Traumatic Brain Injury (TBI) is a neurological disorder resulting from external mechanical forces that induce structural and functional brain damage (1). As one of the most common neurological conditions worldwide, TBI represents a growing public health challenge with substantial socioeconomic implications (2, 3). The pathophysiology of TBI involves a dynamic interplay between primary mechanical injury and subsequent secondary injury cascades, culminating in transient or persistent neurological impairments (4). Global epidemiological data demonstrate that there were 20.84 million incident cases and 37.93 million prevalent cases of TBI worldwide in 2021. Notably, age-standardized incidence, prevalence, and disability-adjusted life years (DALYs) related to TBI have decreased by approximately 20% since 1990, which reflects substantial advances in TBI prevention and clinical care. (1, 5, 6). While advancements in neurosurgical techniques and neurocritical care have markedly reduced TBI-associated mortality, a considerable proportion of survivors experience debilitating long-term sequelae, including Disorders of Consciousness (DoC) (7, 8).

DoC encompasses a spectrum of conditions characterized by impaired arousal and awareness, classified into three primary states: coma, unresponsive wakefulness syndrome (UWS), andminimally conscious state (MCS) (8, 9). Coma is defined by the absence of both spontaneous arousal and stimulus-induced wakefulness. UWS (previously termed vegetative state) describes a condition in which patients exhibit wakefulness without evidence of conscious awareness. In contrast, MCS is distinguished by inconsistent but discernible behavioral signs of awareness, indicating either partial recovery from severe brain injury or progressive neurological deterioration (10). These disorders profoundly diminish patients' quality of life while imposing immense psychological and economic strain on caregivers and healthcare systems. Consequently, the development of effective therapeutic strategies remains a critical priority in neurorehabilitation, with significant clinical and societal implications.

Neuromodulation therapies, defined as non-invasive or minimally invasive interventions that regulate neural electrical activity, synaptic plasticity, or nerve conduction to promote consciousness recovery, have emerged as an innovative and promising therapeutic strategy in restorative medicine for TBI. (11)Among invasive techniques, deep brain stimulation (DBS) has been experimentally shown to reconstruct neural connectivity and sustain neuronal activity in the forebrain, with established clinical applications in movement disorders such as Parkinson's disease and essential tremor (12). However, its widespread adoption in TBI management remains limited due to inherent surgical risks, demanding postoperative care, and high treatment costs (13, 14). In recent years, the field of clinical intervention for DoC after TBI has attracted considerable attention, with safe and practical non-invasive brain stimulation (NIBS)-based neuromodulation therapies and multimodal rehabilitation interventions emerging as mainstream and widely recognized approaches (8, 15). Among them, neuromodulation therapies are classified into central neuromodulation [targeting the cerebral cortex, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS)] and peripheral neuromodulation [targeting peripheral nerves, including median nerve stimulation (MNS), right median nerve stimulation (RMNS), and trigeminal nerve stimulation (TNS)] based on the stimulation site, primarily functioning by regulating cortical excitability and neural activity (16, 17). In addition to neuromodulation therapies, multimodal rehabilitation interventions—defined as non-pharmacological, comprehensive interventions that improve consciousness and cognitive function through multiple action pathways (excluding neuromodulation)—have also been proven effective in improving the consciousness state (18–20).

TMS non-invasively induces neuronal electrical activity through rapidly alternating magnetic fields, whereas tDCS modulates neuronal firing thresholds via low-intensity direct current application (21, 22). Clinical evidence suggests that both tDCS and TMS can effectively enhance consciousness levels in post-TBI comatose patients, leading to their increasing integration into clinical practice (23). Additionally, MNS exerts its effects by modulating electrophysiological signals transmitted from peripheral nerves to the central nervous system, demonstrating considerable therapeutic potential (24). Preliminary findings indicate that RMNS may exhibit superior arousal-promoting effects, though further clinical validation is warranted (25, 26). Similarly, TNS facilitates consciousness recovery by activating neuronal circuits in the lateral hypothalamus and spinal trigeminal nucleus, positioning it as a highly promising intervention for coma arousal (27).

