The role of diaschisis in stroke recovery.

BACKGROUND AND PURPOSE: Recovery from hemiparesis after stroke has been shown to involve reorganization in motor and premotor cortical areas. However, whether poststroke recovery also depends on changes in remote brain structures, ie, diaschisis, is as yet unresolved. To address this question, we studied regional cerebral blood flow in 7 patients (mean+/-SD age, 54+/-8 years) after their first hemiparetic stroke. METHODS: We analyzed imaging data voxel by voxel using a principal component analysis by which coherent changes in functional networks could be disclosed. Performance was assessed by a motor score and by the finger movement rate during the regional cerebral blood flow measurements. RESULTS: The patients had recovered (P<0. 001) from severe hemiparesis after on average 6 months and were able to perform sequential finger movements with the recovered hand. Regional cerebral blood flow at rest differentiated patients and controls (P<0.05) by a network that was affected by the stroke lesion. During blindfolded performance of sequential finger movements, patients were differentiated from controls (P<0.05) by a recovery-related network and a movement-control network. These networks were spatially incongruent, involving motor, sensory, and visual cortex of both cerebral hemispheres, the basal ganglia, thalamus, and cerebellum. The lesion-affected and recovery-related networks overlapped in the contralesional thalamus and extrastriate occipital cortex. CONCLUSIONS: Motor recovery after hemiparetic brain infarction is subserved by brain structures in locations remote from the stroke lesion. The topographic overlap of the lesion-affected and recovery-related networks suggests that diaschisis may play a critical role in stroke recovery.     

Resting state alpha-band functional connectivity and recovery after stroke

After cerebral ischemia, disruption and subsequent reorganization of functional connections occur both locally and remote to the lesion. However, the unpredictable timing and extent of sensorimotor recovery reflects a gap in understanding of these underlying neural mechanisms. We aimed to identify the plasticity of alpha-band functional neural connections within the perilesional area and the predictive value of functional connectivity with respect to motor recovery of the upper extremity after stroke. Our results show improvements in upper extremity motor recovery in relation to distributed changes in MEG-based alpha band functional connectivity, both in the perilesional area and contralesional cortex. Motor recovery was found to be predicted by increased connectivity at baseline in the ipsilesional somatosensory area, supplementary motor area, and cerebellum, contrasted with reduced connectivity of contralesional motor regions, after controlling for age, stroke onset-time and lesion size. These findings support plasticity within a widely distributed neural network and define brain regions in which the extent of network participation predicts post-stroke recovery potential.     

The differential roles of contralesional frontoparietal areas in cortical reorganization after stroke

BackgroundStudies examining the contribution of contralesional brain regions to motor recovery after stroke have revealed conflicting results comprising both supporting and disturbing influences. Especially the relevance of contralesional brain regions beyond primary motor cortex (M1) has rarely been studied, particularly concerning the temporal dynamics post-stroke.MethodsWe, therefore, used online transcranial magnetic stimulation (TMS) interference to longitudinally assess the role of contralesional (right) frontoparietal areas for recovery of hand motor function after left hemispheric stroke: contralesional M1, contralesional dorsal premotor cortex (dPMC), and contralesional anterior intraparietal sulcus (IPS). Fourteen stroke patients and sixteen age-matched healthy subjects performed motor tasks of varying complexity with their (paretic) right hand. Motor performance was quantified using three-dimensional kinematic data. All patients were assessed twice, (i) in the first week, and (ii) after more than three months post-stroke.ResultsWhile we did not observe a significant effect of TMS interference on movement kinematics following the stimulation of contralesional M1 and dPMC in the first week post-stroke, we found improvements of motor performance upon interference with contralesional IPS across motor tasks early after stroke, an effect that persisted into the later phase. By contrast, for dPMC, TMS-induced deterioration of motor performance was only evident three months post-stroke, suggesting that a supportive role of contralesional premotor cortex might evolve with reorganization.ConclusionWe here highlight time-sensitive and region-specific effects of contralesional frontoparietal areas after left hemisphere stroke, which may influence on neuromodulation regimes aiming at supporting recovery of motor function post-stroke.     

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.     

