Ipsilesional M1 Research Articles

Stroke Lesion Volume and Injury to Motor Cortex Output Determines Extent of Contralesional Motor Cortex Reorganization

Background After stroke, increases in contralesional primary motor cortex (M1CL) activity and excitability have been reported. In pre-clinical studies, M1CL reorganization is related to the extent of ipsilesional M1 (M1IL) injury, but this has yet to be tested clinically. Objectives We tested the hypothesis that the extent of damage to the ipsilesional M1 and/or its corticospinal tract (CST) determines the magnitude of M1CL reorganization and its relationship to affected hand function in humans recovering from stroke. Methods Thirty-five participants with a single subacute ischemic stroke affecting M1 or CST and hand paresis underwent MRI scans of the brain to measure lesion volume and CST lesion load. Transcranial magnetic stimulation (TMS) of M1IL was used to determine the presence of an electromyographic response (motor evoked potential (MEP+ and MEP−)). M1CL reorganization was determined by TMS applied to M1CL at increasing intensities. Hand function was quantified with the Jebsen Taylor Hand Function Test. Results The extent of M1CL reorganization was related to greater lesion volume in the MEP− group, but not in the MEP+ group. Greater M1CL reorganization was associated with more impaired hand function in MEP− but not MEP+ participants. Absence of an MEP (MEP−), larger lesion volumes and higher lesion loads in CST, particularly in CST fibers originating in M1 were associated with greater impairment of hand function. Conclusions In the subacute post-stroke period, stroke volume and M1IL output determine the extent of M1CL reorganization and its relationship to affected hand function, consistent with pre-clinical evidence. ClinicalTrials.gov Identifier: NCT02544503

Motor network reorganization after motor imagery training in stroke patients with moderate to severe upper limb impairment.

Motor imagery training (MIT) has been widely used to improve hemiplegic upper limb function in stroke rehabilitation. The effectiveness of MIT is associated with the functional neuroplasticity of the motor network. Currently, brain activation and connectivity changes related to the motor recovery process after MIT are not well understood. We aimed to investigate the neural mechanisms of MIT in stroke rehabilitation through a longitudinal intervention study design with task-based functional magnetic resonance imaging (fMRI) analysis. We recruited 39 stroke patients with moderate to severe upper limb motor impairment and randomly assigned them to either the MIT or control groups. Patients in the MIT group received 4 weeks of MIT therapy plus conventional rehabilitation, while the control group only received conventional rehabilitation. The assessment of Fugl-Meyer Upper Limb Scale (FM-UL) and Barthel Index (BI), and fMRI scanning using a passive hand movement task were conducted on all patients before and after treatment. The changes in brain activation and functional connectivity (FC) were analyzed. Pearson's correlation analysis was conducted to evaluate the association between neural functional changes and motor improvement. The MIT group achieved higher improvements in FM-UL and BI relative to the control group after the treatment. Passive movement of the affected hand evoked an abnormal bilateral activation pattern in both groups before intervention. A significant Group × Time interaction was found in the contralesional S1 and ipsilesional M1, showing a decrease of activation after intervention specifically in the MIT group, which was negatively correlated with the FM-UL improvement. FC analysis of the ipsilesional M1 displayed the motor network reorganization within the ipsilesional hemisphere, which correlated with the motor score changes. MIT could help decrease the compensatory activation at both hemispheres and reshape the FC within the ipsilesional hemisphere along with functional recovery in stroke patients.

Resting-state functional connectivity for determining outcomes in upper extremity function after stroke: A functional near-infrared spectroscopy study

