| BackgroundInsomnia disorder(ID)is a common sleep continuity disorder.In recent years,especially during the COVID-19 epidemic and the post-epidemic era,the incidence of insomnia has been increasing year by year and has affected up to one third of the adult population in the world.As the second most common mental disorder,ID seriously affects the health and quality of life of the people,and brings a huge mental and economic burden to patients.At present,treatment methods mainly include medication,cognitive behavioral therapy for insomnia(CBT-I),physical therapy and therapies based on the theory of traditional Chinese medicine.Although there are many kinds of drugs and they take effect quickly,long-term administration often cause many adverse effects,such as drug dependence,memory decline,slow response and daytime fatigue.Although CBT-I is the first-line treatment for insomnia,it still has some shortcomings such as delayed onset,low response rate,and lack of sufficient professional therapists.Therefore,it is urgent to find more safer and more effective nonpharmacologic therapies than medication for treating ID.As a representative of traditional medicine,auriculotherapy has a long history and plays an important role in the treatment of insomnia.In the past 20 years,our team creatively proposed transcutaneous auricular vagus nerve stimulation(taVNS)based on the neuroanatomy of auricle,auricular acupoints and vagus nerve stimulation.TaVNS is widely used in treating brain disorders such as depression,epilepsy,insomnia and mild cognitive impairment.For the clinical efficacy of taVNS in patients with ID,our team and many studies at home and abroad have confirmed that taVNS is effective in treating ID in the past two years,and it has the advantages of safety and convenience.However,the stimulation parameters in treating insomnia are single and the course of treatment is fixed.There is a lack of relevant evidence of the factors influencing the effectiveness of taVNS and of long-term follow-up.Stimulation frequency,intensity and treatment course are the key factors affecting the effectiveness of taVNS.Therefore,this study is aimed to investigate the effectiveness differences among different intensities,and to observe the influence of treatment course on effectiveness and the long-term effect.The mechanism of taVNS for treating ID is still in its initial stage.Referring to a number of studies that have explained the effect of taVNS on brain function under physiological and pathological conditions,this study is to compare the impact of different intensities of taVNS on brain function within the range of abnormal brain regions in patients with ID by using resting state functional magnetic resonance(fMRI)technology so as to explain the effect of intensities on the therapeutic effect from clinical symptoms and biological phenomena.In summary,this study is aimed to provide scientific basis for optimizing the clinical regimen of taVNS in treating insomnia,and further promote taVNS to become an innovative nonpharmacologic therapy and the clinical application.Objective(1)To screen abnormal brain areas and distribution range in patients with insomnia by comparing the difference of brain function activities between patients with insomnia and healthy subjects,and to analyze the correlation of abnormal brain regions functional activities and insomnia.(2)To observe the effectiveness difference between moderate intensity and low intensity in patients with ID.(3)To observe the effect of treatment course on the effectiveness taVNS and the long-term effect of taVNS on ID.(4)To observe the modulation effect of taVNS on abnormal brain regions in patients with ID,compare the differences of brain effects under two intensities,and analyze the correlation between the changes of brain function before and after treatment and the improvement of clinical symptoms.MethodsA total of 72 patients with insomnia were enrolled and randomly divided into conventional stimulus intensity(High-taVNS)group and low stimulus intensity(LowtaVNS)group,36 cases in each group.At the same time,36 healthy subjects(HCs)matched with gender,age and education level were enrolled.In High-taVNS group,the stimulation intensity was mainly tolerated by patients without pain(0.8-1.5 mA).In Low-taVNS group,the stimulation intensity was 0.1mA,and the patients may feel the fluctuation of the stimulation site.In both groups,the ear point heart(CO15)and kidney(CO10)in the vagus nerve distribution area of bilateral auricular concha