Effect of Repetitive Transcranial Magnetic Stimulation (rTMS) Combined with Repetitive Magnetic Stimulation at Taichong Acupoint (LR3) on Depression: A Protocol for a Randomized Controlled Study

Huitao SU, Wenting LIU, Jie YUAN, Hui LI, Lu ZHANG, Fei CHEN, Yaling LEI*

1. Shaanxi University of Chinese Medicine, Xianyang 712046, China; 2 Shaanxi Traditional Chinese Medicine Hospital, Xi’an 710000, China; 3. Community Health Service Center of Weiyang Lake Medical College, Xi’an 710016, China; 4. Huayin Traditional Chinese Medicine Hospital, Huayin 714200, China

Abstract [Objectives] To explore the clinical treatment effect of repetitive transcranial magnetic stimulation (rTMS) combined with repetitive magnetic stimulation at Taichong acupoint (LR3) therapy in the treatment of depression. [Methods] 60 patients who met the inclusion standard were chosen as the research subjects. They were split into two sets using a randomized parallel control method, with 30 cases each in the experimental and control groups. The experimental group adopted the treatment with rTMS+repetitive magnetic stimulation at Taichong acupoint (LR3), and the control group adopted the treatment with rTMS alone. The course of treatment was 8 weeks. Then the clinical efficacy, Hamilton Depression Scale 17 item score (HAMD-17), Symptom Check List-90 (SCL-90), Patient Health Questionnaire-15 (PHQ-15) and Pittsburgh Sleep Quality Index (PSQI) were compared. [Results] After treatment, the scores of HAMD-17, SCL-90, PHQ-15 and PSQI in the two groups were lower than those before and 4 weeks after treatment (P<0.05 or P<0.01), and the scores in the experimental group were inferior to those in the control group (P<0.01), The effective rate was 96.66% in the experimental group and 76.47% in the control group (P<0.05). In the course of treatment, no serious adverse reactions happened in either group. [Conclusions] The rTMS combined with repetitive magnetic stimulation at Taichong acupoint (LR3) can enhance the control of depression in the right frontal lobe, significantly improve the symptoms of depression and somatic discomfort, and improve the sleep quality of patients. It has a wide range of application, and is safe and noninvasive, so it is worthy of clinical promotion.

Key words Repetitive transcranial magnetic stimulation (rTMS), Repetitive magnetic stimulation at Taichong acupoint, Depression, Clinical randomized control

1 Introduction

Depression is a common psychological disease characterized by conspicuous and lasting depressed mood and lack of pleasant sensation, especially inducing sleep disorder and cognitive dysfunction along with the high risk of suicide. It poses a serious threat to people’s physical and mental health and quality of life[1-2]. At present, the treatment of depression is still dominated by medication, but 30%-40% of patients still have poor outcomes from medication[3]. According to the WHO, about 350 million people all over the world are afflicted with depression[4]. Currently, the treatment of depression is still dominated by drug therapy, but there are significant side effects, including medicine addictions and restricted use for the elderly, children, pregnant women, and people with liver and kidney dysfunction[5]. Repetitive Transcranial Magnetic Stimulation (rTMS) is considered to be a safe, well-tolerated and exciting new therapeutic approach for depression, and depression can be effectively treated by rTMS alone[6](Grade I evidence/Grade A recommendation)[2-9].

Studies have shown that mental diseases such as depression are organic encephalopathy with damage to the microstructure of the brain. Central-peripheral-central closed-loop rehabilitation is superior to simple central and simple peripheral treatment. Acupoint stimulation is a common treatment for peripheral nerve regulation, and Taichong is an important acupoint of liver meridian and the preferred acupoint for the treatment of depression[10]. Some studies[11]have pointed out that the application of rTMS combined with other depression interventions can synergistically exert the additive effects, improve the therapeutic effect, help patients get rid of depression early, and reduce the burden on patients, their families and society.

At present, the efficacy of rTMS combined with magnetic stimulation of Taichong (LR3) in the treatment of depression needs to be further investigated. Based on this, we conducted a randomized controlled study. First, we selected 60 depression patients for this research to provide a new way of thinking about the clinical non-pharmacological treatment of depression.

2 Information

2.1 General dataWe selected 60 patients who received treatment in the outpatient department of Encephalopathy in Shaanxi Traditional Chinese Medicine Hospital from November 2019 to October 2021 as the research subjects. We randomly divided them into the rTMS group and the rTMS+magnetic stimulation of Taichong (LR3) group (30 cases in each group) according to the method of actual randomized controlled study. There were 10 men and 20 women in the experimental group, and their mean age was (40.42±10.71) years old; educational background: 7 below high school, 20 undergraduate and 3 postgraduates; average course of disease (7.00±5.06) years. Among the 30 cases in the control group, there were 9 men and 21 women, with the mean age of (40.78±12.07) years old; educational level: 7 below high school, 18 undergraduate and 5 postgraduates; average course of disease (6.69±5.13) years. Compared with baseline data such as sex, age and course of disease, there was no obvious difference between the two groups (P>0.05). All the participants joined this study with informed consent, and this research was approved by the Medical Ethics Committee of Shaanxi Traditional Chinese Medicine Hospital.

