Trigeminal Nerve Stimulation for Disorders of Consciousness: A Narrative Review of Potential Mechanisms, Clinical Evidence, and Future Perspectives.

BACKGROUND

Disorders of consciousness (DoC), including the vegetative state/unresponsive wakefulness syndrome (VS/UWS) and the minimally conscious state (MCS), present a major clinical challenge due to limited therapeutic options. Trigeminal nerve stimulation (TNS) has recently emerged as a promising neuromodulatory intervention.

MECHANISMS AND CURRENT EVIDENCE: The trigeminal nuclei send efferent fibers to the thalamus and the ascending reticular system, which then broadly innervate multiple brain areas via the ascending reticular activating system (ARAS) through both direct and indirect pathways. Capitalizing on the trigeminal nerve's distinctive anatomy, TNS has been hypothesized to potentially promote consciousness recovery in preclinical models by activating specific pathways, modulating the release of key neurotransmitters (e.g., hypocretin, dopamine, and norepinephrine), and influencing cerebral hemodynamics. Furthermore, randomized controlled trials (RCTs) involving both external TNS (eTNS) and acoustic-electric TNS have highlighted a possible direction for its application as a novel therapy for DoC; the findings appear to suggest potential clinical relevance, although current evidence remains constrained by small samples, patient heterogeneity, variable stimulation protocols, and limited long-term follow-up.

CHALLENGES: The clinical translation of TNS, however, faces pressing obstacles, including uncertainty regarding optimal stimulation targets and parameters, insufficient long-term safety and efficacy data, incompletely elucidated mechanisms of action, and a lack of suitable preclinical models.

CONCLUSIONS

TNS may represent a promising therapeutic approach for DoC, but further high-quality studies are needed to establish its mechanisms, safety, efficacy, and optimal stimulation strategies.