Functional near-infrared spectroscopy (fNIRS) is a non-invasive and promising tool to map the brain functional networks in stroke recovery. Our study mainly aimed to use fNIRS to detect the different patterns of resting-state functional connectivity (RSFC) in subacute stroke patients with different degrees of upper extremity motor impairment defined by Fugl-Meyer motor assessment of upper extremity (FMA-UE). The second aim was to investigate the association between FMA-UE scores and fNIRS-RSFC among different regions of interest (ROIs) in stroke patients. Forty-nine subacute (2 weeks-6 months) stroke patients with subcortical lesions were enrolled and were classified into three groups based on FMA-UE scores: mild impairment (n = 17), moderate impairment (n = 13), and severe impairment (n = 19). All patients received FMA-UE assessment and 10-min resting-state fNIRS monitoring. The fNIRS signals were recorded over seven ROIs: bilateral dorsolateral prefrontal cortex (DLPFC), middle prefrontal cortex (MPFC), bilateral primary motor cortex (M1), and bilateral primary somatosensory cortex (S1). Functional connectivity (FC) was calculated by correlation coefficients between each channel and each ROI pair. To reveal the comprehensive differences in FC among three groups, we compared FC on the group level and ROI level. In addition, to determine the associations between FMA-UE scores and RSFC among different ROIs, Spearman's correlation analyses were performed with a significance threshold of p < 0.05. For easy comparison, we defined the left hemisphere as the ipsilesional hemisphere and flipped the lesional right hemisphere in MATLAB R2013b. For the group-level comparison, the one-way ANOVA and post-hoc t-tests (mild vs. moderate; mild vs. severe; moderate vs. severe) showed that there was a significant difference among three groups (F = 3.42, p = 0.04) and the group-averaged FC in the mild group (0.64 ± 0.14) was significantly higher than that in the severe group (0.53 ± 0.14, p = 0.013). However, there were no significant differences between the mild and moderate group (MD ± SE = 0.05 ± 0.05, p = 0.35) and between the moderate and severe group (MD ± SE = 0.07 ± 0.05, p = 0.16). For the ROI-level comparison, the severe group had significantly lower FC of ipsilesional DLPFC-ipsilesional M1 [p = 0.015, false discovery rate (FDR)-corrected] and ipsilesional DLPFC-contralesional M1 (p = 0.035, FDR-corrected) than those in the mild group. Moreover, the result of Spearman's correlation analyses showed that there were significant correlations between FMA-UE scores and FC of the ipsilesional DLPFC-ipsilesional M1 (r = 0.430, p = 0.002), ipsilesional DLPFC-contralesional M1 (r = 0.388, p = 0.006), ipsilesional DLPFC-MPFC (r = 0.365, p = 0.01), and ipsilesional DLPFC-contralesional DLPFC (r = 0.330, p = 0.021). Our findings indicate that different degrees of post-stroke upper extremity impairment reflect different RSFC patterns, mainly in the connection between DLPFC and bilateral M1. The association between FMA-UE scores and the FC of ipsilesional DLPFC-associated ROIs suggests that the ipsilesional DLPFC may play an important role in motor-related plasticity. These findings can help us better understand the neurophysiological mechanisms of upper extremity motor impairment and recovery in subacute stroke patients from different perspectives. Furthermore, it sheds light on the ipsilesional DLPFC-bilateral M1 as a possible neuromodulation target.

Individual electric field predicts functional connectivity changes after anodal transcranial direct-current stimulation in chronic stroke

The neuromodulation effect of anodal tDCS is not thoroughly studied, and the heterogeneous profile of stroke individuals with brain lesions would further complicate the stimulation outcomes. This study aimed to investigate the functional changes in sensorimotor areas induced by anodal tDCS and whether individual electric field could predict the functional outcomes. Twenty-five chronic stroke survivors were recruited and divided into tDCS group (n = 12) and sham group (n = 13). Increased functional connectivity (FC) within the surrounding areas of ipsilesional primary motor cortex (M1) was only observed after anodal tDCS. Averaged FC among the ipsilesional sensorimotor regions was observed to be increased after anodal tDCS (t(11) = 2.57, p = 0.026), but not after sham tDCS (t(12) = 0.69, p = 0.50). Partial least square analysis identified positive correlations between electric field (EF) strength normal to the ipsilesional M1 surface and individual FC changes in tDCS group (r = 0.84, p < 0.001) but not in sham group (r = 0.21, p = 0.5). Our results indicated anodal tDCS facilitates the FC within the ipsilesional sensorimotor network in chronic stroke subjects, and individual electric field predicts the functional outcomes.

Structural plasticity of motor cortices assessed by voxel-based morphometry and immunohistochemical analysis following internal capsular infarcts in macaque monkeys.

Compensatory plastic changes in the remaining intact brain regions are supposedly involved in functional recovery following stroke. Previously, a compensatory increase in cortical activation occurred in the ventral premotor cortex (PMv), which contributed to the recovery of dexterous hand movement in a macaque model of unilateral internal capsular infarcts. Herein, we investigated the structural plastic changes underlying functional changes together with voxel-based morphometry (VBM) analysis of magnetic resonance imaging data and immunohistochemical analysis using SMI-32 antibody in a macaque model. Unilateral internal capsular infarcts were pharmacologically induced in 5 macaques, and another 5 macaques were used as intact controls for immunohistochemical analysis. Three months post infarcts, we observed significant increases in the gray matter volume (GMV) and the dendritic arborization of layer V pyramidal neurons in the contralesional rostral PMv (F5) as well as the primary motor cortex (M1). The histological analysis revealed shrinkage of neuronal soma and dendrites in the ipsilesional M1 and several premotor cortices, despite not always detecting GMV reduction by VBM analysis. In conclusion, compensatory structural changes occur in the contralesional F5 and M1 during motor recovery following internal capsular infarcts, and the dendritic growth of pyramidal neurons is partially correlated with GMV increase.

