Citation: Liu Li, Ding Yi, Wang Jian, et al. Clinical efficacy of the "Pentatonic Theological Method" in the treatment of patients with mild to moderate hepatic depression and spleen deficiency post-stroke depression and its effect on intestinal flora and serum serotonin levels[J] . China General Practice, 2021, 24(30): 3882-3887. DOI: 10.12114/j.issn.1007-9572.2021.02.025.
Stroke is one of the common cardiovascular and cerebrovascular diseases of Chinese residents, according to statistics, the number of existing stroke patients in China has reached 13 million, accounting for about 25% of all patients with cerebrovascular diseases; in recent years, the incidence of stroke in China has shown a rising trend, and has become a major disease that seriously endangers the health and public health safety of Chinese residents [1]. Post-stroke depression (PSD) is the most common mood disorder in stroke patients, mainly manifested as apathy, interest, irritability, slow thinking, etc., studies have found that about 58.51% of stroke patients are diagnosed with PSD within 3 months after the onset of the disease [2], about 75% of PSD patients have 1 or more somatic symptoms and due to somatic symptoms leading to missed diagnosis, misdiagnosis, delay in rehabilitation, increased risk of stroke recurrence, Patients have a reduced sense of self-efficacy and motivation to participate in rehabilitation exercises [3].
PSD with gastrointestinal symptoms is a specific subtype of PSD. At present, most of the clinical treatment of PSD and its accompanying gastrointestinal symptoms is treated with drugs, but the long-term effect of drug treatment and patient treatment compliance are poor. The author's research group is committed to the inheritance and development of traditional Chinese medicine characteristic rehabilitation technology, and has formed a series of diagnosis and treatment schemes of five elements music therapy combined with acupuncture treatment of PSD in long-term clinical practice, and named it "five-tone divine method". This study was a randomized controlled trial to explore the clinical efficacy of the "pentatonic theory" in the treatment of patients with mild to moderate hepatic depression and spleen deficiency PSD and its effect on the intestinal microbiota and serum serotonin (5-hydroxytryptamine, 5-HT) levels, in order to provide a reference for safer and more effective clinical individualized treatment of such patients.
1 Information and methods
1.1 General Information
From December 2019 to December 2020, 72 patients with mild to moderate hepatic depression and spleen deficiency PSD admitted to the ward and outpatient clinic of the Department of Rehabilitation Medicine of the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine were selected, and the random number table method was divided into a control group and a test group, with 36 cases in each group; the diagnosis of stroke was referred to the "Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke in China 2018" [4] and the "Guidelines for the Diagnosis and Treatment of Cerebral Hemorrhage in China (2019)"[5], and the diagnosis of depression was referred to Chinese Classification and Diagnostic Criteria for Mental Disorders (Third Edition) (CCMD-3)[6], the dialectical classification of hepatic depression and spleen deficiency type refers to "Yu Evidence" in the 7th edition of "Internal Medicine of Traditional Chinese Medicine"[7]. There was no statistically significant difference between the two groups of patients by sex, age, course, stroke type, and PSD severity (P>0.05), see Table 1. This study was approved by the Medical Ethics Committee of the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine (Approval No.: 2019SDZYDEY-001), and the clinical trial registration number was ChiCTR-1900023741; all patients gave informed consent to this study and signed an informed consent form.
Table 1 Comparison of general data of the two groups of patients
Table 1 Comparison of general information between control and experimental groups
The research is innovative:
Based on the traditional Chinese medicine theory of "taking the pulse as the guideline and taking the relevant organ function as the basis", this study organically combines the five elements of music therapy with acupuncture therapy to form the "five-tone divine method" and is used to treat patients with post-stroke depression with mild to moderate hepatic depression and spleen deficiency, and explores its mechanism of action through changes in intestinal flora and serum-serotonin levels, which has a good clinical practice basis and theoretical innovation.
1.2 Criteria for Inclusion and Exclusion
Inclusion criteria: (1) age 35 to 75 years; (2) PSD onset 2 to 36 weeks after stroke; (3) PSD severity is mild to moderate, that is, hamilton depression scale-17 (HAMD-17) score of 8 to 23 points; (4) clear consciousness, able to complete the corresponding scale assessment, no dementia, aphasia, apraxia, etc. Exclusion criteria: (1) HAMD-17 suicidal tendency single score >3 points; (2) life signs are not stable or there are serious heart, liver, kidney disease; (3) due to severe cognitive impairment, aphasia and inability to communicate; (4) there is a history of major mental trauma and alcohol and drug dependence in the past 1 year; (5) antidepressants have been taken in the past 2 weeks; (6) accompanied by dementia, Parkinson's disease, depression and other diseases that may affect the assessment of PSD severity; (7) antipathy or unacceptable to music ;(8) There are contraindications to acupuncture therapy.
