Delineating network integration and segregation in the pathophysiology of functional neurological disorder

Functional neurological disorder (FND) is a neuropsychiatric condition that is framed as a multi-network brain problem. Despite this conceptualization, studies have generally focused on specific regions or connectivity features, under-characterizing the complex and nuanced role of resting-state networks in FND pathophysiology. This study employed three complementary graph theory analyses to delineate the functional network architecture in FND. Specifically, we investigated whole-brain weighted-degree, isocortical integration and isocortical segregation extracted from resting-state functional MRI data prospectively collected from 178 participants: 61 individuals with mixed FND; 58 psychiatric controls matched on age, sex, depression, anxiety and post-traumatic stress disorder severity; and 59 age- and sex-matched healthy controls. All analyses were adjusted for age, sex and antidepressant use and focused on differences between FND versus psychiatric controls, with individual-subject maps normalized to healthy controls. Compared to psychiatric controls, patients with mixed FND exhibited increased weighted-degree in the right dorsal anterior cingulate and superior frontal gyrus and the left inferior frontal gyrus and supplementary motor area. Isocortical integration analyses revealed increased <i>between-network</i> connectivity for somatomotor network areas, with widespread heightened connections to regions of the default mode, frontoparietal and salience networks. Isocortical segregation analyses revealed increased <i>within-network</i> connectivity for the frontoparietal network. Secondary analyses of functional motor disorder (<i>n</i> = 46) and functional seizure (<i>n</i> = 23) subtypes (versus psychiatric controls) revealed both shared and unique patterns of altered connectivity across subtypes, including increased weighted-degree and integrated connectivity in the left posterior insula and anterior/mid-cingulate in functional motor disorder and increased segregated connectivity in the right angular gyrus for functional seizures. In <i>post hoc</i> between-group analyses, findings remained significant adjusting for depression, anxiety and post-traumatic stress disorder severity, as well as for childhood maltreatment. <i>Post hoc</i> correlations revealed significant relationships between connectivity metrics in several of these regions and somatic symptom severity across FND and psychiatric control participants. Notably, individual connectivity values were predominantly within the range of healthy controls (with patients with FND generally showing tendencies for increased connectivity and psychiatric controls showing tendencies towards decreased connectivity), indicating subtle shifts in the network architecture rather than gross abnormalities. This study provides novel mechanistic insights (i.e. increased somatomotor integration) and specificity regarding the neurobiology of FND, highlighting both shared mechanisms across subtypes and subtype-specific patterns. The results support the notion that FND involves aberrant <i>within</i>- and <i>between-network</i> communication, setting the stage for biologically informed treatment development and large-scale replication.