Effects of robot-assisted task-oriented upper limb motor training on neuroplasticity in stroke patients with different degrees of motor dysfunction: A neuroimaging motor evaluation index.

IntroductionAlthough robot-assisted task-oriented upper limb (UL) motor training had been shown to be effective for UL functional rehabilitation after stroke, it did not improve UL motor function more than conventional therapy. Due to the lack of evaluation of neurological indicators, it was difficult to confirm the robot treatment parameters and clinical efficacy in a timely manner. This study aimed to explore the changes in neuroplasticity induced by robot-assisted task-oriented UL motor training in different degrees of dysfunction patients and extract neurological evaluation indicators to provide the robot with additional parameter information.Materials and methodsA total of 33 adult patients with hemiplegic motor impairment after stroke were recruited as participants in this study, and a manual muscle test divided patients into muscle strength 0–1 level (severe group, n = 10), 2–3 level (moderate group, n = 14), and 4 or above level (mild group, n = 9). Tissue concentration of oxyhemoglobin and deoxyhemoglobin oscillations in the bilateral prefrontal cortex, dorsolateral prefrontal cortex (DLPFC), superior frontal cortex (SFC), premotor cortex, primary motor cortex (M1), primary somatosensory cortex (S1), and occipital cortex were measured by functional near-infrared spectroscopy (fNIRS) in resting and motor training state. The phase information of a 0.01 −0.08 Hz signal was identified by the wavelet transform method. The wavelet amplitude, lateralization index, and wavelet phase coherence (WPCO) were calculated to describe the frequency-specific cortical changes.ResultsCompared with the resting state, significant increased cortical activation was observed in ipsilesional SFC in the mild group and bilateral SFC in the moderate group during UL motor training. Patients in the mild group demonstrated significantly decreased lateralization of activation in motor training than resting state. Moreover, the WPCO value of motor training between contralesional DLPFC and ipsilesional SFC, bilateral SFC, contralesional, S1, and ipsilesional M1 showed a significant decrease compared with the resting state in the mild group.ConclusionRobot-assisted task-oriented UL motor training could modify the neuroplasticity of SFC and contribute to control movements and continuous learning motor regularity for patients. fNIRS could provide a variety of real-time sensitive neural evaluation indicators for the robot, which was beneficial to formulating more reasonable and effective personalized prescriptions during motor training.

Contralaterally controlled neuromuscular electrical stimulation-induced changes in functional connectivity in patients with stroke assessed using functional near-infrared spectroscopy.

Contralaterally controlled neuromuscular electrical stimulation (CCNMES) is an innovative therapy in stroke rehabilitation which has been verified in clinical studies. However, the underlying mechanism of CCNMES are yet to be comprehensively revealed. The main purpose of this study was to apply functional near-infrared spectroscopy (fNIRS) to compare CCNMES-related changes in functional connectivity (FC) within a cortical network after stroke with those induced by neuromuscular electrical stimulation (NMES) when performing wrist extension with hemiplegic upper extremity. Thirty-one stroke patients with right hemisphere lesion were randomly assigned to CCNMES (n = 16) or NMES (n = 15) groups. Patients in both groups received two tasks: 10-min rest and 10-min electrical stimulation task. In each task, the cerebral oxygenation signals in the prefrontal cortex (PFC), bilateral primary motor cortex (M1), and primary sensory cortex (S1) were measured by a 35-channel fNIRS. Compared with NMES, FC between ipsilesional M1 and contralesional M1/S1 were significantly strengthened during CCNMES. Additionally, significantly higher coupling strengths between ipsilesional PFC and contralesional M1/S1 were observed in the CCNMES group. Our findings suggest that CCNMES promotes the regulatory functions of ipsilesional prefrontal and motor areas as well as contralesional sensorimotor areas within the functional network in patients with stroke.

EEG Based Resting State Connectivity Changes in the Motor Cortex Associated with Upper Limb Motor Recovery in the Subacute Period Post-Stroke.

Stroke is a heterogeneous condition that would benefit from valid biomarkers of recovery for research and in the clinic. We evaluated the change in resting state connectivity (RSC) via electroencephalography (EEG) in motor areas, as well as motor recovery of the affected upper limb, in the subacute phase post-stroke. Fifteen participants who had sustained a subcortical stroke were included in this study. The group made significant gains in upper limb impairment as measured by the Upper Extremity Fugl-Meyer Assessment (UEFMA) from baseline to four months post-stroke (24.78 (SD 5.4)). During this time, there was a significant increase in RSC in the beta band from contralesional M1 to ipsilesional M1. We propose that this change in RSC may have contributed to the motor recovery seen in this group. Clinical Relevance- This study evaluates resting state connectivity measured via EEG as a neural biomarker of recovery post-stroke. Biomarkers can help clinicians understand the potential for recovery after stroke and thus help them to establish therapy goals and determine treatment plans.

