Transcutaneous electrical cranial-auricular acupoints stimulation (TECAS) for treatment of the depressive disorder with insomnia as the complaint (DDI): A case series

Epidemiologic studies have shown that above 80% of Major depressive disorder (MDD) patients have insomnia disorder (ID) [[1]Steiger A. Pawlowski M. Depression and Sleep.Int J Mol Sci. 2019; 20: 607PubMed Google Scholar], MDD and ID are highly comorbid, with insomnia symptoms amplifying the chronicity and severity of MDD. Meanwhile, ID is one of the primary manifestations and diagnostic criteria for MDD [[2]Dudek B. Koniarek J. Relationship between sense of coherence and post-traumatic stress disorder symptoms among firefighters.Int J Occup Med Environ Health. 2000; 13: 299-305Google Scholar]. Furthermore, the depressive disorder with insomnia as the complaint(DDI) is associated with a poorer response to depression-focused psychological and pharmacological treatments, making it more difficult diagnostic and treatment decisions for clinicians [[3]Wichniak A. Wierzbicka A. Walęcka M. Jernajczyk W. Effects of antidepressants on Sleep.Curr Psychiatr Rep. 2017; 19 (Published 2017 Aug 9): 63https://doi.org/10.1007/s11920-017-0816-4Google Scholar]. Acupuncture as a major complementary and alternative medicine therapy, is utilized extensively in Asia. Auricular acupoints liver(CO12), heart (CO15) distributed in the cymba conchae, cavum conchae, and Cranial acupoints Bai Hui (GV20), Yin Tang (GV29) distributed in the forehead are considered to be the most commonly used and effective acupuncture treatment for ID and MDD [[4]Yeung W.F. Chung K.F. Tso K.C. Zhang S.P. Zhang Z.J. Ho L.M. Electroacupuncture for residual insomnia associated with major depressive disorder: a randomized controlled trial.Sleep. 2011; 34: 807-815Google Scholar,[5]Dong B. Chen Z. Yin X. Li D. Ma J. Yin P. The efficacy of acupuncture for treating depression-related insomnia compared with a control group: a systematic review and meta-analysis.BioMed Res Int. 2017; 2017: 9614810Google Scholar]. However, as an invasive treatment, acupuncture is prone to clinical side effects such as infection, needling pain, and subcutaneous hematoma. In addition, an experienced acupuncturist is required to perform the treatment. All these reasons reduced adherence as well as cost-effectiveness of acupuncture treatment [[6]Wu J. Yeung A.S. Schnyer R. Wang Y. Mischoulon D. Acupuncture for depression: a review of clinical applications.Can J Psychiatr. 2012; 57: 397-405Google Scholar]. In recent decades, a novel method for acupoints stimulation called transcutaneous electrical acupoints stimulation (TEAS) was developed to increase safety by avoiding the process of needling and the resulting side effects of pain and needle phobia. Interestingly, the stimulation location of transcutaneous auricular vagus nerve stimulation (taVNS) on the ear overlapped with that of auricular acupoints liver(CO12), heart (CO15), both located in the distribution area of the auricular branch of vagus nerve [[7]Liu J. Li C. Peng H. Yu K. Tao J. Lin R. Chen L. Electroacupuncture attenuates learning and memory impairment via activation of α7nAChR-mediated anti-inflammatory activity in focal cerebral ischemia/reperfusion injured rats.Exp Ther Med. 2017; 14: 939-946Google Scholar]. In addition, we were amazed to find that GV20 and GV29 are located in the trigeminal innervation area, which is the stimulation site of transcutaneous trigeminal nerve stimulation (TNS) [[8]Cook I.A. Abrams M. Leuchter A.F. Trigeminal nerve stimulation for comorbid posttraumatic stress disorder and major depressive disorder.Neuromodulation. 2016; 19: 299-305Google Scholar]. In view of this, we combined TEAS of the GV20 and GV29 with taVNS of the C012 and C015 to create a novel stimulation method called transcutaneous electrical cranial-auricular acupoints stimulation (TECAS). It has the advantages of portability, quantifiable stimulation parameters and comfort, especially for home treatment under the normal situation of COVID-19, which can avoid the risk of infection due to frequent hospital trips. In this study, we tested TECAS to target 10 patients with DDI. Consent for treatment was obtained from all patients. Two experienced psychiatrists conducted a clinical interview to collect information for rating with the Hamilton Depression Scale-17(HAMD-17), and Pittsburgh Sleep Quality Index (PSQI). Patients had a high baseline of depressive symptoms (mean HAMD-17 score of 20.90 ± 2.64) and insomnia symptoms (mean PSQI score of 14.20 ± 2.57). The average duration of ID and MDD conditions across patients was 5.30 ± 3.92 months. None of the patients had suicidal intentions. Patient characteristics are shown in Supplementary Table 1. All 10 patients had the first attack of MDD and ID, with early awakening being the most common (7/10). They all were white-collar workers with