Ipsilesional M1 Research Articles

Brain imaging and clinical outcome of embodied VR-BCI training in chronic stroke patients: a longitudinal pilot study

ABSTRACT Introduction Restorative Brain–Computer Interfaces (BCIs) provide an alternative non-muscular channel for stroke patients lacking volitional movement by enhancing sensorimotor rhythm modulation through motor imagery (MI). MI practice can be augmented with embodied feedback via virtual reality (VR). However, the clinical impact of embodied VR-BCI training remains under-explored. Methods This study examines the effects of embodied VR-BCI training on brain activity patterns (measured through EEG and fMRI) and clinical outcomes (assessed by the Fugl–Meyer Assessment, FMA) in four chronic stroke patients. Over a 3-week MI-BCI intervention, patients performed a bimanual rowing task (NeuRow) in VR. EEG data were used to extract Event-related desynchronization (ERD) and lateralization indices, while fMRI data focused on the primary motor (M1) and supplementary motor (SMA) regions of interest. Results Results indicated that all patients significantly induced ERD power, though the affected side exhibited reduced ERD compared to baseline during contralateral MI. Post-intervention, significant ERD differences from both hemispheres were observed, with decreased ERD correlating with no clinical improvement. Patients showing decreased ERD lateralization had no FMA score improvement. Activity within ipsilesional M1 and SMA correlated with FMA scores. Conclusions The findings suggest a relationship between brain activity and clinical outcomes, highlighting that increased ERD lateralization is associated with clinical improvement.

Individual contralesional recruitment in the context of structural reserve in early motor reorganization after stroke

The concept of structural reserve in stroke reorganization assumes that the relevance of the contralesional hemisphere strongly depends on the brain tissue spared by the lesion in the affected hemisphere. Recent studies, however, have indicated that the contralesional hemisphere's impact exhibits region-specific variability with concurrently existing maladaptive and supportive influences. This challenges traditional views, necessitating a nuanced investigation of contralesional motor areas and their interaction with ipsilesional networks.Our study focused on the functional role of contralesional key motor areas and lesion-induced connectome disruption early after stroke.Online TMS data of twenty-five stroke patients was analyzed to disentangle interindividual differences in the functional roles of contralesional primary motor cortex (M1), dorsal premotor cortex (dPMC), and anterior interparietal sulcus (aIPS) for motor function. Connectome-based lesion symptom mapping and corticospinal tract lesion quantification were used to investigate how TMS effects depend on ipsilesional structural network properties.At group and individual levels, TMS interference with contralesional M1 and aIPS but not dPMC led to improved performance early after stroke. At the connectome level, a more disturbing role of contralesional M1 was related to a more severe disruption of the structural integrity of ipsilesional M1 in the affected motor network. In contrast, a detrimental influence of contralesional aIPS was linked to less disruption of the ipsilesional M1 connectivity.Our findings indicate that contralesional areas distinctively interfere with motor performance early after stroke depending on ipsilesional structural integrity, extending the concept of structural reserve to regional specificity in recovery of function.

MiR-100-5p-rich small extracellular vesicles from activated neuron to aggravate microglial activation and neuronal activity after stroke

Ischemic stroke is a common cause of mortality and severe disability in human and currently lacks effective treatment. Neuronal activation and neuroinflammation are the major two causes of neuronal damage. However, little is known about the connection of these two phenomena. This study uses middle cerebral artery occlusion mouse model and chemogenetic techniques to study the underlying mechanisms of neuronal excitotoxicity and severe neuroinflammation after ischemic stroke. Chemogenetic inhibition of neuronal activity in ipsilesional M1 alleviates infarct area and neuroinflammation, and improves motor recovery in ischemia mice. This study identifies that ischemic challenge triggers neuron to produce unique small extracellular vesicles (EVs) to aberrantly activate adjacent neurons which enlarge the neuron damage range. Importantly, these EVs also drive microglia activation to exacerbate neuroinflammation. Mechanistically, EVs from ischemia-evoked neuronal activity induce neuronal apoptosis and innate immune responses by transferring higher miR-100-5p to adjacent neuron and microglia. MiR-100-5p can bind to and activate TLR7 through U18U19G20-motif, thereby activating NF-κB pathway. Furthermore, knock-down of miR-100-5p expression improves poststroke outcomes in mice. Taken together, this study suggests that the combination of inhibiting aberrant neuronal activity and the secretion of specific EVs-miRNAs may serve as novel methods for stroke treatment.Graphical

Brain state-dependent repetitive transcranial magnetic stimulation for motor stroke rehabilitation: a proof of concept randomized controlled trial.

