International Multi-Site Brain Network Harmonization via the ENIGMA Bipolar Working Group

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Summary of  Biological Psychiatry, . https://doi.org/10.1016/j.biopsych.2026.04.020
Dr. Leila Nabulsi et al.

Points

Investigators conducted a large-scale diffusion neuroimaging analysis across 16 international sites to evaluate structural white matter network organization in 449 individuals with bipolar disorder.
Patients with bipolar disorder demonstrated less densely connected neural pathways, lower information processing efficiency, and an increased reliance on highly centralized structural brain hubs.
The most prominent connectomic differences appeared within fronto-limbic and basal ganglia networks which are the core systems responsible for regulating emotion and reward processing.
Extended illness duration correlated with broader efficiency drops and altered wiring between the amygdala and hippocampus while history of psychosis predicted severe global network desynchronization.
Pharmacological profiling showed that specific psychotropic classes including selective serotonin reuptake inhibitors and anticonvulsants correlate with distinct structural changes in cognitive control circuits.

Summary

This study evaluated large-scale structural brain network topology using graph theory to identify macro-connectomic abnormalities associated with bipolar disorder (BD) severity and pharmacological treatment. While prior neuroimaging research established localized gray matter volumetric reductions, the systemic organization of white matter communications across functional circuits has remained poorly characterized. Utilizing diffusion-weighted MRI (dMRI) data harmonized across 16 international research sites via the ENIGMA Bipolar Disorder Working Group, investigators mapped neural pathways as an interconnected system of nodes and routes. The objective was to determine how structural network architecture correlates with disease duration, age of onset, psychosis, and distinct mechanisms of psychotropic medication.

The study sample comprised brain scans from 449 individuals diagnosed with bipolar disorder and 510 psychiatrically healthy controls. Graph-theoretic analysis revealed that patients with bipolar disorder exhibit subtle but widespread reductions in global structural network connectivity, demonstrating significantly lower information exchange efficiency and lengthened communication pathways between distant brain regions. To compensate for these compromised tracts, the structural network demonstrates an increased topological reliance on highly connected, centralized hub regions. The most pronounced connectivity deficits localized to fronto-limbic, basal ganglia, default mode, and salience networks, which directly regulate emotional processing, reward motivation, attention, and internal thought.

Connectomic architecture varied significantly based on individual clinical history, psychosis status, and therapeutic drug exposure. Longer illness duration correlated with progressive reductions in global communication efficiency and altered connectivity between the amygdala and hippocampus. Conversely, a later age of onset presented with isolated tractography modifications connecting the cerebellum, thalamus, and fronto-limbic pathways. Psychosis exacerbated overall network desynchronization, while high-frequency manic episodes tracked with elevated fronto-limbic connectivity. Mechanistic profiling of current treatments linked selective serotonin reuptake inhibitors (SSRIs) to reduced global efficiency within limbic zones, whereas anticonvulsants and antipsychotics uniquely modified cognitive control circuits. Longitudinal imaging trials remain necessary to establish causal hazard ratios regarding treatment and structural disease progression.

Link to the article: https://www.biologicalpsychiatryjournal.com/article/S0006-3223(26)01221-7/fulltext

References

Nabulsi, L., Kang, M. J. Y., Jahanshad, N., McPhilemy, G., Martyn, F. M., Haarman, B., McDonald, C., Hallahan, B., O’Donoghue, S., Stein, D. J., Howells, F. M., Scheffler, F., Temmingh, H. S., Glahn, D. C., Rodrigue, A., Pomarol-Clotet, E., Vieta, E., Radua, J., Salvador, R., … Cannon, D. M. (2026). Structural brain network alterations in relation to treatment and illness severity in bipolar disorder. Biological Psychiatry, S0006322326012217. https://doi.org/10.1016/j.biopsych.2026.04.020