Functional MRI and motor behavioral changes obtained with constraint‐induced movement therapy in chronic stroke

Background: The clinical benefits of intensive stroke rehabilitation vary individually. We used multimodal functional imaging to assess the relationship of clinical gain and imaging changes in patients with chronic stroke whose voluntary motor control improved after constraint‐induced movement therapy (CIMT). Methods: Eleven patients (37.6 ± 36.8 months from stroke) were studied by functional MRI (fMRI), transcranial magnetic stimulation (TMS), and behavioral assessment of hand motor control (Wolf Motor Function Test) before and after 2 weeks of CIMT. Individual and group‐level changes in imaging and behavioral parameters were investigated. Results: Increase in fMRI activation in the sensorimotor areas was greater amongst those subjects who had poor hand motor behavior before therapy and/or whose motor behavior improved notably because of therapy than amongst subjects with relatively good motor behavior already before therapy. The magnitude of CIMT‐induced changes in task‐related fMRI activation differed between lesioned and non‐lesioned hemispheres, and the fMRI laterality index was different for paretic and non‐paretic hand tasks. The corticospinal conduction time in TMS was significantly decreased after CIM therapy. Conclusions: Alterations in sensorimotor cortical activations (fMRI) and corticospinal conductivity (TMS) were observed after intensive rehabilitation in patients with chronic stroke. Activation and functional changes in fMRI and TMS correlated significantly with the degree of clinical improvement in hand motor behavior. The present data advance the understanding of the functional underpinnings of motor recovery, which may be obtained even years after the stroke.     

Ipsilateral motor cortex activation by unaffected hand movements in patients with cerebral infarct

Many studies have reported that stroke patients can be accompanied by motor deficit of the unaffected extremities as well as the affected extremities. This suggests that neural control of motor function of unaffected extremities might be changed following stroke. However, very little is known about this topic. Using functional MRI (fMRI), we investigated changes in neural control of motor function of the unaffected hand in hemiparetic patients with cerebral infarct. Thirty-five hemiparetic stroke patients were recruited for this study. fMRI was performed at 1.5T during either affected or unaffected hand flexion-extension movements. We evaluated motor function of the affected upper extremity using the upper Motricity index (UMI) and the medical research council (MRC) scale for finger extensor. From fMRI, LI (laterality index) was calculated for assessment of relative activity in the ipsilateral versus the contralateral primary sensorimotor cortex. Positive correlation between LIs was observed during affected and unaffected hand movements (r=0.670, p=0.000). LI of unaffected hand movements was also correlated with the affected UMI (r=0.408, p=0.015) and MRC of the affected hand extensor (r=0.362, p=0.033). We demonstrated that the ipsilateral (affected) motor cortex was recruited by unaffected hand movements in proportion to poor motor function of the affected upper extremity.     

Functional MRI finding by proprioceptive input in patients with thalamic hemorrhage

Little is known about the recovery mechanism of somatosensory function in thalamic hemorrhage. We investigated the recovery mechanism of somatosensory function, using functional MRI (fMRI) findings by proprioceptive input in chronic patients with thalamic hemorrhage. Eleven consecutive chronic patients with thalamic hemorrhage who showed severe proprioceptive dysfunction were recruited. The subscale for kinesthetic sensation of the Nottingham Sensory Assessment (NSA) was used for determination of proprioceptive function. fMRI was performed during passive movements of the metacarpophalangeal joint. From fMRI, the laterality index (LI) was calculated for assessment of the relative activity in the ipsilateral versus the contralateral primary sensori-motor cortex (SM1). The average LI for affected and unaffected hand stimulation was 0.89 and 0.90, respectively, and there was no significant difference between LIs (p> 0.05). In addition, LI of the affected hand stimulation was positively related to NSA scores (r=0.790, p< 0.05). Our results for LI suggest that the cortical activation pattern of SM1 was similar in the affected and unaffected hemispheres. Therefore, it appears that the proprioceptive function of the affected hand likely recovered by the normally existing medial lemniscus and its thalamocortical pathway in our patients.     

