Neurophysiological Mapping of Genetic Etiologies to Optimize Deep Brain Stimulation in Movement Disorders

Movement disorders, including Parkinson’s disease and dystonia, arise from complex dysfunctions in motor circuits, sometimes with an underlying genetic basis. While deep brain stimulation (DBS) has revolutionized symptom management, variability in therapeutic response remains a significant challenge, particularly in genetically mediated cases. This thesis investigates the role of genetic etiology in shaping pathological neural activity at the circuitry level within different basal ganglia nuclei, which are the primary targets for DBS treatment. Additionally, it explores how these neural activities are connected to DBS response, and how they can be utilized to optimize DBS strategies. Through a detailed investigation of neural behavior influenced by genetic conditions, I aimed to elucidate the impact of genetic causes on the micro- and mesoscale neural dynamics. At the microscale, gene-specific single-neuron patterns were characterized, exploring convergence and divergence among dystonia-related genes. A strong link was established between neural signatures and the responses of dystonia genetic profiles to DBS treatment, with particular emphasis on the desynchronization mechanisms underpinning its therapeutic efficacy. At the mesoscale, the spectral components of micro-local field potentials (LFPs) across dystonia syndromes were examined, revealing the varying effects of genetic etiology on pathophysiological synchronization in low-frequency pallidal activity (4-12 Hz). Herein, I proposed that an adaptive DBS paradigm for dystonia based on the spectral fluctuations of recorded activity should then take into account potential differences between genetic dystonia profiles. Additionally, this work further taps into other aspects such as the identification of novel pathogenic gene variants, detailed clinical phenotyping, and DBS responses of rare genetic conditions, thereby enhancing genotype-phenotype mapping, particularly in dystonia. I further investigated the neural mechanisms underlying the variable DBS responses across different genetic profiles, identifying etiology-specific "sweet" and "sour" spots for optimal stimulation. By integrating electrophysiology with genetic profiling, this thesis aims to advance our understanding of movement disorder pathophysiology and offers a framework for optimizing DBS therapy in dystonia, ultimately contributing to the development of precision medicine in neuromodulation.