In healthy subjects, repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex (M1) demonstrated plasticity effects contingent on electroencephalography (EEG)-derived excitability states, defined by the phase of the ongoing sensorimotor μ-oscillation. The therapeutic potential of brain state-dependent rTMS in the rehabilitation of upper limb motor impairment post-stroke remains unexplored. Proof-of-concept trial to assess the efficacy of rTMS, synchronized to the sensorimotor μ-oscillation, in improving motor impairment and reducing upper-limb spasticity in stroke patients. We conducted a parallel group, randomized double-blind controlled trial in 30 chronic stroke patients (clinical trial registration number: NCT05005780). The experimental intervention group received EEG-triggered rTMS of the ipsilesional M1 [1,200 pulses; 0.33 Hz; 100% of the resting motor threshold (RMT)], while the control group received low-frequency rTMS of the contralesional motor cortex (1,200 pulses; 1 Hz, 115% RMT), i.e., an established treatment protocol. Both groups received 12 rTMS sessions (20 min, 3× per week, 4 weeks) followed by 50 min of physiotherapy. The primary outcome measure was the change in upper-extremity Fugl-Meyer assessment (FMA-UE) scores between baseline, immediately post-treatment and 3 months' follow-up. Both groups showed significant improvement in the primary outcome measure (FMA-UE) and the secondary outcome measures. This included the reduction in spasticity, measured objectively using the hand-held dynamometer, and enhanced motor function as measured by the Wolf Motor Function Test (WMFT). There were no significant differences between the groups in any of the outcome measures. The application of brain state-dependent rTMS for rehabilitation in chronic stroke patients is feasible. This pilot study demonstrated that the brain oscillation-synchronized rTMS protocol produced beneficial effects on motor impairment, motor function and spasticity that were comparable to those observed with an established therapeutic rTMS protocol. ClinicalTrials.gov, identifier [NCT05005780].

Use of cortical hemodynamic responses in digital therapeutics for upper limb rehabilitation in patients with stroke

BackgroundStroke causes long-term disabilities, highlighting the need for innovative rehabilitation strategies for reducing residual impairments. This study explored the potential of functional near-infrared spectroscopy (fNIRS) for monitoring cortical activation during rehabilitation using digital therapeutics.MethodsThis cross-sectional study included 18 patients with chronic stroke, of whom 13 were men. The mean age of the patients was 67.0 ± 7.1 years. Motor function was evaluated through various tests, including the Fugl–Meyer assessment for upper extremity (FMA-UE), grip and pinch strength test, and box and block test. All the patients completed the digital rehabilitation program (MotoCog®, Cybermedic Co., Ltd., Republic of Korea) while being monitored using fNIRS (NIRScout®, NIRx Inc., Germany). Statistical parametric mapping (SPM) was employed to analyze the cortical activation patterns from the fNIRS data. Furthermore, the K-nearest neighbor (K-NN) algorithm was used to analyze task performance and fNIRS data to classify the severity of motor impairment.ResultsThe participants showed diverse task performances in the digital rehabilitation program, demonstrating distinct patterns of cortical activation that correlated with different motor function levels. Significant activation was observed in the ipsilesional primary motor area (M1), primary somatosensory area (S1), and contralateral prefrontal cortex. The activation patterns varied according to the FMA-UE scores. Positive correlations were observed between the FMA-UE scores and SPM t-values in the ipsilesional M1, whereas negative correlations were observed in the ipsilesional S1, frontal lobe, and parietal lobe. The incorporation of cortical hemodynamic responses with task scores in a digital rehabilitation program substantially improves the accuracy of the K-NN algorithm in classifying upper limb functional levels in patients with stroke. The accuracy for tasks, such as the gas stove-operation task, increased from 44.4% using only task scores to 83.3% when these scores were combined with oxy-Hb t-values from the ipsilesional M1.ConclusionsThe results advocated the development of tailored digital rehabilitation strategies by combining the behavioral and cerebral hemodynamic data of patients with stroke. This approach aligns with the evolving paradigm of personalized rehabilitation in stroke recovery, highlighting the need for further extensive research to optimize rehabilitation outcomes.

