:Prefrontal Cortex / Q000503:physiopathology*; D012720:Severity of Illness Index; D055815:Young Adult
keywords: bipolar disorder; cognitive control; computational psychiatry; imaging; neuropsychiatry