Abstract
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: Among PTSD+ patients, adjunctive nVNS was associated with a significant reduction in overall symptom burden, with mean total NSI scores decreasing from 2.50 ± 0.60 at baseline to 2.03 ± 0.46 at follow-up (FDR-corrected, q < 0.05). Improvements were most pronounced in affective (-0.58, q = 0.010) and cognitive (-0.64, q = 0.015) symptom domains, with additional reductions in somatic (-0.34, q = 0.040) and vestibular (-0.58, q = 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.