| Background:Insomnia is a common comorbidity of depression and one of the diagnostic criteria for depression.It is not only related to the prognosis of the patient,but also an indicator for evaluating the clinical efficacy.However,there are fewer studies on Depression-related Insomnia（DRI）.At present,both front-line antidepressants and sedative-hypnotics have some adverse reactions.Clinical trials have found that acupuncture has the effect of antidepression and insomnia,but its pathogenesis is not yet clear.Recent studies have shown that impairment of the attention network may be a target for the interactive onset of depression and insomnia.Objective:This study was carried out through a multi-center randomized controlled trials,based on Attention Network Test（ANT）,and resting functional magnetic resonance（rs-fMRI）studies to explore:（1）The overall efficacy of“shugantiaoshen”integrated acupuncture and moxibustion（iAM）treatment in patients with DRI;（2）The differences and correlation of the characteristics of attention network and neuroimaging between DRI patients and healthy controls;（3）The use of voxel-based Regional Homogeneity（ReHo）and fractional Amplitude of Low frequency Flutions（fALFF）Analysis method to observe the neuroimaging effects of iAM treatment on the Attention Network Test of DRI patients.MethodsStudyl:“shugantiaoshen”integrated acupuncture and moxibustion treatment in DRI disease:a randomized controlled trialThis multicenter,single-blind randomized trial was finally enrolled patients with DRI of moderate severity from three hospitals（Guangdong Provincial Hospital of Chinese Medicine,the First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine,and the Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine）.A total of 131 patients with DRI were randomized,in a ratio of 2:2:2:1,through a computerized central randomization system,into active iAM and sertraline（here after referred to as combined group）,active iAM and placebo（iAM-only group）,sham iAM and sertraline（sertraline-only group）,and sham iAM and placebo（placebo group）.In the end,there were 38 cases in the combined group,35 cases in the iAM-only group,37 cases in the sertraline-only group and 21cases in the placebo group.（1）InterventionThe Integrative Acupuncture-Moxibustion TreatmentThe iAM treatment protocol are include three interventions:a.①manual acupuncture:Baihui（GV20）,Yintang（GV29）,Touwei（ST8）,Jiuwei（C V15）,Zhongwan（CV 12）,Qihai（CV6）,Taichong（LR3）,Hegu（LI4）,Sanyinjiao（SP6）②moxibustion:The alternate groups of selected acupoints are Feishu（BL13）,Geshu（BL17）,Danshu（BL19）.and Yongquan（KI1）in one group,and Pohu（BL42）,Geguan（BL46）,Yanggang（BL48）,and Yongquan（KI1）in the other.③auricular acupuncture:the heart（CO15）,liver（CO12）,and kidney（CO 10）will be selected for the intervention.b.Operation:①manual acupuncture:The patient were in supine position,and the acupoints were routinely disinfected.φ0.25 ×25mm/φ0.25 × 40mm acupuncture needle was used to insert the needle,and the needle was kept for 30 minutes until the patient“deqi”;②moxibustion:Patients will be asked to lie in the prostrate position,Wanhua oil will be smeared on the skin to fix moxa cones and prevent heating.A moxa cone,2 mm in diameter and 3mm in height,will be placed and ignited using a joss stick.It will be removed when two-thirds of it have burned off.Two moxa cones will be applied at each point.③auricular acupuncture:Auricular needles（0.2 mm in diameter,0.6 mm in length）will be used on the points of the unilateral auricle and removed by the acupuncturists in the subsequent treatment.Acupuncture point positioning:refer to the National Standard Meridian Points of the People’s Republic of China（GB/T 12346-2021）;The location of auricular acupuncture points refer to the national standard "Name and Location of Auricular Points"（GB/T 13734-2008）.Sham Integrative Acupuncture-Moxibustion Treatment:a.Acupuncture points are selected with integrated acupuncture and moxibustion protocol.b.Operation:①The same procedure will be performed for the sham conditions,but without percutaneous puncture using blunt-tipped needles,meaning that the“Deqi”sensation will not be achieved;②moxibustion:In sham moxibustion,the moxa cones will not be ignited;③For sham auricular acupuncture,fake auricular needles will be used.The participants in the combined treatment and sertraline-only groups will be given a bottle filled with the antidepressant medication sertraline,and instructed to take 50mg orally after breakfast,once a day,last 12 weeks.The patients with DRI in the iAM-only group and placebo groups will receive a bottle filled with placebo pills made of starch instead.