Changes in serial optical topography and TMS during task performance after constraint-induced movement therapy in stroke: a case study

The authors examined serial changes in optical topography in a stroke patient performing a functional task, as well as clinical and physiologic measures while undergoing constraint-induced therapy (CIT). A 73-year-old right hemiparetic patient, who had a subcortical stroke 4 months previously, received 2 weeks of CIT. During the therapy, daily optical topography imaging using near-infrared light was measured serially while the participant performed a functional key-turning task. Clinical outcome measures included the Wolf Motor Function Test (WMFT), Motor Activity Log (MAL), and functional key grip test. Transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) were also used to map cortical areas and hemodynamic brain responses, respectively. Optical topography measurement showed an overall decrease in oxy-hemoglobin concentration in both hemispheres as therapy progressed and the laterality index increased toward the contralateral hemisphere. An increased TMS motor map area was observed in the contralateral cortex following treatment. Posttreatment fMRI showed bilateral primary motor cortex activation, although slightly greater in the contralateral hemisphere, during affected hand movement. Clinical scores revealed marked improvement in functional activities. In one patient who suffered a stroke, 2 weeks of CIT led to improved function and cortical reorganization in the hemisphere contralateral to the affected hand.     

EFFICACY OF MIRROR THERAPY AND CONSTRAINT INDUCED MOVEMENT THERAPY ON UPPER EXTREMITY FUNCTION AND ACTIVITIES OF DAILY LIVING IN STROKE

BackgroundStroke has been identified as an epidemic and an important cause of morbidity and mortality globally, and at least 85% of stroke survivors experience hemiplegia and upper-extremity function of at least 69% of patients are affected. Over 50% of stroke survivors have impairment of motor function of the upper extremity; therefore there is pertinent need to use functional rehabilitation approaches such as; mirror therapy and constraint induced movement therapy for stroke survivors to regain upper extremity motor function.AimsTo compare the efficacy of mirror therapy (MT) with constraint induced movement therapy (CIMT) on the upper extremity motor function and activities of daily living (ADL) in chronic stroke survivors.Methods30 stroke survivors were recruited for this study. They were randomized into three groups, the MT plus conventional therapy group, CIMT plus conventional therapy group and control group. Upper extremity motor function and ADL were assessed. Participants were assessed at baseline and after seven weeks of intervention.ResultsThe MT and CIMT groups’ intervention both had significant improvement on upper extremity motor function and ADL, however, there was no significant difference on upper motor function (p=0.503) and ADL (p=0.133) across the three groups.ConclusionThis study concluded that neither of MT nor CIMT had an additional significant improvement compared to conventional therapy alone on recovery of motor function in the upper extremity and performance of ADL.     

Congenital mirror movement: a study of functional MRI and transcranial magnetic stimulation

Two male patients (a child and an adult) with congenital mirror movement were studied using functional MRI (fMRI) and transcranial magnetic stimulation (TMS). Bilateral primary sensorimotor cortices were activated during unilateral hand gripping on fMRI when the child patient was 8 years old andthe adult was 37 years old. Bilateral motor evoked potentials were induced from the hand and forearm muscles after TMS of each hemisphere. Bilateral motor responses were also induced from the arm muscles in the adult patient. Bilateral motor responses had short and similar latencies. Contralateral motor responses to TMS were smaller than ipsilateral ones in the hand muscles, while contralateral responses were larger than ipsilateral ones in the arm muscles. Contralateral hand motor responses reduced in amplitude or disappeared with increasing age while in the child patient, mirror movements decreased gradually. Our results suggest that bilateral activation of the primary sensorimotor cortices during intended unilateral hand movement and bilateral motor responses to TMS account, at least in part, for the pathophysiology of congenital mirror movement. Reduction of contralateral hand motor responses may be related to the decrease in mirror movements during development.     

Cortical activation changes associated with motor recovery in patients with precentral knob infarct

We investigated the cortical activation changes associated with motor recovery in six hemiparetic patients with precentral knob infarct. fMRI at 1.5 T with finger movements at a fixed rate was performed twice in each patient, 1 and 6 months after stroke onset. From the images obtained, the LI (laterality index) for the primary sensorimotor cortex (SM1) was calculated to measure the degree of the cortical activity concentration in the contralateral hemisphere. Our results showed that a greater improvement in motor function scores was significantly correlated with a greater increment in LI induced by affected finger movements (p < 0.05). Motor recovery after precentral knob infarct was found to be positively related with the concentration of SM1 activity in the ipsilesional hemisphere. This finding may imply motor recovery through cortical reorganization after precentral knob infarct in the human brain.     