were stimulated with dilatational wave,4/20Hz,wave width of 0.2ms,once in the morning and once in the evening,30min each time,continuous treatment for 8 weeks,follow-up for 12 weeks.Clinical scales including Pittsburgh sleep quality index(PSQI),Insomnia severity index(ISI),Hamilton Depression Scale(HAMD),Hamilton Anxiety Scale(HAMA),Epworth Sleepiness scale(ESS)and Fatigue scale(FFS)were evaluated before treatment,after 4 and after 8 weeks of treatment and at follow-up.Safety indicators were evaluated before and after 8 weeks of treatment.The fMRI data of patients with ID before and after treatment and at the baseline of HCs were collected.Study 1 Characteristics of regional brain function in patients with insomniaIn this study,fMRI indicators of patients with ID and HCs,such as amplitude of low frequency fluctuation(ALFF)and fractional amplitude of low frequency fluctuation(fALFF),were compared to observe the distribution range of abnormal brain regions of ALFF and fALFF in patients with ID,and to analyze the correlation between abnormal brain functional activities and clinical symptoms in patients with ID,so as to explain the disease characteristics of ID.Study 2 Efficacy of taVNS of different intensities in the treatment of IDThe primary outcome measures was PSQI score.The secondary outcome measures were response rate,7-factor-score of PSQI,and scores of ISI,HAMD,HAMA,ESS and FFS scores.The response rate and the changes of clinical scales were observed before treatment,after 4 and 8 weeks of treatment,and at follow-up.The effectiveness difference was compared between 4 and 8 weeks of treatment,so as to optimize the clinical protocol of taVNS in treating insomnia.Study 3 To explore the effects of taVNS with different intensities on brain functional activity and FC in patients with ID based on fMRI technologyIn this part of the study,a 2×2 mixed analysis of variance was performed on the brain function indicators of ALFF/fALFF and FC within the function abnormal brain regions of Study 1 to obtain the interaction effect of group(High-taVNS group and Low-taVNS group)× time(before and after treatment),and a post hoc test was performed to compare the differences within and between groups.The effects of different intensities of taVNS on brain functional activity and FC in patients with ID were analyzed.Pearson or Spearman correlation analysis was used to analyze the correlation between the changes of ALFF/fALFF and FC before and after treatment and the changes of clinical scales,so as to explore the brain function characteristics among two intensities.ResultsStudy 11.Abnormal function brain regions in patients with ID were mainly distributed in multiple resting-state brain networks,including default mode network(DMN),visual network(VN),salience network(SN),sensorimotor network(SMN)and limbic system(such as Medial prefrontal cortex,Precuneus,Cingulate cortex,Striatum,Insula,Occipital lobe and Temporal lobe,etc.).2.Compared with HCs,patients with ID showed significantly increased ALFF values in bilateral angular gyrus,left posterior cingulate cortex(PCC),right precuneus,bilateral putamen and bilateral pallidum.ALFF values were decreased in bilateral calcarine gyrus and bilateral lingual gyrus.3.The fALFF values in patients with ID in the left angular gyrus,right supramarginal gyrus,left PCC and right precuneus were significantly higher than those of HCs.Compared with HCs,patients with ID showed significantly decreased fALFF values in the left inferior occipital gyrus,right superior temporal gyrus and bilateral lingual gyrus.4.The ALFF value of the left PCC in ID patients was positively correlated with the course of ID(r=0.261,P=0.035).The ALFF of the left lingual gyrus was negatively correlated with sleep efficiency scores(r=-0.341,P=0.005).The fALFF value of the left inferior occipital gyrus was negatively correlated with ESS score(r=-0.249,P=0.045),and there was no significant correlation between the other brain regions and the scale.Study 21.After 4 weeks and 8 weeks of treatment and at follow-up,the reduction score of PSQI in the High-taVNS group was significantly higher than that in the Low-taVNS group(P<0.001).And the PSQI scores of the two groups were lower than those before treatment,and the differences were statistically significant(P<0.001).2.The response rate of High-taVNS group was higher than that of Low-taVNS group(4 weeks,18.2%;8 weeks,33.3%;20 weeks,24.2%)after 4 weeks(51.4%),8 weeks(71.4%)and 20 weeks of follow-up(74.3%),and the difference was