The effect of coupled inhibitory-facilitatory repetitive transcranial magnetic stimulation on shaping early reorganization of the motor network after stroke

Neural plasticity is a major factor driving cortical reorganization after stroke. This study aimed to evaluate functional connectivity (FC) changes in the cortical motor network after coupled inhibitory-facilitatory repetitive transcranial magnetic stimulation (rTMS) treatment and to assess the correlation between FC changes and functional recovery, further characterizing the neural mechanisms underlying the beneficial effects of rTMS. We randomly divided 63 patients with acute stroke into four groups: (1) Group A received coupled inhibitory-facilitatory rTMS [1 Hz over the contralesional primary motor cortex (M1) and 10 Hz over ipsilesional M1]; (2) Group B received a contralesional sham stimulation and ipsilesional 10 Hz stimulation; (3) Group C received a contralesional 1 Hz rTMS and ipsilesional sham stimulation; and (4) Group D received bilateral sham stimulation only. Standardized rehabilitation therapy was performed immediately after rTMS, and each group was treated with their respective treatment modalities for 4 weeks. Twenty-four hours before and after the intervention, participants underwent resting-state functional magnetic resonance imaging. Additional functional assessments were conducted at baseline, after treatment, and at the 3 month follow-up. The rTMS treatment significantly changed the FCs of intra- and inter-hemispheric cortical motor networks in the rTMS groups (A and B) compared with the sham group (Group D). This effect was more pronounced in Group A, which displayed a changed FC between the contralesional postcentral gyrus and contralesional superior parietal gyrus, between the contralesional precentral gyrus and contralesional postcentral gyrus, and between the ipsilesional postcentral gyrus and contralesional superior parietal gyrus, when compared with Groups B and C. Importantly, FC changes were significantly correlated with improvement of motor function. In the early stages of ischemic stroke, coupled rTMS was more conducive to motor recovery by modulating the FCs of intra-hemispheric and inter-hemispheric motor networks. Our results suggested that FC changes were related to motor function recovery for early-stage cerebral stroke patients treated with coupled rTMS. These findings could help to understand the mechanism of coupled rTMS and further the use of this therapy as an adjunct rehabilitation technique in motor recovery.

Evaluating the Abnormality of Bilateral Motor Cortex Activity in Subacute Stroke Patients Executing a Unimanual Motor Task With Increasing Demand on Precision

Abnormal contralesional M1 activity is consistently reported in patients with compromised upper limb and hand function after stroke. The underlying mechanisms and functional implications of this activity are not clear, which hampers the development of treatment strategies targeting this brain area. The goal of the present study was to determine the extent to which contralesional M1 activity can be explained by the demand of a motor task, given recent evidence for increasing ipsilateral M1 activity with increasing demand in healthy age-matched controls. We hypothesized that higher activity in contralesional M1 is related to greater demand on precision in a hand motor task. fMRI data were collected from 19 patients with ischemic stroke affecting hand function in the subacute recovery phase and 31 healthy, right-handed, age-matched controls. The hand motor task was designed to parametrically modulate the demand on movement precision. Electromyography data confirmed strictly unilateral task performance by all participants. Patients showed significant impairment relative to controls in their ability to perform the task in the fMRI scanner. However, patients and controls responded similarly to an increase in demand for precision, with better performance for larger targets and poorer performance for smaller targets. Patients did not show evidence of elevated ipsilesional or contralesional M1 blood oxygenation level-dependent (BOLD) activation relative to healthy controls and mean BOLD activation levels were not elevated for patients with poorer performance relative to patients with better task performance. While both patients and healthy controls showed demand-dependent increases in BOLD activation in both ipsilesional/contralateral and contralesional/ipsilateral hemispheres, patients with stroke were less likely to show evidence of a linear relationship between the demand on precision and BOLD activation in contralesional M1 than healthy controls. Taken together, the findings suggest that task demand affects the BOLD response in contralesional M1 in patients with stroke, though perhaps less strongly than in healthy controls. This has implications for the interpretation of reported abnormal bilateral M1 activation in patients with stroke because in addition to contralesional M1 reorganization processes it could be partially related to a response to the relatively higher demand of a motor task when completed by patients rather than by healthy controls.

Recovered grasping performance after stroke depends on interhemispheric frontoparietal connectivity.