（2）Treatment courseParticipants had undergoed a 12 consecutive week intervention with either 50 mg of sertraline or a placebo once a day and active/sham iAM treatment three times per week.The iAM treatment will take 30 minutes each time and with each interval>24 hours.A followup was carried 8 weeks after the end of treatment.（3）Study Visits and MeasuresFive visits will be performed in this study,these visits will take place during before treatment（week 0）,the treatment period（weeks 4,8,and 12）and with one follow-up visit at week 20.The primary outcome is the change between the end of week 12 and baseline of the Pittsburgh sleep quality index（PSQI）.The secondary outcomes include Hamilton Depression Scale-17（HAMD-17）and PSQI（including subjective sleep quality,sleep time,sleep time,sleep efficiency,sleep disorders,hypnotic drugs.daytime dysfunction 7 factors）.Safety will be evaluated through liver and kidney function tests conducted before and after treatment and through monitoring of daily adverse events.Study2:Differences of attention network and neuroimaging characteristic betw een patients with DRI and healthy controls40 patients with DRI and 38 Healthy controls（HC）were recruited.All subjects completed the PSQI、HAMD-17、Attention Network（ANT）and functional magnetic resonance imaging（fMRI）before treatment.The differences of Attention Network and ReHo/fALFF were compared between DRI patients and HCs,besides pearson correlation analysis was used to analyze the correlation between them.Study3:Neuroimaging changes of Integrative Acupuncture and Moxibustion Treatment on the attention network of patients with DRITo investigate the changes of spontaneous brain activity of attention network in patients with DRI treated with Integrative Acupuncture and Moxibustion Treatment.A total of 44 DRI patients from Study 1 who is willing for the Attention Network Test（ANT）and rs-fMRI examination before and after treatment（week 0 and 12）were enrolled in this study.The PSQI and HAMD-17 were also collected at the same time.Results1.Study 1:“shugantiaoshen”integrated acupuncture and moxibustion treatment in DRI disease:a randomized controlled trial（1）The total PSQI scoreAt week 12,the level of PSQI in the combined group changed from baseline by 5.00（1.75,7.00）,the iAM-only group changed by 3.00（1.00,8.00）,the sertraline-only group changed by 1.00（0.00,5.00）,the placebo group changed by5.00（1.50,6.00）,and differences between four groups were not statistically significant（P>0.05）.After 12 weeks of treatment,the PSQI evaluation of the four groups of patients was significantly lower than the baseline level（all P<0.001）.（2）Secondary outcomes①PSQI total score changes at 5 time pointsRepeated Measurements Analysis:the scores of all four groups decreased with time（time effect P<0.001）.There was no statistical difference between groups（grouping effect P=0.199）,and the trend of difference changed with time increase（interactive effect P=0.004）.Comparison between groups:In the 4th,8th and 12th weeks of treatment,the differences between the four groups of PSQI scale scores were not statistically significant（P>0.05）.In the 8th week of follow-up,the difference between the iAM-only and sertraline-only group was statistical significant（P=0.015）;there was no statistical significant between the combined group and sertraline-only group（P=0.052）;the placebo group and sertraline-only group were not statistically significant too（P=0.202）.The four groups all decreased after 12 weeks treatment compared to baseline,which was statistically significant（all P<0.05）.（2）HAMD-17Repeated Measurements Analysis:the scores of all four groups decreased with time（time effect P<0.001）.There was statistical difference between groups（grouping effect P=0.003）,and the trend of difference changed with time increase（interactive effect P=0.008）.Comparison between groups:At the end of the 4th week,there was no significant difference in HAMD scores among the four groups（P=0.244）.At the 8th week of treatment,the total score of the iAM-only group was lower than that of the sertraline-only group,the difference was statistically significant（P=0.016）,whereas there was no statistical between the combined group and the sertraline-only group（P=0.060）。