| With the progress of China’s population aging,the prevalence of knee osteoarthritis（KOA）is increasing year by year,resulting in a huge economic and social burden.Tuina is widely used in the treatment of KOA.Professor Shi Qi believes that three-point syndrome differentiation can be used as a theoretical basis when formulating Tuina intervention programs.While balancing the muscles and bones,it is necessary to reconcile the qi and blood of the viscera.Research on the analgesic mechanism of Tuina has shown that the regulation of the brain center is the key link for its analgesic effect.The current multimodal magnetic resonance imaging（MRI）promotes the objectification of the therapeutic evaluation of Tuina and the targeting of treatment.Therefore,this project is based on the systematic review and data mining of Tuina in the treatment of KOA,guided by Professor Shi Qi’s three-point syndrome differentiation theory,to provide a basis for the formulation of Tuina programs,and then use randomized controlled trials to evaluate the analgesic effect of Tuina in the treatment of KOA,and discusses the central analgesic effect of Tuina in the treatment of KOA based on multimodal MRI.Part Ⅰ: Systematic Review and Data Mining of Literature on the Treatment of Knee Osteoarthritis with TuinaObjective: Provide basis for the formulation of KOA programs with Tuina under the guidance of Professor Shi Qi’s three-point syndrome differentiation theory.Methods:1.The randomized controlled trials of Tuina in the treatment of KOA were searched in Cochrane Library,Medline,China National Knowledge Infrastructure,Wanfang Data Knowledge Service Platform,VIP Journals and other databases,and the clinical efficacy of Tuina and other intervention methods in the treatment of KOA were compared based on meta-analysis.2.The clinical research literatures of KOA published in China National Knowledge Infrastructure,Wanfang Data Knowledge Service Platform,VIP Journals and other Chinese sci-tech journals were searched by computer,and data mining was carried out based on the Chinese Medicine Inheritance Computing System.The Tuina,acupoints,treatment site,treatment course and treatment frequency of KOA were summarized.Under the guidance of Professor Shi Qi’s three-point syndrome differentiation theory,the treatment plan of Tuina was discussed.Results:1.The clinical effective rate of Tuina was better than other intervention methods,WOMAC score was better than oral western medicine,external use of traditional Chinese medicine,while the incidence of adverse events was less.2.Kneading method was the most frequently used Tuina,followed by rolling method,take method,and so on.The most frequently used acupoints were Xuehai,followed by Xiyan,Yanglingquan and so on.The most frequently used treatment site was quadriceps femoris,followed by patella,patellar ligament and so on.The most choice of treatment course was 4 weeks,followed by 10 days,2 weeks and so on.The most frequent choice of treatment frequency was 1 time / day,followed by 1 time / 2 days,3times / 1 week and so on.Conclusion:1.Tuina has good clinical efficacy in the treatment of KOA.2.There is a good theoretical basis for setting up a 6-week,1 time / 2 days pressing local acupoints plus adjustion of the knee joint in a sitting position combination protocol,but its clinical effectiveness needs to be further validated using randomized controlled trials.Part II: Study on the Clinical Analgesic Effect of Tuina in the Treatment of Knee OsteoarthritisObjective: To reveal the clinical analgesic effect of Tuina on KOA.Methods: Under the guidance of Professor Shi Qi’s three-point syndrome differentiation theory,a Tuina programs was formulated.Using a randomized parallel controlled trial design,104 subjects with KOA were randomly divided into two groups:Tuina group and drug group.The subjects in the Tuina group received pressing local acupoints plus adjustion of the knee joint in a sitting position treatment every 2 days,3times as a course of treatment,with a rest of 2 days during the course of treatment,a total of 18 times for 6 courses of treatment.The subjects in the drug group took celecoxib capsule 0.2 g per day for 7 times as a course of treatment,a total of 6 courses of treatment,a total of 42 times.The outcome indexes were recorded before intervention,2 weeks after intervention,4 weeks after intervention,6 weeks after intervention and follow-up.The main outcome index was PPTs.Secondary outcome indicators:（1）NRS score at rest and activity;（2）HAMA score;（3）HAMD score;（4）WOMAC score;（5）Clinical effective rate.At the same time,the compliance of the subjects and the safety of the test were evaluated.Results:1.Baseline data such as demographic data,medical variables and clinical behavior of the two groups of subjects are balanced and comparable（P > 0.05）.2.PPTs:（1）Lateral point PPTs: Regarding the analysis of individual effects of groups,the drug group was higher than the Tuina group at Week 2（P < 0.05）,and the Tuina group was higher than the drug group at Week 4,Week 6,and follow-up（P < 0.05）;Regarding the time alone effect analysis,Week 6 was higher in Tuina group than before（P < 0.05）,and Week 2 was higher than Week 0 in drug group（P < 0.05）.