Activity changes in the ipsi- and contralesional parietal cortex and abnormal interhemispheric connectivity between these regions are commonly observed after stroke, however, their significance for motor recovery remains poorly understood. We here assessed the contribution of ipsilesional and contralesional anterior intraparietal cortex (aIPS) for hand motor function in 18 recovered chronic stroke patients and 18 healthy control subjects using a multimodal assessment consisting of resting-state functional MRI, motor task functional MRI, online-repetitive transcranial magnetic stimulation (rTMS) interference, and 3D movement kinematics. Effects were compared against two control stimulation sites, i.e. contralesional M1 and a sham stimulation condition. We found that patients with good motor outcome compared to patients with more substantial residual deficits featured increased resting-state connectivity between ipsilesional aIPS and contralesional aIPS as well as between ipsilesional aIPS and dorsal premotor cortex. Moreover, interhemispheric connectivity between ipsilesional M1 and contralesional M1 as well as ipsilesional aIPS and contralesional M1 correlated with better motor performance across tasks. TMS interference at individual aIPS and M1 coordinates led to differential effects depending on the motor task that was tested, i.e. index finger-tapping, rapid pointing movements, or a reach-grasp-lift task. Interfering with contralesional aIPS deteriorated the accuracy of grasping, especially in patients featuring higher connectivity between ipsi- and contralesional aIPS. In contrast, interference with the contralesional M1 led to impaired grasping speed in patients featuring higher connectivity between bilateral M1. These findings suggest differential roles of contralesional M1 and aIPS for distinct aspects of recovered hand motor function, depending on the reorganization of interhemispheric connectivity.

FV 19 Tracking complexity and causality during cortical reorganization and motor recovery after stroke

I: Combined TMS and EEG represents a non-invasive approach that informs about the local neural state as well as signal propagation within the functional network. Particularly, it has proven powerful at an individual level. In the context of stroke, the individual understanding of the neural mechanisms of reorganization that underlie recovery of function would, in consequence, enable the optimization of rehabilitation strategies including non-invasive neuromodulation. Again, in the context of stroke, TMS-EEG has recently not only revealed the occurrence of the phenomenon of local sleep-like slow waves in conscious awake stroke patients, but has also put these in association to the level of motor deficits and, crucially, the potential of neurological recovery in the chronic phase after stroke. However, a profound mechanistic understanding of the causal underpinnings of stroke recovery and a systematic link from the presence of sleep-like waves after stroke to their behavioral consequences require longitudinal measurements paralleled by clinical assessments. We, therefore, applied the method of TMS-EEG in a cohort of stroke patients in the first two weeks post-stroke, and followed both the course of functional recovery and the development of alterations of TMS-EEG responses through motor reorganization to the chronic stage. M: TMS over ipsilesional M1 combined with EEG in 40 patients with unilateral mild to severe motor deficits due to first-ever ischemic stroke was acquired in the first two weeks after stroke. 35 patients could be re-assessed behaviorally and 28 patients also participated in the TMS-EEG experiments in the chronic phase. TMS-evoked EEG activity of ipsilesional M1 was quantified by spectral and phase domain analysis yielding (i) the occurrence of TMS-evoked slow waves, (ii) cortical off-periods, i.e. high frequency suppression of EEG power, and (iii) local causal interactions quantified by means of phase-locking factor (PLF). Moreover, (iv) alterations of complex global interactions were indexed by the Perturbational Complexity Index (PCI). R: We demonstrated that the slow wave response locally evoked by the perturbation of ipsilesional M1 is associated with a cortical off-period and underpinned by a loss of global signal complexity and a rapid disruption of causal effects in the first weeks post-stroke. However, tracking these signal alterations in combination to the course of motor recovery during the reorganization after stroke revealed that sleep-like waves, independent on the degree of recovery, disappeared in the chronic stage, though their occurrence in the acute stage post-stroke is an indicator for a subsequent poor functional recovery. C: By linking slow waves and the deterioration of global brain dynamics to recovery after stroke, our findings not only link stroke to cortical bistability, a neuronal mechanism precisely characterized in NREM sleep, but put it in a behaviorally and clinically meaningful perspective.

Comparison of Transcallosal Inhibition Between Hemispheres and Its Relationship with Motor Behavior in Patients with Severe Upper Extremity Impairment After Subacute Stroke

ObjectiveTo compare corticospinal excitability and transcallosal inhibition between contralesional primary motor cortex (M1) and ipsilesional M1. We also investigated the correlation between transcallosal inhibition and upper extremity motor behavior. Materials and methods19 individuals with unilateral ischemic subacute stroke who had severe upper extremity impairment participated in this study. Corticospinal excitability was assessed by measuring the resting motor threshold, active motor threshold and motor evoked potential amplitude. Transcallosal inhibition was investigated by measuring the duration and depth of the ipsilateral silent period (ISP). The data from the two hemispheres were compared and the relationships of transcallosal inhibition with upper extremity motor impairment, grip strength and pinch strength were analyzed. ResultsResting motor threshold (p = 0.001) and active motor threshold (p = 0.001) were lower and motor evoked potential amplitude was higher (p = 0.001) in the contralesional M1 compared to the ipsilesional M1. However, there were no differences between the two M1s in ISP duration (p = 0.297) or ISP depth (p =0. 229). Transcallosal inhibition from the contralesional M1 was positively associated with motor impairment (ISP duration, p = 0.003; ISP depth, p = 0.017) and grip strength (ISP duration, p = 0.016; ISP depth, p = 0.045). ConclusionsSymmetric transcallosal inhibition between hemispheres and positive association of transcallosal inhibition from contralesional M1 with upper extremity motor behavior indicate that recruitment of contralesional M1 may be necessary for recovery in patients with severe upper extremity impairment after subacute ischemic stroke.