high work pressure and all refused drug treatment and cannot come to the hospital on time, so we recommended TECAS. The TECAS treatment consisted of two sessions per day for 8 consecutive weeks. The patients took a supine position or sitting position and used the SDZ-V (Hwato, Jiangsu) electronic acupuncture instrument equipped with two cranial electrodes (conductive rubber, circular electrodes: 15mm × 15mm) and a pair of auricular electrodes (conductive rubber, ears clip) (see supplementary eFig.1). The electrodes were put on after the skin was cleaned and conductive gel was applied. The cranial electrodes will be located in GV20 and GV29 Cranial acupoints (GV20, Located on the head, the front hairline is straight up 5 cun(≈100 mm); GV29, Located on the head, in a caldera between the medial ends of the eyebrows) by two annular headbands, and the auricular electrodes will be located on C012 and C015 auricular acupoints (C012, Located in region 12 of the auricle, under the back of the cymba conchae; C015, Located in region 15 of the auricle, in the median caldera of the cavum conchae), where the bilateral distribution area of the vagus nerve of the cavity and cymba of the auricular concha (Fig. 1A). Waveform parameters: 4/20Hz asymmetric biphasic pulsed (4Hz for 5 seconds, 20Hz for 10 seconds, alternately), 200μs pulse width, 0.5–2.0mA current intensity (preferably with the skin around the acupoints shivering mildly without pain), 30min/twice a day, 8 weeks duration. Patients could be treated at home twice a day as required, once in the morning and once in the evening (the evening treatment could be done 30 minutes before bedtime). Patients showed a robust therapeutic response in both MDD (HAMD-17) and ID (PSQI) in treatment 4 and 8 weeks are displayed in Fig. 1B. Compared with 0 week, both the scores of PSQI and HAMD-17 decreased significantly in 4 weeks and 8 weeks (all p < 0.005). While, there was no significant difference between 4 weeks and 8 weeks(p > 0.05). HAMD-17 and PSQI scores of each patient in treatment 4 and 8 weeks are displayed in Fig. 1-b1 and Fig. 1-b2. HAMD-17 score of 10 patients and PSQI score of 8 patients was lower at 4 and 8 weeks than before treatment, and the reduction was greater at 4 weeks than at 8 weeks. PSQI score of 2 patients improved at 4 weeks of treatment, while became worse in the eighth week. During the fifth and sixth week, 2 patients suffered from insomnia aggravation due to acute adverse events. Specifically speaking, patient 03 suffered from high work pressure, and patient 06 went through fierce family quarrels. 7 out of 10 patients showed full insomnia response (50% reduction in PSQI) and 8 patients showed full depression response (50% reduction in HAMD-17). 2 patients showed almost no response of ID and partial response of MDD symptoms (6–7% reduction in PSQI, 37–43% reduction in HAMD-17) (see Supplementary Fig. 1). There were not any adverse events leading to treatment discontinuation. Electrical stimulation of auricular acupoint vagus nerve distribution area, nerve impulse along with the vagus nerve auricular branch transfer to the solitary tract nucleus (NTS), in the NTS relay, to the locus coeruleus(LC) and the parabrachial nuclei(PBN), and then transferred from the latter into the brain areas related to MDD and ID, such as hippocampus, amygdala, prefrontal cortex [[9]Kong J. Fang J. Park J. Li S. Rong P. Treating depression with transcutaneous auricular vagus nerve stimulation: state of the art and future perspectives.Front Psychiatr. 2018; 9: 20Google Scholar]. Trigeminal nerve afferent fibers carry messages from head facial stimulation to NTS, locus coeruleus, raphe nucleus, medullary reticular activating system and structure of the thalamus, and then to feel, edge, cortical and subcortical structures [[10]Shiozawa P. Duailibi M.S. da Silva M.E. Cordeiro Q. Trigeminal nerve stimulation (TNS) protocol for treating major depression: an open-label proof-of-concept trial.Epilepsy Behav. 2014; 39: 6-9Google Scholar]. In conclusion, we suggest TECAS is a good new therapeutic strategy to modulate the vagus nerve and trigeminal nerve propagate through the electrical stimulation projected by neurons from peripheral sites to the central nervous system, and ultimately form the neurobiological basis of the central nervous system. These preliminary results in this group of DDI patients are encouraging. Nonetheless, with all the inherent limitations of a case-series, our results call for prospective sham-controlled studies with larger sample sizes. In addition, for patients with insomnia and depression, it is important to consider combining TECAS with psychotherapy to avoid the interference of acute adverse emergency events. This work is supported by the National Key R&D Program of China (No. 2018YFC1705800) and Acupuncture & Chronobiology Key Laboratory of Sichuan Province (No.2021004).