Evolution of cortical activation during recovery from corticospinal tract infarction

BACKGROUND AND PURPOSE: Recovery from hemiparesis due to corticospinal tract infarction is well documented, but the mechanism of recovery is unknown. Functional MRI (fMRI) provides a means of identifying focal brain activity related to movement of a paretic hand. Although prior studies have suggested that supplementary motor regions in the ipsilesional and contralesional hemisphere play a role in recovery, little is known about the time course of cortical activation in these regions as recovery proceeds. METHODS: Eight patients with first-ever corticospinal tract lacunes causing hemiparesis had serial fMRIs within the first few days after stroke and at 3 to 6 months. Six healthy subjects were used as controls. Statistically significant voxels during a finger-thumb opposition task were identified with an automated image processing program. An index of ipsilateral versus contralateral activity was used to compare relative contributions of the 2 hemispheres to motor function in the acute and chronic phases after stroke. RESULTS: Controls showed expected activation in the contralateral sensorimotor cortex (SMC), premotor, and supplementary motor areas. Stroke patients differed from control patients in showing greater activation in the ipsilateral SMC, ipsilateral posterior parietal, and bilateral prefrontal regions. Compared with the nonparetic hand, the ratio of contralateral to ipsilateral SMC activity during movement of the paretic hand increased significantly over time as the paretic hand regained function. CONCLUSIONS: The evolution of activation in the SMC from early contralesional activity to late ipsilesional activity suggests that a dynamic bihemispheric reorganization of motor networks occurs during recovery from hemiparesis.     

Bilateral primary sensori-motor cortex activation of post-stroke mirror movements: an fMRI study

This fMRI study was undertaken to test whether the pathophysiological mechanism of mirror movements in hemiparetic stroke patients involves activation of the unaffected motor cortex. We studied 16 control subjects and 51 stroke patients. fMRI was performed at 1.5 T using a finger flexion-extension movement paradigm. The incidence of bilateral primary sensorimotor cortex activation was significantly increased during movements of the affected hand of stroke patients who showed mirror movements. Moreover, the incidence of bilateral primary sensorimotor cortex activation increased with the severity of mirror movements and primary sensorimotor cortex was activated bilaterally in all patients who showed sustained mirror movements. We conclude that the motor cortex activation on the non-stroke side is associated with mirror movements and is correlated with the severity of mirror movements. It seems that the pathophysiological mechanism of sustained mirror movements in stroke patients involves the unaffected motor cortex.     

Cortical reorganization after modified constraint-induced movement therapy in pediatric hemiplegic cerebral palsy

Constraint-induced movement therapy improves motor function in the affected hand of children with hemiplegic cerebral palsy and results in cortical changes in adults with stroke. This study measured clinical improvement and cortical reorganization in a child with hemiplegia who underwent modified constraint-induced movement therapy for 3 weeks. Clinical, functional magnetic resonance imaging and magnetoencephalography measurements were done at baseline, after therapy, and 6 months after therapy. Modified constraint-induced movement therapy resulted in clinical improvement as measured by the Pediatric Motor Activity Log. Functional magnetic resonance imaging showed bilateral sensorimotor activation before and after therapy and a shift in the laterality index from ipsilateral to contralateral hemisphere after therapy. Magnetoencephalography showed increased cortical activation in the ipsilateral motor field and contralateral movement evoked field after therapy. Cortical reorganization was maintained at the 6-month follow-up. This is the first study to demonstrate cortical reorganization after any version of constraint-induced movement therapy in a child with hemiplegia.     

