Ipsilesional Motor Cortex Activation with High-force Unimanual Handgrip Contractions of the Less-affected Limb in Participants with Stroke.

Stroke is a leading cause of severe disability that often presents with unilateral motor impairment. Conventional rehabilitation approaches focus on motor practice of the affected limb and aim to suppress brain activity in the contralesional hemisphere. Conversely, exercise of the less-affected limb promotes contralesional brain activity which is typically viewed as contraindicated in stroke recovery due to the interhemispheric inhibitory influence onto the ipsilesional hemisphere. Yet, high-force unimanual handgrip contractions are known to increase ipsilateral brain activation in control participants, and it remains to be determined if high-force contractions with the less-affected limb would promote ipsilateral brain activation in participants with stroke (i.e., the ipsilesional hemisphere). Therefore, this study aimed to determine how parametric increases in handgrip force during repeated contractions with the less-affected limb impacts brain activity bilaterally in participants with stroke and in a cohort of neurologically intact controls. Participants performed repeated submaximal contractions at 25%, 50%, and 75% of their maximum voluntary contraction during separate functional magnetic resonance imaging brain scans. Brain activation during the tasks was quantified as the percent change from resting levels. In this study, higher force contractions were found to increase brain activation in the ipsilesional (stroke)/ipsilateral (controls) hemisphere in both groups (p = .002), but no between group differences were observed. These data suggest that high-force exercise with the less-affected limb may promote ipsilesional cortical plasticity to promote motor recovery of the affected-limb in participants with stroke.

An fMRI, DTI and Neurophysiological Examination of Atypical Organization of Motor Cortex in Ipsilesional Hemisphere Following Post-Stroke Recovery.

OBJECTIVES: We report a 61-year-old woman who developed left hemiparesis following a right frontal stroke. She underwent rehabilitation and regained function of the left side of her body. Three years after her first stroke, she developed a large left subdural hematoma and again presented with left hemiparesis. MATERIALS AND METHODS: Prior to the cranioplasty, an fMRI scan involving left and right hand movement, arm movement, and foot peddling were conducted in order to determine whether the patient showed ipsilateral activation for the motor tasks, thus explaining the left hemiparesis following the left subdural hematoma. Diffusion tensor imaging (DTI) tractography was also collected to visualize the motor and sensory tracts. RESULTS: The fMRI results revealed activation in the expected contralateral left primary motor cortex (M1) for the right-sided motor tasks, and bilateral M1 activation for the left-sided motor tasks. Intraoperative neurophysiology confirmed these findings, whereby electromyography revealed left-sided (i.e., ipsilateral) responses for four of the five electrode locations. The DTI results indicated that the corticospinal tracts and spinothalamic tracts were within normal limits and showed no displacement or disorganization. CONCLUSIONS: These results suggest that there may have been reorganization of the M1 following her initial stroke, and that the left hemisphere may have become involved in moving the left side of the body thereby leading to left hemiparesis following the left subdural hematoma. The findings suggest that cortical reorganization may occur in stroke patients recovering from hemiparesis, and specifically, that components of motor processing subserved by M1 may be taken over by ipsilateral regions.

Paired associated magnetic stimulation promotes neural repair in the rat middle cerebral artery occlusion model of stroke.

Paired associative stimulation has been used in stroke patients as an innovative recovery treatment. However, the mechanisms underlying the therapeutic effectiveness of paired associative stimulation on neurological function remain unclear. In this study, rats were randomly divided into middle cerebral occlusion model (MCAO) and paired associated magnetic stimulation (PAMS) groups. The MCAO rat model was produced by middle cerebral artery embolization. The PAMS group received PAMS on days 3 to 20 post MCAO. The MCAO group received sham stimulation, three times every week. Within 18 days after ischemia, rats were subjected to behavioral experiments-the foot-fault test, the balance beam walking test, and the ladder walking test. Balance ability was improved on days 15 and 17, and the foot-fault rate was less in their affected limb on day 15 in the PAMS group compared with the MCAO group. Western blot assay showed that the expression levels of brain derived neurotrophic factor, glutamate receptor 2/3, postsynaptic density protein 95 and synapsin-1 were significantly increased in the PAMS group compared with the MCAO group in the ipsilateral sensorimotor cortex on day 21. Resting-state functional magnetic resonance imaging revealed that regional brain activities in the sensorimotor cortex were increased in the ipsilateral hemisphere, but decreased in the contralateral hemisphere on day 20. By finite element simulation, the electric field distribution showed a higher intensity, of approximately 0.4 A/m2, in the ischemic cortex compared with the contralateral cortex in the template. Together, our findings show that PAMS upregulates neuroplasticity-related proteins, increases regional brain activity, and promotes functional recovery in the affected sensorimotor cortex in the rat MCAO model. The experiments were approved by the Institutional Animal Care and Use Committee of Fudan University, China (approval No. 201802173S) on March 3, 2018.