1.3 Treatment
1.3.1 Conventional medical treatment
Both groups of patients received conventional medical treatment, including blood pressure regulation, blood glucose control, neurotrophic therapy, etc., and at the same time, they performed hemiplegic limb function recovery with reference to the Chinese Guidelines for the Prevention and Treatment of Cerebrovascular Disease[8].
1.3.2 Control group
On the basis of conventional medical treatment, the control group patients were treated with escitalopram (produced by Xi'an Jansen Pharmaceutical Co., Ltd., Sinopharm Junzi J20150119) at an initial dose of 5 mg/day, and the dose was increased to 10 mg/day within 2 to 3 weeks of treatment, and the treatment was continued for 4 weeks.
1.3.3 Test groups
On the basis of conventional internal medicine treatment, the patients in the experimental group adopted the "five-tone divine method" for treatment: (1) acupuncture treatment: the patient took the supine position, and after the routine disinfection of the local skin, the 0.30 mm × 40.00 mm Huatuo brand disposable sterile acupuncture needles were used for acupuncture, and the selected acupuncture points included Yintang acupoint, Shenting acupoint, Baihui acupoint, Mid-neck acupuncture point, foot sanli acupoint, and each acupuncture point was evenly twisted, and the flattening and flattening method was used to the degree of the patient's local slight soreness (stop when the qi was stopped); the needle was left for 30 min After the needle is issued, the sterile cotton ball or cotton swab is pressed for 1 to 2 minutes to prevent bleeding and prevent infection; the acupuncture treatment and acupuncture method and angle are all referred to the national acupuncture operation standards. (2) Five elements music therapy: instruct the patient to empty the bladder before treatment, play the angle mode music once, about 30 min each time, the volume is appropriate for the patient to feel comfortable, generally 40 ~ 60 db; during the treatment, the patient lies flat in the music therapy room, keeps the light in the room soft, the surrounding environment is quiet, selects the palace mode music in the "Chinese Traditional Five Elements Music (Positive Mode)" recommended by the Chinese Medical Association as the basic music, and the patient selects the favorite track after audition and adopts the Philips EP200 DVD player. Sony WH-CH510 Bluetooth wireless stereo headphones for loop playback. In addition, it is also necessary to play the five elements of music at the same time in acupuncture treatment, 30 min/time, 1 time/day, 5 times/week, 5 times for 1 course, and 4 courses of continuous treatment.
1.4 Observe the indicator
1.4.1 HAMD-17 rating
HAMD-17 was developed by HAMILTON[9] in 1960 and is the most commonly used depressive state assessment scale in clinical practice; HAMD-17 contains a total of 17 items, each of which is divided into none, mild, moderate, severe, and extremely severe, with a score of 1, 2, 3, 4, and 5, respectively, with a total score of 85 points. Studies have shown that the overall parallel validity and structural validity of HAMD-17 are ideal [10].
1.4.2 Gastrointestinal Symptom Rating Scale (GSRS) score
GSRS is composed of 15 self-assessment entries, covering the intensity of gastrointestinal symptoms, the frequency of episodes, the duration of episodes and the impact on daily life, each item is 1 to 7 points, and the higher the overall score, the more serious the gastrointestinal symptoms. Studies have shown that the internal consistency of GSRS is 0.58 to 0.88 [11].
1.4.3 Clinical efficacy
Clinical efficacy is judged according to the HAMD-17 score reduction rate: 75% of the HAMD-17 score reduction rate> is clinically controlled, 50% to 75% is effective, 25% to 49% is effective, and 25% of the < is ineffective; THE HAMD-17 score deduction rate = (total score before treatment - total score after treatment) / total score before treatment×100%. The HAMD-17 score and clinical efficacy determination were independently completed by the members of the research group who did not participate in the study group and the treatment of patients.