Transcranial direct current stimulation–induced changes in motor cortical connectivity are associated with motor gains following ischemic stroke

Understanding the response of the injured brain to different transcranial direct current stimulation (tDCS) montages may help explain the variable tDCS treatment results on poststroke motor gains. Cortical connectivity has been found to reflect poststroke motor gains and cortical plasticity, but the changes in connectivity following tDCS remain unknown. We aimed to investigate the relationship between tDCS-induced changes in cortical connectivity and poststroke motor gains. In this study, participants were assigned to receive four tDCS montages (anodal, cathodal, bilateral, and sham) over the primary motor cortex (M1) according to a single-blind, randomized, crossover design. Electroencephalography (EEG) and Jebsen-Taylor hand function test (JTT) were performed before and after the intervention. Motor cortical connectivity was measured using beta-band coherence with the ipsilesional and contralesional M1 as seed regions. Motor gain was evaluated based on the JTT completion time. We examined the relationship between baseline connectivity and clinical characteristics and that between changes in connectivity and motor gains after different tDCS montages. Baseline functional connectivity, motor impairment, and poststroke duration were correlated. High ipsilesional M1–frontal–temporal connectivity was correlated with a good baseline motor status, and increased connectivity was accompanied by good functional improvement following anodal tDCS treatment. Low contralesional M1–frontal-central connectivity was correlated with a good baseline motor status, and decreased connectivity was accompanied by good functional improvement following cathodal tDCS treatment. In conclusion, EEG-based motor cortical connectivity was correlated with stroke characteristics, including motor impairment and poststroke duration, and motor gains induced by anodal and cathodal tDCS.

Local neuronal sleep after stroke: The role of cortical bistability in brain reorganization

BackgroundAcute cerebral ischemia triggers a number of cellular mechanisms not only leading to excitotoxic cell death but also to enhanced neuroplasticity, facilitating neuronal reorganization and functional recovery. ObjectiveTransferring these cellular mechanisms to neurophysiological correlates adaptable to patients is crucial to promote recovery post-stroke. The combination of TMS and EEG constitutes a promising readout of neuronal network activity in stroke patients. MethodsWe used the combination of TMS and EEG to investigate the development of local signal processing and global network alterations in 40 stroke patients with motor deficits alongside neural reorganization from the acute to the chronic phase. ResultsWe show that the TMS-EEG response reflects information about reorganization and signal alterations associated with persistent motor deficits throughout the entire post-stroke period. In the early post-stroke phase and in a subgroup of patients with severe motor deficits, TMS applied to the lesioned motor cortex evoked a sleep-like slow wave response associated with a cortical off-period, a manifestation of cortical bistability, as well as a rapid disruption of the TMS-induced formation of causal network effects. Mechanistically, these phenomena were linked to lesions affecting ascending activating brainstem fibers. Of note, slow waves invariably vanished in the chronic phase, but were highly indicative of a poor functional outcome. ConclusionIn summary, we found evidence that transient effects of sleep-like slow waves and cortical bistability within ipsilesional M1 resulting in excessive inhibition may interfere with functional reorganization, leading to a less favorable functional outcome post-stroke, pointing to a new therapeutic target to improve recovery of function.

Effects of Priming Intermittent Theta Burst Stimulation With High-Definition tDCS on Upper Limb Function in Hemiparetic Patients With Stroke: A Randomized Controlled Study

Background Preconditioning with cathodal high-definition transcranial direct current stimulation (HD-tDCS) can potentiate cortical plasticity induced by intermittent theta burst stimulation (iTBS) and enhance the after-effects of iTBS in healthy people. However, it is unclear whether this multi-modal protocol can enhance upper limb function in patients with stroke. Objective The aim of this study was to investigate whether priming iTBS with cathodal HD-tDCS over the ipsilesional M1 can augment upper limb motor recovery in poststroke patients. Methods A total of 66 patients with subacute stroke were randomly allocated into 3 groups. Group 1 received priming iTBS with HD-tDCS (referred to as the tDCS + iTBS group), Group 2 received non-priming iTBS (the iTBS group), and Group 3 received sham stimulation applied to the ipsilesional M1. One session was performed per day, 5 days per week, for 3 consecutive weeks. In Group 1, iTBS was preceded by a 20-minute session of cathodal HD-tDCS at a 10-minute interval. The primary outcome measure was the Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score. Moreover, the secondary outcome measures for muscle strength and spasticity were the Motricity Index-Upper Extremity (MI-UE) and the Modified Ashworth Scale Upper-Extremity (MAS-UE), respectively, and the Hong Kong Version of the Functional Test for the Hemiplegic Upper Extremity (FTHUE-HK) and the Modified Barthel Index (MBI) for activity and participation. Results Significant differences were detected in the changes in FMA-UE, MI-UE, and MBI scores between the 3 groups from baseline to post-intervention (χ2FMA-UE = 10.856, P = .004; χ2MI-UE = 6.783, P = .034; χ2MBI = 9.608, P = .008). Post hoc comparisons revealed that the priming iTBS group demonstrated substantial improvements in FMA-UE (P = .004), MI-UE (P = .028), and MBI (P = 0.006) compared with those in the sham group. However, no significant difference was observed between the iTBS group and the sham group. Moreover, no significant differences were found in the changes in MAS-UE or FTHUE-HK between the groups. Conclusions Priming iTBS with HD-tDCS over the ipsilesional M1 cortex had beneficial effects on augmenting upper limb motor recovery and enhancing daily participation among subacute stroke patients.

