The Role of Stress in Neuropathophysiological Mechanisms of Functional Neurological Disorders

Weber, Samantha (2022). The Role of Stress in Neuropathophysiological Mechanisms of Functional Neurological Disorders (Unpublished). (Dissertation, University of Bern, Medicine)

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Functional neurological disorders (FND) comprise the appearance of diverse neurological symptoms without an underlying classical neurological condition. “Medically unexplained neurological symptoms” have been stigmatized for a long time, and patients were often not been taken serious in their suffering. As historically FND has often been explained as a psychogenic disorder, underpinning the importance of psychological stress, contemporary models aim at integrating a multifactorial origin of FND by means of a biopsychosocial or stress-diathesis model unifying neuroscientific, psychological, and biological concepts in FND. Nowadays, FND is considered a neuropsychiatric disorder, and various risk factors could be identified, reliable clinical signs have been validated, and successful treatment options have been developed. Notwithstanding the enormous effort that has been devoted to identifying why and how FND develops, a satisfactory model of underlying pathophysiological mechanisms of FND remain elusive, and thus, objective biomarkers are lacking.
To fill this gap, this thesis aimed at connecting the questions on why and how FND emerges by studying the neurological, psychological, and physiological aspects of stress and unifying them within the context of a stress-diathesis model for FND. As such, potential biomarkers are investigated, and novel concepts of potential pathophysiological mechanisms are discussed.
First, the robustness and generalizability of resting-state functional magnetic resonance imaging (fMRI) was tested and evaluated in a multi-centre setting, as this has previously been suggested to serve as a potential positive imaging-based biomarker for FND. Second, stress biomarkers were examined and how they potentially relate to psychological and neurological correlates of FND. Third, large-scale functional brain network dynamics and their possible implication in the clinical presentation of symptoms were analysed.
The findings presented in this thesis demonstrate the applicability as well as the persisting technical limitations of resting-state fMRI as an imaging-based biomarker for FND. Further, it could be shown that FND patients have a flattened cortisol awakening response – a common biomarker for psychosocial stress – which was associated to emotional neglect as a precipitating risk factor for FND. Moreover, volumetric brain alterations have been identified in FND and their hypothetical role as predisposing factor was discussed. Lastly, distinct dynamic functional alterations encompassing the salience and limbic network were identified in FND patients, which appeared to correlate with symptom severity and stress biomarkers.
To conclude, the findings are discussed in the context of pre-existing pathophysiological models for FND and introduce novel points of view. Furthermore, the limitations of this work are thoroughly evaluated, and future directions and their applications are addressed. Lastly, the clinical importance and contribution to the field is comprehensively highlighted.
Altogether, the findings presented in this thesis support and expand previous literature by 1) demonstrating the predictive power of imaging-based biomarkers, 2) identifying potential abnormalities in the biological stress axis within a standardized setting and discussing their novelty in the framework of the stress-diathesis model, and 3) firstly adopting a spatio-temporal network analysis in FND and reflecting on its neurophysiological relevance. In summary, this thesis supports a stress-diathesis model of FND and highlights potential psychological, neurological, and physiological attributes in the pathophysiological mechanisms of FND.

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