Exploration Of The Brain Functional Features And Mechanism Of The Auricular Stimulation In Hemodialysis Patients With Sleep Disorders Based On FMRI

BackgroundChronic kidney disease is a common disease with a global prevalence of 8-16%.As the disease progresses,about 1%of patients eventually developed end-stage renal disease each year,requiring permanent renal replacement therapy,and hemodialysis is the preferred treatment.Maintenance hemodialysis(MHD)refers to continuous and regular hemodialysis over 3 months.MHD therapy can not completely replace renal function.Patients with life maintenance often have multiple complications,especially maintenance hemodialysis with sleep disorder(MHDSD).The incidence rate is as high as 40-85%,which seriously affects the quality of life and prognosis of patients.At present,behavioral cognitive therapy and drug therapy are the main treatments for MHDSD,but sedative-hypnotic drugs have many drawbacks such as large adverse reactions and drug dependence,while cognitive behavioral therapy is time-consuming and poor compliance of patients.As an important part of traditional Chinese medicine,auricular acupoint stimulation therapy such as electroacupuncture therapy has definite efficacy in the treatment of primary insomnia in recent years,but there is no randomized controlled clinical study of this therapy for MHDSD patients.Therefore,it is an urgent problem to investigate the efficacy of auricular acupuncture in the treatment for MHDSD.Functional magnetic resonance imaging(fMRI)has become a powerful tool to explore the mechanism of neuropsychiatric diseases.By extracting brain functional features with fMRI,the pathogenesis and therapeutic mechanism of diseases can be analyzed.However,the pathogenesis of MHDSD is unclear,and the specific therapeutic mechanism of auricular stimulation is also unclear.fMRI can provide new ideas and methods for studying the neural basis of MHDSD.Part Ⅰ Exploration of the brain function features based on fMRI in maintenance hemodialysis patients with sleep disordersObjectiveTo observe the differences in brain function and autonomic nervous function in MHDSD patients,MHD patients with non-sleep disorder(non-SD)and Healthy control(HC),and explore the pathogenesis of MHDSD based on fMRI to lay the foundation for further study of curative effect mechanism.MethodsSixty MHD patients were recruited in the hemodialysis department of Guangdong Hospital of Traditional Chinese Medicine,including 30 MHDSD patients and 30 non-SD patients,and 30 healthy matched patients were recruited in Guangdong Hospital of Traditional Chinese Medicine and Guangzhou University of Traditional Chinese Medicine.Baseline demographic data(age,sex,height,weight and education level),clinical symptom scale,heart rate variability(HRV)and fMRI data were collected to compare the differences in clinical scale,autonomic nervous function and brain function features among the three groups.The clinical symptom scale included the sleep scale:Pittsburgh Sleep Quality Index(PSQI),Insomnia Severity Index(ISI),Epworth sleepiness scale(ESS);anxiety and depression mood scale:Self-rating Anxiety Scale(SAS),Self-rating Depression Scale(SDS);quality of life scale:36-item Short from Health Survey(SF-36);fatigue degree and cognitive function scale:Fatigue scale-14(FS-14),Mini-mental state examination(MMSE),to assess sleep,mood,quality of life,fatigue and cognitive function.HRV indexes include the inter-beat interval(NN or RR),the root mean square successive difference(RMSSD),Standard deviation of RR interval(SDNN),the percentage of successive normal sinus RR intervals more than 50ms(PNN50),high frequency(HF),low frequency(LF),and peak rate(LF/HF),which are used as evaluation indexes for the functional activities of the autonomous nervous system(ANS).fMRI indicators used amplitude of low-frequency fluctuation(ALFF)to measure the strength of spontaneous neuron activity in the brain and to evaluate brain functional activities.Results1.General dataFinally,28 MHDSD patients,28 non-SD patients and 28 HCs with complete clinical scale data,HRV and fMRI data were included in the analysis.There were no significant differences in age,sex,height,weight,BMI and education level between the two groups(P > 0.05).2.Clinical scale The results of clinical scale analysis showed that there were