| BackgroundInsomnia is the most common clinical sleep disorder and the second most common neuropsychiatric disorder.Its increasing prevalence and the correlation of many physical and mental diseases,as well as huge and extensive economic pressure,have brought a heavy burden to the patients’ family and society.Drug therapy is currently the most widely used in clinical practice,but long-term application takes the risk of adverse reactions and potential risks such as tolerance and dependence.Therefore,it is very important to carry out research on non-drug therapy that is convenient and safe for patients to use.In recent years,it has been reported that transcutaneous auricular vagus nerve stimulation(ta-VNS)is convenient,safe and effective in the treatment of insomnia.However,the number of studies and the sample size are both small,and there are few control groups designed,so the level of evidence is low.Therefore,exploring the clinical efficacy and potential mechanism of ta-VNS can provide more high-quality clinical and basic research evidence for ta-VNS in the treatment of insomnia disorder,and will also help promote non-invasive neuromodulation technology for insomnia disorder.Objective:Through a randomized controlled clinical study,the clinical efficacy and safety of ta-VNS in the treatment of insomnia disorder are evaluated from scale scores and polysomnographic indexes.Through EEG power spectrum analysis(PSA),heart rate variability(HRV)and EEG functional connectivity analysis,the effects of ta-VNS on cortical arousal and physiological arousal in insomnia disorder regulating autonomic nervous function are explored,and the hypothesis that ta-VNS inhibits hyperarousal(cortical,physiological arousal)is verified.This provides a scientific basis for ta-VNS intervention in insomnia disorder.Methods:Part 1 Clinical efficacy and safety research of ta-VNS in the treatment of insomnia disorder1.Using a randomized,controlled study method,adopting the diagnostic criteria for insomnia disorders in the American Diagnostic and Statistical Manual of Mental Disorders,5th edition(DSM-V),74 patients with insomnia disorder were recruited from the Acupuncture Hospital of China Academy of Chinese Medical Sciences,Xuanwu Hospital of Capital Medical University,Institute of Drug Dependence of Peking University.A total of 66 subjects completed the study,of which 33 patients in the treatment group were treated with ta-VNS,and 33 patients in the control group were treated with transcutaneous non-auricular vagus nerve stimulation(tn-VNS).2.The total score of Pittsburgh Sleep Quality Index(PSQI)scale was used as the main outcome measurement.Scores of Epworth sleepiness scale(ESS),the Flinders fatigue scale(FFS),Hamilton Depression Scale(HAMD),Hamilton Anxiety Scale(HAMA)and indexes of polysomnography(PSG)were used as secondary outcome measurements.The scores of six PSQI factors,ESS and FFS scales between and within the two groups were compared at the 0th,2nd,4th week and the 6th week of follow-up.The scores of HAMD and HAMA scales between and within the two groups were compared at the 0th,4th and 6th weeks.And the changes of PSG indexes between and within the two groups were compared before and after treatment.Based on the above analyses,the clinical efficacy and safety of taVNS in the treatment of insomnia were evaluated.Part 2 Clinical mechanism research of ta-VNS in the treatment of insomnia disorder1.30 patients with insomnia disorder were recruited by the Institute of Drug Dependence of Peking University,one of the clinical research centers in the first part of the research plan.Among them,23 completed the study,including 12 in the ta-VNS group and 11 in the tnVNS group.2.Using the EEG signal analysis methods of EEG spectrum,nonlinear dynamics,functional connectivity,and ECG analysis methods of heart rate and heart rate variability,the above indexes in each stage were analyzed before and after treatment,and the comparisons between groups and within groups were carried out,and the correlation analysis of EEG spectrum and heart rate variability indexes before and after treatment was carried out.Based on the above analysis,the mechanism of ta-VNS improving insomnia by inhibiting hyperarousal and the similarities and differences between ta-VNS and tn-VNS in the treatment of insomnia were discussed.Results:Part 1 Clinical efficacy and safety research of ta-VNS in the treatment of insomnia disorder1.General demographic data showed that there were no statstical differences in gender,age,course of disease,family history,marriage,occupation,and education between the twogroups(P>0.05).2.Results of main outcome measurement:There was no significant difference in PSQI total score between the two groups at the 0th,2nd,4th,and 6th weeks(P>0.05).There were extremely significant differences in PSQI total scores within the two groups at different time points(P<0.001),and the total scores of both groups were extremely lower in the 2nd,4th,and 6th weeks than those in the 0th week(P<0.001).There were also significant reductions in the 4th weeks compared with the 2nd week(P<0.01).3.Secondary index results:(1)Six factor scores of PSQI scale:Comparison between groups:There were no statistical differences in scores of sleep disturbance and daytime dysfunction between the two groups in week 0,week 2,week 4 and week 6(P>0.05),the sleep quality score of the ta-VNS group was statistically lower than that of the tn-VNS group at the 6th week(P<0.05),the sleep onset time score of the ta-VNS group was statstically lower than that of the tn-VNS group in the 2th week(P<0.05),while the sleep duration and efficiency scores of the tn-VNS group were statistically lower than those of the ta-VNS group at the 6th week(P<0.05).Within-group comparison:There were extremely significant differences in sleep quality,sleep onset time,sleep efficiency scores at different time points in both groups,the same as the daytime dysfunction score of the ta-VNS gyroup(P<0.001).(2)ESS score:comparison between groups:There were no statistical differences in the EES scores between the two groups in the 0th,2nd,4th,and 6th weeks(P>0.05).Within-group comparison:There were statistical differences in EES scores at different time points in both groups(P<0.05).The score of ta-VNS group were lower in the 6th week than that in the 0th week(P<0.05).