Fronto-limbic, Fronto-parietal and Default-mode Involvement in Functional Dysconnectivity in Psychotic Bipolar Disorder

Abstract Background Functional abnormalities, mostly involving functionally specialized subsystems have been associated with disorders of emotion regulation such as bipolar disorder (BD). Understanding how independent functional subsystems integrate globally and how they relate with anatomical cortico-subcortical networks is key to understanding how the human brain’s architecture constrains functional interactions and underpins abnormalities of mood and emotion, particularly in BD. Methods Resting-state functional magnetic resonance time-series were averaged to obtain individual functional connectivity matrices (AFNI); individual structural connectivity matrices were derived using deterministic non-tensor-based tractography (ExploreDTI), weighted by streamline count and fractional anisotropy. Structural and functional nodes were defined using a subject-specific cortico-subcortical mapping (Desikan-Killiany, Freesurfer). Whole-brain connectivity alongside a permutation-based statistical approach and structure-function coupling were employed to investigate topological variance in predominantly euthymic BD relative to psychiatrically-healthy controls. Results Bipolar disorder (n=41) exhibited decreased (synchronous) connectivity in a subnetwork encompassing fronto-limbic and posterior-occipital functional connections (T>3, p=0.039), alongside increased (anti-synchronous) connectivity within a fronto-temporal subnetwork (T>3, p=0.025); all relative to controls (n=56). Preserved whole-brain functional connectivity, and comparable structural-functional relationships amongst whole-brain and edge-class connections were observed in BD relative to controls. Conclusions We present a functional map of BD dysconnectivity that differentially involves communication within nodes belonging to functionally specialized subsystems – default-mode, fronto-parietal and fronto-limbic systems; these changes do not extend to be detected globally and may be necessary to maintain a remitted clinical state of BD. Preserved structure-function coupling in BD despite evidence of regional anatomical and functional deficits suggests a dynamic interplay between structural and functional subnetworks.