| Objective1.Previous literature on acupuncture treatment for comorbid depression and insomnia was searched and a systematic review was conducted on the included studies.The effectiveness and treatment characteristics of acupuncture in patients with comorbid depression and insomnia were analyzed to provide evidence based on medicine for the clinical trial section;2.The effectiveness and safety of the combination of "regulating liver and calming the mind" acupuncture technique and repetitive transcranial magnetic stimulation(rTMS)in the treatment of moderate depression with comorbid insomnia were evaluated through clinical trials,and changes in cortical excitability in the brain were assessed;3.Based on resting-state functional magnetic resonance imaging(fMRI),the study explores the underlying mechanisms of the combined "regulating liver and calming the mind"acupuncture technique and rTMS in patients with depression and insomnia,focusing on the brain effects.Methods1.Literature evaluationA comprehensive search of Chinese and English literature on acupuncture treatment for comorbid depression and insomnia was conducted from January 1,2012,to January 31,2023.The quality assessment and meta-analysis were performed to evaluate the effectiveness of acupuncture treatment,treatment characteristics,existing issues,and future prospects in patients with comorbid depression and insomnia.The databases searched included China National Knowledge Infrastructure(CNKI),Chinese Biomedical Literature Database(CBM),Wanfang Data,VIP,PubMed,Embase,and Cochrane Library.NoteExpress literature management software was used for initial screening and deduplication of the retrieved literature.The titles,abstracts,and full texts of the selected studies were reviewed to identify randomized controlled trials that met the inclusion criteria.Data from the included studies were extracted,classified,and organized into tables.The quality assessment of the included studies was performed according to the Cochrane Handbook for Systematic Reviews of Interventions-Meta-analysis was conducted using Revman 5.3 and Stata 12.0 software.2.Clinical studiesExperiment 1:Clinical efficacy evaluationParticipants were recruited from the outpatient department of Bao’an District Traditional Chinese Medicine Hospital in Shenzhen.A total of 111 patients were randomly assigned into three groups:the "acupuncture combined with rTMS" group(referred to as the,combined group"),the "placebo acupuncture combined with rTMS" group(referred to as the "rTMS group"),and the "acupuncture combined with placebo rTMS" group(referred to as the acupuncture group").The study was conducted in a blinded manner for participants,evaluators,and data analysts.All three groups received oral administration of sertraline hydrochloride tablets(Zoloft,50mg,Pfizer Inc.,China Food and Drug Administration Approval No.H10980141)as the basic medication.The combined group received acupuncture at the following acupoints:Baihui(GV20),Yintang(EX-HN3),Touwei(ST8),Hegu(LI4),Taichong(LR3),Shenmai(BL62),Zhaohai(KI6),Zhongwan(CV12),Xiawan(CV10),Qihai(CV6),and Guanyuan(CV4).After a 30-minute needle retention period,transcranial magnetic stimulation(TMS)was applied to the right dorsolateral prefrontal cortex(DLPFC)at 1Hz,while the left DLPFC received intermittent theta burst stimulation(iTBS).The rTMS group received the same acupuncture points,but placebo acupuncture stimulation was administered using sterile blunt needles and fixed devices for 30 minutes,followed by the same TMS treatment protocol as the combined group.The acupuncture group underwent the same acupuncture procedure as the combined group,while a sham coil placement was used for TMS stimulation to ensure that the magnetic field did not stimulate the cortical region.Acupuncture and rTMS treatments were administered three times a week,with an interval of at least 24 hours between each session,for a total of 18 treatments over a 6-week period.The oral administration of sertraline continued for 6 weeks.A follow-up assessment was conducted in the 10th week.The efficacy evaluation included the between-group and within-group comparisons of the Pittsburgh Sleep Quality Index(PSQI)total score,PSQI subscores,and Hamilton Depression Rating Scale(HAMD-17)total score at various time points:0 weeks,2 weeks,4 weeks,6 weeks,and 10 weeks.Measures of-cortical excitability,including resting motor thr-eshold(rMT),motor evoked potential amplitude(MEP-A),and cortical silent period(CSP),were used as indicators of brain cortical excitability.Safety was assessed using the Side Effect Rating Scale(SERS).All assessments were performed at 0 weeks and 6 weeks.Data statistics:Statistical analysis was performed using SPSS 26.0 software.For normally distributed and homogeneous variance continuous data,the mean± standard deviation(x±s)was used to express the data.Paired t-tests were used for within-group comparisons.while one-way analysis of variance(ANOVA)was used for between-group comparisons.Non-normally distributed data were presented as median with interquartile range[M(P25,P75)],and nonparametric tests,such as the Mann-Whitney U test,were used for comparisons.Categorical data were presented as proportions or rates,and the chi-square test(or Fisher’s exact test)was used for