In the 12th week of treatment,the total score of iAM-only group was lower than that of the sertraline-only group and the placebo group,and there were statistical differences（P=0.001,P=0.049）.There was no significant statistical between the other two groups（P>0.05）.At follow-up visit at week 20,the differences between the combined group and the sertraline-only group were statistically significant（P=0.018）,the differences between the iAM-only group and the sertraline-only group were statistically significant（P=0.000）.There was no significant statistical between the other two groups（P>0.05）.（3）PSQI Scale 7 Dimension Factor ScoresRepeated Measurements Analysis:the factor scores of hypnotic drugs in all four groups decreased with time（time effect P<0.05）,the scores of the other 6 factors decreased with the increase of time（time effect P<0.001）.The scores of sleep quality factor and daytime dysfunction factor were different between groups（group effect P was 0.022 and 0.015 respectively）,while the sleep time factor,sleep time factor,sleep efficiency factor,sleep disorder factor,and hypnotic drug factor scores as a whole did not differ significantly between groups.（The grouping effect P is 0.603、0.649、0.636、0.157、0.959）;The differences of sleep time factor and daytime dysfunction factor were more obvious with the increase of time（the interaction effect P is 0.037 and 0.015,respectively）,while the trend of differences between groups of sleep quality factors,sleep time factors,sleep efficiency factors,sleep disorder factors,and hypnotic drug factors is not obvious（the interaction effect Pis 0.071、0.276、0.222、0.369、0.488,respectively）。Comparison between groups:Sleep quality factor:at the 4th week of treatment,the difference between the placebo group and the sertraline-only group was statistically significant（P=0.044）;at the 20th week of follow up,the difference between the iAM-only group and the sertraline-only group was statistically significant（P=0.029）;daytime dysfunction in the 20th week of follow up.the difference between the combined group and the sertraline-only group was statistically significant（P=0.026）,the difference between the iAM-only group and the sertraline-only group was statistically significant（P=0.001）;the others were not statistically significant（P was 0.603,0.649,0.636,0.157,0.959.respectively）.Intra-group comparisonThe combined group The scores of sleep quality factor were decreased at 8th,12th and 20th week compared with baseline（P<0.001 or P<0.05）,the score of sleep time factor at 20th week of follow up was lower than that before treatment（P<0.05）;the score of sleep time factor at the 8th,12th and 20th week were lower than that before treatment（P<0.001 or P<0.05）;The scores of sleep efficiency factor at the 12th and 20th week were lower than those before treatment（P<0.001 or P<0.05）,the score of sleep disturbance factor at the 20th week was lower than that before treatment（P<0.05）,The scores of daytime dysfunction at 8th,12th and 20th week were lower than those before treatment（P<0.001 or P<0.05）;There was no significant difference in scores of hypnotic factors between pretreatment and post-treatment（P>0.05）。The iAM-only group The scores of sleep quality factor were decreased at the 8th,12th and 20th week（P<0.001 or P<0.05）,the score of sleep time factor at the 20th week of treatment was lower than that before treatment（P<0.05）,the score of sleep time factor at the 8th,12th and 20th week was lower than that before treatment（P<0.001 or P<0.05）;The scores of sleep efficiency factor at the 12th and 20th week were lower than those before treatment（P<0.001 or P<0.05）,the score of sleep disturbance factor at the 20th week of treatment was lower than that before treatment（P<0.05）,Daytime dysfunction The scores at the 8th,12th and 20th week of treatment were lower than those before treatment（P<0.001 or P<0.05）;There was no significant difference in scores of hypnotic factors between pretreatment and post-treatment（P>0.05）。The sertraline-only group The scores of sleep quality factor were decreased at the 12th and 20 th week（P<0.05）,The scores of ay time dysfunction at the 8th,12th and 20th week were lower than those before treatment（P<0.05）,the scores of falling asleep time factor,asleep time factor,falling asleep efficiency factor,sleep disturbance factor and hypnotic drug factor at each time point had no significant difference compared with those before treatment（P>0.05）。