Priming constraint-induced movement therapy with intermittent theta burst stimulation to enhance upper extremity recovery in patients with stroke: protocol for a randomized controlled study.

The treatments based on motor control and motor learning principles have gained popularity in the last 20 years, as well as non-invasive brain stimulations that enhance neuroplastic changes after stroke. However, the effect of intermittent theta burst stimulation (iTBS) in addition to evidence-based, intensive neurorehabilitation approaches such as modified constraint-induced movement therapy (mCIMT) is yet to be investigated. We aim to establish a protocol for a randomized controlled study investigating the efficiency of mCIMT primed with iTBS after stroke. In this randomized controlled, single-blind study, patients with stroke (N = 17) will be divided into 3 groups: (a) mCIMT + real iTBS, (b) mCIMT + sham iTBS, and (c) mCIMT alone. 600-pulse iTBS will be delivered to the primary motor cortex on the ipsilesional hemisphere, and then, patients will receive mCIMT for 1h/session, 3 sessions/week for 5weeks. Upper extremity recovery will be assessed with Fugl-Meyer Test-Upper Extremity and Wolf Motor Function Test. Electrophysiological assessments, such as Motor-Evoked Potentials, Resting Motor Threshold, Short-Intracortical Inhibition, and Intracortical Facilitation, will also be included. In this study, a protocol of an ongoing intervention study investigating the effectiveness of iTBS on ipsilesional M1 prior to the mCIMT in patients with stroke is proposed. This will be the first study to research priming mCIMT with iTBS and it may have the potential to reveal the true effect of the iTBS when it is added to the high-quality neurorehabilitation approaches. Trial registration number: NCT05308667.

Evidence of mirror therapy for recruitment of ipsilateral motor pathways in stroke recovery: A resting fMRI study

Mirror therapy (MT) has been proposed to promote motor recovery post-stroke through activation of mirror neuron system, recruitment of ipsilateral motor pathways, or/and increasing attention toward the affected limb. However, neuroimaging evidence for these mechanisms is still lacking. To uncover the underlying mechanisms, we designed a randomized controlled study and used a voxel-based whole-brain analysis of resting-state fMRI to explore the brain reorganizations induced by MT. Thirty-five stroke patients were randomized to an MT group (n ​= ​16) and a conventional therapy (CT) group (n ​= ​19) for a 4-week intervention. Before and after the intervention, the Fugl-Meyer Assessment Upper Limb subscale (FMA-UL) and resting-state fMRI were collected. A healthy cohort (n ​= ​16) was established for fMRI comparison. The changes in fractional amplitude of low-frequency fluctuation (fALFF) and seed-based functional connectivity were analyzed to investigate the impact of intervention. Results showed that greater FMA-UL improvement in the MT group was associated with the compensatory increase of fALFF in the contralesional precentral gyrus (M1) region and the re-establishment of functional connectivity between the bilateral M1 regions, which facilitate motor signals transmission via the ipsilateral motor pathways from the ipsilesional M1, contralesional M1, to the affected limb. A step-wise linear regression model revealed these two brain reorganization patterns collaboratively contributed to FMA-UL improvement. In conclusion, MT achieved motor rehabilitation primarily by recruitment of the ipsilateral motor pathways. Trial Registration Information: http://www.chictr.org.cn. Unique Identifier. ChiCTR-INR-17013644, submitted on December 2, 2017.

Uncovering the Neural Mechanisms of Inter-Hemispheric Balance Restoration in Chronic Stroke through EMG-Driven Robot Hand Training: Insights from Dynamic Causal Modeling.

EMG-driven robot hand training can facilitate motor recovery in chronic stroke patients by restoring the interhemispheric balance between motor networks. However, the underlying mechanisms of reorganization between interhemispheric regions remain unclear. This study investigated the effective connectivity (EC) between the ventral premotor cortex (PMv), supplementary motor area (SMA), and primary motor cortex (M1) using Dynamic Causal Modeling (DCM) during motor tasks with the paretic hand. Nineteen chronic stroke subjects underwent 20 sessions of EMG-driven robot hand training, and their Action Reach Arm Test (ARAT) showed significant improvement (β=3.56, p<0.001). The improvement was correlated with the reduction of inhibitory coupling from the contralesional M1 to the ipsilesional M1 (r=0.58, p=0.014). An increase in the laterality index was only observed in homotopic M1, but not in the premotor area. Additionally, we identified an increase in resting-state functional connectivity (FC) between bilateral M1 (β=0.11, p=0.01). Inter-M1 FC demonstrated marginal positive relationships with ARAT scores (r=0.402, p=0.110), but its changes did not correlate with ARAT improvements. These findings suggest that the improvement of hand functions brought about by EMG-driven robot hand training was driven explicitly by task-specific reorganization of motor networks. Particularly, the restoration of interhemispheric balance was induced by a reduction in interhemispheric inhibition from the contralesional M1 during motor tasks of the paretic hand. This finding sheds light on the mechanistic understanding of interhemispheric balance and functional recovery induced by EMG-driven robot training.

