Study On The Effect And Functional Brain Regulation Mechanism Of Transcutaneous Auricular Vagal Nerve Stimulation For Primary Insomnia

Part Ⅰ The effect and brain regulation mechanism of taVNS for primary insomniaBackgroud:Primary insomnia is a common chronic refractory disease in clinic.The current treatment for primary insomnia is mainly rely on hypnotic drugs and cognitive behavioural therapy for insomnia(CBT-I).However,the hypnotic drugs have large side effects which seriously affect the daytime function of patients,the long-term use of it will increase the risk of various nervous system diseases.Despite the CBT-I has been proven to have long-term effect on insomnia,it sti ll face limited efficacy on the attacking periods pat ients.In addi tion,CBT-I also has the problem of inconvenient appointments,long treatment period and high costs.In recent years,there are some clinical researches reported that stimulating the acupoint in vagus nerve distribution area in auricular concha have efficacy on insomnia.However,some scholars believed that these researches lack strict inclusion criteria,standard operation and high level evidence.So we used the relatively strict inclusion criteria and unified stimulation parameters,made the Pittsburgh Sleep Quality Index(PSQI),Insomnia Severity Index(ISI),Self-Rating Anxiet y Scale(SAS),Self-Rating Depression Scale(SDS),Composite Autonomic Symptom Score 31(COMPASS-31),and Short-form 36 Item Health Survey Questionnaire(SF-36)as subjective index,make the functional magnetic resonance imaging(fMRI)and heart rate variablity(HRV)as objective indicators tn validale the efficacy of taVNS on primary insomnia and explored its neuro-brain functional mechanisms of treatment.Objective:The study aimed to validate the efficacy of taVNS on chronic primary insomnia,observe the differences of brain activity before and after taVNS treatment,and explore the neuro-brain functional mechanisms of taVNS in treating chronic primary insomnia by combining heart rate variability,in order to provide a clinical and theoretical basis for the promotion of taVNS.Methods:1.A single blind,randomized and controlled study method was used in our study,50 patients with chronic primary insomnia were recruited in the Department of sleep disorders,Guangdong Provincial Hospital of Chinese Medicine according to the“Chinese Guideline of Insomnia Disorder Diagnosis and its Treatment" and "International Classification of Sleep Disorders(ICSD-3)Diagnostic Criteria for Chronic Insomnia".Among these patients,26 were randomly divided into treatment group and 24 were divided into control group.Patients in the treatment group were treated by stimulating the vagus nerve distribution area in auricular concha of left ear,while patients in control groups were treated by stimulating the fossa helicis of left ear which was a non-vagus nerve distribution area.2.The PSQI and ISI were used as the main evaluation indexes;SAS,SDS,CCOMPASS-31 and SF-36 were used as secondary e valuation indexes to evaluate efficacy of taVNS for insomnia by compare the alteration of these scales in patients before or after treatment.3.The fMRI was used to observe the alteration of brain activity before and after the treatment in each groups,The HRV was used to observe the influence of true or sham vagus nerve stimulation on the autonomic nervous system.Results:1.The clinical results:(1)The clinical results between groups showed:①There is no difference in the general demographic data,PSQI,SAS,SDS,COMPASS-31 and SF-36 before treatment between treatment group and control group(P>0.05).it indicated the these clinical scales of the two groups are comparable.②After treatment,the treatment group get a better total scores in PSQI,ISI,SAS,SF-36 and the difference of total score that before and after treatment comparing with the control group(P<0.05).it only have some insignificant differences in some small aspect of PSQI,SF-36,such as the sleep latency score(P=0.11),somnipathy score(P=0.098),daytime function score(P=0.06)in PSQI,Physical function,Role-physical score and general health in SF-36 and the total score of COMPASS-31(P>0.05).This results showed the patients in treatment group have better performande in sleep improvement in sleep,anxiety,depression and quality of life than control group after control group.More ever,there was no significant difference in the total score and each items of compass-31 between the two groups after treatment(P>0.05),indicating that both the true and sham taVNS stimulation have no significant difference on the symptoms of autonomic nervous state.(2)The results in each groups showed:①The patients in treatment group have great improvement in total score of all scale and almost all the small score items(P<0.05),except the orthostatic intolerance score,vasomotor score,and bladder score in COMPASS-31,and the general health score in SF-36(P<0.05).this results showed the taVNS can greatly improve the insomnia symptoms,quality,anxiety,depression and the life quality.However,the influence on the symptoms of autonomic nervous system was relatively little.