Neurological disorders such as spinal cord injury and Parkinsonian syndromes often result in sustained autonomic dysfunction, leading to hemodynamic instabilities that threaten neurological recovery and impact quality of life. Among these populations, hemodynamic instabilities are gaining more attention as they deter individuals from partaking in daily life activities, rehabilitation, and regaining more appreciated functions such as mobility. One such instability is orthostatic hypotension (OH), or a severe drop in blood pressure upon standing. The underlying pathophysiology often involves a failing baroreflex, a homeostatic mechanism that spans the brain stem, spine, and heart. When communication from the brain to the spine and periphery is compromised via an injury or neurodegeneration, and the baroreflex is compromised, individuals face increased risk of chronic fatigue, fainting, and long-term cardiovascular and cerebral risks such as heart attacks and stroke.

Hence, this thesis aims to develop a neuroprosthetic-based solution combining spinal cord stimulation and hemodynamic monitoring to help individuals with neurological conditions manage their blood pressure instabilities in an autonomous fashion.

This thesis first quantifies the clinical burden of OH in SCI in 1,479 individuals and exposes the ineffective treatment of autonomic complications despite the use of conservative measures such as pharmacology and supportive garments. To address this clinical burden, we developed a purpose-built implantable system based on biomimetic epidural electrical stimulation (EES) of the spinal cord that immediately triggered robust pressor responses. The system durably reduced the severity of hypotensive complications in 14 individuals with SCI, removed the necessity for conservative treatments, improved quality of life, and enabled superior engagement in activities of daily living. Detailed spatial and temporal mapping identified the lower thoracic spinal cord as the optimal stimulation target, and a purpose-built stimulation platform, the ARC\textsuperscript{IM}, enabled flexible, programmable delivery of open- and closed-loop stimulation. Longitudinal assessments confirmed the safety, efficacy, and durability of this therapy and established the foundation for a pivotal regulatory trial.

Although the etiology of orthostatic hypotension in Parkinsonian syndromes differs from that of spinal cord injury, both conditions disrupt descending commands from the brainstem vasomotor centers that modulate sympathetic neurons in the thoracic spinal cord. We hypothesized that individuals with Parkinsonism with spared sympathetic pathways could benefit from spinal cord stimulation. To understand these mechanisms, we developed an experimental framework to induce orthostatic hypotension after neurodegeneration in rodent and non-human primate models. These preclinical findings were translated into a series of compassionate-use clinical cases, where EES mitigated hypotension, improved mobility, and enhanced patient-reported outcomes in individuals with Parkinson's disease and multiple system atrophy. These results support the broader applicability of spinal cord neuromodulation to restore autonomic stability across neurological conditions characterized by baroreflex dysfunction.