| Primary insomnia(PI)is a disease with sleep disorder as its only symptom.It is characterized by difficulty in falling asleep,easily waking up,and daytime dysfunction,and these symptoms last for more than a month.Despite the high prevalence rate of PI disease,the treatment of PI is far from satisfactory.Intervention strategies for insomnia commonly focus on the regulation of sleep through pharmacological therapies.However,its use is still limited due to side effects such as drug dependence,memory impairment,liver and kidney damage,or exacerbation of symptoms caused by sudden withdrawal of drugs.Therefore,alternative treatments are recommended urgently.Acupuncture,as a traditional Chinese healing technique with minor adverse effects,has been proved effective in a spectrum of diseases including insomnia.In recent years,it has been shown that acupuncture can activate the brain area by stimulating the sensation of the body surface,so as to improve the brain activity,which may be the potential central mechanism of the curative effect of acupuncture.However,the difference of clinical efficacy caused by acupuncture at sham point,single acupoint or combination of multiple acupoints needs to be further studied.And the modulate effect of long-term acupuncture on brain activity produced by different acupoints also needs to be discussed.In our study,PI patients were recruited and randomly accepted acupuncture at single acupoint,combination of acupoints and sham point.Clinical symptoms were evaluated with the Athens Insomnia Scale(AIS),Pittsburgh Sleep Index scale(PSQI)and polysomnography(PSG)at the baseline and after the long term acupuncture treatment,which were aiming at to compare the efficacy of acupuncture at different acupoints.The encephalofluctuograph technology(ET)and functional magnetic resonance imaging(fMRI)were employed to study the mechanism of acupuncture.In this study,the level of neurotransmitter before and after acupuncture in the PI patients was evaluated and compared with ET,and the possible physiological mechanism was discussed.Resting state flVIRI was performed at baseline and after the long-term acupuncture treatment,which was aiming at to explore the modulate effect of acupuncture treatment by estimating the brain function state at rest time.The detail study as follow:1.The clinical trials of acupuncture on primary insomnia Study Objective:To investigate the effectiveness of acupuncture in the treatment of PI and the difference of clinical efficacy of acupuncture at different acupoints in the treatment of PI.Methods:This study is a multi-center randomized controlled trial(No.NCT02448602),which is studied by China-Japan Union Hospital of Jilin University,Changchun University of Chinese Medicine and Hunan University of Chinese Medicine.This study has been registered with the National Health Graduate students of the United States(No.NCT02448602).The trial protocol was filed with Ethics Committee of the Affiliated Hospital of Changchun University of Traditional Chinese Medicine(Review No.CCZYFYLL2014043).According to the diagnostic criteria of primary insomnia(DSM-5)(a:patients complained that sleep difficulties,sleep maintenance difficulties,early wake-up,symptoms can exist alone or at the same time;b:sleep disorders occur at least three times a week and last not less than 3 months;c:sleep disorders have obvious effects on emotional and/or diurnal social activities and occupational function;d:sleep disorders still occur in sleep conditions and suitable for sleep environments;e:sleep disorders are not caused by other mental disorders,physical diseases,non-drug or other substance abuse).The inclusion and exclusion criteria have been developed strictly.129 patients with primary insomnia(27 male,102 female)who met the criteria were randomly divided into the single acupoint group(Shenmen,HT-7),the combination of acupoints group(Shenmen HT-7;Baihui GV-20;Sanyinjiao SP-6).The intervention method is to connect the electroacupuncture stimulator after the injection of the corresponding point,and select the continuous wave with frequency of 60 HZ.The stimulation time is 30 minutes,1 time/day,one course for 5 days,rest for2 days between each course,and total of 5 courses of treatment.The evaluation of clinical efficacy included two aspects:(1)Efficacy were evaluated at the beginning of acupuncture treatment period(0±3 days),the end of acupuncture treatment period(5 weeks ±3 days),and the end of follow-up period(9 weeks±3 days)by AIS and PSQI,in which AIS observed sleep time,awakened at night,woke up earlier than expected time,total sleep quality,daytime emotion,physical function in the daytime,sleepy in the daytime,and so on,judge whether there are symptoms of insomnia;PSQI recorded sleep quality,sleep time,sleep efficiency,sleep disorders situation,drug hypnosis,daytime function,and evaluated sleep quality.