Brain-Computer Interface-Robot Training Enhances Upper Extremity Performance and Changes the Cortical Activation in Stroke Patients: A Functional Near-Infrared Spectroscopy Study.

IntroductionWe evaluated the efficacy of brain–computer interface (BCI) training to explore the hypothesized beneficial effects of physiotherapy alone in chronic stroke patients with moderate or severe paresis. We also focused on the neuroplastic changes in the primary motor cortex (M1) after BCI training.MethodsIn this study, 18 hospitalized chronic stroke patients with moderate or severe motor deficits participated. Patients were operated on for 20 sessions and followed up after 1 month. Functional assessments were performed at five points, namely, pre1-, pre2-, mid-, post-training, and 1-month follow-up. Wolf Motor Function Test (WMFT) was used as the primary outcome measure, while Fugl-Meyer Assessment (FMA), its wrist and hand (FMA-WH) sub-score and its shoulder and elbow (FMA-SE) sub-score served as secondary outcome measures. Neuroplastic changes were measured by functional near-infrared spectroscopy (fNIRS) at baseline and after 20 sessions of BCI training. Pearson correlation analysis was used to evaluate functional connectivity (FC) across time points.ResultsCompared to the baseline, better functional outcome was observed after BCI training and 1-month follow-up, including a significantly higher probability of achieving a clinically relevant increase in the WMFT full score (ΔWMFT score = 12.39 points, F = 30.28, and P < 0.001), WMFT completion time (ΔWMFT time = 248.39 s, F = 16.83, and P < 0.001), and FMA full score (ΔFMA-UE = 12.72 points, F = 106.07, and P < 0.001), FMA-WH sub-score (ΔFMA-WH = 5.6 points, F = 35.53, and P < 0.001), and FMA-SE sub-score (ΔFMA-SE = 8.06 points, F = 22.38, and P < 0.001). Compared to the baseline, after BCI training the FC between the ipsilateral M1 and the contralateral M1 was increased (P < 0.05), which was the same as the FC between the ipsilateral M1 and the ipsilateral frontal lobe, and the FC between the contralateral M1 and the contralateral frontal lobe was also increased (P < 0.05).ConclusionThe findings demonstrate that BCI-based rehabilitation could be an effective intervention for the motor performance of patients after stroke with moderate or severe upper limb paresis and represents a potential strategy in stroke neurorehabilitation. Our results suggest that FC between ipsilesional M1 and frontal cortex might be enhanced after BCI training.Clinical Trial Registrationwww.chictr.org.cn, identifier: ChiCTR2100046301.

Functional Connectivity Changes in Multiple-Frequency Bands in Acute Basal Ganglia Ischemic Stroke Patients: A Machine Learning Approach.

Purpose Several functional magnetic resonance imaging (fMRI) studies have investigated the resting-state functional connectivity (rs-FC) changes in the primary motor cortex (M1) in patients with acute basal ganglia ischemic stroke (BGIS). However, the frequency-specific FC changes of M1 in acute BGIS patients are still unclear. Our study was aimed at exploring the altered FC of M1 in three frequency bands and the potential features as biomarkers for the identification by using a support vector machine (SVM). Methods We included 28 acute BGIS patients and 42 healthy controls (HCs). Seed-based FC of two regions of interest (ROI, bilateral M1s) were calculated in conventional, slow-5, and slow-4 frequency bands. The abnormal voxel-wise FC values were defined as the features for SVM in different frequency bands. Results In the ipsilesional M1, the acute BGIS patients exhibited decreased FC with the right lingual gyrus in the conventional and slow-4 frequency band. Besides, the acute BGIS patients showed increased FC with the right medial superior frontal gyrus (SFGmed) in the conventional and slow-5 frequency band and decreased FC with the left lingual gyrus in the slow-5 frequency band. In the contralesional M1, the BGIS patients showed lower FC with the right SFGmed in the conventional frequency band. The higher FC values with the right lingual gyrus and left SFGmed were detected in the slow-4 frequency band. In the slow-5 frequency band, the BGIS patients showed decreased FC with the left calcarine sulcus. SVM results showed that the combined features (slow-4+slow-5) had the highest accuracy in classification prediction of acute BGIS patients, with an area under curve (AUC) of 0.86. Conclusion Acute BGIS patients had frequency-specific alterations in FC; SVM is a promising method for exploring these frequency-dependent FC alterations. The abnormal brain regions might be potential targets for future researchers in the rehabilitation and treatment of stroke patients.

