Use of Paired Vagus Nerve Stimulation in Mobilization of Patients with Prolonged Disorders of Consciousness: Protocol for a Single Cohort Open Label Interventional Study

Introduction Severe acquired brain injury (SABI) is a significant global health concern that can lead to prolonged disorders of consciousness (pDOC). Rehabilitation in the current standard of care is limited to sensory stimulation interventions exclusive to the acute and subacute phases of injury. This work seeks to demonstrate the safety, feasibility, and preliminary efficacy use of the novel pairing of neural stimulation (taVNS) and robotic tilt table mobilization (RTTM) in the rehabilitation of patients with pDOC.

and Analysis Fifteen (15) participants with pDOC (>3 months since onset of disorder of consciousness) will participate in three rehabilitation intervention phases: 1) observation of standard of care; 2) intervention phase (2a: RTTM only and 2b: RTTM plus taVNS);and 3) long term follow up at 3, 6, and 12 months post interventions. Primary outcomes will include reporting of adverse and serious adverse events and adverse and serious adverse reactions; they will be collected throughout the study duration. Secondary feasibility outcomes will include number of sessions completed, time on therapy task completed, number of steps taken with robotic stepping, maximal limb loading or the maximal amount of weight distribution through single limb stance of the robotic gait cycle, and maximal tilt angle and will be collected each study session. Exploratory outcomes will include the Coma Recovery Scale-Revised (CRS-R), Glasgow Coma Scale (GCS), and Glasgow Outcomes Scale- Extended (GOSE), Nociceptive Coma Scale- Revised (NCS-R) and hemodynamics (blood pressure [BP], heart rate [HR], oxygen saturation [SpO2]) assessments to be collected at baseline, immediately following phase 1; immediately following phase 2a, immediately following phase 2b and at long term follow up time points. Additionally, quantitative electroencephalography (qEEG) will be collected at the end of phase 1, end of phase 2 (end of study intervention) and at the each longitudinal follow up study visits. The aim will be to evaluate proof of concept in this safety feasibility trial. Ethics and Dissemination The study protocol has been approved the Program for the Protection of Human Subjects (PPHS) at the Icahn School of Medicine at Mount Sinai (Study 24-01339) Registration NCT06930716 Strengths and limitations of this study - This work seeks to evaluate a novel paired neuromodulation and physical therapy intervention for patients with prolonged Disorders of Consciousness (pDOC) - This work exclusively will evaluate the benefits of rehabilitation and subsequent outcomes in a disparate population with limited treatment options - This trial is not randomized, limiting rigor of the study design - This trial is unpowered, limiting generalizability to the larger pDOC population - Future work will seek to address these limitations Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by The Foundation for Physical Therapy Research Magistro Family Foundation Grant Number 1333107. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol has been approved the Program for the Protection of Human Subjects (PPHS) at the Icahn School of Medicine at Mount Sinai (Study 24-01339) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability No data has been collected as this is a protocol.