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 Table of Contents  
Year : 2022  |  Volume : 1  |  Issue : 2  |  Page : 110-114

Trigeminal nerve stimulation for disorders of consciousness: evidence from 21 cases

Department of Rehabilitation Medicine, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China

Date of Submission17-Apr-2022
Date of Decision17-May-2022
Date of Acceptance10-Jun-2022
Date of Web Publication29-Jun-2022

Correspondence Address:
Zhen Feng
Department of Rehabilitation Medicine, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2773-2398.348256

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According to previous case reports, trigeminal nerve stimulation (TNS) can be successfully used to wake a non-responsive unconscious patient. However, no studies have comprehensively investigated the effect of TNS on patients with disorders of consciousness (DOC). Therefore, the present study aimed to assess the safety and efficacy of TNS in DOC patients recruited at the First Affiliated Hospital of Nanchang University. We used Coma Recovery Scale-Revised (CRS-R) scores to assess patients at baseline and after 1–4 weeks of TNS. The patients were further followed up for 4 weeks after the last stimulation to evaluate the safety of the procedure. The participant group comprised 21 DOC patients with an acquired brain injury who were more than 3 months post-injury. The participants were 44.29 ± 12.55 years old and 5.52 ± 1.83 months post-DOC onset, and included 12 patients who were in a vegetative state or had unresponsive wakefulness syndrome and 9 patients who were in a minimally conscious state. Compared with CRS-R scores at baseline, those at weeks 4 and 8 showed no significant improvements in any of the DOC patients. Nonetheless, CRS-R scores improved throughout the study period in 8 out of the 21 DOC patients. Among those with improved scores, two patients in a minimally conscious state had improved CRS-R scores at week 4, while five had improved scores at 4 weeks later. Only one patient with vegetative state/unresponsive wakefulness syndrome had recovered to a minimally conscious state at week 4. Importantly, no obvious treatment-related adverse events were considered to be related to TNS. Taken together, these data provide early evidence that TNS may be an effective and safe approach for promoting the recovery of consciousness in patients with neurological disorders.

Keywords: disorders of consciousness; minimally conscious state; trigeminal nerve stimulation; vegetative state/unresponsive wakefulness syndrome

How to cite this article:
Dong XY, Tang YL, Fang LJ, Feng Z. Trigeminal nerve stimulation for disorders of consciousness: evidence from 21 cases. Brain Netw Modulation 2022;1:110-4

How to cite this URL:
Dong XY, Tang YL, Fang LJ, Feng Z. Trigeminal nerve stimulation for disorders of consciousness: evidence from 21 cases. Brain Netw Modulation [serial online] 2022 [cited 2023 Sep 22];1:110-4. Available from: http://www.bnmjournal.com/text.asp?2022/1/2/110/348256

Funding: The study was supported by the Science and Technology Department of Jiangxi Province Project (Nos. 20212BAG70023, 20202BBG72002) and the Health Commission of Jiangxi Province Project (Nos. 20204202, 2019A117).

  Introduction Top

Disorders of consciousness (DOC) can result from a variety of neurological conditions such as brain injury and stroke. However, no curative treatments to facilitate recovery exist at present (Septien and Rubin, 2018; Edlow et al., 2021). Most treatment options for these patient populations involve attempts to accelerate the recovery of consciousness via hyperoxygenation, sensory stimulation, pharmacological treatments, or neuromodulatory stimulation of the brain, such as transcranial direct current stimulation, deep brain stimulation, median nerve stimulation, and vagus nerve stimulation (Dong and Feng, 2018; Thibaut et al., 2019; Dong et al., 2021). Although many studies have examined the application of deep brain stimulation, median nerve stimulation, and vagus nerve stimulation in promoting arousal, the use of trigeminal nerve stimulation (TNS) for this purpose has not been comprehensively examined. The trigeminal nerve (cranial nerve V) is the largest cranial nerve and it offers a high-bandwidth pathway for high frequency signals to enter the brain bilaterally. At present, TNS has been widely used to treat acute chronic pain disorders, epilepsy, and depression (Generoso et al., 2019; Mehra et al., 2021). Recently, a case report showed that TNS was successful in waking one patient with unconsciousness caused by severe brain injuries (Fan et al., 2019). Nonetheless, the effect of TNS in DOC patients has not been comprehensively investigated. Therefore, the current study was designed to assess the safety and efficacy of TNS in DOC patients.