Structural Covariance of the Ipsilesional Primary Motor Cortex in Subcortical Stroke Patients with Motor Deficits.

The analysis of structural covariance has emerged as a powerful tool to explore the morphometric correlations among broadly distributed brain regions. However, little is known about the interactions between the damaged primary motor cortex (M1) and other brain regions in stroke patients with motor deficits. This study is aimed at investigating the structural covariance pattern of the ipsilesional M1 in chronic subcortical stroke patients with motor deficits. High-resolution T1-weighted brain images were acquired from 58 chronic subcortical stroke patients with motor deficits (29 with left-sided lesions and 29 with right-sided lesions) and 50 healthy controls. Structural covariance patterns were identified by a seed-based structural covariance method based on gray matter (GM) volume. Group comparisons between stroke patients (left-sided or right-sided groups) and healthy controls were determined by a permutation test. The association between alterations in the regional GM volume and motor recovery after stroke was investigated by a multivariate regression approach. Structural covariance analysis revealed an extensive increase in the structural interactions between the ipsilesional M1 and other brain regions in stroke patients, involving not only motor-related brain regions but also non-motor-related brain regions. We also identified a slightly different pattern of structural covariance between the left-sided stroke group and the right-sided stroke group, thus indicating a lesion-side effect of cortical reorganization after stroke. Moreover, alterations in the GM volume of structural covariance brain regions were significantly correlated to the motor function scores in stroke patients. These findings indicated that the structural covariance patterns of the ipsilesional M1 in chronic subcortical stroke patients were induced by motor-related plasticity. Our findings may help us to better understand the neurobiological mechanisms of motor impairment and recovery in patients with subcortical stroke from different perspectives.

Effects of Repetitive Peripheral Sensory Stimulation in the Subacute and Chronic Phases After Stroke: Study Protocol for a Pilot Randomized Trial.

BackgroundRepetitive peripheral nerve sensory stimulation (RPSS) is a potential add-on intervention to motor training for rehabilitation of upper limb paresis after stroke. Benefits of RPSS were reported in subjects in the chronic phase after stroke, but there is limited information about the effects of this intervention within the 1st weeks or months. The primary goal of this study is to compare, in a head-to-head proof-of-principle study, the impact of a single session of suprasensory vs. subsensory RPSS on the upper limb motor performance and learning in subjects at different phases after stroke subacute and chronic phases and mild upper limb motor impairments after stroke. In addition, we examine the effects of RPSS on brain perfusion, functional imaging activation, and γ-aminobutyric acid (GABA) levels. Subjects with mild upper limb motor impairments will be tested with MRI and clinical assessment either at an early (7 days to 3 months post-stroke) or at a chronic (>6 months) stage after stroke.MethodsIn this multicenter, randomized, parallel-group, proof-of-principle clinical trial with blinded assessment of outcomes, we compare the effects of one session of suprasensory or subsensory RPSS in patients with ischemic or hemorrhagic stroke and upper limb paresis. Clinical assessment and MRI will be performed only once in each subject (either at an early or at a chronic stage). The primary outcome is the change in performance in the Jebsen–Taylor test. Secondary outcomes: hand strength, cerebral blood flow assessed with arterial spin labeling, changes in the blood oxygenation level-dependent (BOLD) effect in ipsilesional and contralesional primary motor cortex (M1) on the left and the right hemispheres assessed with functional MRI (fMRI) during a finger-tapping task performed with the paretic hand, and changes in GABA levels in ipsilesional and contralesional M1 evaluated with spectroscopy. The changes in outcomes will be compared in four groups: suprasensory, early; subsensory, early; suprasensory, chronic; and subsensory, chronic.DiscussionThe results of this study are relevant to inform future clinical trials to tailor RPSS to patients more likely to benefit from this intervention.Trial RegistrationNCT03956407.

Combining inhibitory and facilitatory repetitive transcranial magnetic stimulation (rTMS) treatment improves motor function by modulating GABA in acute ischemic stroke patients.