between-group comparisons.For multiple time point repeated measurements,repeated measures ANOVA or generalized estimating equations were applied.Two-tailed tests were used for all statistical analyses,and a significance level of α=0.05 was considered statistically significant.Experiment 2:Investigation of Cortical Functional Changes in Moderate Depression and Insomnia Patients Treated with" Regulating liver and calming the mind " Acupuncture Combined with rTMS using fMRIA subset of participants from the combined group and the acupuncture group who expressed willingness to participate in the mechanistic study were recruited for two fMRI examinations before and after the treatment.In addition,a control group consisting of healthy individuals matched for age,gender,and education level was recruited for comparative analysis of resting-state functional connectivity(rs-FC)differences among the combined group,acupuncture group,and healthy control group.Changes in rs-FC before and after 6 weeks of treatment with acupuncture combined with rTMS and acupuncture alone were observed.The correlation between changes in clinical efficacy scores and changes in restingstate brain function was analyzed in both the combined group and acupuncture group before and after the 6-week treatment period.Results1.meta-analysis resultsA total of 1,039 relevant articles were retrieved from electronic databases,including 675 Chinese articles and 364 English articles.The distribution of articles across databases was as follows:CNKI(303 articles),CBM(87 articles),Wanfang Data(170 articles),VIP(115 articles),Pubmed(94 articles),Cochrane Library(162 articles),and Embase(108 articles).After removing duplicates using NoteExpress software,there were 548 Chinese articles and 266 English articles.After reviewing the titles and abstracts,an additional 338 Chinese articles and 130 English articles that did not meet the inclusion criteria were excluded.The full texts of the remaining 35 articles were examined,and 7 articles with inappropriate intervention protocols,5 articles with unclear descriptions of the rTMS group settings,and 7 articles that did not use standardized assessment scales for inclusion criteria were excluded.Finally,a total of 16 articles with 1,185 patients were included in the meta-analysis.The analysis revealed that acupuncture treatment for comorbid depression and insomnia may have better efficacy and safety compared to Western medication treatment.Combining acupuncture with Western medication or multiple acupuncture techniques may enhance the efficacy of acupuncture treatment for comorbid depression and insomnia and alleviate gastrointestinal adverse reactions caused by Western medication.Acupuncture treatment showed favorable effectiveness at 4 and 6 weeks of intervention.Results from the HAMD and PSQI scales indicated that acupuncture treatment may demonstrate superior improvement in insomnia at 4 weeks and antidepressant effects at 6 weeks of treatment duration.2.Clinical study results(1)General Characteristics ResultsA total of 196 patients were initially screened for the study,and eventually,111 patients were included.Among them,103 participants(36 in the combined group,34 in the rTMS group,and 33 in the acupuncture group)completed the entire treatment and follow-up assessments.Due to the impact of the epidemic,1 participant dropped out in the combined group,3 participants dropped out in the rTMS group,and 4 participants dropped out in the acupuncture group.Intention-to-treat(ITT)analysis was conducted to account for these dropouts.Chi-square test(or Kruskal-Wallis H test)was used to compare the general characteristics among the three groups,and the results showed no statistically significant differences between the groups(P>0.05).Comparison of the pre-treatment scores of PSQI total score,PSQI subscale scores,and HAMD total score among the three groups also showed no statistically significant differences(P>0.05),indicating that the three groups were comparable before treatment.(2)PSQI Scale Scores①Inter-group ComparisonThere were significant differences in the overall mean scores of the scale among the three groups at different evaluation time points(P<0.001).The interaction between group and time point was statistically significant(P=0.000).At the 2nd week,there was a statistically significant difference between the combined group and the acupuncture group(P=0.006).At the 4th week,there were statistically significant differences between the combined group and the acupuncture group,and between the rTMS group and the acupuncture group(P=0.000,0.02).At the 6th week,there were statistically significant differences between the combined group and the rTMS group,and between the combined group and the acupuncture group(P=0.000,0.002).At the 1-month follow-up,there were statistically significant differences between the combined group and the rTMS group,and between the combined group and the acupuncture group(P=0.000、0.000).②Intra-group ComparisonWithin each group,the scores at the 2nd,4th,6th,and 10th weeks were significantly lower than the scores before treatment,and the reduction was statistically significant(P<0.01)in all groups.