Contralesional Activity Research Articles

Closed-loop cervical epidural stimulation partially restores ipsilesional diaphragm EMG after acute C2 hemisection

Cervical spinal cord injury creates lasting respiratory deficits which can require mechanical ventilation long-term. We have shown that closed-loop epidural stimulation (CL-ES) elicits respiratory plasticity in the form of increased phrenic network excitability (Malone et. al., E Neuro, Vol 9, 0426–21.2021, 2022); however, the ability of this treatment to create functional benefits for breathing function per se after injury has not been demonstrated. Here, we demonstrate in C2 hemisected anesthetized rats, a 20-minute bout of CL-ES administered at current amplitudes below the motor threshold restores paralyzed hemidiaphragm activity in-phase with breathing while potentiating contralesional activity. While this acute bout of stimulation did not elicit the increased network excitability seen in our chronic model, a subset of stimulated animals continued spontaneous ipsilesional diaphragm activity for several seconds after stopping stimulation. These results support the use of CL-ES as a therapeutic to rescue breathing after high cervical spinal cord injury, with the potential to lead to lasting recovery and device independence.

Homotopic contralesional excitation suppresses spontaneous circuit repair and global network reconnections following ischemic stroke.

Understanding circuit-level manipulations that affect the brain's capacity for plasticity will inform the design of targeted interventions that enhance recovery after stroke. Following stroke, increased contralesional activity (e.g. use of the unaffected limb) can negatively influence recovery, but it is unknown which specific neural connections exert this influence, and to what extent increased contralesional activity affects systems- and molecular-level biomarkers of recovery. Here, we combine optogenetic photostimulation with optical intrinsic signal imaging to examine how contralesional excitatory activity affects cortical remodeling after stroke in mice. Following photothrombosis of left primary somatosensory forepaw (S1FP) cortex, mice either recovered spontaneously or received chronic optogenetic excitation of right S1FP over the course of 4 weeks. Contralesional excitation suppressed perilesional S1FP remapping and was associated with abnormal patterns of stimulus-evoked activity in the unaffected limb. This maneuver also prevented the restoration of resting-state functional connectivity (RSFC) within the S1FP network, RSFC in several networks functionally distinct from somatomotor regions, and resulted in persistent limb-use asymmetry. In stimulated mice, perilesional tissue exhibited transcriptional changes in several genes relevant for recovery. Our results suggest that contralesional excitation impedes local and global circuit reconnection through suppression of cortical activity and several neuroplasticity-related genes after stroke, and highlight the importance of site selection for targeted therapeutic interventions after focal ischemia.

Functional reorganization of language networks for semantics and syntax in chronic stroke: Evidence from MEG.

Using magnetoencephalography, we investigated the potential of perilesional and contralesional activity to support language recovery in patients with poststroke aphasia. In healthy young controls, left-lateralized ventral frontotemporal regions responded to semantic anomalies during sentence comprehension and bilateral dorsal frontoparietal regions responded to syntactic anomalies. Older adults showed more extensive bilateral responses to the syntactic anomalies and less lateralized responses to the semantic anomalies, with decreased activation in the left occipital and parietal regions for both semantic and syntactic anomalies. In aphasic participants, we observed compensatory recruitment in the right hemisphere (RH), which varied depending on the type of linguistic information that was processed. For semantic anomalies, aphasic patients activated some preserved left hemisphere regions adjacent to the lesion, as well as homologous parietal and temporal RH areas. Patients also recruited right inferior and dorsolateral frontal cortex that was not activated in the healthy participants. Responses for syntactic anomalies did not reach significance in patients. Correlation analyses indicated that recruitment of homologous temporoparietal RH areas is associated with better semantic performance, whereas higher accuracy on the syntactic task was related to bilateral superior temporoparietal and right frontal activity. The results suggest that better recovery of semantic processing is associated with a shift to ventral brain regions in the RH. In contrast, preservation of syntactic processing is mediated by dorsal areas, bilaterally, although recovery of syntactic processing tends to be poorer than semantic. Hum Brain Mapp 37:2869-2893, 2016. © 2016 Wiley Periodicals, Inc.

