Weber Samantha, Stoffel Natascha, Ansede-Bermejo Juan, Cruz Raquel, Del Real Bolt Álvaro, Bruckmaier Rupert, Carracedo Ángel, Aybek Selma
Department of Neurology, Psychosomatic Medicine Unit, Inselspital Bern University Hospital, University of Bern, Bern 3012, Switzerland.
Department of Adult Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, Zurich 8032, Switzerland.
Brain Commun. 2024 Dec 16;7(1):fcae455. doi: 10.1093/braincomms/fcae455. eCollection 2025.
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 (), 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 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 [(1109) = 8.92, = 0.003, = 0.541]. Moreover, patients with the AA-genotype (minor allele) of the rs53576 genetic variant of the gene presented with higher methylation levels [(2106) = 10.25, 0.0001, = 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 [(2,38) = 5.36, = 0.025, = 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 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 , 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.
被诊断患有功能性神经障碍的个体经历异常运动、步态、感觉处理或功能性癫痫发作，对此病理生理学研究确定了心理社会促成因素以及有前景的生物标志物。最近的试点研究表明，（表观）遗传变异可能作为易感性因素，例如，作用于催产素途径。本研究旨在探索59名功能性神经障碍患者和65名年龄和性别匹配的健康对照者唾液中的内源性催产素激素水平。首先，我们检查了唾液催产素水平与催产素受体基因（）的遗传等位基因变异（rs53576）、其由甲基化率指示的表观遗传变化以及临床变量（包括童年创伤）之间的关联。其次，由于先前报道催产素会改变杏仁核的体积和功能连接，以及已知杏仁核参与功能性神经障碍的病理生理学，我们进一步研究了杏仁核的结构和功能成像。虽然患者的外周催产素水平与健康对照者无显著差异，但甲基化和外周催产素存在特定的组间相互作用：仅在患者中，较高的甲基化率与较高的唾液催产素相关，而在健康对照者中并非如此[（1109） = 8.92， = 0.003， = 0.541]。此外，基因rs53576遗传变异的AA基因型（次要等位基因）患者表现出较高的甲基化水平[（2106） = 10.25， 0.0001， = 0.58]。最后，仅在患者中，杏仁核与海马体、后扣带回皮质、下顶叶皮质和颞下回皮质的连接以及较小的杏仁核体积与外周催产素水平相关[（2,38） = 5.36， = 0.025， = 0.431]，而在健康对照者中并非如此。未发现与童年创伤有显著相互作用。我们的研究揭示了仅在患者中外周催产素和甲基化之间存在显著相互作用，可能受基因型影响。可以推测，较高的外周催产素表示对基因甲基化增加的一种补偿机制，这可能会影响杏仁核的功能连接。这些发现有助于进一步理解潜在的病理生理机制，考虑到催产素在功能性患者中的作用，并可为未来研究提供潜在的治疗靶点。