significant differences in PSQI,ISI,ESS,SDS,SAS,FS-14 and SF-36 among the three groups(P < 0.05),but no significant difference in MMSE scores(P > 0.05).Further pairwise comparison and Bonferroni correction showed that PSQI,ISI,ESS,SDS,SAS and FS-14 scores in MHDSD group were significantly higher than those in non-SD group and HC group,while SF-36 scores were significantly lower than those in non-SD group and HC group,with statistically significant differences(P < 0.05).3.HRV analysis results HRV analysis results showed that there was statistical significance in the mean RR interval between the three groups(P < 0.05).Further pair-to-pair comparison and Bonferroni correction showed that the mean RR interval in MHDSD group was significantly lower than that in HC group,the difference was statistically significant(P=0.008).4.fMRI analysis results fMRI analysis results showed that compared with HC group,ALFF values of right insula,right anterior/middle cingulate gyrus, right cerebellum,left superior medial frontal gyrus and left parahippocampal in MHDSD group were significantly increased.ALFF values of bilateral cuneus,bilateral precuneus,and left middle occipital/upper gyrus were significantly decreased(A threshold of voxel wise P < 0.001 uncoirected and a cluster-level P < 0.05 corrected by FDR);Compared with HC group,ALFF values of bilateral cuneus,bilateral precuneus and bilateral middle occipital gyrus were significantly reduced in non-SD group(A threshold of voxel wise P < 0.001 uncorrected and a cluster-level P <0.05 corrected by FDR).5.Correlation analysis results Correlation analysis of ALFF value and clinical symptom scale in MHDSD patients showed that ALFF value of right insula was negatively correlated with daytime dysfunction score(r =-0.406,P=0.016);The ALFF value of left parahippocampal gyrus was negatively correlated with sleep efficiency in MHDSD patients(r=-0.399;p=0.018);The ALFF values of bilateral cuneus and left middle occipital/upper gyrus were negatively correlated with ESS scores in MHDSD patients(r =-0.450,p=0.016).ConclusionMHDSD patients showed impaired autonomic nerve function and abnormal brain function.The brain areas with abnormal functions are mainly involved in affective network and sensorimotor network,and the abnormal brain function changes of these brain networks are important pathogenesis of MHDSD.Part II Effect of auricular stimulation on sleep disorder in patients with maintenance hemodialysis Objective To evaluate the efficacy and safety of auricular stimulation in MHDSD Methods Based on study 1,the sample size of MHDSD patients was expanded to 60,and they were randomly assigned to the treatment group(heart and kidney points)and the control group(shoulder and elbow points)to receive auricular stimulation for 4 weeks.Baseline demographic and biochemical data were collected,and clinical symptom scales were collected before and after treatment.PSQI was the primary outcome index,and ISI5 ESS,SAS,SDS, FS-14,MMSE, and SF-36 were the secondary outcome indexes.The improvement rate of PSQI score(pre-treatment-post-treatment)/(pre-treatment)was used as the efficacy evaluation criteria.The differences of clinical symptom scales between the two groups before and after 4-week treatment were compared,and adverse events during treatment were recorded to evaluate the clinical efficacy and safety of auricular acupoint stimulation therapy.Results1.Baseline demographic characteristics,biochemical indices and clinical scale A total of 52 MHDSD patients who completed 4-week treatment with complete clinical data were included in the analysis,including 26 patients in the treatment group and 26 patients in the control group.The intergroup comparison results showed that: there were no significant differences in general demographic characteristics(age, sex,height,weight,BMI,education level),disease data(primary disease,age of dialysis),taking sleeping pills,biochemical indicators(serum creatinine,urea nitrogen,serum calcium,serum phosphorus,etc.)and clinical scales(PSQI,ISI,ESS,SAS,SDS,FS-14,MMSE,SF-36)between the two groups(P>0.05).2.Primary outcome indicator(1)Comparison of PSQI between groups:After treatment,the PSQI score in the treatment group was significantly lower than that in the control group,with statistical significance(P<0.05).