2.2 Diagnostic criteriaThe diagnostic criteria of depression[12]: the International Classification of Diseases, Version 10 (ICD-10) for depressive disorders were used.

2.3 Inclusion criteriaThe patients accord with the western medical diagnostic criteria for depression, and the age is 18-65 years old. Patients voluntarily put their signature to the informed consent form, and when they were included, the Hamilton depression rating scale 7

2.4 Exclusion criteria(i) Anyone suffers from other mental diseases; (ii) patients who have taken antidepressant, antipsychotic drugs and similar traditional Chinese medicine for treatment within 4 weeks before enrollment; (iii) patients who are taking antidepressants or have antidepressant pharmacological effects that have not passed the washout period; (iv) patients who have suicide experience, or a suicidal tendency, and a score of suicide ≥1 in HAMD-17; (v) patients who engaged in or currently engaging in other clinical trials within 1 month before their inclusion in the group; (vi) patients with magnetic metal placed near the head or in the brain, such as intracranial stents, cochlear implant,etc.; (vii) those who are unsupervised or unable to complete the clinical study; (viii) patients with poor adherence.

3 Methodology

3.1 Treatment methodThe control group accepted the rTMS treatment, and the experimental group accepted treatment with rTMS+magnetic stimulation of Taichong acupoint (LR3). Two groups of treatment: once a day; 5 times a week; after 4 weeks of uninterrupted treatment, the treatment was changed to one time per week until the 8thweek, for a total of 24 treatments.

3.1.1Low-frequency rTMS therapy: Transcranial magnetic stimulator and "8" shaped coil (YRD CCY-II type, IRED Thermal Group Company) were used to stimulate the patients’ right dorsolateral frontal lobe (r-DLPFC): the area 8 cm before the continuous midpoint of both ear tips and 6 cm aside to the right was stimulated, with the frequency of 1 Hz, 1 800 pulses, and 100% threshold.

3.1.2Magnetic stimulation of left Taichong (LR3) Acupoint: Acupuncture point selection: Taichong (LR3). We conducted the research with reference to theNomenclatureandLocationofAcupuncturePoints(GB/T12346-2006) issued by the National Bureau of Technical Supervision. The site was taken in the dorsum of the foot, between the first and second metatarsal, in front depressions to the union of the metatarsal bases. No acupoints was added and reduced during the study period. Basic operations of magnetic stimulation of "Taichong" (LR3): we placed the stimulation coil on the left side of the Taichong point (LR3) and adjusted the instrument parameters as follows: the frequency of 1 Hz, 1 800 pulses, and 25% threshold.

3.2 Observation indicatorsMain efficacy indicator is HAMD-17 (HAMD-17 is the most widely applied inventory for clinical evaluation of depressive states). The score directly proportional to the severity of depression was compared before treatment, at 4 and 8 weeks after treatment. Secondary efficacy indicators are SCL-90 and PSQI. SCL-90 has 90 questions in total and covers sensation, thinking, emotion, consciousness and sleep,etc.The higher the score, the worse the mental health level); PHQ-15 (PHQ-15 is a 15-item health questionnaire that includes "stomachache, backache, arthralgia, headache, chest pain, dizziness, constipation, fatigue and weakness, palpitation, shortness of breath, dyspepsia, sleep problems, menstrual problems in women, and other problems", it is the currently applicable scale for screening and assessment of somatization symptoms. The higher the score was, the more obvious the somatization symptom would be). SCL-90 was appraised before treatment, at 4 and 8 weeks after treatment. PSQI is used to observe the patient’s sleep. The higher the score, the more serious the insomnia is. In this study, PSQI was evaluated before treatment, and 8 weeks after treatment.

3.3 Efficacy criteriaThe total treatment efficiency used Hamilton Depression Rating Scale (HAMD) as the efficacy evaluation index, and the minus rate was calculated by the nimodipine method. The efficacy was divided into 3 levels: markedly effective, effective and ineffective. Markedly effective: decrease of HAMD score>75%; effective: 25%-75% reduction in HAMD score; ineffective: decrease in HAMD score<25%.

4 Results and analysis

4.1 Comparison of HAMD-17 scores between the two groups

The comparison of HAMD-17 scores is shown in Table 1. The scores of HAMD-17 in experimental group and treatment group after treatment both decreased compared with those before treatment (P<0.001), and the difference between the HAMD scores of the experimental group and the control group after treatment was statistically significant (P<0.001), suggesting that the experimental group had a better effect in improving the depression level of the patients.

