Salivary oxytocin and amygdalar alterations in functional neurological disorders

Abstract

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.

Keywords: OXTR; amygdala; conversion disorder; epigenetics; rs53576.

Graphical Abstract

Figure 1

Interaction between peripheral oxytocin levels and OXTR methylation. Scatter plot illustrating the association between oxytocin levels (pg/mL) and OXTR methylation (%) in N = 59 FND patients and N = 65 HC. Data points represent individual participants, with their position on the x-axis corresponding to their oxytocin levels (pg/mL), and the y-axis corresponding to their OXTR methylation level (%). In patients with FND, higher peripheral oxytocin levels correlated with increased OXTR methylation [F(1109) = 8.92, P = 0.003, d = 0.541], whereas an inverse (but not significant) correlation was identified in HC.

Figure 2

Oxytocin and OXTR methylation according to genotype. Violin plot representing distribution of raw salivary/peripheral oxytocin levels in (A) patients with FND (N = 59) and (B) HC (N = 65), as well asOXTR methylation levels in (C) patients with FND (N = 59) and (D) HC (N = 65). Boxplots indicate median and interquartile range. A significant main [F(2106) = 10.25, P < 0.0001, d = 0.583] effect of genotype and interaction [F(2106) = 3.27, P = 0.042, d = 0.329) effect between group and genotype on OXTR methylation was found in FND patients (C) using an ANOVA on the fitted data using a linear model indicating higher methylation levels in AA carriers compared with GA (P < 0.0001) and GG (P < 0.0001) carriers. Significance codes: ***P < 0.001, **P < 0.01.

Figure 3

Correlation between amygdala-to-whole-brain FC and peripheral oxytocin levels in (A) patients with FND and (B) HC. The correlation between salivary oxytocin levels and amygdala-to-whole-brain FC was evaluated using Pearson’s correlation coefficient in N = 54 patients with FND compared with N = 64 HC. Significant correlations [with alpha level (α) set to 0.05] are shown with their associated Pearson’s correlation coefficient (r). FND, functional neurological disorder; FrMidOrbMedL, left frontal medial orbital cortex; AmygL/R, left/right amygdala; HippL/R, left/right hippocampus; PccL, left posterior cingulate cortex; ParInfR, right inferior parietal cortex; TempInfR, right inferior temporal cortex; InsL/R, left/right insula; r, Person’s correlation coefficient; RolOpL, left rolandic operculum; ThalL, left thalamus; ParSupL/R, left/right superior parietal cortex; PreCenR, right precentral gyrus. Figure was created using BrainNet Viewer https://www.nitrc.org/projects/bnv/.