Pilot Study Evaluating Functional Outcome Post-Intervention for Patients with Acquired Brain Injury and Their Caregivers

Results: Our results revealed no significant change in FMA and BI scores between the two groups. Although, the participants who received rTMS over the contralesional hemisphere did show some significant improvement in their FMA scores (hand function), as compared to baseline. Conclusions: The role of the contralesional hemisphere is not clear with respect to motor recovery and performance after stroke. Current evidence suggests that the importance and role of contralesional neural activity is probably determined by variables such as the time since stroke, the degree of damage to the motor system and the complexity of the motor task.

The functional anatomy of motor imagery after sub-acute stroke.

The neural correlates of motor imagery (MI) are tightly coupled with the cortical motor control network. Therefore MI may have therapeutic potential for patients with motor deficits after an ischemic stroke. The aim of our study was to assess the hemispheric balance of the cortical motor network during motor imagery (MI) in patients recovering from stroke in the sub-acute stage. We studied 17 patients after cerebral ischemic stroke (sub-acute stage) and 12 healthy subjects using functional Magnetic Resonance Imaging (fMRI) during motor imagery and performance of isometric grip force movements (5 Newton). Laterality indices (LI) were calculated from regional activation analysis to assess hemispheric distribution of activity in pre-specified motor areas. Laterality index (LI) revealed a more balanced cortical activity in MI for both controls (-0.03) and patients (-0.12) in the premotor cortex compared to movement execution (0.48 controls; 0.12 patients) and a trend towards a shift in contra-lesional activity in stroke patients. Our results indicate a preserved interhemispheric balance of patients in the sub-acute stage when activating the cortical motor areas during MI. This could provide a reasonable physiologic baseline for using MI as an additional rehabilitative therapy for improving functional recovery in the sub-acute stage after stroke.

Inhibition of the contralesional hemisphere after stroke: reviewing a few of the building blocks with a focus on animal models.

The last decade of neuroscience research has revealed that the adult brain can undergo substantial reorganization following injury. Plasticity after stroke has traditionally been perceived as adaptive and supporting recovery, but recent studies have suggested that some plasticity may also be detrimental. In particular, increased activity in the unaffected (contralesional) hemisphere has been proposed to contribute to motor deficits of the paretic hand in some patients. Longitudinal imaging studies in humans have reported a progressive behavioral improvement associated with a decrease of contralesional activity and have correlated the intensity of contralesional hemisphere activity with the degree of motor impairment. Consequently, inhibitory neuromodulatory protocols have been applied to the contralesional hemisphere of stroke patients. Such protocols can facilitate the activation of the ipsilesional motor cortex and improve the function of the paretic limb. Although the use of noninvasive techniques after brain injury shows promise, much work needs to be done to understand better how these approaches affect postlesion plasticity and motor recovery. Ultimately, this knowledge will allow for the design of more effective treatments and will potentially lead to protocols adapted to the specific condition of each patient. In this chapter, we review the literature on the basic pathways that can support the effects of contralesional inhibition, interhemispheric interactions, and some of the changes that can occur in the sensorimotor network after stroke. Finally, we show work in rats that demonstrates how parameters of contralesional inactivation can affect postlesion recovery.

Stroke induced reorganization of the neural networks for sentence comprehension, and relationship to perilesional dysfunction revealed by MEG and ASL

Stroke induced reorganization of the neural networks for sentence comprehension, and relationship to perilesional dysfunction revealed by MEG and ASL

Stroke rehabilitation using noninvasive cortical stimulation: aphasia

Poststroke aphasia results from the lesion of cortical areas involved in the motor production of speech (Broca’s aphasia) or in the semantic aspects of language comprehension (Wernicke’s aphasia). Such lesions produce an important reorganization of speech/language-specific brain networks due to an imbalance between cortical facilitation and inhibition. In fact, functional recovery is associated with changes in the excitability of the damaged neural structures and their connections. Two main mechanisms are involved in poststroke aphasia recovery: the recruitment of perilesional regions of the left hemisphere in case of small lesion and the acquisition of language processing ability in homotopic areas of the nondominant right hemisphere when left hemispheric language abilities are permanently lost. There is some evidence that noninvasive cortical stimulation, especially when combined with language therapy or other therapeutic approaches, can promote aphasia recovery. Cortical stimulation was mainly used to either increase perilesional excitability or reduce contralesional activity based on the concept of reciprocal inhibition and maladaptive plasticity. However, recent studies also showed some positive effects of the reinforcement of neural activities in the contralateral right hemisphere, based on the potential compensatory role of the nondominant hemisphere in stroke recovery.