Table 1 Comparison of HAMD total scores between the two groups at each time point

4.2 Comparison of SCL-90 scoresThe score comparison of SCL-90 is shown in Table 2. After treatment, the SCL-90 scores decreased in both groups compared with that before treatment (P<0.001), and the SCL-90 score of the experimental group was lower than that of the control group with a statistical significance (P<0.001), indicating that the experimental group could better improve the mental health level of patients.

Table 2 Comparison of total scores of SCL-90 between the two groups at each time point

4.3 Comparison of total scores of the Somatization Symptom Group Scale (PHQ-15)The comparison of total scores of the PHQ-15 is shown in Table 3. After treatment, the PHQ-15 scores of both groups were lower than the scores before treatment (P<0.01). In addition, the PHQ-15 score of the experimental group was decreased more remarkable, and the results had statistical significance (P<0.001), indicating that the curative effect of the experimental group in improving the somatization symptom group was better.

Table 3 Comparison of PHQ-15 total scores between the two groups at each time point

4.4 Comparison of total scores of Pittsburgh Sleep Quality Index (PSQI)The comparison of PSQI scores is shown in Table 4. The PSQI scores of both groups decreased in contrast to the scores before treatment (P<0.01), and the decrease of PSQI scores in the experimental group was more evidently, and the result had statistical significance (P<0.001), suggesting that the experimental group had better efficacy in improving the sleep quality.

Table 4 Comparison of PSQI between the two groups at each time point (n=30)

4.5 Comparison of clinical effects between the two groups

The comparison of clinical efficacy between the two groups is shown in Table 5. After treatment, the total effective rate was 96.66% in the experimental group and 83.33% in the control group. The difference between the two groups was statistically significant (P<0.05).

Table 5 Comparison of clinical effects between the two groups (n=30, cases/%)

4.6 Safety comparisonIn the course of treatment, no adverse reactions were observed in both groups.

5 Discussion

Depression has become a kind of organic brain disease. Relevant studies[13]suggested that the morphological structure of the frontal lobe and subcortical nucleus in patients with depression is different from that in healthy individuals, and the volume of the prefrontal gray matter is smaller than that of healthy individuals. Structural changes may affect the functions and bring about reduced efficiency and cortical function decline in the frontal lobe, thereby increasing the risk of depression. The hypothalamic-pituitary-adrenal (HPA) axis is continuously activated in sufferers with depressive disorder, which can result in the increase of glucocorticoid level, the decline of nerve in dentate gyrus under high glucocorticoid level, and the decrease of anti-inflammatory cytokines under long-term chronic stress state, which can easily lead to the occurrence of depression[14]. Neurotrophic factors can maintain, protect and repair neurons. Studies[15]have found that serum content of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) were reduced compared with normal subjects, which may be the microscopic factors of depression. Brain structure and function changes, long-term activation and decreased levels of neurotrophic factors may play an important role in the occurrence of depression. It has been confirmed that depression is a brain organic disease. Guo Xiaochuan[16]investigated the efficacy of electroacupuncture combined with transcranial magnetic stimulation and simple transcranial magnetic stimulation in improving the clinical symptoms of patients with depression, and the results showed that electroacupuncture combined with transcranial magnetic stimulation had more advantages than transcranial magnetic stimulation alone. Zhou Yujiaetal.[17]applied transcranial repetitive magnetic stimulation combined with meridian electrical stimulation to treat depression caused by craniocerebral injury and found the therapeutic effect was superior to that of sole application of transcranial repetitive magnetic stimulation. It was confirmed that the rehabilitation center combined with peripheral intervention for brain organic diseases was superior to the simple center intervention.

Our previous clinical and literature review indicated that[18-23]the repeated magnetic stimulation at acupuncture points could generate changes in electroencephalogram and brain functional network. Different acupuncture points can excite the functional brain areas which are consistent with their own functions, and also can avoids possible negative reactions such as needle sickness and blood bruising that can occur with acupuncture therapy. In this study, rTMS combined with magnetic stimulation at Taichong (LR3) was used to treat depression,i.e., central nervous system combined with peripheral nervous system. The main efficacy indicator HAMD-17 was improved in the rTMS group and rTMS+Taichong magnetic stimulation group before treatment, 4 and 8 weeks after treatment, but the improvement of rTMS+Taichong magnetic stimulation was more significant. HAMD-17 score in the rTMS+Taichong magnetic stimulation group showed mild depression or even no symptoms after 8 weeks of treatment. It has been clinically confirmed that rTMS+ magnetic stimulation at Taichong (LR3) has a good effect on improving patients’ depression and sleep, which has a significant clinical effect compared with rTMS alone, and has no adverse reactions after long-term application. This has achieved some clinical research results, provides a basis for the formation of strong clinical program of extrapolation application, and also provides a strong theoretical basis for the clinical development of central combined with peripheral intervention for depression.