Clinical Study Of Acupuncture Paratherapy For Parkinson’s Disease Tremor And Its Underlying Neuromechanism Based On Functional Magnetic Resonance Imaging

ObjectiveThis study is aim to examine the effectivness of acupuncture paratherapy for Parkinson’s disease （PD） tremor and explore it underlying neuromechanism by various methods of brain network analysis, such as network efficiency and node efficiency, degree centrality （DC）, regional homogeneity （ReHo）, amplitude low-frequency fluctuation （ALFF） and fractional amplitude low-frequency fluctuation （fALFF） based on functional magnetic resonance imaging （fMRI）. It may lay a scientific theoretical foundation on acupuncture for PD tremor.MethodsA randomized controlled trial was adopted.41 idiopathic PD patients with resting tremor in the early-to-mid stage were randomized to three groups,14 patients in acupuncture group,13 in waiting group and 14 in sham acupuncture group. All patients were given conventional levedopa treatment and the treatment course lasted 12 weeks. Patients in acupuncture group were acupunctured Baihui, Fengchi and Chorea-tremor Controlled Zone and implemented twirling manipulation. Patients in waiting group were only given conventional levedopa treatment and no acupuncture treatment until 12 weeks after the course was ended. Patients in sham acupuncture group were acupunctured 0.5 inch next to Baihui, Fengchi and Chorea-tremor Controlled Zone and implemented no needling manipulation. Unified Parkinson’s Disease Rating Scale （UPDRS） part Ⅱ and Ⅲ, Parkinson’s Disease Questionnaire-39 （PDQ-39） and Hoehn-Yahr （H-Y） Scale were evaluated before treatment and at the end of week 4,8 and 12 and adverse event would be recorded. Meanwhile, fMRI would be scanned before treatment and at the end of week 12, and network efficiency and node efficiency, DC, ReHo, ALFF and fALFF would be analyzed. Repeated measures analysis of variance was used for UPDRS part Ⅱ,Ⅲ and PDQ-39, while Kruskal-Wallis test was used for H-Y Scale by IBM SPSS Statistics 22.0. Permutation test was used for network efficiency and node efficiency by MATLAB, while t-test was used for data of DC, ReHo, ALFF and fALFF by REST. The nodes or brain regions which had changed significantly would be visualized by BrainNet Viewer and xjview8 respectively.ResultsClinical study:1. Effect on motor function:In acupuncture group, UPDRS Ⅲ total score, UPDRS Ⅲ tremor score and the total tremor score decreased over time. The scores after treatment were lower than those before treatment （P<0.05 or P<0.01）. UPDRS Ⅲ total score and the total tremor score decreased most significantly at the end of week 4 （P<0.01）, while UPDRS Ⅲ tremor score decreased most significantly at the end of week 4 and 12 （P<0.05）. UPDRS Ⅲ total score and the total tremor score in both waiting group and sham acupuncture group and UPDRS Ⅲ tremor score in sham acupuncture group didn’t change significantly before and after treatment （P>0.05）, but UPDRS Ⅲ tremor score in waiting group was much higher after treatment （P<0.05）. UPDRS III rigidity, hypokinesia and postural instability/gait disorder scores and H-Y Scale in all three groups didn’t change significantly before and after treatment （P>0.05）.2. Effect on quality of life:In acupuncture group, UPDRS II total score, PDQ-39 total score and mobility and activities of daily living scores in PDQ-39 all decreased over time. These scores after treatment were lower than those before treatment （P<0.01 or P<0.05） and decreased most significantly at the end of week 4 （P<0.01 or P<0.05）. However, UPDRS Ⅱ total score, PDQ-39 total score and mobility and activities of daily living scores in PDQ-39 in waiting group and sham acupuncture group didn’t change significantly before and after treatment （P>0.05）. Bodily discomfort score in PDQ-39 in acupuncture group and sham acupuncture group had no statistical differences （P>0.05）, but it became higher after treatment in waiting group （P<0.05）. Moreover, at the end of week 8 and 12, bodily discomfort score in waiting group was much higher than that in acupuncture group （P<0.01）. Besides, emotional well being, stigma, cognitions and communication scores in PDQ-39 in all three group didn’t change significantly before and after treatment （P>0.05）, and social support score in PDQ-39 in all three group had got no changes at all.3. Adverse event analysis:Only one adverse event had been reported. That was a patient in sham acupuncture group who had backache and hematuria. It had been judged that it had nothing to do with acupuncture and medications. The number of adverse event in all three groups had no statistical difference （P>0.05）.4. Compliance analysis:3 patients dropped out of the clinical study,1 in waiting group and 2 in sham acupuncture group. The dropout rate was 7.69% （3/39）. There was no statistical difference of compliance between three groups （P>0.05）.Neuromechanism study by fMRI:1. Network efficiency and node efficiency:The global efficiency and local efficiency of the whole brain network in all three groups didn’t change significantly before and after treatment （P>0.05）. Also, there was no statistical difference of global efficiency and local efficiency of the whole brain network between three groups after treatment （P>0.05）. However, global efficiency and local efficiency of some nodes had got changed significantly before and after treatment （P<0.05）. Global efficiency of bilateral anterior cingulate cortex, bilateral anterior prefrontal cortex （PFC）, right dorsal lateral PFC, right ventral frontal cortex and bilateral post occipital cortex in acupuncture group, and medial frontal cortex, left ventral frontal cortex and left parietal lobe in waiting group changed