Combined transcutaneous auricular vagus stimulation (taVNS) with 0.1Hz slow breathing enhances insomnia treatment efficacy: A pilot study

Abstract

Insomnia disorder (ID) afflicts as much as a third of the global adult populace, constituting a substantial public health challenge that profoundly affects individuals' overall well-being, quality of life, and the socioeconomic framework [[1]Perlis M.L. et al.Insomnia. Lancet. 2022; 400: 1047-1060Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. While cognitive-behavioral therapy for insomnia (CBT-I) and pharmacotherapy serve as the primary treatment approaches, they are beset by issues of compliance, cost, and side effects, and their efficacy appears to vary among individuals. Consequently, various neuromodulation techniques endeavor to offer innovative therapeutic alternatives [[2]Krone L.B. et al.Brain stimulation techniques as novel treatment options for insomnia: a systematic review.J Sleep Res. 2023; e13927Crossref Scopus (3) Google Scholar]. Given that ID is linked to an impaired autonomic nervous system (ANS) regulation, which manifests as heightened cardiovascular sympathetic activity and diminished parasympathetic activity [[3]Tamisier R. Weiss J.W. Pepin J.L. Sleep biology updates: hemodynamic and autonomic control in sleep disorders.Metabolism. 2018; 84: 3-10Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar], transcutaneous auricular vagus nerve stimulation (taVNS) has garnered considerable interest due to its safety, convenience, and directly impact on the ANS. While certain studies have unequivocally highlighted the substantial therapeutic promise of taVNS in ID [[4]Bretherton B. et al.Effects of transcutaneous vagus nerve stimulation in individuals aged 55 years or above: potential benefits of daily stimulation.Aging (Albany NY). 2019; 11: 4836-4857Crossref PubMed Scopus (76) Google Scholar,[5]Zhao B. et al.Transcutaneous auricular vagus nerve stimulation in treating post-stroke insomnia monitored by resting-state fMRI: the first case report.Brain Stimul. 2019; 12: 824-826Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar], some research has concurrently pointed out that, when compared to control groups, taVNS fails to manifest statistically significant distinctions in ameliorating the predominant spectrum of ID symptoms [[2]Krone L.B. et al.Brain stimulation techniques as novel treatment options for insomnia: a systematic review.J Sleep Res. 2023; e13927Crossref Scopus (3) Google Scholar]. This underscores the pivotal significance of optimizing treatment regimens and elevating therapeutic efficiency to render taVNS a viable approach within the landscape of ID management. Given the divergent activity levels of the vagus nerve (VN) during inhalation and exhalation phases, investigations have revealed that respiratory-gated taVNS (RAVNS), particularly when synchronized with the expiratory phase, can amplify its regulatory effects [[6]Sclocco R. et al.The influence of respiration on brainstem and cardiovagal response to auricular vagus nerve stimulation: a multimodal ultrahigh-field (7T) fMRI study.Brain Stimul. 2019; 12: 911-921Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar]. Subsequently, researchers have posited that slow-paced breathing (SB) at 0.1Hz can induce cardiorespiratory resonance, consequently intensifying VN activity [[7]Szulczewski M.T. Transcutaneous auricular vagus nerve stimulation combined with slow breathing: speculations on potential applications and technical considerations.Neuromodulation. 2022; 25: 380-394Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]. The integration of a SB regimen with taVNS interventions may represent a strategy to potentially optimize vagal activity levels, thereby enhancing therapeutic efficacy to its utmost potential. Nonetheless, as of the present, there remains a dearth of research concerning the synergistic effects of taVNS and SB (taVNS + SB), especially when assessing their therapeutic efficacy in managing insomnia. Here, we performed an open-label experimental design to investigate the distinctions in therapeutic outcomes between taVNS and taVNS + SB in the management of ID. Forty-two participants (mean age = 36.38 ± 20.21 years, range from 18 to 79, body mass index = 22.69 ± 3.07, 19 females) meeting the criteria of DSM-V i.e., experiencing sleep continuity disturbances for three or more days per week over a duration of at least three months, with an Insomnia Severity Index (ISI) score of ≥8, were enrolled in the study [[8]Buysse D.J. et al.Recommendations for a standard research assessment of insomnia.Sleep. 