Brain functional dynamics linked to depression and anxiety: cross-sectional and longitudinal associations over 9 years

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ABSTRACT Background Resting-state fMRI (rs-fMRI) co-activation patterns (CAPs) capture recurrent whole-brain states that may index neurobiological substrates of affective psychopathology, but whether their temporal dynamics co-evolve with symptom severity over the naturalistic long-term course of depression and anxiety remains unknown. Methods We examined rs-fMRI and clinical data from 340 participants of the NESDA neuroimaging cohort [228 with major depression (MDD) and/or an anxiety disorder (AFF), 112 controls (CTR)] collected at baseline (Y0), 2-year (Y2), and 9-year (Y9) follow-up. Four CAPs were identified, internally validated, externally replicated against an independent dataset, and quantified by dwell time (time spent of each brain CAP) and entries (initiation of each CAP). These metrics were related to depression symptomatology (IDS score), anxiety (BAI), and fear (FQ) severity at two levels: cross-sectionally, between subjects and groups, and longitudinally, through within-person associations between changes in CAP expression and changes in symptoms severity. Results At baseline, attention–somatomotor (AT-SM CAP ) dwell time was negatively associated with depression severity in controls (rho = −0.29, q < 0.05), an association absent in individuals with AFF ( rho = 0.09, q = 0.79;). Longitudinally, group-level CAP trajectories did not differ between AFF and CTR, but within-person changes in frontoparietal–default-mode (FP-DM CAP ) dwell time tracked changes in depression severity exclusively in AFF (Y2→Y9: rho = 0.47, q = 0.04). Patients whose FP-DM CAP dwell time increased were those whose depression failed to improve. Conclusions CAP dwell time carried clinical meaning at two levels: AT-SM CAP distinguished health from illness at baseline, while FP-DM CAP dwell time indexed within-person illness course over nine years. Because FP-DM CAP co-activates frontoparietal control with default-mode regions implicated in rumination, its rebound in dwell time may reflect a shift toward perseverative self-referential processing in patients who fail to remit. These findings position CAP dwell-time–symptom coupling as a neurobiologically grounded, individually resolved marker of naturalistic illness course relevant to precision psychiatry.

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