(2)Intra-group comparison of PSQI:Compared with baseline,PSQI scores in two groups after treatment were significantly decreased,with statistical significance(P<0.05);However,the total PSQI score in the treatment group decreased significantly,and the difference was statistically significant(P<0.05).(3)Comparison of total effective rate between groups:After treatment,the total effective rate of the treatment group(76.9%)was significantly higher than that of the control group(46.2%),the difference was statistically significant(P<0.05).3.Secondary outcome indicators(1)Other sleep scale analysis results:①Comparison of ISI and ESS between groups:After treatment,ISI score in treatment group was significantly lower than that in control group,the difference was statistically significant(P<0.05).②Intra-group comparison of ISI and ESS:Compared with baseline,ISI and ESS scores in the treatment group were significantly decreased after treatment with statistical significance(P<0.05).(2)Anxiety and depression mood scale analysis results:①Comparison of SAS and SDS between groups:After treatment,there were no significant differences in SAS and SDS scores between two groups(P>0.05).②Intra-group comparison of SAS and SDS:After treatment,SAS and SDS scores in two groups were significantly decreased compared with baseline,and the differences were statistically significant(P<0.05).However,SAS and SDS scores in the treatment group decreased significantly,and the difference was statistically significant(P<0.05).(3)Quality of life scale analysis results:①Comparison of SF-36 between groups:After treatment,the total SF-36 score difference and energy score in the treatment group were significantly higher than those in the control group,with statistical significance(P<0.05).②Intra-group comparison of SF-36:Compared with baseline,the total SF-36 score,social functioning,mental health,energy and physical pain score in the treatment group were significantly increased after treatment,with statistically significant differences(P<0.05).(4)Fatigue degree and cognitive function scale analysis results:①Comparison of FS-14 and MMSE between groups:After treatment,there were no significant differences in FS-14 and MMSE scores between two groups(P>0.05).②Intra-group comparison of FS-14 and MMSE:Compared with baseline,FS14 scores in the treatment group were significantly decreased and MMSE scores were significantly increased after treatment,with statistically significant differences(P<0.05).4.Adverse event resultsA total of 5 adverse events were reported,including 1 case of gastric discomfort and 2 cases of earache in the treatment group.In the control group,there was 1 case of earache and 1 case of elevated blood pressure.All the above symptoms occurred at the time of the first treatment,and were relieved after intervention and did not recur with subsequent treatment.No serious adverse events occurred.ConclusionAuricular stimulation(heart and kidney acupoints)is safe and effective in the treatment of MHDSD,which not only significantly improved the sleep and quality of life of MHDSD patients,but also relieved anxiety,depression,fatigue and other accompanying symptoms.Part Ⅲ Exploration of the efficacy mechanism of auricular stimulation based on fMRI in maintenance hemodialysis patients with sleep disordersObjectiveTo observe the changes of brain function and autonomic nerve function in MH DSD patients after auricular stimulation,and clarify the therapeutic mechanism of a uricular stimulation based on fMRI.MethodsThe cases were from study 2,in which MHDSD patients were eligible for fMRI examination.Baseline demographic characteristics and biochemical indicators were collected,and clinical symptom scale,HRV and fMRI data were collected before and after treatment.The differences in clinical symptom scale,autonomic nervous function and brain functional activity between two groups before and after 4 weeks of treatment were compared.Results1.Baseline demographic characteristics,biochemical indices,clinical scale and HRV dataA total of 36 MHDSD patients who completed 4-week treatment with complete clinical data,fMRI and HRV data were included in the analysis,including 18 patients in the treatment group and 18 patients in the control group.The intergroup comparison results showed that:there were no significant differences in general demog raphic characteristics(age,sex,height,weight,BMI,education level),disease data(primary disease,age of dialysis),biochemical indicators(serum creatinine,urea nitrogen,serum calcium,serum phosphorus,etc.),clinical scales(PSQI,ISI,ESS,SAS,SDS,FS-14,MMSE,SF-36)and HRV indicators(mean RR interval,SDNN,RMS SD,PNN50,LF,HF,LF/HF)between the two groups(P>0.05).2.Clinical scale analysis results(1)Sleep scales:①Comparison of PSQI,ISI and ESS between groups:After treatment,the PSQI,ISI and ESS score in the treatment group was significantly lower than that in the control group,with statistical significance(P<0.05).