Functional Connectivity Predictors and Mechanisms of Symptom Change in Functional Neurological Disorder

Clinical trajectories in functional neurological disorder (FND) are variable, and the mechanisms underlying this heterogeneity remain poorly understood.

This longitudinal study examined resting-state functional connectivity predictors and mechanisms of symptom change in FND.

Thirty-two adults with FND (motor and/or seizure phenotypes) completed baseline questionnaires and a functional MRI (fMRI) session, followed by naturalistic treatment for 6.8±0.8 months. All participants completed follow-up questionnaires; 28 individuals completed a follow-up fMRI. At each timepoint, three graph-theory network metrics of functional connectivity were computed: weighted-degree (centrality), integration (between-network connectivity), and segregation (within-network connectivity). Analyses adjusted for age, sex, anti-depressants, head motion, time between sessions, and baseline score-of-interest, with cluster-wise correction. Results were contextualized against 50 age-, sex-, and head motion-matched healthy controls (HCs).

Based on patient-reported Clinical Global Impression of Improvement, 59.4% improved, 31.3% were unchanged, and 9.3% worsened. Psychometric scores of core FND symptoms and non-core physical symptoms showed variable trajectories, with no group-level changes. Greater improvement in core FND symptoms was associated with higher baseline between-network integrated connectivity and reduced integration longitudinally within salience, frontoparietal, and default mode network regions. Right anterior insula integration emerged as a prognostic marker and mechanistic site of reorganization, with the most improved participants showing elevated baseline integration compared to HCs. Increased baseline within-network segregated connectivity in dorsal attention network regions correlated with non-core physical symptom improvement. Findings remained significant adjusting for FND phenotype.

This study identified large-scale network interactions as potential prognostic and mechanistically-relevant sites of reorganization related to symptom change in FND.