(2)And the PSG,which is used for recording the sleep stage duration of the PI patient at the beginning of the treatment period and after the end of the treatment period.The data within the group were analyzed with paired t-test,and the data among three groups were analyzed by ANOVA test.Finally,the efficacy of acupuncture at the single acupoint,the combination of acupoints and the sham points for PI patients were evaluated with AIS,PSQI,PSG.Result:The results of AIS and PAQI showed that all the three groups could improve the clinical symptoms,and the scores before and after treatment were statistically different.The results showed that the combination of acupoints group was better than the sham-point group through the comparison,but there is no significant difference between the single point group and combination of acupoints group.The result of PSG showed that in the single acupoint group and combination of acupoints group after acupuncture treatment,the sleeping time was prolonged(P<0.01),the sleep efficiency was improved(P<0.01),The REM duration of sleep structure was prolonged(P<0.01);For prolonging sleep time and improving sleep efficiency,the efficacy of the combination of acupoints group was better than that of the single acupoint group(P<0.01).Conclusion:(1)Acupuncture could improve the clinical symptoms of primary insomnia and prolong the REM sleep,which may be the cause of improved sleep quality;(2)The combination of acupoints could improve the clinical effect of acupuncture treatment,and had advantages over single acupoint in prolonging sleep time,improving sleep efficiency and improving arousal symptoms during sleep.The mechanism of acupuncture on primary insomnia base on ETstudy Study objectives:Based on the different efficacy of acupuncture at different acupoints for thetreatment of PI,the possible physiological mechanism of acupuncture was further explored by the technique of the ET.Method:The PI patients recruited in The clinical trials of acupuncture on primaryinsomnia accepted the ET examination at the beginning of acupuncture treatment period(0±3 days)and at the end of acupuncture treatment period(5 weeks±3 days).The levels of gamma-aminobutyric acid(GABA),glutamic acid(GLU),acetylcholine(Ach),5-hydroxytryptamine(5-HT),norepinephrine(NE),dopamine(DA)were recorded.And the data within groups were tested by paired-t test and the data among three groups were test by ANOVA test.Results:The results of ET showed that the level of DA increased obviously in the single acupoint group,and tended to change in the normal value,and the DA level in the combination of acupoints group increased significantly,tended to the normal value,and the changes were statistically different(P<0.05),and the Glu and NE levels in the sham point group changed obviously,but did not tend to the normal value,and the changes were statistically different(P<0.05).There were significant differences in acetylcholine(Ach)and norepinephrine(NE)between the sham point group and the combination of acupoints group(P<0.05).Conclusion:(1)Acupuncture therapy with single acupoint or combination of acupoints had the function of regulating neurotransmitters and has the tendency of normal regulation of abnormal neurotransmitters.(2)The effect of acupuncture therapy on the secretion level of DA?Ach and NE is the most significant,which may be the one of the reason for the prolonged REM period of sleep structure in patients with acupuncture on single acupoint or combination fo acupoints.3.Study on the brain activity of PI patients based on resting-state fMRIStudy objectives:PI patients was detected by resting-state fMRI(rs-fMRI)to explore age and gender related difference on brain activity.And to explore the correlation between brain activity and clinical efficacy.Method:10 subjects were randomly selected from each group in The clinical trials of acupuncture on primary insomnia(30 subjects in total)accepted the rs-fMRI at the beginning and the end of acupuncture treatment period.Amplitude of law frequency fluctuation(ALFF)analysis was carried on the fMRI data.ALFF is an effective method of applying the low-frequency signal to reflect the spontaneous activity of the neural element in the resting state,and can accurately reflect the change characteristics of the activity of the brain function in the resting state,and can be used for reflecting the high and low of the local spontaneous neural activity and the physiological state of the brain tissue.The