Mega-Analysis of Structural Brain Imaging in Functional Neurological Disorder

Despite recent advances, the pathophysiology of functional neurological disorder (FND) remains incompletely understood. Structural neuroimaging studies have identified gray matter alterations in somatomotor-, salience-, limbic-, and default mode network-associated areas, although findings have been inconsistent. Mega-analyses, which combine individual-level data across studies, can help clarify structural alterations.

We conducted a mega-analysis of brain structural morphometrics derived from T1-weighted magnetic resonance imaging scans from 15 international research groups. After across-site harmonization with ComBat, we compared 493 patients with functional motor disorder and functional seizures with 564 healthy control participants. Euler numbers were included to account for head motion.

The FND cohort showed reduced cortical thickness in the bilateral superior frontal gyri (left d = 0.22, right d = 0.21) and sulci (d = 0.22 and 0.23), bilateral superior precentral sulcus (d = 0.22 and 0.26), right precentral gyrus (d = 0.25), right paracentral gyrus and sulcus (d = 0.23), right cuneus (d = 0.23), and right inferior opercular gyrus (d = 0.21); we also found reduced left postcentral gyrus surface area (d = 0.25) and right hippocampal volume (d = 0.22). No regions were different in relative surface area. There were no associations between morphometrics and illness duration or lifetime history of depression or anxiety. Differences between motor and seizure variants were not identified.

This large mega-analysis suggests subtle morphometric differences, particularly in prefrontal and motor regions. This may represent predisposing vulnerabilities, compensatory mechanisms, or FND-specific alterations. Improved neuropsychiatric characterization of FND research cohorts will help further contextualize the biological relevance of structural alterations.