(3)FFS score:Comparison between groups:There were no statistical differences in FFS scores between the two groups in the 0th,2nd,4th,and 6th weeks(P>0.05).Withingroup comparison:The scores at different time points in both groups were significantly different(P<0.01).The scores in ta-VNS group in the 4th and 6th weeks were extremely lower than those in the 0th and 2nd weeks(P<0.001);The scores of tn-VNS group in the 2nd,4th,and 6th weeks were lower than those in the 0th week in different statistical degrees(P<0.05,<0.001,<0.01 respectively).(4)HAMD scale score:comparison between groups:There were no statistical differences in HAMD scores between the two groups in the 0th,2nd,4th,and 6th weeks(P>0.05).Within-group comparison:The scores of both groups were extremely lower in the 4th and 6th weeks than those in the 0th week(P<0.001).(5)HAMA scale score:Comparison between groups:There were no statistical difference in HAMA scores between the two groups in the 0th,4th and 6th weeks(P>0.05).Within-group comparison:The scores of both groups in the 4th and 6th weeks were extremely lower than those in the 0th week(P<0.001).(6)PSG monitoring data:Comparison between groups:There were no statistical differences between the two groups of patients in the 0th and 4th weeks,and of the difference value between the 4th and 0th weeks(P>0.05).Within-group comparison:the values of indexes in the ta-VNS group had no statistical change in the 4th week compared with the 0th week(P>0.05);the sleep latency time in the tn-VNS group was statistically decreased in the 4th week compared with the 0th week(P<0.05).Part 2 Clinical mechanism research of ta-VNS in the treatment of insomnia disorder1.PSA:(1)Comparison between groups:the PSA indicators(δ,θ,α,β,γ power),nonlinear indicators(approximate entropy,sample entropy,permutation entropy,LZ complexity)in the 0th week,the 4th week,and the difference value of the above indicators between 4th week and the 0th week had no statistical differences(P>0.05).(2)Within-group comparison:In the N1 stage,ta-VNS treatment reduced the relative power of β and γ waves at the 4th week compared with that at the 0th week with statistical difference(P<0.05).In the wake stage,tnVNS treatment reduced the LZ complexity value at the 4th week compared with that at the 0th week with statistical difference(P<0.05).2.HRV:(1)Comparison between groups:the heart rate and the value of HRV indicators and nonlinear indicators in the 0th week,the 4th week,and the difference value between 4th week and the 0th week had no statistical differences(P>0.05).(2)Within-group comparison:In stage N1,the low-frequency power of the ta-VNS group decreased and the approximate entropy and sample entropy were increased with statistical differences compared with those before treatment(P<0.05).3.Correlation analysis of EEG spectrum and heart rate variability:The correlation analysis of the difference between the power spectrum and indexes of heart rate variability in the ta-VNS group before and after treatment showed that there was a statistical positive correlation between θ power and Root Mean Square of the Successive Differences(RMMSD)as well as the proportion of NN50 divided by total number of NNs(PNN50)(P<0.05,r>0),there was a statistical negative correlation between β wave power and RMSSD and PNN50(P<0.05,r<0),There was a statistical negative correlation between the standard deviation of NN intervals(SDNN)and γ power(P<0.05,r<0).4.Functional Connectivity Analysis:(1)Comparison between groups:in the NREM stage,the difference before and after treatment in the ta-VNS group was compared with the tn-VNS group,and the functional connectivity of the δ frequency band was statistically enhanced(P<0.05),involving bilateral frontal,parietal,and occipital lobes.In the NREM stage,the difference before and after treatment in the tn-VNS group was compared with ta-VNS group,the functional connectivity in the γ band was statistically enhanced(P<0.05),involving bilateral frontal,parietal,and occipital lobes.In REM stage,compared with ta-VNS group,the functional connectivities of a and β frequency bands were statistically enhanced in tnVNS group(P<0.05).The former is dominated by the right frontal-parietal lobe,while the latter is dominated by the frontal lobe.(2)Within-group comparison:In the NREM stage,taVNS treatment enhanced the functional connectivity of frontal and occipital lobes in the αband(P<0.05),while in the REM stage,it weakened the frontal-dominant connectivity in theα-band and enhanced the parietal lobe and the right occipital lobe connectivity of δband(P<0.05).In the NREM stage,tn-VNS treatment enhanced the functional connectivity of the β and γ bands in the frontal,parietal,and occipital lobes(P<0.05);In the REM stage,the functional connectivity of the occipital and parietal lobes in the α-band was enhanced(P<0.05)and the bilateral occipital-dominant functional connectivity were weakened in the slow-wave frequency δ、θband(P<0.05).Conclusion1.ta-VNS can significantly improve insomnia symptoms,daytime sleepiness and fatigue,reduce accompanied depression and anxiety mood in patients with insomnia disorder.It has no adverse effect on human physiological and biochemical indicators,and it is relatively safe.2.The treatment of ta-VNS can significantly reduce the proportion of fast waves in the light sleep period,and has an effect on improving the complexity,change rate and randomness of EEG signal sequence of insomnia disorder,thereby inhibiting cortical hyperarousal.It can reduce sympathetic nerve activity during light sleep,and improve the adaptability of the ECG system in patients with insomnia,thereby inhibiting physiological hyperarousal.3.There are no significant differences between ta-VNS and tn-VNS in most subjective and objective curative effect indicators,and its potential mechanism shows:compared with tnVNS treatment,ta-VNS mainly enhances the functional connectivity of the frontal,parietal and occipital lobes in the slow wave band;while tn-VNS mainly enhances the functional connectivity of frontal,parietal and occipital lobes in fast wave bands. |
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