（2）In the central point of PPTs: Regarding the analysis of individual effects of groups,the drug group was higher than the Tuina group at Week 2 and Week 4（P < 0.05）,and the Tuina group was higher than the drug group at Week 6 and follow-up（P < 0.05）;Regarding the time alone effect analysis,Week 6 was higher in Tuina group than before（P < 0.05）,and Week 2 was higher than Week 0 in drug group（P < 0.05）.（3）Medial point PPTs: Regarding the analysis of individual effects of groups,the drug group was higher than the Tuina group at Week 2（P < 0.05）,and the Tuina group was higher than the drug group at Week 4,Week 6,and follow-up（P < 0.05）;Regarding the time alone effect analysis,Week 4 was higher in Tuina group than before（P <0.05）,and Week 2 was higher than Week 0 in drug group（P < 0.05）.（4）Deltoid PPTs:The individual effects of each group was higher in the drug group than in the Tuina group at Week 2（P < 0.05）,and higher in the Tuina group than in the drug group at Week 4 and Week 6（P < 0.05）,but there was no difference between the drug group and the Tuina group during follow-up（P > 0.05）;Regarding the time alone effect analysis,Week 4 in the Tuina group was higher than that before（P < 0.05）,but there was no difference in the drug group before and after intervention（P > 0.05）.3.NRS score:（1）NRSR score: Regarding the analysis of individual effects of groups,there was no difference between the Tuina group and the drug group at Week 2 and Week 4（P > 0.05）,but it was lower in the Tuina group than in the drug group at Week6 and follow-up（P < 0.05）;Regarding the time alone effect analysis,Week 6 was lower than before in Tuina group（P < 0.05）,and Week 2 was lower than Week 0 in drug group（P < 0.05）.（2）NRSM score: Regarding the analysis of individual effects of groups,the drug group was lower than the Tuina group at Week 2（P < 0.05）,and there was no difference between the Tuina group and the drug group at Week 4（P > 0.05）.At Week 6 and follow-up,the Tuina group was lower than the drug group（P < 0.05）;Regarding the time alone effect analysis,Week 6 was lower than before in Tuina group（P < 0.05）,and Week 2 was lower than Week 0 in drug group（P < 0.05）.4.Negative emotions:（1）HAMA score: Regarding the analysis of individual effects of groups,the Week 2 in the drug group was lower than that in the Tuina group（P < 0.05）,and the Week 4,Week 6 and follow-up in the Tuina group were lower than those in the drug group（P < 0.05）;Regarding the time alone effect analysis,Week 4 in Tuina group was lower than that before,and in drug group Week 2 was lower than that in Week 0（P < 0.05）.（2）HAMD score: Regarding the analysis of individual effects of groups,there was no difference in Week 2 between the drug group and the Tuina group（P > 0.05）,but it was lower in the Tuina group than in the drug group at Week 4,Week6 and follow-up（P < 0.05）;Regarding the time alone effect analysis,Week 6 was lower than before in Tuina group（P < 0.05）,and Week 2 was lower than Week 0 in drug group（P < 0.05）.5.WOMAC pain score:（1）WOMAC pain score: Regarding the analysis of individual effects of groups,Week 2 in the drug group was lower than that in the Tuina group（P< 0.05）,and Week 4,Week 6 and follow-up in the Tuina group were lower than those in the drug group（P < 0.05）;Regarding the time alone effect analysis,Week 6 in the Tuina group was lower than that before（P < 0.05）,and Week 4 in the drug group was lower than that before（P < 0.05）.（2）WOMAC stiffness score: Regarding the analysis of individual effects of groups,there was no difference in Week 2 and Week 4 between the two groups（P > 0.05）,but it was lower in Week 6 and follow-up in the Tuina group than that in the drug group（P < 0.05）;Regarding the time alone effect analysis,Week 6 in the Tuina group was lower than before（P < 0.05）,and in the drug group,Week 4 was lower than before（P < 0.05）.（3）WOMAC function score: Regarding the analysis of individual effects of groups,the levels of Week 2,Week 4,Week 6 and follow up in the Tuina group were lower than those in the drug group（P < 0.05）;Regarding the time alone effect analysis,Week 6 in Tuina group and drug group was lower than that before（P < 0.05）.（4）Total score of WOMAC: Regarding the analysis of individual effects of groups,there was no difference in Week 2 between the two groups（P > 0.05）,but it was lower in the Tuina group than in the drug group at Week4,Week 6 and follow-up（P < 0.05）;Regarding the time alone effect analysis,Week 6was lower than before in Tuina group（P < 0.05）,and Week 4 was lower than before in drug group（P < 0.05）.6.Clinical effective rate: The total effective rate of Tuina group was 92.31%,and that of drug group was 86.54%.The clinically effective rate of pressing local acupoints plus adjustion of the knee joint in a sitting position was better than that of celecoxib capsule.Conclusion:1.Pressing local acupoints plus adjustion of the knee joint in a sitting position can play an analgesic role in many dimensions,such as pain