Functional significance of the ipsilateral hemisphere during movement of the affected hand after stroke

Previous fMRI observations have suggested increased task-related activation of the ipsilateral cerebral motor cortex in patients recovering from stroke. This is generally taken to infer an increased output from this area, although the functional relevance of this has been questioned. Here, we use directed EEG coherence to reveal whether there is increased informational flow from the ipsilateral motor cortex following motor stroke, and through correlation with degree of recovery, establish that this pattern of activity is associated with limited functional improvement. Unrecovered (n = 14), recovered (n = 11) patients and healthy subjects (n = 16) performed an isometric grip task with either hand that corresponded to 25% of individual maximum force, while EEG was recorded. For unrecovered stroke patients, most task-related information flow between the sensorimotor cortices in the low beta band of the EEG came from the ipsilateral (undamaged) hemisphere during grip with the affected hand. This was not the case when they gripped with their unaffected hand, when cortical activity was driven from the contralateral sensorimotor cortex. The latter pattern was also seen in recovered patients and controls. These findings suggest a functional role for the ipsilateral hemisphere in organizing movement of the impaired limb following stroke, but only in those patients that do not make a good functional recovery. Patients making a fuller recovery organize movement-related cortical activity from the hemisphere contralateral to movement.     

Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke.

In order to determine the influence of a single dose of fluoxetine on the cerebral motor activation of lacunar stroke patients in the early phase of recovery, we conducted a prospective, double-blind, crossover, placebo-controlled study on 8 patients with pure motor hemiparesia. Each patient underwent two functional magnetic resonance imaging (fMRI) examinations: one under fluoxetine and one under placebo. The first was performed 2 weeks after stroke onset and the second a week later. During the two fMRI examinations, patients performed an active controlled motor task with the affected hand and a passive one conducted by the examiner with the same hand. Motor performance was evaluated by motor tests under placebo and under fluoxetine immediately before the examinations to investigate the effect of fluoxetine on motor function. Under fluoxetine, during the active motor task, hyperactivation in the ipsilesional primary motor cortex was found. Moreover, fluoxetine significantly improved motor skills of the affected side. We found that a single dose of fluoxetine was enough to modulate cerebral sensory-motor activation in patients. This redistribution of activation toward the motor cortex output activation was associated with an enhancement of motor performance.     

Motor representation in patients rapidly recovering after stroke: a functional magnetic resonance imaging and transcranial magnetic stimulation study

OBJECTIVE: Neuroimaging studies have suggested an evolution of the brain activation pattern in the course of motor recovery after stroke. Initially poor motor performance is correlated with an recruitment of the uninjured hemisphere that continuously vanished until a nearly normal (contralateral) activation pattern is achieved and motor performance is good. Here we were interested in the early brain activation pattern in patients who showed a good and rapid recovery after stroke. METHODS: Ten patients with first-ever ischemic stroke affecting motor areas had to perform self-paced simple or more complex movements with the affected or the unaffected hand during functional magnetic resonance imaging (fMRI). The location and number of activated voxels above threshold were determined. To study possible changes in the cortical motor output map the amplitude of the motor evoked potentials (MEP) and the extent of the excitable area were determined using transcranial magnetic stimulation (TMS). RESULTS: The pattern of activation observed with movements of the affected and the unaffected hand was similar. In the simple motor task significant (P<0.05) increases were found in the primary motor cortex ipsilateral to the movement, the supplementary motor area and the cerebellar hemisphere contralateral to the movement during performance with the affected hand compared to movements with the unaffected hand. When comparing simple with more complex movements performed with either the affected or the unaffected hand, a further tendency to increased activation in motor areas was observed. The amplitude of MEPs obtained from the affected hemisphere was smaller and the extent of cortical output maps was decreased compared to the unaffected hemisphere; but none of the patients showed MEPs at the affected hand when the ipsilateral unaffected motor cortex was stimulated. CONCLUSIONS: Despite a rapid and nearly complete motor recovery the brain activation pattern was associated with increased activity in (bilateral) motor areas as revealed with fMRI. TMS revealed impaired motor output properties, but failed to demonstrate ipsilateral motor pathways. Successful recovery in our patients may therefore rely on the increased bilateral activation of existing motor networks spared by the injury.     