Determining the Optimal Stimulation Sessions for TMS-Induced Recovery of Upper Extremity Motor Function Post Stroke: A Randomized Controlled Trial.

To find out the optimal treatment sessions of repetitive transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) for upper extremity dysfunction after stroke during the 6-week treatment and to explore its mechanism using motor-evoked potentials (MEPs) and resting-state functional magnetic resonance imaging (rs-fMRI), 72 participants with upper extremity motor dysfunction after ischemic stroke were randomly divided into the control group, 10-session, 20-session, and 30-session rTMS groups. Low-frequency (1 Hz) rTMS over the contralesional M1 was applied in all rTMS groups. The motor function of the upper extremity was assessed before and after treatment. In addition, MEPs and rs-fMRI data were analyzed to detect its effect on brain reorganization. After 6 weeks of treatment, there were significant differences in the Fugl-Meyer Assessment of the upper extremity and the Wolf Motor Function Test scores between the 10-session group and the 30-session group and between the 20- and 30-session groups and the control group, while there was no significant difference between the 20-session group and the 30-session group. Meanwhile, no significant difference was found between the 10-session group and the control group. The 20-session group of rTMS decreased the excitability of the contralesional corticospinal tract represented by the amplitudes of MEPs and enhanced the functional connectivity of the ipsilesional M1 or premotor cortex with the the precentral gyrus, postcentral gyrus, and cingulate gyrus, etc. In conclusion, the 20-session of rTMS protocol is the optimal treatment sessions of TMS for upper extremity dysfunction after stroke during the 6-week treatment. The potential mechanism is related to its influence on the excitability of the corticospinal tract and the remodeling of corticomotor functional networks.

High-definition transcranial direct current stimulation for upper extremity rehabilitation in moderate-to-severe ischemic stroke: a pilot study.

Previous studies found that post-stroke motor impairments are associated with damage to the lesioned corticospinal tract (CST) and hyperexcitability of the contralesional cortico-reticulospinal tract (CRST). This proof-of-concept study aims to develop a non-invasive brain stimulation protocol that facilitates the lesioned CST and inhibits the contralesional CRST to improve upper extremity rehabilitation in individuals with moderate-to-severe motor impairments post-stroke. Fourteen individuals (minimum 3 months post ischemic stroke) consented. Physician decision of the participants baseline assessment qualified eight to continue in a randomized, double-blind cross-over pilot trial (ClinicalTrials.gov Identifier: NCT05174949) with: (1) anodal high-definition transcranial direct stimulation (HD-tDCS) over the ipsilesional primary motor cortex (M1), (2) cathodal HD-tDCS over contralesional dorsal premotor cortex (PMd), (3) sham stimulation, with a two-week washout period in-between. Subject-specific MR images and computer simulation were used to guide HD-tDCS and verified by Transcranial Magnetic Stimulation (TMS) induced Motor Evoked Potential (MEP). The motor behavior outcome was evaluated by an Fugl-Meyer Upper Extremity score (primary outcome measure) and the excitability of the ipslesoinal CST and contralesional CRST was determined by the change of MEP latencies and amplitude (secondary outcome measures). The baseline ipsilesional M1 MEP latency and amplitude were correlated with FM-UE. FM-UE scores were improved post HD-tDCS, in comparison to sham stimulation. Both anodal and cathodal HD-tDCS reduced the latency of the ipsilesional M1 MEP. The contralesional PMd MEP disappeared/delayed after HD-tDCS. These results suggest that HD-tDCS could improve the function of the lesioned corticospinal tract and reduce the excitability of the contralesional cortico-reticulospinal tract, thus, improving motor function of the upper extremity in more severely impaired individuals.

