From diffusion to focalization: The age-related divergence of emotional networks in bipolar disorder

Emotional processing abnormalities are a core feature of bipolar disorder (BD), yet neuroimaging studies have yielded inconsistent results. The age-related divergence between pediatric (PBD) and adult (ABD) bipolar disorder has been increasingly highlighted by physiological and clinical evidence. Therefore, previous findings were integrated to construct the emotional networks of PBD and ABD, with the aim of elucidating their age-related divergence.

Activation likelihood estimation was performed on 17 PBD (340 patients, 341 controls) and 20 ABD (681 patients, 582 controls) task-based fMRI studies. Activation network mapping was conducted using age-matched normative connectomes (550 pediatric and 1000 adult participants) to identify group-specific emotional networks, which were characterized through functional decoding. Transcriptomic analysis linked networks to gene expression, followed by enrichment analysis and cross-referencing with the latest BD genome-wide association study.

PBD exhibited a diffuse emotional network spanning frontal, temporal, and subcortical regions involved in reward and cognitive systems. Conversely, ABD showed a focal network restricted to the salience network and basal ganglia-thalamic circuits. Transcriptomic analysis revealed that both networks were spatially associated with immune-inflammatory signaling and a Fringe glycosyltransferase subnetwork. Specifically, the PBD diffuse pattern was enriched for response to external stimulus, whereas the ABD focal pattern was enriched for cell migration. TTC12, which participates in dopaminergic reward processing, was identified as a prioritized convergent candidate across age stages.

These findings suggest an age-related divergence from diffuse multi-system interference in PBD emotional network to focal specialization in ABD, providing new insights into the stage-specific pathophysiological correlates of BD.