The combination of inhibitory and facilitatory repetitive transcranial magnetic stimulation (rTMS) can improve motor function of stroke patients with undefined mechanism. It has been demonstrated that rTMS exhibits a neuro-modulatory effect by regulating the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) in other diseases. To evaluate the effect of combined inhibitory and facilitatory rTMS on GABA in the primary motor cortex (M1) for treating motor dysfunction after acute ischemic stroke. 44 ischemic stroke patients with motor dysfunction were randomly divided into two groups. The treatment group was stimulated with 10 Hz rTMS at the ipsilesional M1 and 1 Hz rTMS at the contralesional M1. The sham group received bilateral sham stimulation at the motor cortices. The GABA level in the bilateral M1 was measured by proton magnetic resonance spectroscopy (1H-MRS) at 24 hours before and after rTMS stimulation. Motor function was measured using the Fugl-Meyer Assessment (FMA). The clinical assessments were performed before and after rTMS and after 3 months. The treatment group exhibited a greater improvement in motor function 24 hours after rTMS compared to the sham group. The increased improvement in motor function lasted for at least 3 months after treatment. Following 4 weeks of rTMS, the GABA level in the ipsilesional M1 of the treatment group was significantly decreased compared to the sham group. Furthermore, the change of FMA score for motor function was negatively correlated to the change of the GABA:Cr ratio. Finally, the effect of rTMS on motor function outcome was partially mediated by GABA level change in response to the treatment (27.7%). Combining inhibitory and facilitatory rTMS can decrease the GABA level in M1, which is correlated to the improvement of motor function. Thus, the GABA level in M1 may be a potential biomarker for treatment strategy decisions regarding rTMS neuromodulatory interventions.

Capturing Neuroplastic Changes after iTBS in Patients with Post-Stroke Aphasia: A Pilot fMRI Study.

Intermittent theta-burst stimulation (iTBS) is a high-efficiency transcranial magnetic stimulation (TMS) paradigm that has been applied to post-stroke aphasia (PSA). However, its efficacy mechanisms have not been clarified. This study aimed to explore the immediate effects of iTBS of the primary motor cortex (M1) of the affected hemisphere, on the functional activities and connectivity of the brains of PSA patients. A total of 16 patients with aphasia after stroke received iTBS with 800 pulses for 300 s. All patients underwent motor, language, and cognitive assessments and resting-state functional MRI scans immediately before and after the iTBS intervention. Regional, seed-based connectivity, and graph-based measures were used to test the immediate functional effects of the iTBS intervention, including the fractional amplitude of low-frequency fluctuation (fALFF), degree centrality (DC), and functional connectivity (FC) of the left M1 area throughout the whole brain. The results showed that after one session of iTBS intervention, the fALFF, DC, and FC values changed significantly in the patients’ brains. Specifically, the DC values were significantly higher in the right middle frontal gyrus and parts of the left parietal lobe (p < 0.05), while fALFF values were significantly lower in the right medial frontal lobe and parts of the left intracalcarine cortex (p < 0.05), and the strength of the functional connectivity between the left M1 area and the left superior frontal gyrus was reduced (p < 0.05). Our findings provided preliminary evidences that the iTBS on the ipsilesional M1 could induce neural activity and functional connectivity changes in the motor, language, and other brain regions in patients with PSA, which may promote neuroplasticity and functional recovery.

Task Complexity and Image Clarity Facilitate Motor and Visuo-Motor Activities in Mirror Therapy in Post-stroke Patients.

Introduction: Mirror therapy is effective in the recovery of upper-limb function among post-stroke patients. An important component of mirror therapy is imagining finger movements. This study aimed to determine the influence of finger movement complexity and mirror image clarity on facilitating motor and visuo-motor activities in post-stroke patients.Methods: Fifteen post-stroke patients and 18 right-handed healthy participants performed simple or complex finger tapping while viewing mirror images of these movements at varying levels of clarity. The physical setup was identical to typical mirror therapy. Functional near infrared spectroscopy (fNIRS) was used to capture the brain activities elicited in the bilateral primary motor cortices (M1) and the precuneus using a block experimental design.Results: In both study groups, the “complex finger-tapping task with blurred mirror image” condition resulted in lower intensity (p < 0.01) and authenticity (p < 0.01) of the kinesthetic mirror illusion, and higher levels of perceived effort in generating the illusion (p < 0.01), relative to the “simple finger-tapping with clear mirror image” condition. Greater changes in the oxygenated hemoglobin (HbO) concentration were recorded at the ipsilesional and ipsilateral M1 in the “complex finger-tapping task with blurred mirror image” condition relative to that recorded in the “simple finger-tapping task with clear mirror image” condition (p = 0.03). These HbO concentration changes were not significant in the precuneus. Post-stroke patients showed greater changes than their healthy counterparts at the ipsilesional M1 (F = 5.08; p = 0.03; partial eta squared = 0.14) and the precuneus (F = 7.71; p < 0.01; partial eta squared = 0.20).Conclusion: The complexity and image clarity of the finger movements increased the neural activities in the ipsilesional motor cortex in the post-stroke patients. These findings suggest plausible roles for top-down attention and working memory in the treatment effects of mirror therapy. Future research can aim to corroborate these findings by using a longitudinal design to examine the use of mirror therapy to promote upper limb motor recovery in post-stroke patients.