The placebo group The score of sleep quality factor at each time point was lower than that before treatment（P<0.05）,the score of sleep disturbance factor at 12th and 20th week was lower than that before treatment（P<0.05）,the score of daytime dysfunction at 12th week after treatment,the scores were lower than those before treatment（P<0.05）;There was no significant difference in the scores of falling asleep time factor,sleep time factor,falling asleep efficiency factor and hypnotic drug factor before and after treatment（P>0.05）.2.Differences of attention network and neuroimaging characteristic between patients with DRI and healthy controlsThe demographic results showed that there was no significant difference in gender and age between the two groups（P>0.05）.（1）ANT comparison between the two groups:①The execution control network effect value was statistically significant between the two groups（P<0.05）,the DRI group was significantly prolonged than HC group;as for alertness and directional network effect value,there was no statistically significant between the two groups（P>0.05）;②The difference in the average response time of the two groups to the two types of target stimuli（inconsistent and consistent）under the conditions of three cues（no cue.center cue.and space cue）was statistically significant（both P<0.05）,and the reaction time of the DRI group was longer than that of the HC group;the comparison difference in the average accuracy rate of the two groups was not statistically significant（P>0.05）.（2）Comparison of fALFF and ReHo between the two groups①Compared with HC,the ReHo values of the right thalamus,the left hippocampus,the bean-shaped nucleus on both sides,and the right central posterior gyrus of the DRI group decreased,and the ReHo values of the left orbital frontal gyrus increased;②Compared with HC,no brain regions with elevated fALFF were found in the DRI group;the left middle occipital gyrus,the left superior occipital gyrus,the right cerebellum6 region,the right lingual gyrus,the right wedge lobe,and the left parietal inferior angular gyrus had lower fALFF values.（3）Correlation between ANT and fALFF/ReHo①The ReHo values of the right superior marginal gyrus and right superior temporal gyrus in the DRI group were negatively correlated with the efficiency values of the executive control network（r=-0.451）;the ReHo values of the left cerebellum8 region were positively correlated with the efficiency values of the executive control network（r=0.684）;②The right fusiform gyrus,right lingual gyrus,and right inferior occipital gyrus in the DRI group were negatively correlated with the efficiency of the directional network（r=-0.451）,and the ReHo values of the left wedge lobe,the left superior occipital gyrus,and the cortex around the left parietal lobe were also negatively correlated with the efficiency of the directional network（r=-0.451）.r=-0.452);ReHo in the left central anterior gyrus was positively correlated with directional network efficiency（r=0.663）;fALFF in the Crus2 region of the right cerebellum was positively correlated with directional network efficiency（r=0.625）.③The fALFF of the left superior temporal gyrus was positively correlated with the efficiency of the alertness network（r=0.683）.3.Neuroimaging changes of Integrative Acupuncture and Moxibustion Treatment on the attention network of patients with DRI（1）ANT Changes before and after treatment①The value of effect of the execution control network:The difference between the iAM-only group and the placebo group is statistically significant（P=0.016）;the difference between the sertraline-only group and the placebo group is statistically significant（P=0.039）;the difference between the combined group and the placebo group is not statistically significant（P>0.05）.The value of alertness network effect:after treatment,the difference between the combined group and the sertraline-only group is statistically significant（P=0.015）;the difference between the iAM-only group and the sertraline-only group is statistically significant（P=0.044）;the difference between the combined group and the placebo group is statistically significant（P=0.007）;the difference between the iAM-only group and the placebo group is statistically significant（P=0.024）;there was no significant difference between the other two groups（P>0.05）.The value of Orientation network effects:the main effect of group is not significant（P=0.329）,the main effect of time is not significant（P=0.411）,and the interactive effect is not significant（P=0.234）.