  Subjects and Methods Top

Study design and participants

All subjects in this observational study were evaluated using Coma Recovery Scale-Revised (CRS-R) scores at baseline (T0), week 1 (T1), week 2 (T2), week 3 (T3), and week 4 (T4: end of treatment) after treatment onset, with a further follow-up assessment 4 weeks after the last stimulation. Heart rate and blood pressure were monitored during all treatment sessions. Additionally, during the first vagus nerve stimulation session, subjects were monitored using a multimodal monitor with a continuous electrocardiogram. The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Nanchang University (approval No. (2016)(003)) on January 13, 2016 (Additional file 1). Written informed consent was obtained from the patients’ legal guardians before the study. This study was conducted in accordance with the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement (von Elm et al., 2007). Data from adult subjects with chronic DOC who were 3 months post-injury (including traumatic brain injury, stroke, and hypoxic-ischemic encephalopathy) were collected prospectively. Patients were eligible for the study if they were 18 to 60 years of age and had a confirmed diagnosis of vegetative state/unresponsive wakefulness syndrome (VS/UWS) or minimally conscious state (MCS) according to CRS-R scores. We excluded patients who had a history of severe cardiac arrhythmias, an implanted pacemaker, low pulse rate, uncontrolled seizures, or pregnancy. All patients received rehabilitation treatments such as medication and hyperbaric oxygen therapy at the Department of Rehabilitation Medicine, the First Affiliated Hospital of Nanchang University from January 2019 to January 2020. The included patients also had no changes in at least five consecutive CRS-R scores (Zhang et al., 2019), measured at an interval of 1 week, for 4 weeks prior to the study. All included participants completed the entire therapy protocol and those with unstable vital signs were excluded from analysis.

Treatment protocol

We delivered TNS using a low-frequency electrical neuromuscular stimulator (KD-2A TENS, Beijing Yaoyang Ltd., Beijing, China). Briefly, two electrode pairs were attached to the suborbital foramen and bilateral superior orbital fissures, so as to stimulate the maxillary nerve (V2) and ophthalmic nerve (V1), respectively. The stimulation parameters were as follows: the current intensity was 18–20 mA, the pulse width was 200 ms, the frequency was 40 Hz, and the stimulation rate was 30 s/min, as previously described (Fan et al., 2019). TNS was conducted continuously for 3 hours/time, twice a day (early morning and late afternoon) in the inpatient ward for a total of 4 weeks. The environment has no special requirements.

Data collection

CRS-R scores are assigned according to behavioral responses that are associated with cognitive function. The total score is 23 points, and a higher score reflects a lower degree of disturbance of consciousness. The CRS-R scale can be used to determine whether patients have VS/UWS or MCS. We evaluated CRS-R scores in each subject at baseline (T0), at weeks 1–4 (T1–4), and conducted follow-up assessments 4 weeks after treatment completion [Figure 1]. We also assessed treatment-related adverse events to determine the safety of TNS. The blood pressure and heart rate of each patient was measured during each TNS session. In the initial treatment session, all patients were monitored using multimodal monitoring equipment with a continuous electrocardiograph.
Figure 1: Study paradigm.
Note: T0: Baseline; T1–4: weeks 1–4 after treatment; T4+4: 4 weeks following treatment completion.

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Statistical analysis

All analyses were performed with SPSS 20.0 software (IBM, Armonk, NY, USA). Continuous data were expressed as means and standard deviations, and were compared using a Student’s t-test or the Mann-Whitney U test, if appropriate. CRS-R scores were compared using a repeated measures analysis of variance. If significant differences were observed, Tukey’s test was used for post hoc analyses. Values of P < 0.05 were considered significant.

  Results Top

Patient responses to TNS treatment

A total of 30 patients were initially recruited. These included individuals with acquired brain injury for 5.52 ± 1.83 months, 9 of whom were excluded from analysis because of unstable vital signs or death. Therefore, 21 patients were included in the final analysis (See [Table 1] and [Table 2] for patient details). Compared with CRS-R scores at T0 (8.62 ± 2.01), those at T4 (8.81 ± 2.11; P = 0.788) and T4+4 (9.24 ± 2.66; P = 0.383) showed no significant improvements. However, 8 out of the 21 patients showed an improvement in CRS-R scores. When we examined the patients according to the different types of DOC, 7 out of 9 patients with MCS showed improvements in total CRS-R scores throughout the study period (including 2 and 5 patients with improved scores at T4 and T4+4, respectively), and only 1 out of 12 patients with VS/UWS had recovered to MCS at T4.
Table 1: Patient information for individuals with disorder of consciousness

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Table 2: Detailed patient information for all treatment sessions

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Adverse effects

Two patients developed a rash at the electrode attachment site. All other emergent adverse events were recognized as common medical conditions that were not markedly correlated with TNS. In addition, no related changes in electrocardiograph activity were detected, and neither blood pressure nor heart rate was modified by TNS.

  Discussion Top

TNS appears to be an efficient way to manage certain neurological diseases, including depression and epilepsy (Ni et al., 2021). A previous case report indicated that TNS facilitated consciousness recovery in a patient with brain injury-induced VS/UWS. Accordingly, the aim of this study was to assess the application of TNS in the management of DOC.

We examined the efficacy and safety of TNS in DOC patients with MCS and VS/UWS resulting from assorted causes and with varied chronicity. We found that CRS-R scores did not significantly improve at T4 or T4+4 compared with those at T0 (P = 0.788/0.383), although 8 out of 21 patients showed improved consciousness levels. Furthermore, 7 out of 9 (78%) MCS patients showed some degree of recovery, while only 1 of 12 (8%) VS/UWS patients showed improved CRS-R scores. Our findings indicate that TNS is feasible and safe in the management of DOC cases, and that it might have a stronger effect on behavioral responses in patients with MCS versus VS/UWS.

