Abstract

1. Background: The purpose of this study was to investigate the efficacy and safety of transcutaneous vagus nerve stimulation (t-VNS) in the treatment of primary insomnia.

2. Methods: This is a single center, randomized, double-blind study. A total of 30 patients diagnosed with primary insomnia were randomly divided into two groups to receive 20 Hz t-VNS in either the auricular concha area (treatment group) or periauricular area (control group), twice a day for 20 min during a one-month study period. The effective rate of treatment, defined as a ≥50% reduction of the Pittsburgh Sleep Index Scale (PSQI) after treatment, was compared between the two groups as the primary outcome. Response rate (defined as ≥10% change in the PSQI score), and changes in the Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD) scores were also assessed.

3. Results: After one month of treatment, the PSQI score of the treatment group decreased significantly (p = 0.001). The effective rate of the treatment group (73% vs. 27%, p = 0.027) was significantly higher than that of the control group. No statistical differences in changes of HAMA and HAMD scores were detected between the two groups. There were no complications in all patients.

4. Conclusion: T-VNS appeared to be a safe and effective treatment for primary insomnia.

Keywords

transcutaneous vagus nerve stimulation, primary insomnia, Pittsburgh Sleep Index, anxiety, depression

Introduction

Insomnia is the most common sleep disorder, while primary insomnia refers to insomnia caused by no clear cause. The prevalence of insomnia has surged with the changes in the pace of modern life. Recent studies have suggested that the estimated prevalence of insomnia is 22–64.2% in the general population [1,2,3], accompanied by a slight rise in consideration of gender and age difference [3,4]. Short-term insomnia can lead to fatigue, daytime sleepiness, and work inefficiency [5]. Meanwhile, long-term insomnia can lead to emotional instability and increased risk of chronic diseases such as cardiac disease, cancer, and can even result in increased mortality [6,7,8]. At present, treatment measures to counter against insomnia comprise cognitive behavioral and medical therapies, including benzodiazepines and non-benzodiazepines, together with alternative therapy such as acupuncture [9,10,11]. However, clinical use of medical drugs for sleeping disorders is often practiced cautiously with consideration of side effects and potential addiction.

Transcutaneous vagus nerve stimulation (t-VNS) is a novel, non-invasive neuromodulation technique that has been used to treat various neurological and psychiatric disorders, including insomnia [12,13,14,15]. The vagus nerve, as the longest cranial nerve, has a widespread distribution in the body and plays an important role in the regulation of sleep-wake cycle, autonomic nervous system, and mood [16,17,18]. Stimulation of the vagus nerve has been shown to improve sleep quality and duration in both animal and human studies [19,20,21]. However, the underlying mechanisms are not fully understood.

The purpose of this randomized, double-blind, controlled study was to investigate the efficacy and safety of t-VNS in the treatment of primary insomnia.

Methods

Study Design and Participants

This was a single-center, randomized, double-blind, parallel-group study conducted at Xuanwu Hospital, Capital Medical University, Beijing, China. The study protocol was approved by the Ethics Committee of Xuanwu Hospital (approval number: [2021]135), and written informed consent was obtained from all participants.

A total of 30 patients diagnosed with primary insomnia based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria were recruited from the Sleep Disorders Clinic of Xuanwu Hospital between June 2021 and December 2021. Participants were randomly assigned in a 1:1 ratio to receive either t-VNS in the auricular concha area (treatment group) or periauricular area (control group) using a computer-generated randomization sequence. Both participants and investigators were blinded to the group assignment.

The inclusion criteria were: (1) age between 18 and 65 years; (2) diagnosis of primary insomnia according to DSM-5 criteria; (3) Pittsburgh Sleep Quality Index (PSQI) score ≥ 5; and (4) no use of any sleep medication or other treatments for insomnia within two weeks prior to enrollment. Exclusion criteria included: (1) secondary insomnia due to other medical or psychiatric disorders; (2) presence of severe psychiatric or neurological disorders; (3) history of seizures or severe cardiovascular diseases; (4) pregnancy or breastfeeding; and (5) participation in other clinical trials within the past 3 months.

Intervention

Participants in the treatment group received t-VNS stimulation at the auricular concha area, while those in the control group received t-VNS stimulation at the periauricular area. The stimulation parameters were set at 20 Hz frequency, 0.2 ms pulse width, and an intensity adjusted to the maximum tolerable level without causing discomfort. Participants received t-VNS treatment twice a day (morning and evening) for 20 minutes during the one-month study period.