The role of the unaffected hemisphere in motor recovery after stroke

The contribution of the ipsilateral (nonaffected) hemisphere to recovery of motor function after stroke is controversial. Under the assumption that functionally relevant areas within the ipsilateral motor system should be tightly coupled to the demand we used fMRI and acoustically paced movements of the right index finger at six different frequencies to define the role of these regions for recovery after stroke. Eight well‐recovered patients with a chronic striatocapsular infarction of the left hemisphere were compared with eight age‐matched participants. As expected the hemodynamic response increased linearly with the frequency of the finger movements at the level of the left supplementary motor cortex (SMA) and the left primary sensorimotor cortex (SMC) in both groups. In contrast, a linear increase of the hemodynamic response with higher tapping frequencies in the right premotor cortex (PMC) and the right SMC was only seen in the patient group. These results support the model of an enhanced bihemispheric recruitment of preexisting motor representations in patients after subcortical stroke. Since all patients had excellent motor recovery contralesional SMC activation appears to be efficient and resembles the widespread, bilateral activation observed in healthy participants performing complex movements, instead of reflecting maladaptive plasticity. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

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 induced by task-oriented training in chronic hemiplegic stroke patients

We investigated the effect of task-oriented training (TT) on the cortical activation pattern in four chronic hemiparetic stroke patients. A TT program, consisting of six tasks, which were designed to improve hemiparetic upper extremity function, was performed for 40 min/day, 4 days/week for 4 weeks. The functional status of the affected hand and fMRI were assessed before and after the TT program. fMRI was performed at 1.5 T in parallel with timed finger flexion-extension exercises at a fixed rate. The main cortical activation changes with functional recovery were a decrease in the unaffected and an increase in the affected primary sensorimotor cortex activities. In conclusion, it seems that cortical reorganization was induced by the TT program in chronic hemiparetic stroke patients.     

Reorganization of sensory and motor systems in hemiplegic stroke patients. A positron emission tomography study.

BACKGROUND AND PURPOSE: Cortical reorganization of motor systems has been found in recovered stroke patients. Reorganization in nonrecovered hemiplegic stroke patients early after stroke, however, is less well described. We used positron emission tomography to study the functional reorganization of motor and sensory systems in hemiplegic stroke patients before motor recovery. METHODS: Regional cerebral blood flow (rCBF) was measured in 6 hemiplegic stroke patients with a single, subcortical infarct and 3 normal subjects with the [(15)O]H(2)O injection technique. Brain activation was achieved by passive elbow movements driven by a torque motor. Increases of rCBF comparing passive movements and rest were assessed with statistical parametric mapping. Significant differences were defined at P<0.01. RESULTS: In normal subjects, significant increases of rCBF were found in the contralateral sensorimotor cortex, supplementary motor area, cingulate cortex, and bilaterally in the inferior parietal cortex. In stroke patients, significant activation was observed bilaterally in the inferior parietal cortex and in the contralateral sensorimotor cortex, ipsilateral prefrontal cortex, supplementary motor area, and cingulate cortex. Significantly larger increases of rCBF in patients compared with normal subjects were found bilaterally in the sensorimotor cortex, stronger in the ipsilateral, unaffected hemisphere, and in both parietal lobes, including the ipsilateral precuneus. CONCLUSIONS: Passive movements in hemiplegic stroke patients before clinical recovery elicit some of the brain activation patterns that have been described during active movements after substantial motor recovery. Changes of cerebral activation in sensory and motor systems occur early after stroke and may be a first step toward restoration of motor function after stroke.     

Large‐scale reorganization of corticofugal fibers after neonatal hemidecortication for functional restoration of forelimb movements

As an experimental model to study the mechanism of large‐scale network plasticity of the juvenile brain, functional compensation after neonatal brain damage was studied in rats that received unilateral decortication at postnatal day 5. These animals exhibited a marked ability in reaching and grasping movements in the contralesional side of the forelimb when tested at 10–14 weeks of age. Additional lesion of the sensorimotor cortex in the remaining contralesional hemisphere at this stage resulted in severe impairment of both forelimbs. It was suggested that the sensorimotor cortex on the contralesional side was controlling the movements of both forelimbs. Following the injection of an anterograde tracer into the remaining sensorimotor cortex, the corticofugal axons from the remaining sensorimotor cortex were found to issue aberrant projections to the contralateral red nucleus, contralateral superior colliculus, contralateral pontine nuclei, ipsilateral dorsal column nucleus and ipsilateral gray matter of the cervical spinal cord, all of which appeared to be necessary for the control of contralesional forelimb movements. These results suggest that the forelimb movements on the contralesional side were compensated by large‐scale reorganization of the corticofugal axons from the remaining sensorimotor cortex.     