resting state data was pre-processed by the DPARSF software based on the MATLAB software,and the statistical analysis was performed with the SPM software and result presentation were reported with the REST software.First,to investigate the difference of brain function level caused by age/sex related factors,the ALFF values of PI patients were analyzed by regression analysis with age and sex factors as covariants;Then,to investigate the correlation between clinical efficacy and brain activity,the ALFF value of patients was analyzed by regression analysis with the AIS score as covariant.Results:The age-related differences in the brain activity of PI patients were mainly in cerebellum posterior lobe,while the older PI patients had lower activity in this region.The gender-related difference of ALFF value in PI patients mainly existed in bilateral middle frontal gyrus,left superior frontal gyrus and right cerebellum posterior lobe.The ALFF value in these regions of male PI patients were lower than female PI patients(P<0.001).A negative correlation was found between ALFF and AIS scores in the following brain regions:right cerebellum posterior lobe,temporal gyrus(left middle temporal gyrus,left superior temporal gyrus),right anterior cingulate,left parahippocampa gyrus,frontal gyrus(bilateral inferior frontal gyrus,left middle frontal gyrus,bilateral superior frontal gyrus),parietal lobule(right precentral gyrus,left postcentral gyrus,left supramarginal gyrus,left inferior parietal lobule,left superior parietal lobule,left precuneus)(P<0.001,FWE correct P=0.05,cluster size>30).Conclusion:(1)There were gender-related and age-related differences in brain function of PI patients,but the difference range was small;(2)The activity of PI's brain regions were affected by sleep quality,and the regions were mainly related to cognitive and emotional processing functions,which may be one of the reason that sleep initiation disorder or sleep maintenance disorder.4.The mechanism of acupuncture on primary insomnia base on a resting-state fMRI studyStudy objectives:Based on the different efficacy of acupuncture at different acupoints for the treatment of PI,the possible physiological mechanism of acupuncture was further explored by the technique of the fMRI.Method:10 subjects were randomly selected from each group in The clinical trials of acupuncture on primary insomnia(30 subjects in total)accepted the rs-fMIRI at the beginning of acupuncture treatment period(0±3 days)and the end of acupuncture treatment period(5 weeks±3 days).The altered ALFF value after treatment of three groups were analyzed by one-way ANOVA with-in subject test(flexible factorial model)with the groups(S-Acu group,M-Acu group,N-Acu group)as the between-subject factor and the repeated measure(baseline and after treatment)as the within-subjects factor(P<0.001,FWE correct P=0.05,cluster size>30).Furthermore,the difference of single acupoint group vs sham point group,and multi-acupoints group vs sham point group were analyzed with post-hoc t-tests(P<0.005,FWE correct P=0.05,cluster size>30).All results were presented by the REST v1.8 software.Results:There was a large overlap between the distribution of brain regions affected by sleep quality and the distribution of brain regions which the activity was modulated by long-term acupuncture.The single acupoint group modulated the activity of the right posterior cerebellar lobe,left superior temporal gyrus and middle temporal gyrus,bilateral superior frontal gyrus and left precuneus;Combination of acupoints group modulated the activity of the right posterior cerebellar lobe,left superior temporal gyrus and middle temporal gyrus,left middle frontal gyrus and inferior frontal gyrus,right precentral gyrus,left postcentral gyrus,left superior parietal lobule and inferior parietal lobule,left precuneus,left supramarginal gyrus,left parahippocampa gyrus;The sham point group modulated the activity of the bilateral superior frontal gyrus,left middle frontal gyrus,right inferior frontal gyrus and the right anterior cingulate gyrus.Combination of acupoints group has an advantage in the number and degree of regulating activity of cerebral regions.Conclusion:(1)Long-term acupuncture can regulate the activity of brain regions,which were mainly related to emotion and cognitive function.And there was a large overlap with the regions which activity were affected by sleep quality;(2)Compared with single acupoint acupuncture,the combination of acupoints group can regulate more brain regions which the activity was affected by sleep quality,thus playing a greater therapeutic role. |
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