Cognitive Network Restoration Therapy for Moderate to Severe Traumatic Brain Injury: A Feasibility Study

Proportion of participants experiencing at least one device or procedure related serious adverse event (SAE) from implantation through Day 90 after stimulation activation, including events such as intracranial hemorrhage, infection requiring explant or IV antibiotics, lead or hardware complications requiring surgical intervention, or other SAEs judged related to the DBS system, implantation procedure, or stimulation therapy.

Overall incidence of all adverse events (serious and non serious), summarized by MedDRA system organ class and preferred term, severity, and relationship to device/procedure from implantation through Day 90 after stimulation activation.

Trail Making Test Part B is a standardized neuropsychological test of executive function, cognitive flexibility, divided attention, and processing speed. Participants are asked to connect alternating numbers and letters in sequence as quickly as possible; completion time in seconds is recorded, with longer times indicating worse performance. Change from baseline in TMT-B completion time will be summarized descriptively to explore trajectories of cognitive performance after neuromodulation and to inform effect size assumptions and endpoint selection for a subsequent pivotal study. This outcome is exploratory and will not be used for formal hypothesis testing

The RPQ is a 16-item self-report questionnaire that assesses the severity of post-concussive symptoms. Higher scores indicating greater symptom severity. Change from baseline will be summarized descriptively to explore trajectories of symptom burden after neuromodulation and to inform endpoint selection and effect size assumptions for a subsequent pivotal study. This outcome is exploratory and will not be used for formal hypothesis testing

WHODAS 2.0 is a validated instrument developed by the World Health Organization to assess disability across multiple domains, including cognition, mobility, self-care, interpersonal interactions, life activities, and participation. Items are rated on a 5-point scale ("none" to "extreme"), and the global disability score is derived from item responses, with higher scores indicating greater disability. Change from baseline in the WHODAS 2.0 global disability score will be analyzed descriptively to characterize trajectories of functional disability after neuromodulation and to inform endpoint selection, effect size assumptions, and assessment timing for a subsequent pivotal study. This outcome is exploratory and will not be used for formal hypothesis testing.

The multidomain composite endpoint at Day 90 is a continuous score summarizing performance across four prespecified component measures: (1) Rivermead Post-Concussion Symptoms Questionnaire (RPQ) Behavioral subscale, (2) RPQ Cognitive subscale, (3) Trail Making Test Part B (TMT-B) completion time, and (4) World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) global disability score. Each component will be standardized (e.g., converted to z-scores, with directionality aligned so that higher composite scores reflect better overall status or lower overall impairment) and combined into a single multidomain composite score.

The Day 90 multidomain composite endpoint is intended to estimate the average multidomain treatment effect of neuromodulation on cognitive symptoms, behavioral/emotional symptoms, objective cognitive performance, and global disability. It will be analyzed as a continuous outcome (e.g., change from baseline) and used descriptively in this study.

A multidomain responder at Day 90 will be defined according to prespecified criteria representing clinically meaningful improvement across domains (for example, meeting or exceeding threshold improvements on both cognitive performance and global disability, with accompanying improvement or no worsening on RPQ behavioral and cognitive subscales). Participants who do not meet these thresholds, or who die or experience clear TBI-related catastrophic worsening before Day 90, will be classified as non-responders.

This multidomain composite responder endpoint is intended to assess clinically meaningful individual-level improvement across symptoms, objective cognition, and disability, in conceptual and statistical alignment with the continuous multidomain composite endpoint.