A functional MRI study of three motor tasks in the evaluation of stroke recovery

Functional brain imaging studies have provided insights into the processes related to motor recovery after stroke. The comparative value of different motor activation tasks for probing these processes has received limited study. We hypothesized that different hand motor tasks would activate the brain differently in controls, and that this would affect control-patient comparisons. Functional magnetic resonance imaging (MRI) was used to evaluate nine control subjects and seven patients with good recovery after a left hemisphere hemiparetic stroke. The volume of activated brain in bilateral sensorimotor cortex and four other motor regions was compared during each of three tasks performed by the right hand: index-finger tapping, four-finger tapping, and squeezing. In control subjects, activation in left sensorimotor cortex was found to be significantly larger during squeezing as compared with index-finger tapping. When comparing control subjects with stroke patients, patients showed a larger volume of activation in right sensorimotor cortex during index-finger tapping but not with four-finger tapping or squeezing. In addition, patients also showed a trend toward larger activation volume than controls within left supplementary motor area during index-finger tapping but not during the other tasks. Motion artifact was more common with squeezing than with the tapping tasks. The choice of hand motor tasks used during brain mapping can influence findings in control subjects as well as the differences identified between controls and stroke patients. The results may be useful for future studies of motor recovery after stroke.     

Functional recovery following motor cortex lesions in non-human primates: experimental implications for human stroke patients

This review discusses selected classical works and contemporary research on recovery of contralesional fine hand motor function following lesions to motor areas of the cerebral cortex in non-human primates. Findings from both the classical literature and contemporary studies show that lesions of cortical motor areas induce paresis initially, but are followed by remarkable recovery of fine hand/digit motor function that depends on lesion size and post-lesion training. Indeed, in recent work where considerable quantification of fine digit function associated with grasping and manipulating small objects has been observed, very favorable recovery is possible with minimal forced use of the contralesional limb. Studies of the mechanisms underlying recovery have shown that following small lesions of the digit areas of primary motor cortex (M1), there is expansion of the digit motor representations into areas of M1 that did not produce digit movements prior to the lesion. However, after larger lesions involving the elbow, wrist and digit areas of M1, no such expansion of the motor representation was observed, suggesting that recovery was due to other cortical or subcortical areas taking over control of hand/digit movements. Recently, we showed that one possible mechanism of recovery after lesion to the arm areas of M1 and lateral premotor cortex is enhancement of corticospinal projections from the medially located supplementary motor area (M2) to spinal cord laminae containing neurons which have lost substantial input from the lateral motor areas and play a critical role in reaching and digit movements. Because human stroke and brain injury patients show variable, and usually poorer, recovery of hand motor function than that of nonhuman primates after motor cortex damage, we conclude with a discussion of implications of this work for further experimentation to improve recovery of hand function in human stroke patients.     

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 relevance of abnormal fMRI activation pattern after unilateral schizencephaly

Brain plasticity was investigated in a child with a hemiplegia due to unilateral schizencephaly involving the sensorimotor cortex. This focal lesion led to a dramatic functional reorganization of the undamaged hemisphere, as evidenced by the unusual pattern of fMRI activation during paretic finger movements. The functional relevance of the activation in the undamaged motor cortex was supported by the finding that TMS of this area yielded a response in the paretic hand, indicating that it controls both hands. However, this reorganization was not restricted to the primary motor cortex, but also concerned other structures involved in the control of movements, as shown by the activation of contralesional SMA and thalamus. In contrast, the fMRI activation in the damaged sensorimotor cortex during paretic hand movements appears functionally irrelevant.     

Evolution of functional reorganization in hemiplegic stroke: a serial positron emission tomographic activation study

We used serial positron emission tomography (PET) to study the evolution of functional brain activity within 12 weeks after a first subcortical stroke. Six hemiplegic stroke patients and three normal subjects were scanned twice (PET 1 and PET 2) by using passive elbow movements as an activation paradigm. Increases of regional cerebral blood flow comparing passive movements and rest and differences of regional cerebral blood flow between PET 1 and PET 2 in patients and normal subjects were assessed by using statistical parametric mapping. In controls, activation was found in the contralateral sensorimotor cortex, supplementary motor area, and bilaterally in the inferior parietal cortex with no differences between PET 1 and PET 2. In stroke patients, at PET 1, activation was observed in the bilateral inferior parietal cortex, contralateral sensorimotor cortex, and ipsilateral dorsolateral prefrontal cortex, supplementary motor area, and cingulate cortex. At PET 2, significant increases of regional cerebral blood flow were found in the contralateral sensorimotor cortex and bilateral inferior parietal cortex. A region that was activated at PET 2 only was found in the ipsilateral premotor area. Recovery from hemiplegia is accompanied by changes of brain activation in sensory and motor systems. These alterations of cerebral activity may be critical for the restoration of motor function.     

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.     