In this study, the outcomes of MCS patients were satisfactory. However, the underlying mechanism of action of TNS remains unclear. According to previous work, TNS-induced promotion of wakefulness may be related to neuroprotective effects, such as improved metabolism (Magis et al., 2017; White et al., 2021). Fan et al. (2019) found that both metabolism and cerebral blood flow were modulated to a certain extent following TNS-induced wakefulness in VS/UWS patients. Furthermore, TNS has been found to significantly enhance neuronal activity in the lateral hypothalamus and the spinal trigeminal nucleus, as well as to improve rat consciousness levels and EEG activity (Zheng et al., 2021). The efficacy of TNS in modulating consciousness levels may also be related to other factors. For instance, branches of the trigeminal nerve may act as portals to other parts of the central nervous system, as evidenced by the large sensory representation of the face within the cortex in comparison with other body parts (Schoenen and Coppola, 2018; Goellner and Rocha, 2020). Meanwhile, nerve fibers in the trigeminal nervous root may be connected to the brain stem reticular formation, and TNS may contribute to the maintenance of physiological arousal by triggering the ascending reticular activating system that plays a vital role in wakefulness (De Cicco et al., 2017; Adair et al., 2020).

In this study, we evaluated several cardiovascular parameters and identified few side effects. Thus, we can confirm the safety and tolerance of TNS in DOC patients, when stimulation parameters are taken into consideration.[18]

This study had several limitations as follows. First, there was no control group, and the sample size was small. Therefore, the results should be interpreted with caution. Second, although the patients had no obvious changes in behavior based on CRS-R scores prior to inclusion, more indicators, such as evoked potential or functional MRI, should be considered.

To summarize, the current study provides primary evidence for the efficacy and safety of TNS for promoting heightened consciousness in patients with DOC, especially those with MCS. Our results should be further confirmed in clinical trials with controls, particularly in terms of the safety, affordability, ease of application, and tolerance of this technique.

Author contributions

Methodology: LJF; data collection: XYD; supervision: YLT; manuscript draft: XYD; manuscript reviewing and editing: ZF. All authors approved the final version of the manuscript.

Conflicts of interest

The authors declared no conflicts of interest.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

Additional file

Additional file 1: Hospital ethics approval (Chinese).

  References Top

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De Cicco V, Tramonti Fantozzi MP, Cataldo E, Barresi M, Bruschini L, Faraguna U, Manzoni D (2017) Trigeminal, visceral and vestibular inputs may improve cognitive functions by acting through the locus coeruleus and the ascending reticular activating system: a new hypothesis. Front Neuroanat 11:130.  Back to cited text no. 2
Dong X, Ye W, Tang Y, Wang J, Zhong L, Xiong J, Liu H, Lu G, Feng Z (2021) Wakefulness-promoting effects of lateral hypothalamic area-deep brain stimulation in traumatic brain injury-induced comatose rats: upregulation of α1-adrenoceptor subtypes and downregulation of gamma-aminobutyric acid β receptor expression via the orexins pathway. World Neurosurg 152:e321-e331.  Back to cited text no. 3
Dong XY, Feng Z (2018) Wake-promoting effects of vagus nerve stimulation after traumatic brain injury: upregulation of orexin-A and orexin receptor type 1 expression in the prefrontal cortex. Neural Regen Res 13:244-251.  Back to cited text no. 4
Edlow BL, Claassen J, Schiff ND, Greer DM (2021) Recovery from disorders of consciousness: mechanisms, prognosis and emerging therapies. Nat Rev Neurol 17:135-156.  Back to cited text no. 5
Fan S, Wu X, Xie M, Li X, Liu C, Su Y, Chen Y, Wu S, Ma C (2019) Trigeminal nerve stimulation successfully awakened an unconscious patient. Brain Stimul 12:361-363.  Back to cited text no. 6
Generoso MB, Taiar IT, Garrocini LP, Bernardon R, Cordeiro Q, Uchida RR, Shiozawa P (2019) Effect of a 10-day transcutaneous trigeminal nerve stimulation (TNS) protocol for depression amelioration: A randomized, double blind, and sham-controlled phase II clinical trial. Epilepsy Behav 95:39-42.  Back to cited text no. 7
Goellner E, Rocha CE (2020) Anatomy of trigeminal neuromodulation targets: from periphery to the brain. Prog Neurol Surg 35:18-34.  Back to cited text no. 8
Magis D, D’Ostilio K, Thibaut A, De Pasqua V, Gerard P, Hustinx R, Laureys S, Schoenen J (2017) Cerebral metabolism before and after external trigeminal nerve stimulation in episodic migraine. Cephalalgia 37:881-891.  Back to cited text no. 9
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  [Figure 1]

  [Table 1], [Table 2]


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