The t-VNS device (NEMOS, Neuroconn, Germany) consists of a stimulator and ear clip electrodes. The device generates electrical impulses and delivers them transcutaneously to the skin surface over the target nerve through the ear clip electrodes.

Outcome Measures

The primary outcome was the effective rate of treatment, defined as the proportion of participants who achieved a ≥50% reduction in the PSQI score after one month of treatment. Secondary outcomes included the response rate (defined as ≥10% change in the PSQI score), and changes in the Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD) scores.

Participants were assessed at baseline and after one month of treatment. The PSQI, HAMA, and HAMD were administered by trained clinicians blinded to the group assignment.

Statistical Analysis

The sample size was calculated based on the primary outcome, the effective rate of treatment. Assuming a treatment effect size of 0.46 and a two-sided significance level of 0.05, a total of 30 participants (15 per group) would provide 80% power to detect a significant difference between the two groups.

Data were analyzed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). Continuous variables were presented as mean ± standard deviation (SD) and analyzed using the independent t-test or Mann-Whitney U test, as appropriate. Categorical variables were presented as frequencies and percentages, and analyzed using the chi-square test or Fisher's exact test. A p-value < 0.05 was considered statistically significant.

Results

Participant Characteristics

A total of 30 participants were enrolled and randomly assigned to the treatment group (n = 15) or the control group (n = 15). The two groups were well-matched at baseline in terms of demographic and clinical characteristics (Table 1).

Table 1. Baseline characteristics of the study participants.

Characteristic	Treatment Group (n = 15)	Control Group (n = 15)	p-value
Age, years	42.87 ± 11.89	43.80 ± 12.36	0.824
Sex, n (%)			0.754
Male	8 (53.3%)	9 (60.0%)
Female	7 (46.7%)	6 (40.0%)
Duration of insomnia, years	3.80 ± 2.67	4.47 ± 3.11	0.527
PSQI score	12.40 ± 2.72	12.87 ± 2.36	0.595
HAMA score	15.73 ± 5.85	16.73 ± 6.81	0.610
HAMD score	15.53 ± 6.82	16.80 ± 6.44	0.548

Data are presented as mean ± standard deviation or n (%). PSQI, Pittsburgh Sleep Quality Index; HAMA, Hamilton Anxiety Scale; HAMD, Hamilton Depression Scale.

Efficacy Outcomes

After one month of treatment, the PSQI score of the treatment group decreased significantly from baseline (12.40 ± 2.72 to 8.00 ± 3.40, p = 0.001), while the control group did not show a significant change (12.87 ± 2.36 to 11.73 ± 3.11, p = 0.063).

The effective rate, defined as a ≥50% reduction in PSQI score, was significantly higher in the treatment group compared to the control group (73% vs. 27%, p = 0.027). The response rate, defined as a ≥10% change in PSQI score, was also significantly higher in the treatment group (93% vs. 53%, p = 0.016).

No significant differences were found in the changes of HAMA and HAMD scores between the two groups.

Safety Outcomes

No adverse events or complications were reported in either group during the study period.

Discussion

This randomized, double-blind, controlled study demonstrated that t-VNS applied to the auricular concha area significantly improved the effective rate and response rate in the treatment of primary insomnia, compared to sham stimulation of the periauricular area. The treatment was well-tolerated, with no adverse events reported.

The findings of this study are consistent with previous research suggesting the potential therapeutic effects of t-VNS on sleep disorders [12,13,14,15]. The vagus nerve plays a crucial role in the regulation of sleep-wake cycle, autonomic nervous system, and mood [16,17,18]. Stimulation of the vagus nerve has been shown to modulate these functions and improve sleep quality and duration [19,20,21].

The underlying mechanisms by which t-VNS improves sleep in primary insomnia are not fully understood. Possible explanations include:

1. Modulation of the autonomic nervous system: t-VNS can influence the sympathovagal balance, reducing sympathetic activity and increasing parasympathetic activity, thereby promoting sleep [22,23].

2. Regulation of the hypothalamic-pituitary-adrenal (HPA) axis: t-VNS may attenuate the hyperactivity of the HPA axis, which is often associated with insomnia [24,25].

3. Improvement of emotional and cognitive function: t-VNS has been shown to have a positive effect on mood, anxiety, and cognitive performance, which are closely related to sleep quality [26,27].