(3)PSQI Scale Subscores(1)Comparison between groups for each factorSleep Quality Subscore:At the 4th week,there was a statistically significant difference between the combined group and the acupuncture group(P=0.001).At the 6th and 10th weeks,there were statistically significant differences between the combined group and the rTMS group,and between the combined group and the acupuncture group(P=0.000).Sleep Latency Subscore:At the 4th week,there was a statistically significant difference between the combined group and the acupuncture group(P=0.003).At the 6th and 10th weeks,there were statistically significant differences between the combined group and the rTMS group,and between the combined group and the acupuncture group(P=0.000).Sleep Duration Subscore:At the 4th week,there was a statistically significant difference between the combined group and the acupuncture group(P=0.010).At the 6th and 10th weeks,there were statistically significant differences between the combined group and the rTMS group(P=0.005;P=0.004).Sleep Efficiency Subscore:At the 6th week,there were still statistically significant differences between the combined group and the rTMS group,and between the rTMS group and the acupuncture group(P=0.044;P=0.017).Sleep Disturbances Subscore:At the 4th week,there were still statistically significant differences between the combined group and the acupuncture group,and between the rTMS group and the acupuncture group(P=0.010;P=0.015).At the 6th week,there was a statistically significant difference between the combined group and the rTMS group(P=0.038).At the 10th week,there were statistically significant differences between the combined group and the rTMS group,and between the rTMS group and the acupuncture group(P=0.000;P=0.001).Sleep Medication Subscore:At the 4th week,there were still statistically significant differences between the combined group and the acupuncture group,and between the rTMS group and the acupuncture group(P=0.001;P=0.039).At the 6th week,there was a statistically significant difference between the combined group and the rTMS group(P=0.008).At the 10th week,there were statistically significant differences between the combined group and the rTMS group,and between the combined group and the acupuncture group(P=0.042;P=0.048).Daytime Dysfunction:At the 2nd week,there were still statistically significant differences between the combined group and the acupuncture group,and between the rTMS group and the acupuncture group(P=0.000;P=0.022).At the 4th,6th and 10th weeks,there were still statistically significant differences between the combined group and the rTMS group,and between the combined group and the acupuncture group(P=0.008;P=0.000)、(P=0.015;P=0.000)、(P=0.000;P=0.000).②Comparisons within groups for each factorSleep Quality Subscore:The combined group and the rTMS group showed a significant decrease in scores at each time point compared to baseline(P<0.001).The acupuncture group also showed a decrease at the 4th,6th,and 10th weeks compared to baseline(P=0.033;P=0.000;P=0.001).Sleep Latency Subscore:The combined group and the rTMS group showed a significant decrease in scores at each time point compared to baseline(P<0.001).The acupuncture group showed a decrease at the 4th and 6th weeks compared to baseline(P=0.012;P=0.000).Sleep Duration Subscore:The combined group and the rTMS group showed a significant decrease in scores at each time point compared to baseline(P<0.001).The acupuncture group showed a decrease only at the 6th week compared to baseline(P=0.009).Sleep Efficiency Subscore:The combined group showed a decrease at the 6th week compared to baseline(P=0.020),while the rTMS group and the acupuncture group showed no significant difference compared to baseline(P>0.05).Sleep Disturbances Subscore:The combined group showed a significant decrease in scores at each time point compared to baseline(P<0.001).The rTMS group showed a decrease at the 4th and 6th weeks compared to baseline(P=0.000;P=0.000).The acupuncture group showed a decrease at the 6th and 10th weeks compared to baseline(P=0.000;P=0.000).Sleep Medication Subscore:The combined group showed a significant difference in scores at each time point(P<0.001).The rTMS group showed a decrease at the 6th week compared to baseline(P=0.041).The acupuncture group showed a decrease at the 6th and 10th weeks compared to baseline(P=0.001;P=0.014).Daytime Dysfunction:The combined group showed a significant decrease in scores at each time point compared to baseline(P<0.001).The rTMS group showed a decrease at the 6th week compared to baseline(P=0.002).The acupuncture group showed a decrease at the 6th and 10th weeks compared to baseline(P=0.000;P=0.009).(4)HAMD-17 scale scores①Inter-group ComparisonThere were significant differences in the overall mean scores of the HAMD-17 scale among the three groups at different evaluation time points(P<0.001).At the 2nd week,there was a significant difference between the combined group and the acupuncture group(P=0.009).At the 4th week,there was a significant difference between the combined group and the acupuncture group(P=0.000).At the 6th and 10th weeks,there were significant differences between the combined group and the rTMS group,as well as between the combined group and the acupuncture group(P=0.003,P=0.000)、(P=0.000,P=0.000).