AUTHOR=Zhou Yifan , Sun Yejing , He Pei , Xiong Qi , Kang Junwei , Tang Yunliang , Feng Zhen , Dong Xiaoyang 

TITLE=The efficacy and safety of transcutaneous auricular vagus nerve stimulation for patients with minimally conscious state: a sham-controlled randomized double-blind clinical trial

JOURNAL=Frontiers in Neuroscience

VOLUME=17

YEAR=2023

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1323079

DOI=10.3389/fnins.2023.1323079

ISSN=1662-453X

ABSTRACT=<sec id="sec1"><title>Background</title><p>Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a potentially effective neuromodulation technique for addressing neurological disorders, including disorders of consciousness. Expanding upon our prior clinical study, which demonstrated the superior effectiveness of a 4-week taVNS treatment in patients with minimally conscious state (MCS) compared to those in a vegetative state/unresponsive wakefulness state, the aim of this investigation was to evaluate the safety and therapeutic efficacy of taVNS in individuals with MCS through a sham-controlled randomized double-blind clinical trial.</p></sec><sec id="sec2"><title>Methods</title><p>A cohort of 50 adult patients (male = 33, female = 17) diagnosed with a MCS were randomly assigned to either the active taVNS (<italic>N</italic> = 25) or sham taVNS (<italic>N</italic> = 25) groups. The treatment period lasted for 4 weeks, followed by an 8-week follow-up period. The Coma Recovery Scale-Revised (CRS-R) and Glasgow Coma Scale (GCS) were administered at baseline and weekly during the initial 4 weeks. Additionally, the Disability Rating Scale (DRS) was used to assess the patients’ functional abilities via telephone at week 12. Furthermore, various neurophysiological measures, including electroencephalogram (EEG), upper-limb somatosensory evoked potentials (USEP), brainstem auditory evoked potentials (BAEP), and P300 event-related potentials (P300), were employed to monitor changes in brain activity and neural conduction pathways.</p></sec><sec id="sec3"><title>Results</title><p>The scores for the active taVNS group in the CRS-R and GCS showed greater improvement over time compared to the sham taVNS group (CRS-R: 1-week, Z = −1.248, <italic>p</italic> = 0.212; 2-week, Z = −1.090, <italic>p</italic> = 0.276; 3-week, Z = −2.017, <italic>p</italic> = 0.044; 4-week, Z = −2.267, <italic>p</italic> = 0.023. GCS: 1-week, Z = −1.325, <italic>p</italic> = 0.185; 2-week, Z = −1.245, <italic>p</italic> = 0.213; 3-week, Z = −1.848, <italic>p</italic> = 0.065; 4-week, Z = −1.990, <italic>p</italic> = 0.047). Additionally, the EEG, USEP, BAEP, and P300 also demonstrated significant improvement in the active taVNS group compared to the sham taVNS group at week 4 (EEG, Z = −2.086, <italic>p</italic> = 0.037; USEP, Z = −2.014, <italic>p</italic> = 0.044; BAEP, Z = −2.298, <italic>p</italic> = 0.022; P300 amplitude, Z = −1.974, <italic>p</italic> = 0.049; P300 latency, t = 2.275, <italic>p</italic> = 0.027). Subgroup analysis revealed that patients with MCS derived greater benefits from receiving taVNS treatment earlier (CRS-R, Disease duration ≤ 1-month, mean difference = 8.50, 95% CI = [2.22, 14.78], <italic>p</italic> = 0.027; GCS, Disease duration ≤ 1-month, mean difference = 3.58, 95% CI = [0.14, 7.03], <italic>p</italic> = 0.044). By week 12, the active taVNS group exhibited lower Disability Rating Scale (DRS) scores compared to the sham taVNS group (Z = −2.105, <italic>p</italic> = 0.035), indicating a more favorable prognosis for MCS patients who underwent taVNS. Furthermore, no significant adverse events related to taVNS were observed during treatment.</p></sec><sec id="sec4"><title>Conclusion</title><p>The findings of this study suggest that taVNS may serve as a potentially effective and safe intervention for facilitating the restoration of consciousness in individuals diagnosed with MCS. This therapeutic approach appears to enhance cerebral functioning and optimize neural conduction pathways.</p></sec><sec id="sec110"><title>Clinical trial registration</title><p><ext-link xlink:href="http://www.chictr.org.cn" ext-link-type="uri" xmlns:xlink="http://www.w3.org/1999/xlink">http://www.chictr.org.cn</ext-link>, Identifier ChiCTR2200066629.</p></sec>