Effect of immersive virtual mirror visual feedback on Mu suppression and coherence in motor and parietal cortex in stroke

We investigated the activation pattern of the motor cortex (M1) and parietal cortex during immersive virtual reality (VR)-based mirror visual feedback (MVF) of the upper limb in 14 patients with chronic stroke and severe upper limb hemiparesis and in 21 healthy controls. Participants performed wrist extension with unaffected wrists (dominant side in controls). In the MVF condition, movement of the affected hand was synchronized with that of the unaffected hand. In the no-MVF condition, only the movement of unaffected hand was shown. Mu suppression in bilateral M1 and parietal cortex and mu coherence were analyzed. In patients with stroke, MVF induced significant mu suppression in both the ipsilesional M1 and parietal lobes (p = 0.006 and p = 0.009, respectively), while mu suppression was observed in the bilateral M1 (p = 0.003 for ipsilesional and p = 0.041 for contralesional M1, respectively) and contralesional parietal lobes in the controls (p = 0.036). The ipsilesional mu coherence between the M1 and parietal cortex in patients with stroke was stronger than controls, regardless of MVF condition (p < 0.001), while mu coherence between interhemispheric M1 cortices was significantly weaker in patients with stroke (p = 0.032). Our findings provide evidence of the neural mechanism of MVF using immersive VR in patients with stroke.

Intracortical and intercortical networks in patients after stroke: a concurrent TMS-EEG study

BackgroundConcurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) recording provides information on both intracortical reorganization and networking, and that information could yield new insights into post-stroke neuroplasticity. However, a comprehensive investigation using both concurrent TMS-EEG and motor-evoked potential-based outcomes has not been carried out in patients with chronic stroke. Therefore, this study sought to investigate the intracortical and network neurophysiological features of patients with chronic stroke, using concurrent TMS-EEG and motor-evoked potential-based outcomes.MethodsA battery of motor-evoked potential-based measures and concurrent TMS-EEG recording were performed in 23 patients with chronic stroke and 21 age-matched healthy controls.ResultsThe ipsilesional primary motor cortex (M1) of the patients with stroke showed significantly higher resting motor threshold (P = 0.002), reduced active motor-evoked potential amplitudes (P = 0.001) and a prolonged cortical silent period (P = 0.007), compared with their contralesional M1. The ipsilesional stimulation also produced a reduction in N100 amplitude of TMS-evoked potentials around the stimulated M1 (P = 0.007), which was significantly correlated with the ipsilesional resting motor threshold (P = 0.011) and motor-evoked potential amplitudes (P = 0.020). In addition, TMS-related oscillatory power was significantly reduced over the ipsilesional midline-prefrontal and parietal regions. Both intra/interhemispheric connectivity and network measures in the theta band were significantly reduced in the ipsilesional hemisphere compared with those in the contralesional hemisphere.ConclusionsThe ipsilesional M1 demonstrated impaired GABA-B receptor-mediated intracortical inhibition characterized by reduced duration, but reduced magnitude. The N100 of TMS-evoked potentials appears to be a useful biomarker of post-stroke recovery.

Reorganization of corticospinal projections after prominent recovery of finger dexterity from partial spinal cord injury in macaque monkeys.

We investigated morphological changes in the corticospinal tract (CST) to understand the mechanism underlying recovery of hand function after lesion of the CST at the C4/C5 border in 7 macaque monkeys. All monkeys exhibited prominent recovery of precision grip success ratio within a few months. The trajectories and terminals of CST from the contralesional (n = 4) and ipsilesional (n = 3) hand area of primary motor cortex (M1) were investigated at 5-29 months after the injury using an anterograde neural tracer, biotinylated dextran amine (BDA). Reorganization of the CST was assessed by counting the number of BDA-labeled axons and bouton-like swellings in the gray and white matters. Rostral to the lesion (at C3), the number of axon collaterals of the descending axons from both contralesional and ipsilesional M1 entering the ipsilesional and contralesional gray matter, respectively, were increased. Caudal to the lesion (at C8), axons originating from the contralesional M1, descending in the preserved gray matter around the lesion, and terminating in ipsilesional laminae VI/VII and IX were observed. In addition, axons and terminals from the ipsilesional M1 increased in the ipsilesional laminae IX after recrossing the midline, which were not observed in intact monkeys. Conversely, axons originating from the ipsilesional M1 and directed toward the contralesional laminae VII decreased. These results suggest that multiple reorganizations of the corticospinal projections to spinal segments both rostral and caudal to the lesion originating from bilateral M1 underlie a prominent recovery in long-term after spinal cord injury.SIGNIFICANCE STATEMENTPrevious studies have shown that dexterous finger movements recover prominently after lesion of the corticospinal tract (CST) at the mid-cervical segments through rehabilitative training in macaque monkeys. Here, we show reorganization of the CST including sprouting of axons originating from the contralesional and ipsilesional motor cortex in the gray matter both caudal and rostral to the lesion, including a re-direction of the CST to hand motoneurons in the monkeys 5-29 months after the lesion. Thus, multiple mechanisms of reorganization of CST axons underlie the recovery of impaired cortico-motoneuronal pathways for the long-term recovery of finger dexterity.