②Intra-group comparison of PSQI,ISI and ESS:Compared with baseline,PSQI,ISI and ESS scores in two groups after treatment were significantly decreased,with statistical significance(P<0.05);However,the total PSQI,ISI and ESS score in the treatment group decreased significantly,and the difference was statistically significant(P<0.05).(2)Anxiety and depression mood scales:①Comparison of SAS and SDS between groups:After treatment,there were no significant differences in SAS and SDS scores between two groups(P>0.05).②Intra-group comparison of SAS and SDS:After treatment,SAS and SDS scores in two groups were significantly decreased compared with baseline,and the differences were statistically significant(P<0.05).(3)Quality of life scale:①Comparison of SF-36 between groups:After treatment,the total SF-36 score difference was significantly higher than those in the control group,with statistical significance(P<0.05).②Intra-group comparison of SF-36:Compared with baseline,the total SF-36 score,social functioning,mental health,energy and physical pain score in the treatment group were significantly increased after treatment,with statistically significant differences(P<0.05).(4)Fatigue degree and cognitive function scales:①Comparison of FS-14 and MMSE between groups:After treatment,there were no significant differences in FS-14 and MMSE scores between two groups(P>0.05).②Intra-group comparison of FS-14 and MMSE:Compared with baseline,FS14 scores in the treatment group were significantly decreased and MMSE scores were significantly increased after treatment,with statistically significant differences(P<0.05).3.HRV analysis results(1)Comparison of HRV between groups:After treatment,there were no significant differences in mean RR interval,SDNN,RMSSD,PNN50,LF,HF and LF/HF between two groups(P>0.05).(2)Intra-group comparison of HRV:Compared with baseline,there were no significant difference in HRV indicatorsmean RR interval,SDNN,RMSSD,PNN50,LF,HF and LF/HF in the treatment group after treatment(P>0.05).4.fMRI analysis resultsInteraction effect areas of the brain after 4 weeks intervention in the treatment group and control group patients:the functional connectivity between right insula and the right fusiform gyrus,right parahippocampal gyrus,right temporal gyrus and bilateral cerebellum significantly reduced(A threshold of voxel wise P<0.05 uncorrected and a cluster-level P<0.05 corrected by FDR),mainly distributed in affective network and sensorimotor network.5.Correlation analysis resultsCorrelation analysis between functional connectivity difference before and after treatment and clinical symptom scale:the functional connectivity difference between the right insula and right fusiform gyrus before and after treatment was positively correlated with SDS improvement score(r=0.489,P=0.040);the functional connectivity difference between the right insula and right inferior temporal gyrus before and after treatment was significantly correlated with SDS,FS-14 and SF-36 scores after treatment(r=0.591,P=0.010;r=0.560,P=0.016;r=0.485,P=0.040);the functional connectivity difference between the right insula and bilateral cerebellum before and after treatment was significantly correlated with FS-14 score after treatment and sleep disorder score before treatment(r=-0.532,P=0.023;r=0.545,P=0.019).ConclusionBased on the clinical efficacy of auricular acupoint stimulation in the treatment of MHDSD,the therapeutic mechanism is to regulate the over-active brain function al activities in the affective network and sensorimotor network,thus producing thera peutic effects on sleep disorder.This study preliminarily reveals the efficacy mechan ism of auricular stimulation(heart and kidney acupoints)in the treatment of MHDSD patients.