feeling,pain emotion,pain cognition and so on.2.The long-term curative effect and aftereffect of pressing local acupoints plus adjustion of the knee joint in a sitting position was better than that of celecoxib capsule.3.Pressing local acupoints plus adjustion of the knee joint in a sitting position can improve the stiffness,anxiety and depression and joint function of patients with KOA.Part III: Revealing the Central Analgesic Mechanism of Tuina in the Treatment of Knee Osteoarthritis based on Multimodal MRIObjective: To explore the central analgesic effect of Tuina in the treatment of KOA pain based on brain structure and brain function.Methods: Using a randomized parallel controlled trial design,40 subjects with KOA were randomly divided into two groups: Tuina group and drug group.The intervention methods and behavioral evaluation indexes were the same as those in the second part.At the same time,the MRI data of the two groups of subjects were collected before and after the intervention.The brain central structure and function were evaluated,and the specific evaluation indexes were gray matter volume,regional homogeneity（Re Ho）,amplitude of low frequency fluctuation（ALLF）and functional connectivity（FC）.Based on the Neuro Synth database,the brain regions of 516 neuroimaging literatures related to pain were analyzed to determine the range of brain regions that need to be selected in the follow-up MRI data statistics.Matlab R2013 b platform,SPM12 toolkit and SPM8 toolkit were used to process and analyze the MRI data to determine the correlation between the course of disease,behavioral indexes and thalamic gray matter volume before and after intervention.At the same time,brain structure and brain function changes and differences within and between groups were compared between Tuina group and drug group before and after intervention.Results:1.Baseline data such as demographic data,medical variables and clinical behavior of the two groups of subjects are balanced and comparable（P > 0.05）.2.（1）PPTs: After treatment,the PPTs of each point around the knee joint and deltoid muscle in the Tuina group was higher than that before treatment（P < 0.05）,the PPTs of each point around the knee joint in the drug group was higher than that before treatment（P < 0.05）,but the PPTs of the deltoid muscle was not improved after treatment（P > 0.05）,and the PPTs of each point around the knee joint and deltoid muscle in the Tuina group after treatment was higher than that in the drug group（P <0.05）.（2）NRS score: NRSR score and NRSM score in Tuina group after intervention were lower than those before treatment（P < 0.05）,while NRSR score in drug group had no improvement after intervention（P > 0.05）,NRSM score was lower than that before treatment（P < 0.05）,NRSR score and NRSM score in Tuina group were lower than those in drug group after intervention（P < 0.05）.（3）Negative emotions: HAMA score and HAMD score in the Tuina group were lower than those before treatment（P< 0.05）,and the HAMA score in the drug group after intervention was lower than that before treatment（P < 0.05）,HAMD score was not improved compared with that before treatment（P > 0.05）.There was no difference in HAMA score between the Tuina group and the drug group after intervention（P > 0.05）.The HAMD score in the Tuina group was lower than that in the drug group（P < 0.05）.（4）WOMAC score:WOMAC pain score,WOMAC stiffness score,WOMAC function score and WOMAC total score in Tuina group and drug group after treatment were lower than those before treatment（P < 0.05）,while WOMAC pain score,WOMAC stiffness score,WOMAC function score and WOMAC total score in Tuina group were lower than those in drug group after treatment（P < 0.05）.（5）Clinical effective rate: The total effective rate was92.31% in the Tuina group and 86.54% in the drug group.The clinically effective rate of pressing local acupoints plus adjustion of the knee joint in a sitting position was better than that of celecoxib capsule.3.Many brain regions closely related to pain signal processing and processing were found based on Neurosynth database,such as right insular,right central sulcus cover,right supramarginal gyrus and so on.After integration,these brain regions can limit the scope of MRI data statistics,effectively solve the possible false positive and false negative problems of the research results,and make the research results more reliable.4.Before intervention,there was a linear negative correlation between the volume of left thalamic gray matter and the course of disease,left lateral point PPTs,WOMAC pain score,WOMAC stiffness score,WOMAC function score and WOMAC total score,while there was a linear negative correlation between right thalamic gray matter volume and WOMAC pain score,WOMAC stiffness score,WOMAC function score and WOMAC total score.5.There was no difference in gray matter volume,Re Ho,ALFF and FC between the two groups before intervention.6.After intervention,there were differences in the volume of gray matter between and within the two groups:（1）Compared with before intervention,the left thalamus and left hippocampus increased in the Tuina group after intervention,and there was no decrease in the area after intervention.