Activation likelihood estimation meta-analysis of motor-related neural activity after stroke

Over the past two decades, several functional neuroimaging experiments demonstrated changes in neural activity in stroke patients with motor deficits. Conclusions from single experiments are usually constrained by small sample sizes and high variability across studies. Here, we used coordinate-based activation likelihood estimation meta-analyses to provide a quantitative synthesis of the current literature on motor-related neural activity after stroke. Of over 1000 PubMed search results through January 2011, 36 studies reported standardized whole-brain group coordinates. Meta-analyses were performed on 54 experimental contrasts for movements of the paretic upper limb (472 patients, 452 activation foci) and on 20 experiments comparing activation between patients and healthy controls (177 patients, 113 activation foci). We computed voxelwise correlations between activation likelihood and motor impairment, time post-stroke, and task difficulty across samples. Patients showed higher activation likelihood in contralesional primary motor cortex (M1), bilateral ventral premotor cortex and supplementary motor area (SMA) relative to healthy subjects. Activity in contralesional areas was more likely found for active than for passive tasks. Better motor performance was associated with greater activation likelihood in ipsilesional M1, pre-SMA, contralesional premotor cortex and cerebellum. Over time post-stroke, activation likelihood in bilateral premotor areas and medial M1 hand knob decreased. This meta-analysis shows that increased activation in contralesional M1 and bilateral premotor areas is a highly consistent finding after stroke despite high inter-study variance resulting from different fMRI tasks and motor impairment levels. However, a good functional outcome relies on the recruitment of the original functional network rather than on contralesional activity.

Speech Facilitation by Left Inferior Frontal Cortex Stimulation

SummaryElectrophysiological studies in humans and animals suggest that noninvasive neurostimulation methods such as transcranial direct current stimulation (tDCS) can elicit long-lasting [1], polarity-dependent [2] changes in neocortical excitability. Application of tDCS can have significant and selective behavioral consequences that are associated with the cortical location of the stimulation electrodes and the task engaged during stimulation [3–8]. However, the mechanism by which tDCS affects human behavior is unclear. Recently, functional magnetic resonance imaging (fMRI) has been used to determine the spatial topography of tDCS effects [9–13], but no behavioral data were collected during stimulation. The present study is unique in this regard, in that both neural and behavioral responses were recorded using a novel combination of left frontal anodal tDCS during an overt picture-naming fMRI study. We found that tDCS had significant behavioral and regionally specific neural facilitation effects. Furthermore, faster naming responses correlated with decreased blood oxygen level-dependent (BOLD) signal in Broca's area. Our data support the importance of Broca's area within the normal naming network and as such indicate that Broca's area may be a suitable candidate site for tDCS in neurorehabilitation of anomic patients, whose brain damage spares this region.

Task-modulated neural activation patterns in chronic stroke patients with aphasia

Background: Neuroimaging research on language recovery in patients with aphasia due to left hemisphere damage has generated some intriguing results. However, it is still not clear what role the right hemisphere plays in supporting recovered language functions in the chronic phase for patients with different site and size of lesion when different tasks are used. Aims: The present study aimed at exploring the role of perilesional, ipsilesional, and contralesional activation in participants with aphasia with different site and size of lesion using two different language tasks. All participants were in the chronic stage with well- recovered or significant improvements in language functions. Methods & Procedures: Functional magnetic resonance imaging (fMRI) was used to characterise brain activations in eight stroke patients and eight age/gender-matched controls during semantic judgement and oral picture naming. An event-related design using jittered interstimulus intervals (ISIs) was employed to present the stimuli. Outcomes & Results: The fMRI scans of both language tasks in patients revealed differences in activation pattern relative to the normal control participants. The nature of this difference was task specific. During the semantic judgement task patients without lesions involving the left frontal region activated the left inferior frontal gyrus similar to observations in the normal control participants. Participants with left frontal lesions activated contralesional regions in addition to perilesional left frontal regions. During the picture-naming task all participants activated bilateral brain regions irrespective of the site or size of lesion, consistent with other published studies utilising this task. Subsequent regions of interest analysis and laterality index analysis revealed that patients with large lesions produced greater right hemisphere activation than patients with small lesions. Conclusions: The results of this study demonstrate that recovery is task, lesion site, and size specific. Further, the results also indicate a role for both activation of homologous contralesional cortex and activity of left hemisphere regions (perilesional and ipsilesional) as efficient mechanisms for supporting language functions in chronic stroke patients.

