Functional connectivity predictors and mechanisms of symptom change in functional neurological disorder

Abstract Clinical trajectories in patients with functional neurological disorder (FND) are variable, and the neural mechanisms underlying this heterogeneity remain poorly understood. This longitudinal brain imaging 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 functional MRI (fMRI), followed by naturalistic treatment for 6.8±0.8 months. All participants completed follow-up questionnaires; 28 completed follow-up fMRI. At each timepoint, three graph-theory network metrics of resting-state functional connectivity were computed: whole-brain weighted-degree (centrality), cortical integration (between-network connectivity), and cortical segregation (within-network connectivity). All 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 ratings, 59.4% improved, 31.3% were unchanged, and 9.3% worsened. Core FND symptom (i.e., Screening for Somatoform Symptoms-7 Subscale for Conversion Disorder) and non-core physical symptom (Patient Health Questionnaire-15) scores showed variable trajectories, with no group-level changes. For whole-brain weighted-degree analyses, baseline centrality in right middle frontal, precentral, and left cerebellar regions was positively associated with core FND symptom change; longitudinally, centrality decreases in right precentral, superior parietal, lateral occipital, and cerebellar regions were associated with symptom improvement. For cortical integration analyses, baseline between-network connectivity in ventral attention, frontoparietal, and default mode network regions was positively associated with core FND symptom change; longitudinally, decreases in between-network connectivity for regions of these same networks were associated with symptom improvement. For cortical segregation analyses, baseline within-network connectivity in frontoparietal network regions was positively associated with core FND symptom change; no regions showed longitudinal segregation changes associated with symptom change. The right anterior insula emerged as a convergent site across baseline and longitudinal integration analyses, with the most improved participants showing elevated baseline between-network connectivity relative to HCs that normalized at follow-up. More modest functional connectivity associations were observed with non-core physical symptom change, spanning baseline within-network connectivity in dorsal attention network regions and longitudinal between-network connectivity increases in visual network regions. Findings remained significant adjusting for FND phenotype, although several attenuated when accounting for baseline affective symptoms or trauma burden. In conclusion, this study identified baseline and longitudinal resting-state functional connectivity features linked to symptom change in FND, highlighting the potential of large-scale network interactions as prognostic markers and providing mechanistic insights that set the stage for novel, biologically-informed interventions.