②The control groups also shows significant differences in the total score of all scale,and some small score part(P<0.05),but there is no significant difference in many small items,such as the sleep time score,somnipathy score,medicine use score,and daytime function score in PSQI,the vasomotor,gastrointestinal,bladder and pupillomotor score in COMPASS-31,and the bodily pain score,general health score,social functioning score,role-emotional score and reported health transition score in SF-36(P>0.05).This results showed the sham-taVNS also has some efficacy on insomnia symptoms,quality,anxiety,depression and the life quality,while the effect of it was relative little.2.The Results of HRV(1)The results between groups showed:①There is no difference among all the indicators of HRV between the groups before stimulation.It indicated the these HRV of the two groups are comparable.②During the stimulation period,the RMSSD was bigger than control group(P<0.05),while the other indicators of HRV has insigni ficant differenco(P>0.05).As RMSSD represcnts the activity of vagus nerve,the results suggested that taVNS can affect the activity of vagus nerve in the body more than the sham stimulation.(2)The results in each groups showed:①In treatment group,the RMSSD,PNN50 and Mean time of R-R interval were larger than the state without stimulation during continuous taVNS(P<0.05),while there is no significant difference in LF,HF,LF/HF.Since HRV mainly reflects changes in human autonomic nervous system activity,the results suggested that taVNS can significantly change the activity of autonomic nervous system in insomnia patients.②The control group only showed the mean time of R-R interval and PNN50 was bigger than the state without stimulation during continuous taVNS between in baseline(no stimulation)and continuous taVNS(P<0.05).The other indicators were insignificant.this results showed sham-taVNS has relatively small influence on the autonomic nervous system.3.The fMRI results(1)treatment groups:①Comparing with the brain activity(ALFF)before treatment,the activity of bilateral calcarine sulcus,bilateral lingual gyrus,left cerebellum,right,superior temporal gyrus(STG),right precentral gyrus,right postcentral gyrus,right central sulcus,right middle temporal gyrus(MTG),right cuneus and right supplementary motor area(SMA)decreased significantly(P<0.05).②the activity(ALFF)of left middle frontal gyrus(MFG),left precentral gyrus,left postcentral gyrus,left superior frontal gyrus(SFG)and right cingulate gyrus increased significantly(P<0.05).(2)control groups:comparing with the brain activity(alff)before treatment,the control group only showed the decreased brain activity in right superior frontal gyrus(SFG),right anterior or middle cingulate gyrus,left anterior cingulate gyrus and left SFG(P<0.05).(3)The significant difference value of brain activity before and after treatment between the groups:The comparison of difference value between the groups showed the significant decreased brain activity in bilateral SFG,right middle cingulate gyrus,right MFG,right inferior frontal gyrus(IFG)comparing with the control group(P<0.05).Conclusion:1.taVNS can change the activity of vagus nerve and relieve the symptom of insomnia and anxiety.2.The taVNS may play therapeutic role on insomnia through influencing the activity of monoaminergic and cholinergic neuron brain region,then regulating the activity of bilateral frontoparietal network(FPN),default mode network(DMN)and Audiovisual network.Part Ⅱ The research on differences of efficacy of taVNS on primary insomnia patientsBackground:In recent years,some studies have reported that the efficacy of taVNS in treating insomnia,major depression or epilepsy.However,some researchers found the effective rate of taVNS was not very high,the ear-acupoint stimulation in traditional Chinese medicine also faced this problem.So exploring the reasons that caused the different outcome is the key to practise individual treatment and save medical expenses.Objective:Our study aimed at comparing the differences of brain activity and HRV between“good outcome group”and“poor outcome group”during the continuous stimulation,and analyzing the neuro-brain functional mechanisms that caused the different outcome,In a bid to provided a clinical and theoretical basis for individualized treatment of taVNS.Methods:1.Grouping method:We continuously recruit patients in treatment groups according to the diagnosis criterion and inclusion criteria in part I.According to the efficacy evaluation standard in "guiding principles for clinical research of Chinese medicine" which carried out by the Ministry of health(China)in 1993 and the score-reduction rate of PSQI.The score-reduction rate of PSQI≥25%was defined as effective and regard as group