significantly before and after treatment （P<0.05）, but no brain region’s global efficiency in sham acupuncture group got changed significantly （P>0.05）. Local efficiency of right superior frontal gyrus, right posterior cingulate cortex, left inferior temporal gyrus, left intraparietal sulcus, left occipital lobe, right anterior PFC, left dorsal lateral PFC, right ventral PFC, left anterior cingulate cortex, left basal ganglia, left posterior insula, right middle insula, left precentral gyrus, left parietal lobe, right inferior cerebellum in acupuncture group, right angular gyrus, left ventromedial PFC, left ventral frontal cortex, right post occipital cortex, left occipital lobe and right middle cerebellum in waiting group, and right dorsal frontal cortex, right parietal lobe, left precentral gyrus and right inferior cerebellum in sham acupuncture group changed significantly before and after treatment （P<0.05）. It may indicate that the nodes in acupuncture group which had changed significantly in global and local information transmission efficiency were more than those in other two groups. These nodes mostly lay in left basal ganglion, left precentral gyrus, PFC, default mode network （DMN）, insula and the brain regions related to visual processing in temporoparietal occipital lobe.2. DC analysis:Compared acupuncture group and waiting group, DC of left cuneus was much higher （P<0.05） and DC of left cerebellum crus 1 was lower （P<0.05）. Compared acupuncture group and sham acupuncture group, DC of right fusiform gyrus and left cuneus were much higher （P<0.05）, and DC of right middle cingulum and left cerebellum crus 1 were lower （P<0.05）. It may indicate that acupuncture could strengthen the global information integration function in cuneus and fusiform gyrus, and weaken the global information integration function in cerebellum peduncle.3. ReHo analysis:Compared acupuncture group and waiting group, ReHo of right cerebellum 4₅, right hippocampus, right supplementary motor area, left precuneus, left insula, left superior parietal lobule, left precentral gyrus and vermis 4₅ were much higher （P<0.05）, and ReHo of right inferior temporal gyrus, right gyrus rectus, right orbital inferior frontal gyrus, right precentral gyrus and left cerebellum crus 1 were lower （P<0.05）. Compared acupuncture group and sham acupuncture group, ReHo of right superior parietal lobule, right middle cingulum, left fusiform gyrus, left middle occipital gyrus, left cuneus, left precuneus and left inferior parietal lobule were much higher （P<0.05）, and ReHo of right middle temporal gyrus, right insula, right anterior cingulum, left cerebellum crus 2 and left orbital inferior frontal gyrus were lower （P<0.05）. It may indicate acupuncture could strengthen the local information integration function in cerebellar hemispheres and vermis, right supplementary motor area and left precentral gyrus, superior parietal lobule, fusiform gyrus and middle occipital gyrus, weaken the local information integration function in right precentral gyrus, cerebellum peduncle and PFC, and modulate the local information integration function of DMN and insula.4. ALFF and fALFF analysis:Compared acupuncture group and waiting group, ALFF of bilateral fusiform gyrus, bilateral cerebellum crus 1 and vermis 4₅ and fALFF of right fusiform gyrus and left cerebellum crus 2 were much higher （P<0.05）, and ALFF of right gyrus rectus and fALFF of right posterior cingulum were lower （P<0.05）. Compared acupuncture group and sham acupuncture group, ALFF of left cerebellum 6 was much higher （P<0.05）, and ALFF of right orbital middle frontal gyrus and right anterior cingulum and fAlFF of right orbital middle frontal gyrus and left triangle inferior frontal gyrus were lower （P<0.05）. It may indicate acupuncture could strengthen the spontaneous neural activity in cerebellum and fusiform gyrus and weaken the spontaneous neural activity in PFC and DMN.Conclusion1. Acupuncture plus levodopa can improve motor dysfunction and the quality of life of PD patients, especially tremor in motor dysfunction and mobility and activities of daily living in the quality of life, with its effectiveness better than conventional levodopa therapy and without acupuncture placebo effect. Although acupuncture plus levodopa can not attenuate bodily discomfort of PD patients, it may delay bodily discomfort in progression compared to conventional levodopa therapy. Besides, acupuncture paratherapy hadn’t showed proven effect in terms of rigidity, hypokinesia, postural and gait disorder, emotional well being, stigma, social support, cognitions, communication and slowing disease progression. No adverse event related to acupuncture and medications had been reported which indicated high safety, and acupuncture paratherapy also got good compliance.2. Although acupuncture may not modulate and restore PD abnormal brain network of the whole brain, it did has effect on some brain regions, such as basal ganglion, cerebellum, precentral gyrus, supplementary motor area, PFC, DMN, insula, et al. The underlying neuromechanism of acupuncture paratherapy for PD tremor may be that it exerted direct effect on basal ganglion, cerebellum and motor cortex in basal ganglion circuit and cerebello-thalamo-cortical circuit to attenuate motor symptoms, and indirectly modulate the function of PFC, DMN, insula and secondary and senior visual cortex and dorsal attention network in temporoparietal occipital area to improve executive function so as to enhance mobility and activities of daily living and improve the quality of life. Moreover, delay bodily discomfort in progression could be the result of modulating local information integration function of insula.