Alterations in learning-related cortical activation and functional connectivity by high-definition transcranial direct current stimulation after stroke: an fNIRS study.

Motor learning is a key component of stroke neurorehabilitation. High-definition transcranial direct current stimulation (HD-tDCS) was recently developed as a tDCS technique that increases the accuracy of current delivery to the brain using arrays of small electrodes. The purpose of this study was to investigate whether HD-tDCS alters learning-related cortical activation and functional connectivity in stroke patients using functional near-infrared spectroscopy (fNIRS). Using a sham-controlled crossover study design, 16 chronic stroke patients were randomly assigned to one of two intervention conditions. Both groups performed the sequential finger tapping task (SFTT) on five consecutive days, either with (a) real HD-tDCS or (b) with sham HD-tDCS. HD-tDCS (1 mA for 20 min, 4 × 1) was administered to C3 or C4 (according to lesion side). fNIRS signals were measured during the SFTT with the affected hand before (baseline) and after each intervention using fNIRS measurement system. Cortical activation and functional connectivity of NIRS signals were analyzed using a statistical parametric mapping open-source software package (NIRS-SPM), OptoNet II®. In the real HD-tDCS condition, oxyHb concentration increased significantly in the ipsilesional primary motor cortex (M1). Connectivity between the ipsilesional M1 and the premotor cortex (PM) was noticeably strengthened after real HD-tDCS compared with baseline. Motor performance also significantly improved, as shown in response time during the SFTT. In the sham HD-tDCS condition, functional connectivity between contralesional M1 and sensory cortex was enhanced compared with baseline. There was tendency toward improvement in SFTT response time, but without significance. The results of this study indicated that HD-tDCS could modulate learning-related cortical activity and functional connectivity within motor networks to enhance motor learning performance. HD-tDCS can be used as an additional tool for enhancing motor learning during hand rehabilitation for chronic stroke patients.

Effect of High-Frequency rTMS combined with bilateral arm training on brain functional network in patients with chronic stroke: An fNIRS study

ObjectiveNeurological evidence for the combinational intervention coupling rTMS with motor training for stroke rehabilitation remains limited. This study aimed to investigate the effects of rTMS combined with bilateral arm training (BAT) on the brain functional reorganization in patients with chronic stroke via functional near-infrared spectroscopy (fNIRS). MethodsFifteen stroke patients and fifteen age-matched healthy participants were enrolled and underwent single BAT session (s-BAT) and BAT immediately after 5-Hz rTMS over the ipsilesional M1 (rTMS-BAT), measured cerebral haemodynamics by fNIRS. Functional connectivity (FC), the clustering coefficient (Ccoef), and local efficiency (Eloc) were applied to evaluate the functional response to the training paradigms. ResultsThe differences in FC responses to the two training paradigms were more pronounced in stroke patients than in healthy controls. In the resting state, stroke patients exhibited significantly lower FC than controls in both hemispheres. rTMS-BAT induced no significant difference in FC between groups. Compared to the resting state, rTMS-BAT induced significant decreases in Ccoef and Eloc of the contralesional M1 and significant increases in Eloc of the ipsilesional M1 in stroke patients. Additionally, these above two network metrics of the ipsilesional motor area were significantly positively correlated with the motor function of stroke patients. ConclusionsThese results suggest that the rTMS-BAT paradigm had additional effects on task-dependent brain functional reorganization. The engagement of the ipsilesional motor area in the functional network was associated with the motor impairment severity of stroke patients. fNIRS-based assessments may provide information about the neural mechanisms underlying combination interventions for stroke rehabilitation.

Effects of bihemispheric transcranial direct current stimulation on motor recovery in subacute stroke patients: a double-blind, randomized sham-controlled trial

