| BackgroundStroke is a serious health hazard with its high incidence,high disability and high recurrence rate.The incidence of stroke increase with the increase of the population aging,seriously affecting the quality of life of patients,bringing a huge financial burden to the family and society.Limb motor dysfunction is the main symptoms of disability post-stroke hemiplegia.The incidence in acute patients is about 80%,seriously affecting the ability of patients' daily activities,caused a heavy burden to patients,families and society.Studies have shown that early rehabilitation training can improve the patient's sensory motor function and behavioral ability.And appropriate rehabilitation can maximize the recovery of stroke patients with dysfunction,help to improve the patient's self-care ability to improve their quality of life.Therefore,exploring the best rehabilitation after stroke has become an important issue in the study of rehabilitation medicine.Constraint-induced movement therapy(CIMT)is a new type of rehabilitation training technique for post-stroke dysfunction in recent years.The technology overcome the limb "Learned non-use" by restraint of the less affected upper limb and forced use of the affected armlimiting,and gradually increase the training intensity.CIMT has been used in peripheral neuropathy,central nervous system disease,Parkinson's disease,stroke and pediatric cerebral palsy and other fields.In which,the most widely used field was the stroke.As to the intervention time,there are a large number of literature reported the CIMT applied in subacute phase and recovery period post-stroke can promote the recovery of neurological function.However,rarely studies involved in the clinical effects of CIMT applied at acute period after stroke.And the results of the study there is still a big controversy.Some scholars think that,CIMT is not suitable for patients in rehabilitation of the acute period post-stroke.And high-intensity exercise even aggravate the damage.While,Some studies suggested that CIMT applied at acute period post-stroke does not aggravate the condition,can significantly improve the patient's limb dysfunction.So it is recommended in early rehabilitation after stroke.Therefore,it is urgent to explore the efficacy and mechanism of CIMT used in patients with acute phase post-stroke.It has become an urgent problem to be solved in the application of CIMT,and it is necessary to study systematically.At the same time,some scholars confirmed by animal experiments,early over-training of limbs can lead to increased nerve damage and limb dysfunction.The causes of worsening may be related to the restriction of exercise on the expression of neuronal cell adhesion molecule(NCAM)in cerebral cortex,and the overexpression of glutamate neurons and the damage of neurons.However,some studies suggest that acute phase involvement of CIMT does not aggravate the condition,can significantly improve the patient's limb dysfunction,it is recommended early intervention.In clinical practice,many patients with acute cerebral ischemia meet the criteria for inclusion in CIMT.Therefore,it is urgent to explore the efficacy and mechanism of CIMT in patients with acute stroke.It has become an urgent problem to be solved in the application of CIMT,and it is necessary to study it systematically.Therefore,the study based on animal experiments,first established the animal model of cerebral infarction.Then,to compare behavior scores and nerve growth factors of constraint induced movement therapy on cerebral infarction at different stages of rat,aimed at providing information for determine the best intervention time of CIMT in clinical practice.ObjectiveThe ischemic rat model was established according to the Zea-Longa line embolism method.The infarct size,neurological function score and recovery of motor function were observed of different rehabilitation training groups were observed and compared.At the same time,the morphological changes of neuronal cells in the marginal area of the cerebral infarction were observed,and the changes of NgR,BDNF and NGF were detected in different rehabilitation training time points.To explore the functional basis of functional recovery of different CIMT rehabilitation training opportunities in rats with cerebral infarction and its possible mechanism.MethodsHealthy male SD rats were selected as experimental animals.The left middle cerebral artery occlusion(MCAO)model was established by Longa's suture method.The neurological function was evaluated at 6 h after model established.The neurological score among 1-3 points were included in this study.In this study,64 rats were randomly divided into four groups according to the intervention method,sham operation group,model group,acute intervention group and chronic intervention group,8 in each time of each group.The model group recovered naturally and did not take any rehabilitation training measures.The acute intervention group began to carry out CIMT training at 1 day after modeling,and the chronic intervention group started CIMT training at 14 days after modeling,and the training time in both group was 7 days.8 rats were randomly selected from each group at 8d and 21 d after animal modeling respectively.The neurological function scores were evaluated according to Zea longa standard.At the same time,the infarct size was calculated,and the changes of neuronal cells were observed by electron microscope.Besides,the changes of protein and gene levels of NgR,BDNF and NGF were detected by Western,blot and RT-PCR methods,respectively.Results1.At 8d,The neurological score of the patients in the acute intervention group was significantly lower than that in the model group and the chronic intervention group,and the difference between the three groups was statistically significant(F=5.32,P=0.013).and the score of acute intervention group was significantly lower than that of model group and chronic intervention group(P<0.05).At 21 days,the score of chronic intervention group was significantly lower than that at 8 days(P<0.05).The results of variance analysis showed that there were