Transauricular vagus nerve stimulation for patients with disorders of consciousness: A randomized controlled clinical trial

Abstract

Introduction: Disorders of consciousness (DoCs) are a frequent complication of brain injury disease, and effective treatments are currently lacking. Transauricular vagus nerve stimulation (tVNS) has been proposed as a promising therapeutic method for neurological disorders such as epilepsy and depression. In our previous study, we demonstrated that vagus nerve stimulation promoted recovery in rats with DoCs caused by traumatic brain injury. However, the clinical effect of vagus nerve stimulation on consciousness disorders is unclear. We aimed to investigate the therapeutic efficacy and safety of tVNS in patients with DoCs.

Methods: We conducted a randomized, double-blinded, sham-controlled trial. Patients (N = 60) with DoCs, including minimally conscious state (MCS) and vegetative state/unresponsive wakefulness syndrome, were enrolled and randomized to groups receiving either active or sham tVNS. A frequency of 20 Hz and pulse wave of 200 us was used in the active-tVNS protocol, which was performed in the auricular branch of the vagus nerve in the left outer ear. The sham-tVNS protocol was the same as the active-tVNS protocol although without current input. Both groups of patients also received conventional treatments. Consciousness was evaluated according to the Coma Recovery Scale-Revised before and after the 4-week intervention. We also recorded the type and number of behavioral responses. Safety was primarily assessed according to the incidence of treatment-emergent adverse events. Each patient's heart rate and blood pressure were monitored during all treatment sessions.

Results: Ultimately, 57 patients completed the study: 28 patients underwent active tVNS and 29 patients underwent sham tVNS. No significant differences were observed in Coma Recovery Scale-Revised scores between the active- and sham-tVNS groups before the tVNS sessions. Compared with patients in the sham-tVNS group (9.28 ± 4.38), patients with DoCs treated with active tVNS showed improved consciousness (10.93 ± 4.99), although not statistically significant. Further analysis revealed obvious differences between patients with MCS receiving active and sham tVNS, but no significant difference in patients with vegetative state/unresponsive wakefulness syndrome in both groups. All side effects were considered common medical conditions with no obvious correlation to tVNS.

Conclusion: These preliminary data provide early evidence that tVNS may be an effective and safe approach for promoting the recovery of consciousness, especially in patients with MCS.

Clinical trial registration: https://www.chictr.org.cn/edit.aspx?pid=175938&htm=4, identifier: ChiCTR2200066629.

Keywords: Coma Recovery Scale-Revised; disorders of consciousness; minimally conscious state (MCS); transauricular vagus nerve stimulation; vegetative state/unresponsive wakefulness syndrome (VS/UWS).

Figure 1

CONSORT flow diagram.

Figure 2

(A) Coma Recovery Scale-Revised (CRS-R) improvement before and after treatment in the groups. (B) Comparison of CRS-R improvement between the two groups before and after treatment.

Figure 3

Improvements in consciousness level between two groups. (A) Active-tVNS group, (B) Sham-tVNS group. We define a CRS-R increase by one point as “minimally improved,” two points as “improved,” and three or more points as “much improved.” Compared with the sham-tVNS group, the active-tVNS group showed greater improvements in consciousness.

Figure 4

(A) Coma Recovery Scale-Revised (CRS-R) improvement in MCS subject before and after treatment in the groups. (B) Comparison of CRS-R improvement MCS subject between the two groups before and after treatment. ^*p < 0.05, ^#p < 0.05.

Figure 5

(A) Coma Recovery Scale-Revised (CRS-R) improvement in VS/UWS subject before and after treatment in the groups. (B) Comparison of CRS-R improvement VS/UWS subject between the two groups before and after treatment.