1.4.4 Number of intestinal flora
Before and after treatment, 5 to 7 g of fresh feces were collected from two groups of patients, 10 ml of phosphate buffer was added, mixed, centrifuged at a rate of 140 000 r/min for 15 min (centrifugal radius 18 cm) and then extracted supernatant, and then centrifuged at a rate of 140 000 r/min for 10 min (centrifugal radius 10 cm), and finally DNA was extracted by DNA extraction kit and 4 intestinal flora (Bifidobacterium bifidum, Escherichia coli, Lactobacillus, Enterococcus) polymerase chain reaction (PCR), primer amplification and making a standard curve to calculate the number of intestinal flora in lg copies/g.
1.4.5 Serum 5-HT levels
Before and after treatment, 4 ml of fasting venous blood was collected from two groups of patients, centrifuged at a rate of 3 000/min for 10 min (centrifugal radius 10 cm), and then the supernatant was taken and stored in a refrigerator at -80 °C; the enzyme-linked immunosorbent assay (ELISA) and the 5-HT kit (produced by Wuhan Gene Mei Biotechnology Co., Ltd.) were used to detect the serum 5-HT level, and the operation was carried out in strict accordance with the instructions of the kit.
1.5 Statistical methods
SPSS 22.0 statistics software was used for data analysis. The metrological data of this study were all in line with the normal distribution, expressed in (x±s), the comparison between the two groups was based on the independent sample t test, and the comparison before and after treatment in the group was used on the paired t test; the counting data was expressed as a relative number, and the comparison between the two groups was χ2 test; and the grade data comparison was compared with the rank test. The bilateral test level α = 0.05.
2 Results
2.1 HAMD-17 rating, GSRS rating
The difference between the HAMD-17 score and GSRS score before treatment was not statistically significant (P>0.05) between the two groups, and the HAMD-17 score and GSRS score after treatment in the experimental group were lower than those in the control group,and the difference was statistically significant (P<0.01). The HAMD-17 score and GSRS score after treatment in both groups were reduced compared with before treatment, and the difference was statistically significant (P<0.01), see Table 2.
Table 2 Comparison of HAMD-17 scores and GSRS scores before and after treatment (x±s) of patients in two groups
Table 2 Comparison of mean HAMD-17 score and GSRS score between control and experimental groups before and after treatment
2.2 Clinical efficacy
The clinical efficacy of patients in the experimental group was better than that in the control group, and the difference was statistically significant (u=2.652, P=0.008), see Table 3.
Table 3 Comparison of clinical efficacy between two groups of patients [n(%)]
Table 3 Comparison of clinical response between control and experiment groups
2.3 Number of intestinal flora
There was no statistically significant difference (P>0.05) in the number of bifidobacterium, Escherichia coli, Lactobacillus escherichia coli and Enterococcus before treatment in the two groups, and the number of Bifidobacterium and Lactobacillus in the experimental group was higher than that in the control group, and the number of Escherichia coli and Enterococcus was less than that in the control group(P<0.01). The number of bifidobacteria and lactobacillus increased after treatment in the two groups increased compared with that before treatment, and the number of Escherichia coli and Enterococcus decreased compared with before treatment, and the difference was statistically significant (P<0.01), see Table 4.
Table 4 Comparison of intestinal flora before and after treatment between the two groups (x±s, lgcopies/g)
Table 4 Comparison of the mean number of species of gut flora between control and experimental groups before and after treatment
2.4 Serum 5-HT level
There was no statistically significant difference in serum 5-HT levels before treatment between the two groups (P>0.05), and the serum 5-HT levels in the experimental group were higher than those in the control group (P<0.01). The serum 5-HT level of the two groups after treatment was increased compared with that before treatment, and the difference was statistically significant (P<0.01), see Table 5.