Preclinical and Clinical Evidence on Ipsilateral Corticospinal Projections: Implication for Motor Recovery.

Motor impairment is the most common complication after stroke, and recovery of motor function has been shown to be dependent on the extent of lesion in the ipsilesional corticospinal tract (iCST) and activity within ipsilesional primary and secondary motor cortices. However, work from neuroimaging research has suggested a role of the contralesional hemisphere in promoting recovery after stroke potentially through the ipsilateral uncrossed CST fibers descending to ipsilateral spinal segments. These ipsilateral fibers, sometimes referred to as "latent" projections, are thought to contribute to motor recovery independent of the crossed CST. The aim of this paper is to evaluate using cumulative evidence from animal models and human patients on whether an uncrossed CST component is present in mammals and conserved through primates and humans, and whether iCST fibers have a functional role in hemiparetic/hemiplegic human conditions. This review highlights that an ipsilateral uncrossed CST exists in human during development, but the evidence on a functionally relevant iCST component in adult humans is still elusive. In addition, this review argues that whereas activity within the ipsilesional cortex is essential for enhancing motor recovery after stroke, the role of iCST projections specifically is still controversial. Finally, conclusions from current literature emphasize the importance of activity in the ipsilesional cortex and the integrity of crossed CST fibers as major determinants of motor recovery after brain injury.

Forelimb training drives transient map reorganization in ipsilateral motor cortex.

Skilled motor training results in reorganization of contralateral motor cortex movement representations. The ipsilateral motor cortex is believed to play a role in skilled motor control, but little is known about how training influences reorganization of ipsilateral motor representations of the trained limb. To determine whether training results in reorganization of ipsilateral motor cortex maps, rats were trained to perform the isometric pull task, an automated motor task that requires skilled forelimb use. After either 3 or 6 months of training, intracortical microstimulation (ICMS) mapping was performed to document motor representations of the trained forelimb in the hemisphere ipsilateral to that limb. Motor training for 3 months resulted in a robust expansion of right forelimb representation in the right motor cortex, demonstrating that skilled motor training drives map plasticity ipsilateral to the trained limb. After 6 months of training, the right forelimb representation in the right motor cortex was significantly smaller than the representation observed in rats trained for 3 months and similar to untrained controls, consistent with a normalization of motor cortex maps. Forelimb map area was not correlated with performance on the trained task, suggesting that task performance is maintained despite normalization of cortical maps. This study provides new insights into how the ipsilateral cortex changes in response to skilled learning and may inform rehabilitative strategies to enhance cortical plasticity to support recovery after brain injury.

Region and task-specific activation of Arc in primary motor cortex of rats following motor skill learning.

Motor learning requires protein synthesis within the primary motor cortex (M1). Here, we show that the immediate early gene Arc/Arg3.1 is specifically induced in M1 by learning a motor skill. Arc mRNA was quantified using a fluorescent in situ hybridization assay in adult Long-Evans rats learning a skilled reaching task (SRT), in rats performing reaching-like forelimb movement without learning (ACT) and in rats that were trained in the operant but not the motor elements of the task (controls). Apart from M1, Arc expression was assessed within the rostral motor area (RMA), primary somatosensory cortex (S1), striatum (ST) and cerebellum. In SRT animals, Arc mRNA levels in M1 contralateral to the trained limb were 31% higher than ipsilateral (p<0.001), 31% higher than in the contralateral M1 of ACT animals (p<0.001) and 48% higher than in controls (p<0.001). Arc mRNA expression in SRT was positively correlated with learning success between two sessions (r=0.52; p=0.026). For RMA, S1, ST or cerebellum no significant differences in Arc mRNA expression were found between hemispheres or across behaviors. As Arc expression has been related to different forms of cellular plasticity, these findings suggest a link between M1 Arc expression and motor skill learning in rats.