Salivary oxytocin and amygdalar alterations in functional neurological disorders

Individuals diagnosed with functional neurological disorder experience abnormal movement, gait, sensory processing or functional seizures, for which research into the pathophysiology identified psychosocial contributing factors as well as promising biomarkers. Recent pilot studies suggested that (epi-)genetic variants may act as vulnerability factors, for example, on the oxytocin pathway. This study set out to explore endogenous oxytocin hormone levels in saliva in a cohort of 59 functional neurological disorder patients and 65 healthy controls comparable in sex and age. First, we examined the association between salivary oxytocin levels with the genetic allelic variant (rs53576) of the oxytocin receptor gene (OXTR), its epigenetic changes indicated by methylation rates, and clinical variables-including childhood trauma. Second, due to previously reported effects of oxytocin changing the volume and functional connectivity of the amygdala, as well as the known involvement of the amygdala in the pathophysiology of functional neurological disorders, we further looked at both structural and functional imaging of the amygdala. While patients did not significantly differ from healthy control in their peripheral oxytocin levels, there was a specific interaction of OXTR methylation and peripheral oxytocin dependent on group: higher methylation rates correlated with higher salivary oxytocin in patients only, while this was not the case in healthy control [F(1109) = 8.92, P = 0.003, d = 0.541]. Moreover, patients with the AA-genotype (minor allele) of the rs53576 genetic variant of the OXTR gene presented with higher OXTR methylation levels [F(2106) = 10.25, P < 0.0001, d = 0.58]. Lastly, amygdalar connectivity to the hippocampus, the posterior cingulate cortex, the inferior parietal cortex and the inferior temporal cortex as well as smaller amygdalar volume were correlated to peripheral oxytocin levels in patients only [F(2,38) = 5.36, P = 0.025, d = 0.431], but not in healthy control. No significant interactions with childhood trauma were identified. Our study revealed a significant interplay between peripheral oxytocin and OXTR methylation in patients only, potentially influenced by genotype. One could hypothesize that higher peripheral oxytocin denotes a compensatory mechanisms for the increased methylation of the OXTR, which might affect amygdalar functional connectivity. These findings help to further understand underlying pathophysiological mechanisms, considering oxytocin's involvement in functional patients and could offer a potential site of treatment for future studies.