Multimodal rehabilitation interventions can be divided into two major categories: first, sensory stimulation interventions, which promote cortical activation via multi-dimensional sensory input and include Multi-sensory stimulation and family-centered sensory and affective stimulation. Multi-sensory stimulation accelerates the awakening of comatose patients by integrating visual, tactile, olfactory, and other sensory inputs (19, 20). Family-mediated sensory and affective stimulation not only enhances consciousness but also promotes the recovery of cognitive and basic sensory functions, highlighting its clinical significance (28). The second category is traditional Chinese medicine (TCM)-derived therapy based on TCM theory, such as Acupuncture (18). In this study, multimodal rehabilitation interventions were included on the premise that they target DoC induced by TBI, have complete efficacy data from clinical studies, and achieve consciousness recovery through non-neuromodulatory mechanisms.

Numerous systematic reviews and meta-analyses have investigated therapeutic interventions for DoC secondary to TBI. Nevertheless, current evidence remains limited by several methodological shortcomings, including substantial heterogeneity in study designs, inadequate sample sizes, and inconsistent outcome measurement criteria. To address these limitations, this study proposes to perform a comprehensive evidence synthesis through a systematic evaluation of the most recent literature comprising systematic reviews and meta-analyses on TBI-induced DoC treatments. The study has three primary objectives: 1) to systematically assess the efficacy and safety profiles of existing therapeutic modalities; 2) to conduct comparative analyses of clinical outcomes across different treatment regimens; and 3) to formulate evidence-based clinical practice recommendations. By implementing this rigorous methodological approach, we intend to identify optimal treatment strategies for post-TBI DoC patients, with the ultimate goal of enhancing clinical outcomes and advancing patient care standards.

This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (29). The study protocol was prospectively registered on the INPLASY PROTOCOL platform (Registration No:INPLASY202480015) (30). Briefly, we systematically searched four major databases from inception to December 2025, supplemented with manual searches and reference tracing, to identify eligible systematic reviews, meta-analyses, and clinical trials focusing on clinical assessment scales for TBI-induced DoC. Studies were screened based on predefined inclusion and exclusion criteria, and methodological quality was evaluated using the AMSTAR 2 tool. Statistical analyses were performed using mean differences (MD) or risk ratios (RR) with 95% confidence intervals (95% CI); random-effects or fixed-effects models were selected based on heterogeneity assessed by the I² statistic, aiming to evaluate the efficacy of the intervention on DoC recovery via four primary outcome measures.

This systematic review evaluates the efficacy and safety of various treatment modalities for patients with DoC following TBI, synthesizing evidence from existing systematic reviews and meta-analyses to inform clinical decision-making.

Our comprehensive analysis demonstrates that several interventions —including tDCS, rTMS, MNS, multisensory stimulation, and acupuncture —significantly improve consciousness levels in TBI-induced DoC patients, corroborating findings from prior studies. The analysis confirms that tDCS, rTMS, MNS, and multisensory stimulation constitute robust therapeutic strategies, as evidenced by their consistent and statistically significant improvements across primary outcome measures including CRS-R, GCS, and GOS. Specifically, tDCS yielded notable improvements in CRS-R scores (MD 2.08). rTMS demonstrated a marked improvement in CRS-R scores (MD 3.00) and GCS scores (MD 2.92), while multisensory stimulation showed substantial benefits in GCS (MD 2.28) and GOS (MD 1.11). Acupuncture also showed strong efficacy across multiple metrics, including GCS, GOS, and Efficacy Rate. These pooled results strengthen the position of these modalities as first-line considerations in clinical protocols by providing higher-level, quantitative summaries of their benefits. Additionally, TNS, family-centered sensory-affective stimulation, and RMNS show promising therapeutic potential, though further validation is required to establish their clinical applicability and evidence strength.

In clinical efficacy assessments, while the TNS group exhibited a significantly greater improvement in GCS scores compared to the sham group (P = 0.028), its effect on CRS-R scores—though numerically superior—did not achieve statistical significance. This discrepancy may stem from several limitations, including the relatively small sample size of patients with post-TBI disorders of consciousness and the study's methodological constraints. Consequently, further large-scale, high-quality trials are warranted to confirm the therapeutic potential of TNS.