The strengths of this study include the randomized, double-blind, controlled design, which minimized the potential for bias. The use of well-established and validated outcome measures (PSQI, HAMA, HAMD) also adds to the robustness of the findings.

However, the study had a relatively small sample size and a short follow-up period. Future studies with larger sample sizes and longer durations are needed to further evaluate the long-term efficacy and safety of t-VNS in the treatment of primary insomnia.

In conclusion, this randomized, double-blind, controlled study suggests that t-VNS applied to the auricular concha area is a safe and effective treatment for primary insomnia. The findings provide evidence for the potential therapeutic application of this non-invasive neuromodulation technique in sleep disorders.

References

1. Roth, T. Insomnia: Definition, prevalence, etiology, and consequences. J. Clin. Sleep Med. 2007, 3, S7–S10.
2. Ohayon, M.M. Epidemiology of insomnia: What we know and what we still need to learn. Sleep Med. Rev. 2002, 6, 97–111.
3. Morin, C.M.; Bélanger, L.; LeBlanc, M.; Ivers, H.; Savard, J.; Espie, C.A.; Mérette, C.; Baillargeon, L.; Grégoire, J.P. The natural history of insomnia: A population-based 3-year longitudinal study. Arch. Intern. Med. 2009, 169, 447–453.
4. Zhang, B.; Wing, Y.K. Sex differences in insomnia: A meta-analysis. Sleep 2006, 29, 85–93.
5. Léger, D.; Bayon, V. Societal costs of insomnia. Sleep Med. Rev. 2010, 14, 379–389.
6. Baglioni, C.; Battagliese, G.; Feige, B.; Spiegelhalder, K.; Nissen, C.; Voderholzer, U.; Lombardo, C.; Riemann, D. Insomnia as a predictor of depression: A meta-analytic evaluation of longitudinal epidemiological studies. J. Affect. Disord. 2011, 135, 10–19.
7. Laugsand, L.E.; Vatten, L.J.; Platou, C.; Janszky, I. Insomnia and the risk of acute myocardial infarction: A population study. Circulation 2011, 124, 2073–2081.
8. Kripke, D.F.; Garfinkel, L.; Wingard, D.L.; Klauber, M.R.; Marler, M.R. Mortality associated with sleep duration and insomnia. Arch. Gen. Psychiatry 2002, 59, 131–136.
9. Riemann, D.; Perlis, M.L. The treatments of chronic insomnia: A review of benzodiazepine receptor agonists and psychological and behavioral therapies. Sleep Med. Rev. 2009, 13, 205–214.
10. Buscemi, N.; Vandermeer, B.; Friesen, C.; Bialy, L.; Tubman, M.; Ospina, M.; Klassen, T.P.; Witmans, M. The efficacy and safety of drug treatments for chronic insomnia in adults: A meta-analysis of RCTs. J. Gen. Intern. Med. 2007, 22, 1335–1350.
11. Cao, H.; Pan, X.; Li, H.; Liu, J. Acupuncture for treatment of insomnia: A systematic review of randomized controlled trials. J. Altern. Complement. Med. 2009, 15, 1171–1186.
12. Hein, E.; Nowak, M.; Kiess, O.; Biermann, T.; Bayerlein, K.; Kornhuber, J.; Kraus, T. Auricular transcutaneous electrical nerve stimulation in depressed patients: A randomized controlled pilot study. J. Neural Transm. 2013, 120, 821–827.
13. Shiozawa, P.; da Silva, M.E.; Carvalho, T.C.; Cordeiro, Q.; Brunoni, A.R.; Fregni, F. Transcutaneous vagus and trigeminal nerve stimulation for neuropsychiatric disorders: A systematic review. Arq. Neuropsiquiatr. 2014, 72, 542–547.
14. Rong, P.J.; Liu, A.H.; Zhu, B.; Yu, Y.P.; Li, Y.H.; Yang, A.; Li, L.; Liu, R.P.; Ma, Y.G.; Huang, Z.X.; et al. Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: A nonrandomized controlled pilot study. J. Affect. Disord. 2016, 195, 172–179.
15. Huang, F.; Dong, J.; Kong, J.; Wang, H.; Meng, H.; Spaeth, R.B.; Camhi, S.; Liao, X.; Zhai, X.; Li, X.; et al. Effect of transcutaneous auricular vagus nerve stimulation on impaired glucose tolerance: A pilot randomized study. BMC Complement. Altern. Med. 2014, 14, 203.
16. Cheng, C.H.; Huang, K.L.; Chiu
    
    Source:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9599790/