statistically significant differences in neurological scores between the three groups at 21 days(F=3.58,P=0.043).2.The difference of balance beam test scores among model group,acute intervention group and chronic intervention group had statistically significant(F=8.79,P<0.001).The scores in acute intervention group was significantly lower than that in the model group and chronic intervention group.And no significant difference founded in model group and chronic intervention group(P>0.05).Compared with 8d,the scores of balance beam in the acute intervention group and the chronic group were significantly lower at 21 d,and the differences were statistically significant(P<0.05).At 21 d,the difference between the three groups was statistically significant(F=3.58,P=0.043).The scores of the acute intervention group and the chronic intervention group were significantly lower than that in the model group(P<0.05),while the difference between the two groups of acute intervention group and the chronic intervention group was not statistically significant(P>0.05).3.The morphological observation showed that the nerve cells in the cortex of the sham operated group showed no obvious lesions.The nuclei were round,the nucleoli were clear,and the cell morphology was clearly visible.The intercellular space was normal.In the model group,the neurons were pyknosis,pyknosis,vacuolar degeneration.neuron number decrease and intercellular space increased in the ischemic penumbra region.At 8d,neuron shrinkage is more obvious,nuclear pyknosis,or even broken,and cytoplasmic vacuolar degeneration increased in the acute intervention group.The number of neurons reduced and the intercellular space increased,accompanied by inflammatory cell infiltration.Compared with the 8d,the severity of the lesions in the acute intervention group at 21d was slightly decreased,but there was no significant improvement compared with the model group.At 8d,there was no significant difference between chronic intervention group and model group,both slightly reduced than the acute intervention group.At 21 d,the severity in the chronic intervention group was slightly reduced compared with the acute intervention group,but also obvious karyopyknosis and few vacuolized cells were observed,but no obvious inflammatory cells were observed.4.The infarct size calculation results show that,the difference of infarction area was statistically significant between the groups at 8d(F=18.76,P<0.001),further comparison showed that acute infarction area in the intervention group was significantly lower than that of model group and chronic intervention group(Q acute vs model=8.407,P<0.01;Q acute vs chronic= 6.014,P<0.01).Compared with 8D,the infarct size in the chronic intervention group was significantly lower than that of 21d(t=6.20,P<0.001).At 21d,infarct size of chronic intervention group and acute intervention group was significantly lower than that of the model group(Q acute vs model =10.485,P<0.01;Q model vs chronic =12.327,P<0.01),and the difference between chronic group was not statistically significant(Q=1.84,P>0.05).5.The western blot analysis showed that,the protein level of NgR,BDNF and NGF were different among the 4 groups at 8d.The ANOVA analysis showed that the difference in NgR,BDNF and NGF expression among 4 groups at 8 days was statistically significant(P<0.05).The BDNF,NgR and NGF levels in the model group,the acute intervention group,and the chronic intervention group were significantly higher than that for the sham operation group.BDNF and NGF levels for the acute intervention group was significantly higher,and the NgR significantly lower,than that for the model group and chronic intervention group,and this difference was also statistically significant(P<0.05).No significant difference was detected between the model group and chronic intervention group(P>0.05).At 21d,a significant difference was also identified in the BDNF expression level among the 4 groups(P<0.05).The relative expression level of BDNF and NGF in the acute and chronic intervention groups were increased,and the NgR decreased,compared to 8 days,and the difference was statistically significant(P<0.05).There was no significant difference between the two groups(P>0.05).But the BDNF and NGF levels for the two groups were both significantly higher than that of the model group and the sham operation group(P<0.05).6.The results of Real-time polymerase chain reaction(RT-PCR)showed that there was significant difference in the expression of NgR,BDNF and NGF among three groups at 8d(P<0.05).the NgR expression in the acute intervention group was significantly lower,while the BDNF and NGF were significantly higher,than that of the model group and the chronic intervention group(P<0.05).However,there is no significant difference between chronic group and model group(P>0.05).At 21d,the mRNA expression levels of BDNF and NGF in the acute intervention group and chronic intervention group were all increased significantly,the NgR decreased,than that in 8d.There was a significant different among four groups at 21d(P<0.05).The expression level of BDNF and NGF in the acute intervention group and chronic intervention group were both higher,and the NgR was lower,than that of the model group(P<0.05),but no significant difference was identified between that of the acute intervention group and chronic intervention group(P>0.05).Conclusion1.CIMT started at acute or chronic period after ischemic stroke both promote the recovery of motor function in cerebral infarction rats.It is safe and reliable to intervene CIMT in acute stage after cerebral infarction.2.In the same intervention time,the chronic intervention group and the acute intervention group had similar improvement in the neurological function of the rats.4.CIMT can promote the recovery of cortical nerve cells in the infarct marginal zone,reduce the necrosis of nerve cells,protect the dying nerve cells.5.The mechanism of CIMT in promoting motor function recovery in rats with cerebral infarction may be related to down regulation of NgR expression and up regulation of BDNF and NGF expression.BackgroundAt