What Can Neuroimaging Tell Us About Aphasia?

What Can Neuroimaging Tell Us About Aphasia?

Single-trial fMRI Shows Contralesional Activity Linked to Overt Naming Errors in Chronic Aphasic Patients

We used fMRI to investigate the roles played by perilesional and contralesional cortical regions during language production in stroke patients with chronic aphasia. We applied comprehensive psycholinguistic analyses based on well-established models of lexical access to overt picture-naming responses, which were evaluated using a single trial design that permitted distinction between correct and incorrect responses on a trial-by-trial basis. Although both correct and incorrect naming responses were associated with left-sided perilesional activation, incorrect responses were selectively associated with robust right-sided contralesional activity. Most notably, incorrect responses elicited overactivation in the right inferior frontal gyrus that was not observed in the contrasts for patients' correct responses or for responses of age-matched control subjects. Errors were produced at slightly later onsets than accurate responses and comprised predominantly semantic paraphasias and omissions. Both types of errors were induced by pictures with greater numbers of alternative names, and omissions were also induced by pictures with late acquired names. These two factors, number of alternative names per picture and age of acquisition, were positively correlated with activation in left and right inferior frontal gyri in patients as well as control subjects. These results support the hypothesis that some right frontal activation may normally be associated with increasing naming difficulty, but in patients with aphasia, right frontal overactivation may reflect ineffective effort when left hemisphere perilesional resources are insufficient. They also suggest that contralesional areas continue to play a role--dysfunctional rather than compensatory--in chronic aphasic patients who have experienced a significant degree of recovery.

Neural Correlates of Proprioceptive Integration in the Contralesional Hemisphere of Very Impaired Patients Shortly After a Subcortical Stroke: An fMRI Study

Background. The effects of physiotherapy are difficult to assess in very impaired early stroke patients. Objective. The aim of the study was to characterize the impact of 4 weeks of passive proprioceptive training of the wrist on brain sensorimotor activation after stroke. Methods. Patients with a subcortical ischemic lesion of the pyramidal tract were randomly assigned to a control or a wrist-training group. All patients had a single pure motor hemiplegia with severe motor deficit. The control group (6 patients) underwent standard Bobath rehabilitation. The second, “trained,” group (7 patients) received Bobath rehabilitation plus 4 weeks of proprioceptive training with daily passive calibrated wrist extension. Before and after the training period, patients were examined with validated clinical scales and functional MRI (fMRI) while executing a passive movement versus rest. The effect of standard rehabilitation on sensorimotor activation was assessed in the control group on the wrist, and the effect of standard rehabilitation plus proprioceptive training was assessed in the trained group. The effect of 4-week proprioceptive training alone was statistically evaluated by difference between groups. Results. Standard rehabilitation along with natural recovery mainly led to increases in ipsilesional activation and decreases in contralesional activation. On the contrary, standard rehabilitation and paretic wrist proprioceptive training increased contralesional activation. Proprioceptive training produced change in the supplementary motor area (SMA), prefrontal cortex, and a contralesional network including inferior parietal cortex (lower part of BA 40), secondary sensory cortex, and ventral premotor cortex (PMv). Conclusion. We have demonstrated that purely passive proprioceptive training applied for 4 weeks is able to modify brain sensorimotor activity after a stroke. This training revealed fMRI change in the ventral premotor and parietal cortices of the contralesional hemisphere, which are secondary sensorimotor areas. Recent studies have demonstrated the crucial role of these areas in severely impaired patients. We propose that increased contralesional activity in secondary sensorimotor areas likely facilitates control of recovered motor function by simple proprioceptive integration in those patients with poor recovery.