2006; 29: 1155-1173Crossref PubMed Google Scholar]. Detailed inclusion criteria and participant characteristics were shown in Supplementary materials. All participants were provided with information about the intervention procedure and wrote the informed consents. The research was conducted according to Declaration of Helsinki and was approved by the local ethics committee. Participants were randomly assigned to taVNS (n = 21) and taVNS + SB (n = 21) groups. After the initiation of the experiment, both groups completed ISI and Pittsburgh Sleep Quality Index (PSQI) questionnaires, and collecting 10-min resting ECG data as baseline measurements at the end of the week1. Subsequently, participants underwent a two-week treatment regimen consisting of daily 20-min sessions, totaling 14 sessions, followed by a two-week follow-up period. At the end of weeks 2–5, ISI and PSQI indices, along with 10-min resting ECG data, were gathered (Fig. 1A). The taVNS stimulation parameters remained uniform across both groups, comprising a 20Hz burst frequency, 2000Hz pulse frequency, 200us pulse width, and a 5s-on, 5s-off cycle. SB process (6 breaths/min) was guided by the instructional video configured on the stimulation device and the current was only delivered during the expiratory phase (Fig. 1B). Participants in the taVNS group adhered to spontaneous breathing. ECG data from the last 5 min were used to analyze heart rate variability (HRV), including root mean square of successive differences (RMSSD) and the absolute power values of high-frequency of HRV (HF) which were reliably index of parasympathetic vagal activity. Logarithmic transformation was performed for HF power data because of its abnormal distribution. A mixed-effects model was employed to analysis the effects of time, group and their interactions (see supplementary materials for method details). The results indicate that both groups showed significant improvement in ISI scores during intervention period(corrected p < 0.001, see Table S2). However, in the two follow-up weeks, a distinctive pattern emerged. The taVNS + SB group demonstrated sustained improvement in insomnia symptoms, while the taVNS group experienced symptom rebound in the fifth week, showing a significant time-intervention interaction (corrected p = 0.046, see Fig. 1C, Table S3). Moreover, we observed a correlation between ISI and PSQI score improvements and baseline scores in the taVNS + SB group at weeks three and five, a relationship not seen in the taVNS group (see Fig. 1D-E and Fig. 1G-H). Analysis of logHF indices, revealed a significant time-intervention interaction tendency (corrected p = 0.06). The taVNS + SB group exhibited a sustained increase in HF activity, significantly higher than baseline at the fifth week, which tendency did not exhibit in taVNS group (see Fig. 1F, Table S3). There was no significant change for RMSSD. Detailed results were presented in supplementary materials. No side-effect was reported by participants. This study demonstrates that the combined impact of taVNS + SB serves to enhance insomnia treatment efficacy compared to taVNS alone. Notably, the beneficial effects persist for two weeks post-treatment, and participants with more severe insomnia and lower sleep quality experience greater improvements—an effect not observed with taVNS group. These findings indicate the capacity of SB to augment taVNS's regulatory impact on the ANS and alleviate insomnia symptoms. Rhythmic or diaphragmatic breathing, often employed as a supplementary therapy within CBT-I [[1]Perlis M.L. et al.Insomnia. Lancet. 2022; 400: 1047-1060Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar], exhibits some improvements in participants’ ANS function and insomnia symptoms [[9]Tsai H.J. et al.Efficacy of paced breathing for insomnia: enhances vagal activity and improves sleep quality.Psychophysiology. 2015; 52: 388-396Crossref PubMed Scopus (60) Google Scholar]. Nevertheless, there are few researches dedicated to investigating the efficacy of SB exercises in ameliorating insomnia. Meanwhile, taVNS can alleviate insomnia symptoms by regulating autonomic activity, but it faces limitations in terms of therapeutic effectiveness. Nonetheless, the combined effects of SB and taVNS may involve mutual influence and integration within the central nervous system, maximally enhancing parasympathetic nervous system activity, resulting in a synergistic effect [[10]Baekey D.M. et al.Effect of baroreceptor stimulation on the respiratory pattern: insights into respiratory-sympathetic interactions.Respir Physiol Neurobiol. 2010; 174: 135-145Crossref PubMed Scopus (74) Google Scholar]. Previous review have summarized that taVNS + SB can enhance HRV in different cohorts [[7]Szulczewski M.T. Transcutaneous auricular vagus nerve stimulation combined with slow breathing: speculations on potential applications and technical considerations.Neuromodulation. 2022; 25: 380-394Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]. This study reveals that taVNS + SB leads to sustained improvements in insomnia symptoms and possible increased HF power in participants. This not only provides a new therapeutic avenue for ID patients but also opens up new directions for the further development of taVNS intervention strategies. Future research may explore the specific effects of different breathing exercises and their synergistic effects with taVNS and assess the therapeutic potential of taVNS + SB in other disorders related to autonomic dysfunction. In summary, this study propose that combining taVNS with 0.1Hz SB can significantly enhance the effectiveness of taVNS in treating insomnia, potentially providing a safe, cost-effective, and convenient treatment option for ID patients. This work was funded by the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (Grant No. ZYYCXTD-C-202004) and Natural Science Basic Research Program of Shaanxi (Grant No. 2022JQ-649).

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