Multidimensional Analysis of Reduced Intracortical Inhibitory Mechanisms and Enhanced Intracortical Facilitation in Functional Tremor: Implications for Central Autonomic Network Remodeling, Neurocardiac Coupling, and the Development of Stress-Induced Cardiovascular Electrical Instability

This six-year longitudinal translational research project was designed to investigate the neurophysiological, autonomic, and cardiovascular interactions underlying functional tremor and its potential relationship with stress-mediated cardiac electrical vulnerability. The study integrated advanced neurophysiological techniques, multimodal neuroimaging, autonomic function testing, and comprehensive cardiovascular electrophysiological assessment to explore the hypothesis that maladaptive cortical excitability contributes to dysregulation of the central autonomic network and downstream neurocardiac instability. Between Year 1 and Year 2, the project focused on protocol development, ethical approvals, and pilot recruitment. Standardized neurophysiological paradigms using paired-pulse transcranial magnetic stimulation were implemented to quantify short-interval intracortical inhibition and intracortical facilitation in patients diagnosed with functional tremor compared with healthy matched controls. Early findings suggested a reproducible pattern of reduced inhibitory interneuron activity accompanied by heightened excitatory cortical responsiveness, supporting the concept of altered cortical gain modulation in functional motor disorders. During Years 2 through 4, the study expanded to incorporate functional magnetic resonance imaging, diffusion tensor imaging, and resting-state connectivity analyses. These investigations revealed significant alterations in functional connectivity across key components of the central autonomic network, including prefrontal, limbic, and brainstem regulatory regions. Network modeling demonstrated that disrupted inhibitory cortical signaling correlated with abnormal autonomic regulation patterns, particularly exaggerated sympathetic responses and impaired parasympathetic recovery during standardized emotional and cognitive stress tasks. Simultaneously, comprehensive cardiovascular evaluation was conducted using continuous ambulatory electrocardiographic monitoring, heart rate variability analysis, signal-averaged electrocardiography, and noninvasive electrophysiological markers of ventricular repolarization heterogeneity. The results demonstrated that individuals with functional tremor exhibited increased temporal dispersion of repolarization and heightened susceptibility to stress-induced arrhythmic surrogate markers. These findings supported the emerging concept of neurocardiac coupling, whereby cortical excitability and autonomic imbalance interact to influence myocardial electrical stability. During Years 4 through 6, the project adopted an integrative systems biology approach, combining neurophysiological, autonomic, and cardiovascular datasets through machine learning modeling and network-based predictive analytics. Multivariate models identified reduced intracortical inhibition as an independent predictor of autonomic dysregulation severity and electrophysiological vulnerability under stress conditions. Furthermore, longitudinal follow-up demonstrated that variability in cortical inhibitory recovery was associated with fluctuations in tremor severity, emotional stress reactivity, and dynamic cardiac repolarization markers. The study ultimately proposes a novel mechanistic framework linking functional motor disorders with cardiovascular risk through shared neuroautonomic pathways. These findings highlight the potential importance of cortical excitability modulation as a therapeutic target not only for motor symptom control but also for reducing stress-related cardiovascular electrical instability. The results provide a foundation for future interventional studies exploring neuromodulatory therapies, autonomic rehabilitation strategies, and personalized cardiovascular risk monitoring in patients with functional neurological disorders.