BackgroundBihemispheric transcranial direct current stimulation (tDCS) of the primary motor cortex (M1) can simultaneously modulate bilateral corticospinal excitability and interhemispheric interaction. However, how tDCS affects subacute stroke recovery remains unclear. We investigated the effects of bihemispheric tDCS on motor recovery in subacute stroke patients.MethodsWe enrolled subacute inpatients who had first-ever ischemic stroke at subcortical regions and moderate-to-severe baseline Fugl-Meyer Assessment of Upper Extremity (FMA-UE) score 2–56. Participants between 14 and 28 days after stroke were double-blind, randomly assigned (1:1) to receive real (n = 13) or sham (n = 14) bihemispheric tDCS (with ipsilesional M1 anode and contralesional M1 cathode, 20 min, 2 mA) during task practice twice daily for 20 sessions in two weeks. Residual integrity of the ipsilesional corticospinal tract was stratified between groups. The primary efficacy outcome was the change in FMA-UE score from baseline (responder as an increase ≥ 10). The secondary measures included changes in the Action Research Arm Test (ARAT), FMA-Lower Extremity (FMA-LE) and explorative resting-state MRI functional connectivity (FC) of target regions after intervention and three months post-stroke.ResultsTwenty-seven participants completed the study without significant adverse effects. Nineteen patients (70%) had no recordable baseline motor-evoked potentials (MEP-negative) from the paretic forearm. Compared with the sham group, the real tDCS group showed enhanced improvement of FMA-UE after intervention (p < 0.01, effect size η2 = 0.211; responder rate: 77% vs. 36%, p = 0.031), which sustained three months post-stroke (p < 0.01), but not ARAT. Interestingly, in the MEP-negative subgroup analysis, the FMA-UE improvement remained but delayed. Additionally, the FMA-LE improvement after real tDCS was not significantly greater until three months post-stroke (p < 0.01). We found that the individual FMA-UE improvements after real tDCS were associated with bilateral intrahemispheric, rather than interhemispheric, FC strengths in the targeted cortices, while the improvements after sham tDCS were associated with predominantly ipsilesional FC changes after adjustment for age and sex (p < 0.01).ConclusionsBihemispheric tDCS during task-oriented training may facilitate motor recovery in subacute stroke patients, even with compromised corticospinal tract integrity. Further studies are warranted for tDCS efficacy and network-specific neuromodulation.Trial registration: This study is registered with ClinicalTrials.gov: (ID: NCT02731508).

Upper limb intelligent feedback robot training significantly activates the cerebral cortex and promotes the functional connectivity of the cerebral cortex in patients with stroke: A functional near-infrared spectroscopy study.

Upper limb intelligence robots are widely used to improve the upper limb function of patients with stroke, but the treatment mechanism is still not clear. In this study, functional near-infrared spectroscopy (fNIRS) was used to evaluate the concentration changes of oxygenated hemoglobin (oxy-Hb) and deoxyhemoglobin (deoxy-Hb) in different brain regions and functional connectivity (FC) of the cerebral cortex in patients with stroke. Twenty post-stroke patients with upper limb dysfunction were included in the study. They all received three different types of shoulder joint training, namely, active intelligent feedback robot training (ACT), upper limb suspension training (SUS), and passive intelligent feedback robot training (PAS). During the training, activation of the cerebral cortex was detected by fNIRS to obtain the concentration changes of hemoglobin and FC of the cerebral cortex. The fNIRS signals were recorded over eight ROIs: bilateral prefrontal cortices (PFC), bilateral primary motor cortices (M1), bilateral primary somatosensory cortices (S1), and bilateral premotor and supplementary motor cortices (PM). For easy comparison, we defined the right hemisphere as the ipsilesional hemisphere and flipped the lesional right hemisphere in the Nirspark. Compared with the other two groups, stronger cerebral cortex activation was observed during ACT. One-way repeated measures ANOVA revealed significant differences in mean oxy-Hb changes among conditions in the four ROIs: contralesional PFC [F(2, 48) = 6,798, p < 0.01], ipsilesional M1 [F(2, 48) = 6.733, p < 0.01], ipsilesional S1 [F(2, 48) = 4,392, p < 0.05], and ipsilesional PM [F(2, 48) = 3.658, p < 0.05]. Oxy-Hb responses in the contralesional PFC region were stronger during ACT than during SUS (p < 0.01) and PAS (p < 0.05). Cortical activation in the ipsilesional M1 was significantly greater during ACT than during SUS (p < 0.01) and PAS (p < 0.05). Oxy-Hb responses in the ipsilesional S1 (p < 0.05) and ipsilesional PM (p < 0.05) were significantly higher during ACT than during PAS, and there is no significant difference in mean deoxy-Hb changes among conditions. Compared with SUS, the FC increased during ACT, which was characterized by the enhanced function of the ipsilesional cortex (p < 0.05), and there was no significant difference in FC between the ACT and PAS. The study found that cortical activation during ACT was higher in the contralesional PFC, and ipsilesional M1 than during SUS, and showed tighter cortical FC between the cortices. The activation of the cerebral cortex of ACT was significantly higher than that of PAS, but there was no significant difference in FC. Our research helps to understand the difference in cerebral cortex activation between upper limb intelligent feedback robot rehabilitation and other rehabilitation training and provides an objective basis for the further application of upper limb intelligent feedback robots in the field of stroke rehabilitation.