Functional Reorganization and Recovery After Constraint-Induced Movement Therapy in Subacute Stroke: Case Reports

Preliminary assessments of the feasibility, safety, and effects on neuronal reorganization measured with transcranial magnetic stimulation (TMS) from Constraint-Induced Movement Therapy (CIMT) of the upper extremity were made in eight cases of subacute stroke. Within fourteen days of their stroke, patients were randomly assigned to two weeks of CIMT or traditional therapy. Baseline motor performance and cortical/subcortical representation for movement with TMS were assessed before treatment. Post-treatment assessments were made at the end of treatment and at three months after the stroke. The TMS mapping showed a larger motor representation in the lesioned hemisphere of the CIMT patients as compared to the controls at the three-month follow-up assessment. The enlarged motor representation in the lesioned hemisphere for hand movement correlated with improved motor function of the affected hand, suggesting a link between movement representation size as measured with TMS and functionality. These results suggest that TMS can be safely and effectively used to assess brain function in subacute stroke and further suggest that CIMT may enhance cortical/subcortical motor reorganization and accelerate motor recovery when started within the first two weeks after stroke.     

Functional reorganization and recovery after constraint-induced movement therapy in subacute stroke: case reports

Preliminary assessments of the feasibility, safety, and effects on neuronal reorganization measured with transcranial magnetic stimulation (TMS) from Constraint-Induced Movement Therapy (CIMT) of the upper extremity were made in eight cases of subacute stroke. Within fourteen days of their stroke, patients were randomly assigned to two weeks of CIMT or traditional therapy. Baseline motor performance and cortical/subcortical representation for movement with TMS were assessed before treatment. Post-treatment assessments were made at the end of treatment and at three months after the stroke. The TMS mapping showed a larger motor representation in the lesioned hemisphere of the CIMT patients as compared to the controls at the three-month follow-up assessment. The enlarged motor representation in the lesioned hemisphere for hand movement correlated with improved motor function of the affected hand, suggesting a link between movement representation size as measured with TMS and functionality. These results suggest that TMS can be safely and effectively used to assess brain function in subacute stroke and further suggest that CIMT may enhance cortical/subcortical motor reorganization and accelerate motor recovery when started within the first two weeks after stroke.     

Constraint-induced movement therapy enhances AMPA receptor-dependent synaptic plasticity in the ipsilateral hemisphere following ischemic stroke

Constraint-induced movement therapy(CIMT) can promote the recovery of motor function in injured upper limbs following stroke, which may be associated with upregulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor(AMPAR) at synapses in the ipsilateral sensorimotor cortex in our previous study. However, AMPAR distribution is tightly regulated, and only AMPARs on the postsynaptic membrane can mediate synaptic transmission. We speculated that synaptic remodeling induced by movement-associated synaptic activity can promote functional recovery from stroke. To test this hypothesis, we compared AMPAR expression on the postsynaptic membrane surface in a rat model of ischemic stroke induced by middle cerebral artery occlusion(MCAO) with versus without CIMT, which consisted of daily running wheel training for 2 weeks starting on day 7 after MCAO. The results showed that CIMT increased the number of glutamate receptor(Glu R)2-containing functional synapses in the ipsilateral sensorimotor cortex, and reduced non-Glu R2 AMPARs in the ipsilateral sensorimotor cortex and hippocampal CA3 region. In addition, CIMT enhanced AMPAR expression on the surface of post-synaptic membrane in the ipsilateral sensorimotor cortex and hippocampus. Thus, CIMT promotes the recovery of motor function of injured upper limbs following stroke by enhancing AMPAR-mediated synaptic transmission in the ischemic hemisphere. These findings provide supporting evidence for the clinical value of CIMT for restoring limb movement in stroke patients. All experimental procedures and protocols were approved by the Department of Laboratory Animal Science of Fudan University, China(approval No. 201802173 S) on March 3, 2018.     

Do patients with congenital hemiparesis and ipsilateral corticospinal projections respond differently to constraint‐induced movement therapy?

