Structural Brain Network Alterations in Relation to Treatment and Illness Severity in Bipolar Disorder

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BACKGROUND: Large-scale T1-weighted magnetic resonance imaging (MRI) studies have established gray matter abnormalities in bipolar disorder (BD), with our group contributing to consensus findings. However, structural connectivity, particularly within emotion- and reward-related circuits, remains poorly understood. Diffusion-weighted MRI (dMRI) enables investigation of white matter pathways, but prior work is constrained by small samples, methodological heterogeneity, and unclear medication effects. We conducted the largest dMRI network analysis in BD, relating symptom burden and polypharmacy to tractography-derived connectivity and graph-theoretical metrics. METHODS: Cross-sectional structural and diffusion MRI scans from 450 individuals with BD (mean ± SD = 35.7 ± 12.6 years) and 509 control participants (33.3 ± 12.6 years), ages 18 to 65 years, were analyzed across 16 ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) BD sites. Standardized segmentation/parcellation and constrained spherical deconvolution tractography generated individual structural connectivity matrices. Graph-theoretical metrics of global and subnetwork organization were related to symptom severity and medications. RESULTS: BD showed widespread network alterations (lower density and efficiency, longer path length, and higher betweenness centrality), altered microstructural organization in a limbic-basal ganglia circuit, and abnormal streamline counts in a default mode/salience/frontolimbic-basal ganglia network. Longer illness duration, later onset, and psychosis history were associated with greater abnormalities in network architecture, whereas more manic episodes were associated with greater frontolimbic connectivity. Antidepressant (particularly selective serotonin reuptake inhibitor), anticonvulsant, and antipsychotic use related to poorer global and frontolimbic connectivity; no clear lithium effects emerged. CONCLUSIONS: As the largest structural connectivity study in BD, we revealed widespread disruption in reward and emotion-regulation networks influenced by illness severity and medication use. Results show that multisite harmonization is feasible and highlight ENIGMA-BD as a scalable framework for identifying reproducible neurobiological markers.

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