Table 5 Comparison of serum 5-HT levels before and after treatment in the two groups (x±s, ng/L)
Table 5 Comparison of the mean serum serotonin level between control and experimental groups before and after treatment
3 Discussion
The pathophysiology of PSD is complex, and although it has undergone extensive clinical research, its exact pathogenesis is still inconclusive. PSD modelling studies suggest that hypothalamus-pituitary-adrenal (HPA) axis excitatory enhancement, stress hormone modulation dysfunction, and monoamine neurotransmitter imbalances (e.g., norepinephrine, 5-HT, dopamine) may be key factors in the development and development of PSD [12]. Traditional Chinese medicine theory holds that "the form exists and the god exists, and the form is destroyed"[13], and people's mental activities depend on the normal physiological function of the internal organs, and the god is the master of form, so Chinese medicine scholars mostly look at PSD from the relationship between "form" and "god"; the main disease of PSD is in the brain, involving liver, spleen, lungs, kidneys and multiple organs, and liver qi depression is its basic disease mechanism [14]. Li Dezhi [15] summarized 6 common symptoms of depression by summarizing a large number of literature, of which hepatic depression and spleen deficiency were the most common. Patients with hepatic depression and spleen deficiency PSD are mainly manifested as depression, chest fullness, good breath, na poor, loose stools, yellowish complexion, light tongue, thin white moss, and gastrointestinal symptoms are more obvious. TCM health care pays attention to tranquility and calmness, which has good reference value for regulating depression, while acupuncture therapy and five elements music therapy are characteristic rehabilitation techniques of TCM and play an important role in the treatment of physical and mental diseases [16].
The pulse is in the spine, intersects with the sutras, reaches the brain, and intersects with the liver meridian at the top, so the pulse is closely related to the brain and liver; in addition, the pulse is the sea of yang pulses, and the yang qi of the main body can regulate the yang qi and the whole body qi and blood of the organs, alleviate the symptoms of yang depression and depression, and promote the recovery of brain function. According to the treatment theory of "taking the supervision pulse as the guideline and taking the relevant organ function as the basis", this study selected the three supervisor pulse acupuncture points of Yintang Acupoint, Shenting Acupoint and Baihui Acupoint, and two related visceral acupuncture points of zhongyi acupoint and foot sanli acupoint, of which the acupuncture points of acupuncture yintang, shenting acupoint and baihui acupuncture point can nourish the brain marrow and regulate the nerve and relieve the liver; the middle acupuncture point is the collection point of the stomach, the intestine meeting of the eight veins, the foot sanli acupoint is the combination point under the stomach, the acupuncture point of the middle spleen, the two related organ acupuncture points of the foot sanli acupoint can adjust the spleen and stomach, the beneficial qi, and the Yintang ace, the Shenting acupoint, and the Yintang ace, the Shenting acupoint, The 3 supervisory acupuncture points of the Baihui Acupoint are matched to play the work of "tongduan tuning god, thinning the liver and spleen, and adjusting the qi machine". In addition, there is a cloud in the "Famous Doctor's Prescription": "The liver is wood qi, thanks to the soil to nourish ... If the qi is weak, then the nine lands are not born, and the wood is depressed", which explains the importance of "yu evidence" from the perspective of the disease mechanism.
In the Book of Rites and Rituals of the Five Classics, it is recorded that "the palace moves the spleen" and "does not flourish, the internal organs should be treated, the five elements belong to the soil, and the five organs pass through the spleen", which is the embodiment of the "corresponding method" and "resonance theory" of the five elements music therapy [17]. Based on the theory of "simultaneous treatment of body and mind", the five elements are combined with the five viscera and the five zhi, which are often used to treat emotional diseases, of which the palace tune music can adjust the middle palace, adjust the qi machine, combine the blood veins, and alleviate worries. In this study, the normal-mode palace tune was selected as the basic music to treat mild to moderate hepatic depression and spleen deficiency PSD, and the acupuncture supervisor pulse should be acupuncture yintang acupoint, Shenting acupoint, and Baihui acupuncture to awaken the brain and open the mind, to nourish the yuan god [18], and the five elements music of acupuncture in the middle of the spleen, foot three mile acupoint and listening to the uterine tune were mainly used to strengthen the spleen and tone the mood, and finally integrate and form the "five-tone tone divine method" to promote the remodeling of the internal organ function of patients with mild to moderate hepatic depression and spleen deficiency PSD, and improve the mental state and gastrointestinal function of the patient. Wang Xiaohong et al. [19] studies have confirmed that the clinical efficacy of acupuncture combined with five elements of music in the treatment of hepatic depression is accurate; Huang Lijun et al. [20] studies have shown that music rehabilitation training can enhance the therapeutic effect of acupuncture, but there is still a lack of discussion of the mechanism of action. The results of this study show that the clinical efficacy of patients in the experimental group is better than that of the control group, and the HAMD-17 score and GSRS score after treatment are lower than those in the control group, indicating that the clinical efficacy of the "pentatonic method" in the treatment of patients with mild to moderate hepatic depression and spleen deficiency PSD is better than that of escitalopram, which can effectively reduce the degree of depression and gastrointestinal symptoms of patients, which is consistent with the above research results.