statistically significant(P<0.01).Compared with the difference of PSQI 7 factors,the reduction of subjective sleep quality,sleep time and daytime function scores in the High-taVNS group was more than that in the Low-taVNS group after 4 weeks of treatment(P<0.01).However,there were no significant differences in the scores of sleep onset time,sleep efficiency,sleep disturbance and hypnotic drug using between the two groups(P>0.05).After 8 weeks of treatment and at follow-up,the reduction of subjective sleep quality,sleep onset latency,sleep time,sleep efficiency and daytime function scores in the High-taVNS group was more than that in the Low-taVNS group(P<0.05).However,there was no significant difference in the scores of sleep disturbance and hypnotic drug using(P>0.05).The reduction of ISI,HAMD,HAMA and FFS scores in the High-taVNS group were significantly higher than those of the Low-taVNS group after 4 weeks and 8 weeks of treatment and at follow-up(P<0.01).There was no significant difference in the reduction of ESS score between the two groups.The ISI,HAMD,HAMA,FFS and ESS scores in the High-taVNS group and the ISI,HAMD,HAMA and ESS scores in the Low-taVNS group were lower after 4 weeks and 8 weeks of treatment and at follow-up than before treatment(P<0.005).The FFS scores after 8 weeks of treatment and at follow-up were lower than those before treatment in the Low-taVNS group(P<0.005).3.The reduction of PSQI score in the two groups after 8 weeks of treatment was significantly more than that after 4 weeks of treatment(P<0.01).The response rate after 8 weeks of treatment was better than that after 4 weeks of treatment in both groups.4.The reduction of ISI score in the two groups after 8 weeks of treatment was significantly more than that after 4 weeks of treatment(P<0.01).Compared with those after 4 weeks of treatment,the scores of HAMD,HAMA,ESS and FFS in the HightaVNS group decreased more significantly after 8 weeks of treatment(P<0.05).After 8 weeks of Low-taVNS treatment,FFS scores decreased more significantly(P<0.01),while HAMD,HAMA and ESS scores did not decrease significantly(P>0.05).Study 31.The ANOVA analysis showed that there was a significant group × time interaction effect on ALFF in the right medial prefrontal cortex(mPFC),right anterior cingulate cortex(ACC),left postcentral gyrus(PoCG)and left precentral gyrus(PreCG).Post hoc tests showed that the ALFF values in the right mPFC,right ACC,left PoCG and left PreCG were significantly increased in the Low-taVNS group,while the ALFF values in the right ACC were significantly decreased in the High-taVNS group.Compared with the Low-taVNS group,High-taVNS decreased ALFF values in the right mPFC,right ACC,left PoCG and left PreCG after treatment.There was no correlation between the change of ALFF value(post-treatment minus pre-treatment)and the change of scale(pre-treatment minus post-treatment)before and after treatment.2.After ANOVA analysis,there was a group × time interaction effect on fALFF in the left insula.Post hoc test showed that the fALFF value of the left insula decreased in the High-taVNS group and increased in the Low-taVNS group after treatment,and the difference was statistically significant compared with before treatment.Compared with Low-taVNS,the fALFF value of High-taVNS group decreased after treatment,and the difference was statistically significant.There was no significant correlation between the changes of fALFF value in the left insula and the changes of the scale before and after treatment in the two groups.3.FC:seed points for FC analysis were selected based on the brain regions,including right mPFC,right ACC,left PoCG,left PreCG and left insula,where there was significant interaction effects of ALFF and fALFF.3.1 ANOVA analysis showed that there was a significant group x time interaction effect of FC between the right mPFC and the left putamen,left inferior parietal gyrus,right precuneus,and right paracentral lobule.Post hoc analysis showed that the FC between the right mPFC and the left putamen,left inferior parietal gyrus,and the right precuneus increased significantly in the High-taVNS group after treatment compared with before treatment.The Low-taVNS group showed a significant decrease in FC between the right mPFC and the left putamen,right precuneus,and right paracentral lobule.Compared with the Low-taVNS group after treatment,High-taVNS enhanced FC values between the right mPFC and the left putamen,right precuneus,and right paracentral lobules.When gender,age and education