②Intra-group ComparisonBoth the combination group and the rTMS group exhibited a significant decrease in scores at each time point compared to the scores at Week 2,with a statistically significant difference in the magnitude of the decrease(P<0.01).The acupuncture group also showed a significant decrease in scores at Week 6 and Week 10 compared to Week 2,with a statistically significant difference(P<0.01).(5)Cortical excitability indexThere were significant intergroup differences in rMT(resting motor threshold)among the three groups after treatment(P=0.000),with statistically significant differences observed between the combination group and the rTMS group,as well as between the combination group and the acupuncture group(P<0.001).Within-group comparisons indicated significant differences in rMT between the combination group and the rTMS group,as well as between the combination group and the acupuncture group,after treatment compared to baseline(P=0.000;P=0.019).After MEP-A(motor evoked potential amplitude)treatment,there were significant intergroup differences observed among the three groups(P=0.012),with statistically significant differences between the combination group and the rTMS group,as well as between the combination group and the acupuncture group(P=0.038;P=0.026).Withingroup comparisons revealed a significant difference in MEP-A between the combination group before and after treatment(P=0.010).Intergroup comparisons of CSP(cortical silent period)ratio demonstrated statistically significant differences(H=30.837,P=0.000),with significant differences observed between the combination group and the rTMS group,as well as between the combination group and the acupuncture group,in terms of CSP ratio(P=0.000;P=0.000).Within-group comparisons indicated a significant difference in CSP between the combination group before and after treatment(P=0.000).3.Results of the study based on the fMRI technique sectionA total of 14 patients and 6 healthy volunteers were included in this section of the study.Among the patients,8 belonged to the combination group,including 2 males and 6 females,with an average age of 33 years.The acupuncture group comprised 6 patients,including 2 males and 4 females,with an average age of 37.20 years.The healthy control group consisted of 6 participants,including 3 males and 3 females,with an average age of 30.83 years.The baseline characteristics of the three groups were comparable(P>0.05).①Inter-group ComparisonUsing the ALFF analysis method,a two-sample t-test was conducted between depressed insomniac patients and healthy controls based on their baseline ALFF values.The results showed that the depressed insomniac patients had higher ALFF values than the healthy controls in the right caudate nucleus,while they had lower ALFF values in the left orbital inferior frontal gyrus and orbital middle frontal gyrus(P<0.05).Using the FC analysis method with bilateral thalamus as the seed region,a two-sample t-test was performed between depressed insomniac patients and healthy controls based on their baseline FC values.The results revealed significant differences in FC values between depressed insomniac patients and healthy controls when using the left anterior thalamic nucleus lateral portion as the seed region(P<0.05)②Intra-group ComparisonUsing the FC analysis method with bilateral hippocampus as the seed region,the baseline FC values of the hippocampus were compared within the combination group.The results showed a significant decrease in FC values between the left hippocampus and the left fusiform gyrus,right inferior temporal gyrus,and right middle temporal gyrus compared to the baseline(P<0.05).③Correlation analysis resultsUsing the left anterior thalamic nucleus lateral portion as the seed region,the baseline FC values between the left anterior thalamic nucleus lateral portion and the right orbital middle frontal gyrus were significantly and positively correlated with the baseline scores on the AIS scale(P=0.03,r=0.64).The baseline ALFF values in the right caudate nucleus,where depressed insomniac patients had higher values than healthy controls,were positively correlated with the baseline scores on the PSQI scale(P=0.048,r=0.60).Conclusion1.The meta-analysis results suggest that acupuncture treatment for comorbid depression and insomnia may be superior to Western medicine treatment,with the addition of Western medicine enhancing efficacy and reducing adverse effects.Acupuncture demonstrates favorable advantages in terms of anti-depression and sleep improvement at 4 weeks and 6 weeks.2.The combination group,rTMS group,and acupuncture group all effectively improve depression and sleep in patients with moderate depression and insomnia.The combination of acupuncture and rTMS shows superior clinical efficacy in terms of treatment response rate,PSQI scale,and its factors compared to the rTMS group and acupuncture group,while also better regulating cortical excitability.3.Mechanistic studies based on fMRI have revealed the potential involvement of the thalamus,caudate nucleus,and orbital frontal lobe in the pathogenesis of depression and insomnia.The hippocampus may be one of the key brain regions in the therapeutic mechanism of acupuncture combined with rTMS for moderate comorbid depression and insomnia. |
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