A,the score-reduction rate<25%was defined as ineffective and regarded as group B.2.The PSQI and ISI were used as the main evaluation index,the SAS,SDS,COMPASS-31,and SF-36 were used as secondary evaluation indexes to evaluate efficacy and to compare the changes of conditions in patients.3.The fMRI and HRV were used to observe the differences of ateration in patients that belonged to diffcront groups,when they were accept ing continuous taVNS.Then analyzing the corrclation among the ef ficacy,fMRI and HRV during the continuous stimulation.Results:1.The clinical results:(1)The results between groups showed:①There is no difference between the 2 groups in the general demographic data,PSQI,SAS,SDS,COMPASS-31 and SF-36 before treatment(P>0.05).It indicated the these clinical scales of the two groups are comparable.②Comparing with the group B,the group A get a better improvement in PSQI,ISI,SAS and COMPASS-31’s total scores,and almost all the small score item in all sacle(P<0.05),only existed insignificant score in medicine use score in PSQI,the physical function score,role-physical score,social function score,body pain score,general health score,social function score,total score and the differences of total score between before and after treatment in SF-36(P>0.05).It showed the performance of sleep,anxiety and depression in group A were better than those in group B after taVNS treatment.(2)The results in each groups showed:①Comparing with the state before treatment.The patients in group A have great improvement in total score of all scale and almost all the small score items(P<0.05),only except the vasomotor score,gastrointestinal score,bladder score and pupillomotor score in COMPASS-31,the role-physical score,general health score in SF-36(P>0.05).This showed the patient achieved great improvement in sleep,anxiety,depression,autonomic nervous system symptoms and life quality after taVNS treatment.②The group B only showed the improvement in the sleep quality score of PSQI,the score of ISI,and the physical function score,role-physical score,body pain score,vitality,social function score,role-emotional score and the total score in SF-36(P<0.05),the other scale or small score parts showed insignificant difference.It suggested that patients in group B had only slight improvement in sleep and quality of life after taVNS treatment,but no significant improvement in general insomnia symptoms,anxiety,depression and autonomic nervous system symptoms.2.The Results of HRV(1)The results between groups showed:①There is no difference among these indicators of HRV between the groups without stimulation(P>0.05).It indicated the the HRV indicators of the two groups are comparable.②Comparing with the group B,there are significant differences in 4 indicators(RMSSD、PNN50、TINN、HF)(P<0.05).Since HRV mainly reflects changes of activity in human autonomic nervous system,it shows that the influence of taVNS on the autonomic nervous system in patients in group A was larger than patients in group B.(2)The results in each groups showed:①In group A,The HF was the only indicator that has significant difference,comparing with the state without stimulation(P<0.05).② There was no significant difference of all HRV indicators in group B between baseline(without stimulation)and continuous taVNS state(P>0.05).it indicated that taVNS failed to change the activities of autonomic nervous system in patients that belong to group B.3.The Results of fMRIComparing with Group B,the activity(ALFF)of right SFG,right cerebellum,bilateral SMA in group A decreased significantly(P<0.005).4.The correlation resultsDuring the continuous taVNS stimulation,the HRV of group A showed a correlation in the list below:(1)TINN was correlated with the efficacy(difference between total PSQI scores before and after treatment)of group A(r=0.507,P=0.023),and associated with the difference of brain activity in right cerebellum(r=-0.469,P=0.037)and the left SMA(r=-0.477,P=0.033).(2)SDNN was associated with the efficacy(difference between total PSQI score before and after treatment)of taVNS(r=0.586,P=0.007).(3)Mean value of RR interval was associated with the difference of brain activity in right SMA(r=0.496,P=0.026).(4)LF was correlated with the difference of brain activity in right cerebellum(r=-0.45,P=0.047).(5)LF/HF was associated with the difference of brain activity in right SMA(rs=-0.523,P=0.018).The results suggested that HRV during the taVNS stimulation was closely related to alteration of brain activity and the efficacy of insomnia patients.Conclusion:1.the vagus nerve of patients that belong to di fferent outcomes may have different sensitivities to stimulation.2.The different HRV regulation of brain function for insomnia patients during the continuous taVNS are might the reasons that caused different efficacy.3.The HRV during the continuous taVNS might be the image bio-marker that can predict the efficacy of taVNS for primary insomnia.