Table 2_Retrospective post-hoc subgroup analysis of adjunctive non-invasive vagus nerve stimulation in chronic mTBI with comorbid PTSD.docx

IntroductionPersistent 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.
MethodsThis 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.
ResultsAmong 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.
ConclusionAdjunctive 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.