level were used as covariates,the changes of FC between the right mPFC and left putamen were positively correlated with the changes of HAMD in the High-taVNS group(r=0.407,P=0.017).3.2 ANOVA analysis showed that there were significant group × time interaction effects between right ACC and left dorsolateral prefrontal cortex(dlPFC),left posterior cingulate gyrus(PCC),right medial prefrontal cortex(mPFC),and left middle temporal gyrus.Post hoc test showed that after treatment,the High-taVNS group had significantly decreased FC in the right ACC,left dlPFC,left PCC,right mPFC and left middle temporal gyrus.After treatment,the FC between the right ACC and the left dlPFC,the right mPFC,and the left middle temporal gyrus were significantly increased in the Low-taVNS group,and there was no significant difference between the FC of the right ACC and the left PCC.Compared with the Low-taVNS group,the High-taVNS group had significantly lower FC between the right ACC and left dlPFC,right mPFC,and no significant difference in FC between the left PCC and left middle temporal gyrus after treatment.In the Low-taVNS group,the FC of the right ACC and the left PCC was positively correlated with the change of PSQI score after 8 weeks of treatment(r=0.377,P=0.036),but no significant correlation was found in the High-taVNS group.3.3 ANOVA analysis showed that there was a significant group x time interaction effect of FC between the left postcentral gyrus(PoCG)and the right precentral gyrus(PreCG),right PoCG,left PreCG and left PoCG.Post hoc test showed that after treatment,the FC between the left PoCG and right PreCG,and left PreCG in HightaVNS group was significantly lower than that before treatment,and there was no significant difference in the FC between the left PoCG and right PoCG,and left PoCG.The FC between left PoCG and left PoCG,and left PreCG was significantly increased in the Low-taVNS group.After treatment,the FC between left PoCG and right PreCG,left PreCG,left PoCG,and right PoCG in High-taVNS group was significantly lower than that in Low-taVNS group.In the High-taVNS group,the changes of PSQI were positively correlated with the changes of FC between left PoCG and left PoCG(r=0.369,P=0.032),and right PoCG(r=0.340,P=0.049)before and after treatment.The changes of FC between left PoCG and left PoCG were positively correlated with the changes of ESS(r=0.364,P=0.034).In the Low-taVNS group,the changes of FC between left PoCG and right PreCG were negatively correlated with the changes of ESS(r=-0.386,P=0.032).Conclusion1.There are functional abnormalities in multiple resting-state brain networks in patients with ID,including DMN,VN,SN,SMN and limbic network.Compared with HCs,ID patients showed decreased functional activity in the brain regions related to vision,hearing and attention,and increased functional activity in the DMN related to self-reference information processing and the brain regions related to reward and emotion processing.2.TaVNS is effective for treating ID.Both at conventional and low intensity can improve the sleep quality of ID patients,decrease the severity of insomnia,and relieve the accompanying symptoms like anxiety,depression,sleepiness and fatigue.3.The effectiveness of taVNS at conventional intensity is better than that at low intensity.4.The effectiveness of taVNS after 8 weeks of treatment is better than that after 4 weeks of treatment.The efficacy can maintain for 3 months.5.TaVNS at low intensity enhanced the functional activity of the right medial prefrontal cortex(mPFC),right anterior cingulate cortex(ACC),left postcentral gyrus(PoCG),left precentral gyrus(PreCG)and left insula,and enhanced cortical hyperarousal in ID patients.While taVNS at conventional intensity reduced cortical hyperarousal by reversing the functional activity of the above brain regions,and then improve the sleep quality of ID patients.6.TaVNS at conventional intensity may enhance FC between the anterior and posterior DMN(right mPFC and left inferior parietal gyrus,right precuneus),frontostriatal circuits(right mPFC and left putamen),and between the DMN and SMN(right mPFC and right PreCG),reduce the FC between the SN and DMN(right ACC and left PCC,left middle temporal gyrus),SN and cognitive control network(right ACC and left dlPFC),and the FC within SMN,thereby playing a role in improving sleep quality and relieving the accompanying symptoms such as anxiety,depression,fatigue and sleepiness.While taVNS at low intensity had the opposite effect. |
PDF Full Text Request