Clinical Efficacy And Mechanism Of Transcutaneous Neuromodulation In The Treatment Of Functional Dyspepsia

Background:Functional dyspepsia(FD)is a group of symptoms originating in the gastroduodenal region,including epigastric pain,epigastric burning,postprandial fullness and early satiety.According to Rome Ⅳ criteria,FD includes three subtypes:Postprandial distress syndrome(PDS),Epigastric pain syndrome(EPS)and the overlap.At present,prokinetics and proton pump inhibitors(PPI)are the first-line drugs for treatment.Although clinical symptoms can be partially alleviated,most patients require long-term maintenance therapy and have a high rate of clinical recurrence.The main reason is that the existing clinical treatment does not have specific drugs for pathological mechanism.The main physiological and pathological mechanisms of FD include impaired gastric accommodation,delayed gastric emptying,increased visceral sensitivity,and slow wave rhythm disorder of the stomach.In addition,gastrointestinal hormones/neuropeptides and low grade inflammation are also associated with FD.At present,transcutaneous neuromodulation(TN)has been used to improve digestive tract symptoms as a non-invasive nerve electrical stimulation method,but the application of TN in FD is rarely reported.Objective:Theoretically discuss the understanding and treatment progress of FD from different angles of traditional Chinese and western medicine;to evaluate the clinical efficacy of neuro-regulated Neiguan(PC6)and Zusanli(ST36)on FD through clinical studies;to investigate the possible mechanism of TN in the treatment of FD.Methods:Fifty-seven FD patients were enrolled in the study and randomly divided into 3 groups(TN PC6 group,TN ST36 group,and sham TN group),which received corresponding treatment respectively for 4 weeks.Then,all patients enrolled received TN PC6 combined with ST36 treatment for another 4 weeks.The stimulation parameters of PC6 was:pulse trains of 0.1 seconds on and 0.4 seconds off,pulse width of 0.25 ms,pulse frequency of 100 Hz,and amplitude of 2-6mA.The stimulation parameters of ST36 was:pulse trains of 2 seconds on and 3 seconds off,pulse width of 0.5 ms,pulse frequency of 25 Hz,and amplitude of 2-6mA.Dyspepsia symptom questionnaire,Medical outcomes study(MOS)item short from health survey(SF-36),Hospital Anxiety and Depression Scale(HADS)were used to assess the severity of symptoms.The gastric accommodation was detected by liquid nutrient load test,and the gastric emptying rate was detected by barium strip test method.The gastric electrical parameters were obtained by electrogastrography(EGG)to further evaluate the pathophysiological mechanism of FD.Serum levels of ghrelin,neuropeptide Y(NPY)and vasoactive intestinal peptide(VIP)were measured by ELISA to evaluate the changes of gastrointestinal hormones before and after treatment.Duodenal mucosa samples were collected for hematoxylin-eosin(HE)staining and immunohistochemical staining,and the total number of duodenal eosinophils and mast cells were counted to further evaluate the changes of duodenal inflammation before and after treatment.Results:(1)Clinical baseline data of patients:A total of 57 FD patients(19 males and 38 females)were enrolled in this study,with an average age of 55.1±8.9 years and an average disease course of 25.39±29.6 months were included.The dyspepsia symptom score was 27.77±8.35,and there was no significant difference in clinical baseline data among the three groups.(2)Effect of TN on FD:In stage V2,the dyspepsia scores in TN PC6 group(P<0.01)and TN ST36 group(P<0.01)were significantly lower than the baseline in stage V1.There was no significant change in sham TN group before and after treatment.In stage V3,the scores of TN PC6 group and TN ST36 group were higher than stage V2,but lower than stage V1.In stage V4,the dyspepsia scores in all three groups were significantly lower than stage V2.In addition,TN PC6 and TN ST36 significantly improved the quality of life,and improved mood disorders in FD patients to a certain extent.(3)Dynamic regulation mechanism in FD treated by TN:In stage V2,gastric accommodation(p<0.01)and gastric empting rate(p<0.01)in TN PC6 group were significantly higher than the baseline of V1.Gastric accommodation(p<0.01)and gastric empting rate(p<0.01)in TN ST36 group were also significantly higher than the baseline of stage V1.The percentage of preprandial and postprandial gastric slow waves(GSW)of the two groups also increased significantly(P<0.01),and the proportion of gastric electrical rhythm disturbance before and after meal in both groups was significantly lower than stage V1(P<0.01).There were no significant changes in gastric accommodation,gastric empting rate,percentage of preprandial and postprandial GSW,and proportion of preprandial and postprandial gastric electrical rhythm disturbance in sham TN group.In stage V4,the gastric accommodation and gastric empting rate in the three groups increased compared with that in stage V2.The preprandial GSW in TN ST36 group was higher than that in stage V2(P<0.05),and the postprandial GSW in TN PC6 group was significantly higher than that in stage V2(P<0.01).There was no significant change in gastric electrical rhythm disturbance before and after meal compared with V2.Compared with stage V2,sham TN group had significantly increased preprandial and postprandial GSW(P<0.01),and decreased preprandial and postprandial electrical rhythm(p<0.05).In addition,TN treatment could normalize abnormal dominant frequency.By using the correlation analysis,we found that TN treatment on the improvement of GSW was related to the reduction of the proportion of bradygastria.(4)Changes of gastrointestinal hormone levels in FD before and after TN treatment:In stage V4,the level of ghrelin and neuropeptide Y(NPY)in FD patients were significantly increased compared with stage V1(P<0.001),while the level of vasoactive intestinal peptide(VIP)was significantly decreased compared with stage V1(P<0.001).(5)Mucosal inflammatory changes in FD before and after TN treatment:In stage V4,the total number of eosinophils in duodenal bulb of FD patients did not change significantly compared with stage V1(P=0.898),while the total number of mast cells in duodenal bulb of FD patients decreased significantly compared with stage V1(P<0.001).Conclusions:(1)TN could significantly increase the gastric accommodation and gastric empting rate,increase the percentage of GSW,reduce the gastric electrical rhythm disorder and improve the clinical symptoms.Dual acupoint synergistic therapy may be superior to single acupoint therapy,and the therapeutic effect would be further enhanced with the prolongation of treatment time.(2)The effect of TN on FD might be related to the regulation of gastrointestinal hormones.(3)The effect of TN on FD might be related to alleviating local inflammatory response of duodenum.