Bipolar disorder and gender are associated with frontolimbic and basal ganglia dysconnectivity: A study of topological variance using network analysis

Well-established structural abnormalities, mostly involving the limbic system, have been associated with disorders of emotion regulation. Understanding the arrangement and connections of these regions with other functionally specialized cortico-subcortical subnetworks is key to understanding how the human brain's architecture underpins abnormalities of mood and emotion. We investigated topological patterns in bipolar disorder (BD) with the anatomically improved precision conferred by combining subject-specific parcellation/segmentation with nontensor-based tractograms derived using a high-angular resolution diffusion-weighted approach. Connectivity matrices were constructed using 34 cortical and 9 subcortical bilateral nodes (Desikan-Killiany), and edges that were weighted by fractional anisotropy and streamline count derived from deterministic tractography using constrained spherical deconvolution. Whole-brain and rich-club connectivity alongside a permutation-based statistical approach was used to investigate topological variance in predominantly euthymic BD relative to healthy volunteers. BP patients (n=40) demonstrated impairments across whole-brain topological arrangements (density, degree, and efficiency), and a dysconnected subnetwork involving limbic and basal ganglia relative to controls (n=45). Increased rich-club connectivity was most evident in females with BD, with frontolimbic and parieto-occipital nodes not members of BD rich-club. Increased centrality in females relative to males was driven by basal ganglia and fronto-temporo-limbic nodes. Our subject-specific cortico-subcortical nontensor-based connectome map presents a neuroanatomical model of BD dysconnectivity that differentially involves communication within and between emotion-regulatory and reward-related subsystems. Moreover, the female brain positions more dependence on nodes belonging to these two differently specialized subsystems for communication relative to males, which may confer increased susceptibility to processes dependent on integration of emotion and reward-related information. This research is supported by the Irish Research Council (IRC) Postgraduate Scholarship, Ireland awarded to Leila Nabulsi, and by the Health Research Board (HRA-POR-324) awarded to Dr Dara M. Cannon. We gratefully acknowledge the participants and the support of the Wellcome-Trust HRB Clinical Research Facility and the Centre for Advanced Medical Imaging, St. James Hospital; Andrew Hoopes, Research Technician I, MGH/HST Martinos Center for Biomedical Imaging, for Freesurfer software support, Christopher Grogan, MSc, for his contribution to data processing, Jenna Pittman, BSc, and Fiona Martyn, BSc, for their contribution to data handling. peer-reviewed 2020-12-16