This study investigates whether the type of corticospinal reorganization (identified by transcranial magnetic stimulation) influences the efficacy of constraint-induced movement therapy (CIMT). Nine patients (five males, four females; mean age 16y [SD 6y 5mo], range 11-30y) controlling their paretic hand via ipsilateral corticospinal projections from the contralesional hemisphere and seven patients (three males, four females; mean age 17y [SD 7y], range 10-30y) with preserved crossed corticospinal projections from the affected hemisphere to the paretic hand underwent 12 consecutive days of CIMT. A Wolf motor function test applied before and after CIMT revealed a significant improvement in the quality of upper extremity movements in both groups. Only in patients with preserved crossed projections, however, was this amelioration accompanied by a significant gain in speed, whereas patients with ipsilateral projections tended to show speed reduction. These data, although preliminary, suggest that patients with congenital hemiparesis and ipsilateral corticospinal projections respond differently to CIMT.     

Mirror movements complicate interpretation of cerebral activation changes during recovery from subcortical infarction

In recovered stroke patients, performance of motor tasks with the affected limb has been reported to activate cortical areas ipsilateral to the affected side. The better to determine the causal role these areas play in recovery of motor function, we assessed cerebral activation during motor activity longitudinally after hemiparesis due to cerebral infarction. A secondary goal was to ascertain the relation between mirror movements and activation ipsilateral to motor activity. Positron emission tomography with oxygen-15 water measured regional cerebral blood flow during wrist movement early and late in the course of recovery from hemiparesis. Surface electromyography recorded muscular activity, and computer-assisted video analysis quantified movement during the scans. Mirror movements, movements contralateral to the instructed movement of the hemiparetic arm, were often seen. Activation of motor areas in the hemisphere ipsilateral to the affected limb roughly correlated with presence of mirror movements. Other changes in cerebral activation were small, when the task was controlled for rate, but high-rate-specific recruitment of ipsilateral cortical areas occurred in one case. However, the common occurrence of mirror movements, particularly with effortful tasks, complicates interpretation of data regarding the role of the ipsilateral hemisphere in recovery.     

功能磁共振成像在脑梗死患者运动功能评价中的作用探讨

目的 利用功能磁共振成像（functional magnetic resonance imaging,fMRI）分析单侧放射冠梗死患者大脑半球的激活部位及偏侧化指数（laterality index,LI）与运动功能康复水平的关系。方法 选取12例单侧放射冠梗死的患者为卒中组,5例正常志愿者为对照组。所有入选者均进行血氧水平依赖功能磁共振成像（blood oxygenation level dependent-functional magnetic resonance imaging,BOLD-fMRI）检查,扫描设备为德国西门子3.0T磁共振扫描系统。试验采用Block设计,采取患手顺序对指任务。扫描结果采用统计参数图（Statistical Parametric Mapping,SPM2）进行数据分析和脑功能区定位,计算不同感兴趣区激活体素数目及LI。扫描结束后记录患者上肢运动功能评分（Fugl-Meyer评分,F-M评分）,分析LI与F-M评分之间的相关性。结果 与对照组相比,卒中组脑部激活范围较广泛,表现为双侧运动传导通路的激活;双侧大脑半球、初级感觉运动区（sensory motor cortex,SMC）、第一躯体运动区（M1区）LI明显减少（P=0.004,0.008,0.027）。卒中组LI（半球、SMC、M1）与F-M评分之间的相关性无统计学意义（r=0.133,P=0.618;r=0.558,P=0.059;r=0.297,P=0.348）;卒中组最强激活点位于中央前回（Precentral gyrus,PRE）患者F-M评分较高（52±22）,最强激活点位于中央后回（postcentral gyrus,POS）患者F-M评分较低（36±27）,以上两组F-M评分之间差异无统计学意义（P>0.05）。结论 fMRI可以显示卒中患者运动康复过程中功能区的变化;单侧放射冠脑梗死后,与运动任务相关的脑区激活范围存在明显偏侧化现象;偏侧化程度与患者上肢运动功能之间可能无明显关系。     

Longitudinal fMRI study for locomotor recovery in patients with stroke

The authors investigated bihemispheric motor network reorganization supporting locomotor recovery after stroke over time. They determined longitudinal changes in locomotor function and fMRI in 10 stroke patients at the subacute stage and the chronic stage. The results suggest that the bihemispheric reorganization mechanism underlying locomotor recovery evolved from the ipsilateral (contralesional) primary sensorimotor cortex (SM1) activation at the subacute stage to the contralateral (ipsilesional) SM1 activation at the chronic stage.