Individuals based on comorbidities of depression and somatic symptoms may have the same causative factors, and RIEF et al. [21] speculate that the correlation of the 5-HT pathway may be the biological mechanism of depression and somatic symptom comorbidities by establishing modeling symptom development. Studies have shown that 5-HT is closely related to nerve development and plasticity [22], with reduced utilization of tryptophan in the brain of patients with PSD, while the availability of tryptophan is associated with nerve conduction through the 5-HT pathway; at the same time, tryptophan is a precursor to the synthesis of 5-HT, which enters the central nervous system through the blood-cerebrospinal fluid barrier and eventually synthesizes 5-HT in the middle suture nucleus [23]. Thus, serum 5-HT levels can be used as an indirect indicator of 5-HT levels in the central nervous system. Wang Fenghua et al. [24] Found that the content of 5-HT and 5-serotonin indoleacetic acid in the hippocampal tissue of mice with depressive behavior was significantly reduced by building a desperate mouse model, suggesting that the 5-HT pathway may be closely related to the depressed mood and somatic symptoms of PSD patients. The results of this study show that the serum 5-HT level of the patients in the experimental group after treatment is higher than that of the control group, suggesting that the "pentatonic theology method" is more advantageous for regulating the neurotransmitter balance of patients with mild to moderate hepatic depression and spleen deficiency PSD compared with escitalopram, and its mechanism of action may be: acupuncture therapy and five elements music therapy can increase the 5-HT content in patients with mild to moderate hepatic depression and spleen deficiency PSD, thereby regulating neurotransmitter levels and improving nerve function.
The intestinal flora plays an important role in both innate and adaptive immunity, can mediate the formation, maturation and function of immune cells, reduce the occurrence of intestinal inflammation, and also play an important role in repairing the intestinal barrier. Studies have shown that PSD causes intestinal flora disorders and intestinal inflammation through the neuroimmune system, which in turn affects the synthesis, transfer, and disruption of 5-HT signaling of tryptophan metabolites, further aggravating PSD, and this two-way cerebrointestinal communication pathway connected by intestinal flora is known as the "brain-gut axis" [25]. In addition, about 95% of the 5-HT in the human body is synthesized, stored and released in the intestine, 5-HT plays an important role in promoting intestinal peristalsis and secretory reflexes by binding to several receptor subtypes mediated Na+/Cl-dependent serotonin transporter (SERT): 5-HT activates intrinsic intestinal reflexes, mediates the "communication" and "brain-intestinal axis" pathways of the gut-central nervous system, regulates the balance of cerebral intestinal peptides (gastrointestinal peptides, 5-HT), and thus relieves abdominal pain in patients with PSD. Gastrointestinal symptoms such as diarrhea, loss of appetite, belching (symptoms of hepatic depression and spleen deficiency). Clinical studies have shown significant intestinal dysbiosis in older patients with depression [26], and supplementation with probiotic bifidobacteria and lactobacilli may serve as an alternative therapy to improve anxiety and depressive behavior, as well as to reduce stress response and cortisol levels [27]. The results of this study show that the number of bifidobacteria and lactobacillus in the experimental group is more than that in the control group, and the number of Escherichia coli and Enterococcus is less than that in the control group, indicating that the "pentatonic magic method" can effectively regulate the intestinal flora of patients with mild to moderate hepatic depression and spleen deficiency PSD, which is conducive to alleviating the gastrointestinal symptoms of PSD patients. In addition, because the intestinal flora reacts to neurotransmitters through the "brain-intestine axis", it is also beneficial to improve the neurological function of patients with PSD and reduce depression.
In summary, the "five-tone divine method" can achieve the purpose of co-treatment of body and mind, which can effectively reduce the depression and gastrointestinal symptoms of patients with mild to moderate hepatic depression and spleen deficiency PSD while regulating the intestinal flora and serum 5-HT levels, thereby improving the patient's nerve function, neurotransmitter disorders, etc., which is worthy of clinical promotion and application, but this study is a single-center study, the sample size is small, and the results and conclusions need to be further confirmed by large sample size and multi-center research.
conflict of interest
There is no conflict of interest in this article.
References Abbreviated