Table 4_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.

引言
轻度创伤性脑损伤（mild traumatic brain injury, mTBI）后出现的持续性症状仍是一项重大临床难题。共病创伤后应激障碍（post-traumatic stress disorder, PTSD）的mTBI患者通常症状负荷更高、预后更差。二者存在重叠病理机制——即中枢自主神经、边缘系统与认知网络功能障碍——提示神经调节干预可能发挥潜在作用。非侵入性迷走神经刺激（non-invasive vagus nerve stimulation, nVNS）已被证实对神经创伤与精神疾病均有治疗潜力，但目前针对慢性mTBI共病PTSD患者的真实世界疗效尚未得到充分阐明。

方法
本研究为一项事后亚组分析，数据源自已发表的一项回顾性观察队列，纳入接受辅助性nVNS治疗的成人慢性mTBI症状患者。分别于基线及治疗3~4个月后，采用神经行为症状量表（Neurobehavioral Symptom Inventory, NSI）评估症状严重程度。采用DSM-5创伤后应激障碍检查表（PTSD Checklist for DSM-5, PCL-5；得分≥31）筛选出事后富集PTSD的亚组。评估NSI总分、症状维度及条目水平应答的变化以判断症状改善情况。采用多变量分析对比伴PTSD（PTSD+）与不伴PTSD患者的基线脑震荡症状特征。

结果
在PTSD+患者中，辅助性nVNS与总体症状负荷显著降低相关，NSI平均总分从基线的2.50±0.60降至随访时的2.03±0.46（错误发现率（false discovery rate, FDR）校正，q<0.05）。症状改善在情感（-0.58，q=0.010）与认知（-0.64，q=0.015）症状维度最为显著，躯体（-0.34，q=0.040）及前庭（-0.58，q=0.050）症状也出现显著降低。40%的PTSD+患者实现了症状总负荷≥30%的降低，29%的患者在≥50%的追踪症状中表现出具有临床意义的改善。多变量分析显示，PTSD+患者聚集于高症状负荷表型，且该表型患者的绝对症状降幅与其他患者相当。

结论
辅助性nVNS耐受性良好，且可改善mTBI+PTSD患者的症状——这类通常被视为难治的患者群体。本研究结果证实了迷走神经调节的可行性，同时凸显了一类具有独特症状模式的高症状负荷亚组，该亚组仍可从治疗中获益，因此需开展进一步的前瞻性评估。