Retrospective post-hoc subgroup analysis of adjunctive non-invasive vagus nerve stimulation in chronic mTBI with comorbid PTSD

Introduction: Persistent symptoms following mild traumatic brain injury (mTBI) remain a major clinical challenge. Patients with comorbid post-traumatic stress disorder (mTBI + PTSD) typically exhibit greater symptom burden and poorer outcome. Overlapping pathology-dysfunction in central autonomic, limbic, and cognitive networks-suggests a potential role for neuromodulatory interventions. Non-invasive vagus nerve stimulation (nVNS) has shown promise as a treatment for both neurotraumatic and psychiatric conditions, but its real-world impact in patients with chronic mTBI and comorbid PTSD has not been well characterized. Methods: This study represents a post-hoc subgroup analysis of a previously published retrospective observational cohort in adults with chronic mTBI symptoms treated with adjunctive nVNS. Symptom severity was assessed using the Neurobehavioral Symptom Inventory (NSI) at baseline and after 3-4 months of treatment. A post-hoc PTSD-enriched subgroup was identified using the PTSD Checklist for DSM-5 (PCL-5; score ≥31). Changes in total NSI scores, symptom domains, and item-level responses were evaluated for improvement. Multivariate analyses were used to characterize baseline concussion symptom profiles with (PTSD+) and without PTSD. Results: = 0.050) symptoms. Forty percent of PTSD+ patients achieved a ≥30% reduction in total symptom burden, and 29% demonstrated potentially clinically meaningful improvement across 50% or more of tracked symptoms. Multivariate analyses showed that PTSD+ patients clustered within a high-symptom-burden phenotype that exhibited comparable absolute symptom reductions. Conclusion: Adjunctive nVNS was well tolerated and associated with symptom improvement in patients with mTBI + PTSD, a population often considered refractory to treatment. These findings support the feasibility of vagal neuromodulation and highlight a high-symptom-burden subgroup with distinct symptom patterns that may retain treatment responsiveness, warranting further prospective evaluation.