Study On The Response Characteristics Of Cranial Nerve Response In Patients With Active Crohn's Disease Treated By Acupuncture And Moxibustion

Objective: 1.To observe the clinical efficacy and safety of acupuncture and moxibustion(acupuncture combined with mild moxibustion)in the treatment of patients with mild to moderate active Crohn's disease(CD);2.To observe the differences of neuroimaging features between CD patients in active and remission phases and healthy subjects,and to elucidate the effect of acupuncture and moxibustion treatment on the response characteristics of cerebral nerve function in patients with active CD patients,in order to provide a scientific basis for the mechanism of acupuncture and moxibustion treatment of CD.Method: Part I: Clinical Observation of Acupuncture and Moxibustion Treatment on Patients with Active Crohn's Disease Sixty-six CD patients who met the inclusion criteria were randomly divided into acupuncture and moxibustion(AM)group and sham acupuncture and moxibustion(SAM)group.Patients in the AM group were treated with acupuncture plus mild moxibustion,and patients in the SAM group were treated with sham acupuncture plus fake mild moxibustion.Same acupoints were used for acupuncture and moxibustion in the two groups: KI3,ST37,SP4,LR3,LI4,LI11 and SP6(both side)as acupuncture points;while ST25 and ST36(both side)as moxibustion points.Patients in both groups were treated 3 times a week and once every other day.The use of western medicine shall be in accordance with the basic drug requirements of this study.The course of treatment was 12 weeks,followed up to 24 weeks.The total effective rate was used as the main efficacy index of clinical efficacy in the two groups,Crohn's disease activity index(CDAI),laboratory tests(PLT count,ESR level and CRP level),fecal calprotectin content,inflammatory bowel disease questionnaire(IBDQ),Hospital Anxiety and Depression Scale(HADS)as the secondary efficacy indicator.Part II: Study on the response characteristics of acupuncture and moxibustion on brain neural function in patients with active CD Magnetic resonance imaging(MRI)was used to measure the differences of brain gray matter structure and resting brain function in patients with active CD,patients with remission CD and healthy subjects,and to observe the response characteristics of cerebral nerve function of patients with active CD by acupuncture and moxibustion treatment.Results: Part I: Clinical Observation of Acupuncture and Moxiustion Treatment on Patients with Active Crohn's Disease 1.Total efficiency evaluation: PPS analysis showed that the effective rate of AM group was 81.25%,and that of SAM group was 25.81%,and the effective rate of AM group was significantly better than that of SAM group(P<0.01).FAS analysis showed that the effective rate of AM group was 78.79%,and that of SAM group was 24.24%,and the effective rate of AM group was also significantly better than that of SAM group(P<0.01).2.Crohn's disease activity index(CDAI)score: Compared with the baseline,the CDAI scores of AM group and SAM group at 12 and 24 weeks were both significantly reduced(P<0.001 in the AM group and P<0.01 in the SAM group).Comparison between the two groups at 12 week and 24 week: The change of CDAI scores in the AM group was significantly better than that in the SAM group(all P<0.01).3.Laboratory examination: Compared with the baseline,PLT count,ESR and CRP levels of AM group were significantly reduced at 12 week(P<0.01?P<0.01?P<0.001).Comparison between the two groups at 12 week: the changes of PLT count and CRP level of CD patients in the AM group were significantly better than those in SAM group(P<0.05).4.Comparison of fecal calprotectin content: Compared with the baseline,the fecal calprotectin content of AM group was significantly reduced at 12 week(P<0.001);comparison between the two groups at 12 week: the changes of fecal calprotectin of CD patients in AM group were significantly better than those in SAM group(P<0.05).5.Quality of life(IBDQ)score: Compared with the baseline,the IBDQ total scores and four dimensions(intestinal,general,emotional,social)scores of AM group and SAM group were significantly increased at 12 and 24 weeks(P<0.05).Comparison between the two groups at 12 and 24 weeks,the changes of IBDQ total scores and intestinal dimension scores of CD patients in the AM group were significantly better than those in the SAM group(P<0.05).6.Emotional psychology(HADS)score: Compared with the baseline,the HADS-A scores of AM group were significantly decreased at 12 and 24 weeks(P<0.01,P<0.001),the change of HADS-A score in the SAM group at 12 week was not significant;compared with the baseline,the HADS-D scores of AM group were significantly decreased at 12 and 24 weeks(P<0.05,P<0.01),and the HADS-D score in the SAM group was significantly decreased at 24 week(P<0.05).Comparison between the two groups at 12 week and 24 week,the change of HADS-A score in the AM group at 12 week was significantly better than that in the SAM group(P<0.05).7.Pathological observation of intestinal mucosa: Compared with that before treatment,the colonic