Hippocampal temporal dynamics and spatial heterogeneity unveil vulnerability markers in the offspring of bipolar patients

Objectives: Bipolar disorder (BD) is a highly heritable disorder characterized by emotion dysregulation and recurrent oscillations between mood states. Despite the proven efficacy of early interventions, vulnerability markers in high-risk individuals are still lacking. BD patients present structural alterations of the hippocampus, a pivotal hub of emotion regulation networks composed of multiple subregions with different projections. However, the hippocampal dynamic functional connectivity (dFC) in BD remains unclear. We aim to investigate whether the dFC of hippocampal subdivisions differentiates BD patients, offspring of BD patients (BDoff), and healthy controls (HC); and whether it correlates with symptoms differently between these groups.

Methods: We studied for the first time the dFC of the hippocampus through a cutting-edge micro-co-activation patterns (μCAPs) analysis of resting-state functional MRI data of 97 subjects (26 BD, 18 BDoff, 53 HC). μCAPs allow a data-driven differentiation within the seed region.

Results: dFC between the hippocampal body and a somatomotor-μCAP was lower both in BD patients (p-value_FDR:0.00015) and in BDoff (p-value_FDR:0.020) than in HC. Inversely, dFC between the hippocampal head and a limbic-μCAP was higher in BD patients than in HC (p-value_FDR: 0.005). Furthermore, the correlations between a frontoparietal-μCAP and both depression and emotion dysregulation symptoms were significantly higher in BD than HC (p-value_FDR <0.02).

Conclusion: Overall, we observed alterations of large-scale functional brain networks associated with decreased cognitive control flexibility and disrupted somatomotor, saliency, and emotion processing in BD. Interestingly, BDoff presented an intermediate phenotype between BD and HC, suggesting that dFC of hippocampal subregions might represent a marker of vulnerability to BD.