Correspondence between altered functional and structural connectivity in the contralesional sensorimotor cortex after unilateral stroke in rats: a combined resting-state functional MRI and manganese-enhanced MRI study

This study shows a significant correlation between functional connectivity, as measured with resting-state functional magnetic resonance imaging (MRI), and neuroanatomical connectivity, as measured with manganese-enhanced MRI, in rats at 10 weeks after unilateral stroke and in age-matched controls. Reduced interhemispheric functional connectivity between the contralesional primary motor cortex (M1) and ipsilesional sensorimotor cortical regions was accompanied by a decrease in transcallosal manganese transfer from contralesional M1 to the ipsilesional sensorimotor cortex after a large unilateral stroke. Increased intrahemispheric functional connectivity in the contralesional sensorimotor cortex was associated with locally enhanced neuroanatomical tracer uptake, which underlines the strong link between functional and structural reorganization of neuronal networks after stroke.     

The sensorimotor transformation of cross-modal spatial information in the anterior intraparietal sulcus as revealed by functional MRI

The parietal cortex in monkeys and humans has been shown to play an important role in the transformation of sensory information to motor commands. However, it is still unclear whether in humans, these areas are divided functionally into subregions based on different combinations of sensory and motor modalities. To identify subregions in the parietal cortex involved in the sensorimotor information transformation between different modalities, functional MRI was used to examine brain areas activated during tasks requiring different sensorimotor transformations--i.e., various combinations of eye (saccade) or finger movements triggered by visual or somatosensory cues. We then compared the activations between cross-modal conditions (eye movements triggered by somatosensory cues and finger movements triggered by visual cues) and intramodal (eye movements triggered by visual cues and finger movements triggered by somatosensory cues) conditions. Although the parietal cortex was involved in all tasks regardless of sensorimotor combinations, the only region activated to a greater degree in the cross-modal conditions compared to the intramodal conditions was the anterior portion of the intraparietal sulcus (a-IPS). The results suggest that the a-IPS plays an important role in the sensorimotor transformation of cross-modal spatial information.     

Changes of cortico-cortical neural connections associated with motor functional recovery after stroke

ObjectivesDuring functional recovery after stroke, some neural connections in the brain are augmented and new neural networks are constructed to compensate for impaired neurological functions. Recently, it was reported that the extent of cortico-cortical neural connections can be estimated by correlation analysis based on electroencephalography (EEG). The purpose of this study was to investigate changes of correlation coefficients in the cerebral cortex with motor functional recovery after stroke.Materials and methodsTwenty-two post-stroke hemiparetic patients admitted to our rehabilitation ward (mean age at admission: 71.4 ± 12.9 years old), were studied. For the evaluation of hemiparesis, Fugl-Meyer Assessment (FMA) was applied. All subjects underwent EEG with electrodes placed according to the international 10-20 system for correlation analysis, on admission to our ward and 4 weeks after admission. EEG data were analyzed with the program software FOCUS (NIHON KOHDEN, Japan), and squared correlation coefficients in some cortico-cortical areas of the cerebral cortex were calculated.ResultsThe correlation coefficients in some cortico-cortical areas of the lesional hemisphere, such as C3-F3 or C4-F4, C3-F7 or C4-F8, and F3-F7 or F4-F8, significantly increased with rehabilitation training. The change of the correlation coefficient in F3-F7 or F4-F8 and F7-T3 or F8-T4 in the lesional hemisphere was significantly correlated with the change of the upper-limb FMA.ConclusionsThe augmentation of cortico-cortical connections, represented by an increase of the correlation coefficient in the lesional hemisphere, may contribute to motor functional recovery, especially in hemiparetic upper limbs, after stroke.     

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.     

Microstructural status of ipsilesional and contralesional corticospinal tract correlates with motor skill in chronic stroke patients

Greater loss in structural integrity of the ipsilesional corticospinal tract (CST) is associated with poorer motor outcome in patients with hemiparetic stroke. Animal models of stroke have demonstrated that structural remodeling of white matter in the ipsilesional and contralesional hemispheres is associated with improved motor recovery. Accordingly, motor recovery in patients with stroke may relate to the relative strength of CST degeneration and remodeling. This study examined the relationship between microstructural status of brain white matter tracts, indexed by the fractional anisotropy (FA) metric derived from diffusion tensor imaging (DTI) data, and motor skill of the stroke‐affected hand in patients with chronic stroke. Voxelwise analysis revealed that motor skill significantly and positively correlated with FA of the ipsilesional and contralesional CST in the patients. Additional voxelwise analyses showed that patients with poorer motor skill had reduced FA of bilateral CST compared to normal control subjects, whereas patients with better motor skill had elevated FA of bilateral CST compared to controls. These findings were confirmed using a DTI‐tractography method applied to the CST in both hemispheres. The results of this study suggest that the level of motor skill recovery achieved in patients with hemiparetic stroke relates to microstructural status of the CST in both the ipsilesional and contralesional hemispheres, which may reflect the net effect of degeneration and remodeling of bilateral CST. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.