②reaction under the five cue conditions after treatmentComparison between groups:there was no significant difference among the four groups（P>0.05）.Intra-group comparison:The difference in the average response time of the two types of target stimuli（inconsistent and consistent）under the conditions of three cues（no cue,center cue,and space cue）before and after treatment in the combined group was statistically significant（P was 0.022、0.035、0.029、0.03,respectively）;The difference in the average response time of the iAM-only group to the two types of target stimuli（inconsistent and consistent）under the conditions of three cues（no,center,and space）before and after treatment was statistically significant（P was 0.011、0.003、0.007、0.001、0.019,respectively）;The differences before and after treatment in the sertraline-only group under the five clue conditions were not statistically significant（P>0.05）;the differences before and after treatment in the placebo group under the no clue conditions and the central clue conditions were statistically significant（P was 0.034,0.018,respectively）.The comparative differences in the accuracy rates of the four groups under the five cue conditions after treatment were not statistically significant between groups and within groups（P>0.05）.Correlation analysis:the iAM-only group found that the value of alertness effect was negatively correlated with the difference before and after HAMD treatment（r=-0.555,P=0.049）;it was also negatively correlated with the difference between the sleep disorder factor score of the PSQI scale before and after treatment（r=-0.606,P=0.028）.（2）Changes in the whole brain ReHo/fALFF values of four groups of patients with DRI①In the combined group,the fALFF value of the left insula and the right triangular inferior frontal gyrus increased after treatment;the ReHo value of the right superior frontal gyrus and the right inferior temporal gyrus increased;②In the iAM-only group,the fALFF value of the right superior frontal gyrus increased after treatment;the ReHo value of the cerebellum8 area increased,and the ReHo value of the left auxiliary motor area,the right auxiliary motor area,the left inferior parietal gyrus,and the right middle frontal gyrus decreased;③In the sertraline-only group,the fALFF value of the left wedge lobe and the right angular gyrus increased,and the fALFF value of the right cerebellumCrus2 area decreased;the left anterior cingulate and parietal cingulate brain gyrus,left The ReHo values of the cerebellum8 area,the right cerebellum8 area,and the cortex around the left parietal lobe increased,and the ReHo values of the right anterior wedge lobe,the left lingual gyrus,and the left anterior wedge lobe decreased;④In the placebo group,the right middle temporal gyrus,the right inferior temporal gyrus,the right orbital inferior frontal gyrus,the right orbital middle frontal gyrus,and the left anterior wedge fALFF values decreased;the right medial and collateral cingulate brain gyrus,the left lingual gyrus ReHo values increased,and the right central parietal lobule and the right orbital superior frontal gyrus ReHo values decreased.Conclusion（1）The efficiency of“Shugantiaoshen”Integrative Acupuncture and Moxibustion Treatment is better than sertraline in subjective sleep quality factor、daytime dysfunction factor of PSQI scale and HAMD-17 scale to patients with Depression-Related Insomnia.（2）Compared with the healthy controls,the patients with Depression-Related Insomnia had impaired attention function,which was mainly characterized by impaired executive control network function;Acupuncture can reduce the function of the alert network;Both acupuncture and sertraline can improve the function of executive control network,and acupuncture combined with sertraline and the iAM-only can also reduce the function of alert network.（3）The Integrative Acupuncture and Moxibustion Treatment and sertraline may both improve the efficiency of the executive control network in patients with Depression-Related Insomnia by regulating the local consistency of cerebellar function. |
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