Multimodal imaging of brain reorganization in motor areas of the contralesional hemisphere of well recovered patients after capsular stroke

Clinical recovery after stroke can be significant and has been attributed to plastic reorganization and recruitment of novel areas previously not engaged in a given task. As equivocal results have been reported in studies using single imaging or electrophysiological methods, here we applied an integrative multimodal approach to a group of well-recovered chronic stroke patients (n = 11; aged 50-81 years) with left capsular lesions. Focal activation during recovered hand movements was assessed with EEG spectral analysis and H2(15)O-PET with EMG monitoring, cortico-cortical connectivity with EEG coherence analysis (cortico-cortical coherence) and corticospinal connectivity with transcranial magnetic stimulation (TMS). As seen from comparisons with age-matched controls, our patients showed enhanced recruitment of the lateral premotor cortex of the lesioned hemisphere [Brodmann area (BA) 6], lateral premotor and to a lesser extent primary sensorimotor and parietal cortex of the contralesional hemisphere (CON-H; BA 4 and superior parietal lobule) and left cerebellum (patients versus controls, Z > 3.09). EEG coherence analysis showed that after stroke cortico-cortical connections were reduced in the stroke hemisphere but relatively increased in the CON-H (ANOVA, contrast analysis, P < 0.05), suggesting a shift of functional connectivity towards the CON-H. Nevertheless, fast conducting corticospinal transmission originated exclusively from the lesioned hemisphere. No direct ipsilateral motor evoked potentials (MEPs) could be elicited with TMS over the contralesional primary motor cortex (iM1) in stroke patients. We conclude that (i) effective recovery is based on enhanced utilization of ipsi- and contralesional resources, (ii) basic corticospinal commands arise from the lesioned hemisphere without recruitment of ('latent') uncrossed corticospinal tract fibres and (iii) increased contralesional activity probably facilitates control of recovered motor function by operating at a higher-order processing level, similar to but not identical with the extended network concerned with complex movements in healthy subjects.

Reorganization of Motor Execution Rather Than Preparation in Poststroke Hemiparesis

The aim of the present study was to examine movement-related potentials (MRPs) in patients in the "chronic" stage after cortical stroke with recovered hemiparesis compared with healthy control subjects. Right index finger MRPs were derived from 12 patients > or =1 year after infarction in the territory of the left middle cerebral artery as well as from 12 control subjects. MRP components were compared between groups. In the patient group, the component directly preceding movement onset (negative slope [NS]) was significantly reduced over the lesioned hemisphere contralateral to the movement. Furthermore, increased motor potentials (MPs) were observed over the contralesional hemisphere during movement execution. No changes in the early MRP (Bereitschaftspotential) reflecting movement preparation were found. Because the NS is supposed to be generated by the primary motor cortex, the decreased component over the lesioned hemisphere is interpreted to represent impaired contralateral M1 functioning in stroke patients. Contralesional activity has been reported as a probable sign of brain plasticity by functional imaging studies. Our results broaden these findings, giving new insights into the temporal course of movement-related brain activity in recovered cortical stroke patients. The data point to a functional reorganization of motor execution rather than preparation in poststroke hemiparesis.

Motor Impairment and Recovery in the Upper Limb After Stroke

Motor recovery after stroke is associated with cerebral reorganization. However, few studies have investigated the relationship directly, and findings are equivocal. We therefore aimed to characterize the relationship between motor impairment, motor recovery, and task-related changes in regional cerebral blood flow (DeltarCBF) longitudinally. We obtained a profile of motor impairment and recovery in the upper limb and conducted positron emission tomography motor activation studies using a simple finger-tapping task in 9 stroke patients 2 to 7 weeks after stroke and 6 months later. For correlation analysis, mean images of task-related DeltarCBF for each individual were linearly regressed with motor impairment scores. Motor recovery was correlated with longitudinal DeltarCBF images. Patients (7 males; 72.0+/-9.8 years) demonstrated a wide range of impairment severity and variable recovery. Upper-limb motor function was linearly correlated with task-related DeltarCBF. Importantly, sites of correlated DeltarCBF differed over time. Subacutely correlated DeltarCBF was observed in supplementary motor area (SMA), bilateral cingulate, and contralesional insula with a small area in ipsilesional primary sensorimotor cortex (SM1). Conversely, at the 6-month study, correlated DeltarCBF was primarily in ipsilesional SM1, extending to the cingulate gyrus. Better motor recovery was correlated with reduction in contralesional activity and increase in ipsilesional SM1. Upper-limb motor function and recovery are correlated with DeltarCBF in SMA, cingulate, insula, and SM1, highlighting the role of these areas in the recovery process. The dynamic nature of the relationship suggests ongoing adaptation within motor networks.

Evolution of cortical activation during recovery from corticospinal tract infarction.

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. 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. 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. 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.