mucosa of AM group at 24 week was slightly hyperemic and edema,with a small amount of inflammatory cell infiltration(+),and the degree of intestinal inflammation was relieved;in the SAM group,the mucosal epithelial cells at 24 week were partially regenerated and repaired,and the mucosal lamina propria tissue was mildly hyperemic and edema,and inflammatory cells were infiltrated(+),which was no significant change compared with that before treatment.Part II: Study on the response characteristics of acupuncture and moxibustion on cerebral nerve function in patients with active CD 1.Differences of gray matter volume among the three groups of subjects and the correlation analysis with CD inflammation level : Compared with healthy subjects,the volume of gray matter in the right frontal gyrus,right hippocampus,and right amygdale of active CD patients were elevated,with statistically significant differences(P<0.05);and the volume of gray matter in the right central anterior gyrus,central posterior gyrus,right inferior parietal lobule were decreased,the difference was statistically significant(P<0.05).Compared with CD patients in remission,the volume of gray matter in the right central anterior and right nucleus of active CD patients were decreased,the difference was statistically significant(P<0.05).In the right central anterior gyrus,the 6th subregion(outer ventral region)and the right hippocampus were negatively correlated with calcitonin content;the right hippocampus was positively correlated with CRP.There was a negative correlation between the volume of gray matter in the 6th subregion of the right anterior central gyrus(coperitoneally lateral coperitoneally),right hippocampus and the content of calprotectin;the right hippocampus was positively correlated with CRP level.2.Differences of cortical thickness among the three groups of subjects and the correlation analysis with CD inflammation level: Compared with healthy subjects,the cortical thickness in the upper right frontal gyrus,right lower frontal gyrus,right central anterior gyrus,right temporal gyrus,and left axillary gyrus of active CD patients were decreased,the difference was statistically significant(P<0.05);compared with CD patients in remission,the cortical thickness in the left central posterior gyrus of active CD patients were decreased,the difference was statistically significant(P<0.05).The 6th subregion of the right anterior central gyrus(coperitoneally lateral coperitoneally)was negatively correlated with calprotectin content and CRP level.3.Differences of resting brain function(low frequency amplitude)among the three groups of subjects and the correlation analysis with CD inflammation level: compared with healthy subjects and patients with remission CD,the low-frequency fluctuation amplitude in medial occipital lobe and lateral occipital lobe of active CD patients was decreased,the low-frequency fluctuation amplitude in insula was increased.The brain regions in which the ALFF values were positively correlated with calprotectin content were the third subregion of right insula(dorsal non-granular insula),the sixth subregion(dorsal transitional insula),and the left hippocampal subregion 2(Tail hippocampus),right hippocampal subregion 2(tail hippocampus).The brain regions in which the ALFF values were positively correlated with CRP level were the third subregion of the right insula(dorsal non-granular insula)and the sixth subregion(dorsal transitional insula),the left hippocampus subregion 2(tail hippocampus),and the right hippocampal subregion 2(tail hippocampus).4.Differences of brain function connectivity among the three groups of subjects and the correlation analysis with CD inflammation level:(1)Total brain functional connectivity(FC)of the third subregion of right insula(dorsal non-granular insula)that as seed point and correlation analysis with CD inflammation level: compared with healthy subjects and patients with remission CD,the brain functional connectivity in the left basal ganglia,left paracentral lobule,left thalamus and dorsal non-granular insula of active CD patients was decreased(P<0.05);the brain functional connectivity in left amygdala,cingulate gyrus,cingulate gyrus,hippocampal area,left inferior parietal lobule,left inferior temporal gyrus,left lateral occipital lobe,left middle frontal gyrus,middle temporal gyrus,orbital gyrus,anterior wedge lobe,para hippocampus,superior frontal gyrus,left superior temporal gyrus and dorsal non-grainy insula was increased(P<0.05).The brain regions in which the FC values were positively correlated with calprotectin content were the left cingulate gyrus subregion 1(dorsal region),the second subregion of the left hippocampus(the tail hippocampus),the second subregion of right hippocampus(the tail hippocampus);FC values that were negatively correlated with calprotectin content were the second subregion of the left basal ganglia(globus pallidum),the fifth subregion of the left superior temporal gyrus(lateral region),and the third subregion of the right thalamus(sensory thalamus);FC values that were positively correlated with CRP level were the left hippocampal subregion 2(tail hippocampus),left orbital gyrus subregion 4(middle region).