From adaptive to maladaptive hippocampal resting-state functional connectivity over the course of multiple sclerosis...

It remains unclear how resting-state functional connectivity (rsFC) changes in the hippocampus modulate the negative impact of white matter (WM) lesions on memory performance over the course of multiple sclerosis (MS). This study investigates whether hippocampal rsFC alterations at each MS clinical stage affect memory performance.

This cross-sectional study included 109 individuals: 30 healthy controls and 79 patients (20 with clinically or radiologically isolated syndrome (CIS-RIS), 24 with relapsing-remitting MS (RRMS) and 35 with progressive MS (PMS)). Verbal memory was assessed using a modified Rey's Auditory Verbal Learning Test. Magnetic resonance imaging measured WM lesions and hippocampal rsFC. Between-group memory differences were analyzed using linear regression, while rsFC differences using ANOVA and two-sample t-tests. Final regression models tested whether hippocampal rsFC changes in MS subgroups modified the link between memory performance and WM lesion volume.

CIS/RIS patients showed preserved memory performance, while RRMS and PMS exhibited progressive impairment. Stage-dependent hippocampal rsFC alterations emerged: in CIS/RIS, increased hippocampal-angular gyrus rsFC suggested memory compensation, whereas in RRMS, decreased hippocampal-rostral anterior cingulate cortex rsFC appeared adaptive, but changes involving the rsFC with frontal and occipital cortices were not associated with memory improvement. Similarly, in PMS altered hippocampal rsFC with frontal and occipital cortices was unrelated to memory preservation, consistent with disease progression.

Hippocampal rsFC evolves from compensatory engagement of default mode network regions to non-beneficial reorganization involving frontal and posterior areas, paralleling the progression from preserved to impaired memory function across MS stages.