Evidence indicates that multisensory stimulation nursing significantly enhances clinical recovery in patients with DoC. Notably, family-involved stimulation introduces an affective dimension beyond conventional sensory input that could further facilitate consciousness recovery (28, 40–42). However, a comparative analysis reveals an intriguing discrepancy: While family-centered affective stimulation outperforms both standard care and nurse-administered interventions, its effect size on GCS improvement appears smaller than that of structured multisensory stimulation. This inconsistency may stem from heterogeneity across included studies, suggesting that the additive benefits of emotional stimulation require further validation through rigorously controlled trials.

Current evidence suggests that both right-sided and bilateral MNS demonstrate efficacy in promoting consciousness recovery. Theoretical considerations have posited that RMNS might yield superior clinical outcomes due to its more extensive cortical projections within sensorimotor areas (25, 38, 43). However, our meta-analytic findings present a paradoxical result: while both MNS and RMNS showed statistically significant efficacy, the effect size for RMNS was unexpectedly smaller than that of conventional MNS. This apparent contradiction with prior research may be attributed to several methodological and clinical factors: 1) potential inclusion of lower-quality studies in the RMNS subgroup analysis; 2) inadequate sample size for detecting true effect size differences; 3) significant heterogeneity in baseline patient characteristics, including etiology, disease duration, and severity levels.

Our systematic evaluation reveals that several neuromodulation approaches—including tDCS, rTMS, TNS, multi-sensory stimulation, and acupuncture therapy—demonstrate clinically meaningful benefits for patients with post-traumatic brain injury (TBI) disorders of consciousness (DoC). These findings underscore the need for future research to implement more rigorous experimental designs, including standardized patient stratification, larger multicenter cohorts, and improved methodological quality. Such advancements will enable more precise evaluation of efficacy differences between various stimulation modalities and facilitate optimal treatment protocol development for DoC patients.

While this comprehensive analysis provides important insights into interventions for DoC induced by TBI, critical consideration is required to avoid misinterpretation of the findings. Several interconnected limitations collectively compromise the robustness, generalizability, and clinical applicability of the results of this study, as detailed below:

First, methodological heterogeneity and inconsistent study quality among included literature, coupled with a relatively small number of systematic reviews, meta-analyses, and RCTs and the exclusion of some high-quality studies due to non-target disease samples, have undermined the credibility of pooled results and the completeness of the evidence chain.

Second, the lack of direct comparative effectiveness research between different interventions precludes definitive conclusions regarding the selection of optimal therapeutic strategies for clinical practice. This is because without head-to-head comparisons, it is difficult to objectively evaluate which intervention yields superior efficacy, thus limiting the ability to provide clear clinical guidance for practitioners.

Third, the absence of standardized intervention protocols across included studies, coupled with insufficient systematic safety evaluation of all involved interventions, further undermines the reliability of the pooled conclusions and their practical reference value in clinical settings. The inconsistency in intervention protocols (e.g., varying parameters, implementation procedures) hinders the reproducibility of research results, while the lack of comprehensive safety assessments fails to fully address potential risks associated with the application of these interventions.

To address these limitations, we recommend targeted research efforts including high-quality multicenter RCTs with standardized protocols, mechanistic studies on neural recovery pathways, development of personalized therapy tools, and systematic safety assessments in future studies.

This comprehensive evidence synthesis demonstrates the significant therapeutic potential of neuromodulation therapies and multimodal rehabilitation interventions (sensory stimulation interventions and TCM-derived therapy) for TBI-induced DoC. Our analysis reveals that tDCS, rTMS, MNS, and multisensory stimulation constitute effective non-invasive therapeutic strategies, as evidenced by consistent improvements across standardized clinical outcome measures. The therapeutic armamentarium is further augmented by acupuncture and right median nerve RMNS. The integration of these evidence-based approaches into clinical practice promises to enhance recovery trajectories for patients with DoC, with consequent improvements in long-term functional outcomes and quality of life. Future research priorities should include the development of personalized treatment algorithms and the standardization of outcome assessment methodologies to advance the field of neurorehabilitation.