(2)Total brain functional connectivity(FC)of the sixth subregion of right insula(dorsal transitional insula)that as seed point and correlation analysis with CD inflammation level: compared with healthy subjects and patients with remission CD,the brain functional connectivity in the left basal ganglia,right insula subarea 1(hypergranular insula),thalamus and right insula subarea 6 were decreased(P<0.05);the brain functional connectivity in the cingulate gyrus,right fusiform gyrus,left inferior temporal gyrus,lateral occipital lobe,left middle frontal gyrus,left middle temporal gyrus,ventral occipital lobe,anterior wedge lobe,parietal lobule and right dorsal transitional insula were increased(P<0.05).The brain regions in which the FC values were positively correlated with calprotectin content were the left basal ganglia subregion 2(pallidum),right basal ganglia subregion 2(pallidum),left cingulate gyrus subregion 1(dorsal region),left hippocampus subregion 2(tail hippocampus),right hippocampus subregion 2(tail hippocampus),left precuneus subregion 1(medial region);FC values that were negatively correlated with calprotectin content were the left basal ganglia subregion 6(dorsolateral putamen nucleus),right insula subregion 1(hypergranular insula),right middle temporal gyrus subregion 1(tail region),right thalamus subregion 1(medial prefrontal thalamus);FC values that were positively correlated with CRP level were the second subregion of the right hippocampus(carenal hippocampus)and the first subregion of the left precuneus(medial region);FC values that were negatively correlated with CRP level were the right thalamus subregion 1(medial prefrontal thalamus).5.Effect of acupuncture and moxibustion on the functional connectivity of the right insula in active CD patients:(1)Effect of acupuncture and moxibustion on the functional connectivity of right insula subregion 3(dorsal non-granular region)in active CD patients: after 12 weeks of acupuncture and moxibustion treatment,the functional connectivity in the right dorsal non-granular area,superior frontal gyrus,orbital gyrus,left parietal hippocampus,anterior wedge lobe,lateral left occipital lobe,cingulate gyrus,hippocampus,right thalamus of CD patients in the AM group were significantly decreased(P<0.05);the functional connectivity in the left basal ganglia were significantly increased(P<0.05),and after treatment,the functional connectivity values of the above brain areas tended to that of healthy subjects or CD patients in remission.The functional connectivity in the right dorsal non-granular area,left precuneus,left inferior parietal lobule,and the right superior temporal gyrus of CD patients in the SAM group were significantly decreased(P<0.05),but this therapy aggravated the functional connectivity of abnormal brain regions;the functional connectivity in the left precuneus and left parietal hippocampus were significantly increased(P<0.05),tending to the value of healthy subjects.(2)Effect of acupuncture and moxibustion on the functional connectivity of right insula subregion 6(dorsal transition region)in active CD patients: after 12 weeks of acupuncture and moxibustion treatment,the functional connectivity in the right insula dorsal transitional area,left superior frontal gyrus,right orbital gyrus,right anterior central gyrus,right cingulate gyrus,left basal ganglia of CD patients in the AM group were significantly decreased(P<0.05);the functional connectivity in hippocampus,right fusiform gyrus,right insula,left thalamus were significantly increased(P<0.05);and the functional connectivity values of the above brain areas tended to that of healthy subjects or CD patients in remission.The functional connectivity in the right insula dorsal transitional area and right para-hippocampus of CD patients in the SAM group were significantly decreased(P<0.05);the functional connectivity in the right inferior frontal gyrus,left anterior wedge,right orbital gyrus were significantly increased(P< 0.05),but this therapy aggravated the functional connectivity of abnormal brain regions.Conclusion: 1.Acupuncture and moxibustion(acupuncture combined with mild moxibustion)treatment is significantly better than sham acupuncture and moxibustion in improving the disease activity,pathological manifestations of intestinal mucosa,anxiety,quality of life,PLT count in peripheral blood,serum CRP level and fecal calprotectin content of patients with mild to moderate active CD,which is a safe and effective treatment for patients with mild and moderate CD.2.There are significant differences in the sensorimotor network,default mode network,gray matter structure and resting state functional activity(low-frequency amplitude value and functional connectivity)in three groups of subjects: active CD patients,remission CD patients and healthy subjects.3.The brain neural responses of acupuncture and moxibustion treatment for active CD are mainly the insula-default mode network/sensorimotor network and the insula-limbic system resting functional connections.