present,it has reached a consensus of CIMT on the rehabilitation effects to neurological and motor function in stroke patients.Especially for upper limb function recovery in post-stroke patients,CIMT has a very significant advantage.For the clinical effects of appropriate time beginning CIMT after stroke,the present studies had consistence results for the chronic stage.Besides,The related systematic review(Meta analysis)also showed that the effect of CIMT on the recovery of the limbs of stroke patients was significantly better than the traditional rehabilitation methods.The effect of CIMT on upper extremity motor function after stroke was confirmed from the perspective of evidence-based medicine.However,the results are inconsistent with regard to whether CIMT is appropriate for the recovery of upper limb motor function in the acute phase.A prospective multicenter randomized controlled trial(EXCITE)study showed that the CIMT applied to the patients with subacute stroke,results in the motor function of upper limb in patients increased significantly,had better effects than the routine rehabilitation rehabilitation measures,and the curative effect of rehabilitation can last more than 1 years.At the same time,the author conducted a systematic review on the rehabilitation effects of CIMT on post-stroke patients in acute and subacute stage,the results also demonstrated that CIMT or mCIMT might be more beneficial than traditional rehabilitation therapy in the acute and sub-acute stroke.Furthermore,the subgroup analysis showed that low intensity(less than 2 hours/day)CIMT may be better than high intensity(>2 hours/day)rehabilitation training group.Although the relevant rehabilitation guidelines suggested the rehabilitation intervention should be the conducted as soon as possible.The optimal interventions timing for CIMT is rarely reported.In the first part,the authors have systematically compared the effects of CIMT on limb motor function and related nerve growth factors in the acute and chronic phases in rats.The results showed that the rehabilitation effect of CIMT was better than that of routine rehabilitation therapy in acute or chronic stage,and the effects on acute phase and chronic phase was equivalent.The results of the study was consistent with the relevant studies.However,it is not enough to to identify the optimal interventional timing of CIMT after cerebral ischemia only rely on the animal experiments,which need to be further confirmed clinically.ObjectiveTo explore the clinical effects of Constraint-induced movement therapy for upper limb motor function and ability of daily living on cerebral ischemia patients at different period from clinical perspective based on the previous two parts,aimed at providing clinical basis for identifying best intervention opportunity after cerebral ischemia.MethodIn this study,114 cases of first stroke patients treated in the rehabilitation medicine department of Affiliated Hospital of Shandong Traditional Chinese Medicine University from August 2015 to September 2016 were selected as the subjects.All patients were randomly divided into subacute stage CIMT group(E-CIMT),chronic stage CIMT group(L-CIMT)and traditional rehabilitation group(Control group),38 cases in each group.Action Research Arm Test(ARAT),Fugl-Meyer Motor Assessment(FMA)and modified Barthel index(MBI)were used to evaluate the upper limb motor function level and activities of daily living before treatment and 4 weeks after intervention,respectively.SPSS 19.0 statistical software was used for statistical analysis.Results1.In the 114 patients with ischemic stroke,2 excluded,6 lost,and 106 completed in this study.In E-CIMT group,1 cases were excluded,3 cases were lost,34 cases finished.In the L-CIMT group,1 cases excluded,2 cases dropped,and finally 35 cases completed in the study.In the control group,1 cases lost,and 37 cases completed the experiment finally.2.The scores of FMA,ARAT and MBI were similar among the three groups before rehabilitation intervention.Although the scores of FMA,ARAT and MBI in the L-CIMT group were higher than those in the other two groups,the difference between the three groups was not statistically significant(P>0.05).3.Analysis of patients' upper extremity motor function showed,the FMA scores in the E-CIMT group,the L-CIMT group and the control group increased in different degrees after intervention.In which,the difference in control group was not statistically significant(P>0.05).However,the differences of E-CIMT group and the L-CIMT group before and after treatment were statistically significant(P<0.05).After intervention,the scores of the three groups showed that the differences of FMA and ARAT scores among the three groups were all statistically significant(P<0.05).SNK test showed that the E-CIMT group and the L-CIMT group were both significantly higher than the control group(P<0.05).And there was significant difference between the E-CIMT group and the L-CIMT group(P<0.05).4.Analysis of patients' daily living ability showed,MBI scores of E-CIMT group,L-CIMT group and control group increased after intervention,and there was significant difference before and after treatment in each group(P<0.05).which suggested that both the CIMT and the traditional rehabilitation programs can improve the patient's daily living ability.After treatment,the difference among the three groups were statistically significant(F=16.80,P<0.05).Further SNK test showed that the MBI scores of E-CIMT group and L-CIMT group were significantly higher than those of control group(P<0.01).Besides,the MBI score in E-CIMT group were also significantly higher than that in L-CIMT group(P<0.05).Conclusion1.CIMT started at subacute or chronic period after ischemic stroke,is superior to the traditional rehabilitation measures in promoting the recovery of upper limb function and patients' activities of daily living2.CIMT started at subacute period post-stroke had better clinical effects than chronic period in promoting the recovery of upper limb function on the short-term effect. |
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