（2）Compared with before intervention,the increase in the drug group after intervention was as follows: right temporal pole:superior temporal gyrus,right insular,no reduced area.（3）Compared with the drug group after intervention,the Tuina group had more left thalamus,less Cerebelum3R,left deltoid inferior frontal gyrus,left island tegmental inferior frontal gyrus,right caudate nucleus,right paracentric lobule and right precuneate lobe.7.After intervention,there were differences in ReHo,ALFF and FC between and within the two groups: Re Ho:（1）Compared with those before intervention,there was no increase in the area in the Tuina group after intervention,but there was a left marginal superior gyrus in the Tuina group after intervention.（2）There was no difference in brain area before and after intervention in the drug group.（3）Compared with the drug group after intervention,the left superior marginal gyrus and left superior temporal gyrus increased in the Tuina group after intervention,but there was no decreasing area.ALFF:（1）Compared with before intervention,the right lentiform putamen and right insular increased in the Tuina group after intervention,but there was no decrease after intervention.（2）There was no difference in brain area before and after intervention in the drug group.（3）Compared with the drug group after intervention,the Tuina group increased left fusiform gyrus,left middle temporal gyrus,left inferior temporal gyrus,right middle temporal gyrus,right inferior frontal gyrus of insular tectum and right inferior frontal gyrus of triangular area.after intervention,the decreasing area in the Tuina group was located in the right precentral gyrus and the right dorsolateral superior frontal gyrus.FC: There were differences in brain regions of FC before and after intervention in Tuina group:（1）Compared with that before intervention,there was left insular enhancement of PAG in the Tuina group after intervention,and there was no weakening area of PAG in the left side after intervention.（2）Compared with those before intervention,the left thalamus and lenticular putamen were enhanced in the Tuina group after intervention,but there was no weakening area in the left thalamus after intervention.There were differences in brain regions of FC before and after intervention in drug group:（1）Compared with those before intervention,there were left insular,left superior temporal gyrus and left temporal pole:superior temporal gyrus in the drug group after intervention,and there was no weakening area of PAG in the right side after intervention.（2）Compared with those before intervention,there was no enhancement area of the left thalamus after intervention in the drug group,but there were right insular,right central sulcus cover,left superior marginal gyrus,left superior temporal gyrus and right superior marginal gyrus in the left thalamus after intervention.（3）Compared with that before intervention,there was no enhancement area of the right thalamus after intervention in the drug group,and there was a left superior marginal gyrus with the weakening of the right thalamus after intervention.There were differences in FC between Tuina group and drug group after intervention:（1）Compared with the drug group after intervention,the left triangular inferior frontal gyrus,the left precentral gyrus,the left superior parietal gyrus and the left inferior parietal angular gyrus were enhanced in the Tuina group after intervention.Compared with the drug group,there was no weakening area of PAG compared with the left side in the Tuina group.（2）Compared with the drug group after intervention,the PAG of the Tuina group was enhanced with the right postcentral gyrus and the right central sulcus cover,and there was no weakening area of PAG compared with the right side in the Tuina group compared with the drug group.（3）Compared with the drug group after intervention,the left thalamus in the Tuina group was enhanced with right insular,right lenticular putamen,right middle frontal gyrus,right triangular inferior frontal gyrus,left superior temporal gyrus and left superior marginal gyrus.Compared with the drug group,there was no weakening area of the left thalamus in the Tuina group.（4）Compared with the drug group,the left insular,the right insular and the right superior marginal gyrus were enhanced in the Tuina group compared with the right thalamus,and there was no weakening area of the right thalamus in the Tuina group compared with the drug group.Conclusion:1.Pressing local acupoints plus adjustion of the knee joint in a sitting position may play an analgesic effect by regulating the structure and function of the thalamus,hippocampus,superior marginal gyrus and other brain regions of KOA patients.2.The central analgesic mechanism of pressing local acupoints plus adjustion of the knee joint in a sitting position on KOA may be the neuroimaging evidence of the three-point syndrome differentiation theory. |
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