Identifying Residual Connectivity in Veterans with Spinal Cord Injury for Precision Neurorehabilitation

Significance to VA: Spinal cord injury (SCI) is a devastating disease that results in permanent motor, sensory, and autonomic dysfunction below the SCI lesion. However, recent clinical spinal neuromodulation research using epidural electrical stimulation (EES) and transcutaneous spinal stimulation (TSS) has shown promise in restoring voluntary control of motor function and locomotion in participants diagnosed with sensorimotor complete SCI. EES and TSS are hypothesized to take advantage of the neuroplasticity of residual neural fibers crossing the SCI lesion to amplify sensorimotor activity in dormant neural circuits below the SCI lesion, enabling participants to regain motor function. Anatomical, physiological, and functional studies have indicated that most patients with clinically complete SCI retain connectivity through the SCI lesion. However, neuromodulation research in SCI has been restricted to case studies, and therefore, there is no diagnostic criteria to determine how SCI lesion profile affects the ability to restore sensorimotor function using spinal neuromodulation. Furthermore, the outcomes and priorities of Veterans with chronic SCI that could be addressed by spinal neuromodulation protocols have not been evaluated. Therefore, there is a pressing need to develop clinically viable techniques to assess potential functional capacity in Veterans with chronic SCI to determine which patients could benefit from neuromodulation therapy to enhance functional outcomes. Development of this knowledge is necessary to design spinal neuromodulation technologies and clinical trials that could restore function and improve quality of life for Veterans with chronic SCI. Innovation and Impact: Our novel, individualized approach to spinal neuromodulation represents a fundamental step forward in VA research and clinical practice for Veterans with SCI. Specifically, we 1) define the priorities of the Veteran with SCI community to determine how neurorehabilitation approaches can be used to maximize function and reduce barriers to care; 2) evaluate multi-modal aspects of residual spinal circuitry to define a clinically-viable approach to identifying the residual connections remaining across a chronic SCI lesion; 3) assess rapid functional outcomes from non-invasive spinal neuromodulation to enhance sensorimotor ability during activities of daily living. Overall, the proposed research, career development plan, and mentoring team will create the unique and necessary environment to launch my career towards my goal of becoming an independent VA- based biomedical engineer, leveraging neurophysiological insights and novel neurotechnology to address neural dysfunction in Veterans. Specific Aims: 1) We will engage stakeholders in the Veteran and SCI clinician communities to define the research priorities, meaningful outcomes, and barriers to participation in neuromodulation trials. 2) We will establish baseline anatomical and physiological connectivity measurements in Veterans with chronic SCI. Specifically, we will use neuroimaging, transcranial magnetic stimulation, and somatosensory evoked potentials to establish residual connectivity that can be assessed through clinically viable techniques. 3) We will determine the functional capacity of the residual spinal connections during the application of non-invasive TSS. Methodology: We plan to enroll a cohort of 60 adult Veterans with chronic SCI and 40 SCI caretakers to take a survey in Aim 1.1, 40 SCI clinicians to take a survey in Aim 1.2, and a prospective cohort of 40 adult Veterans with chronic cervical SCI to provide qualitative assessments, undergo anatomical and neurophysiological testing, and perform functional tasks during TSS in Aims 1.3, 2, and 3. Path to Translation/Implementation: The findings from this study will provide foundational data for a future VA Merit study focused on longitudinal outcomes of spinal neuromodulation in Veterans with neural dysfunction and lay the groundwork Project Number: 1IK2RD000441-01A2 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Jonathan Calvert | Institution: VA NORTHERN CALIFORNIA HEALTH CARE SYS, MATHER, CA | Activity Code: IK2 | Study Section: Career Development Program - Panel I[RRD8] View on NIH RePORTER: https://reporter.nih.gov/project-details/11241602