OBJECTIVE:The aim of the study was to compare the effects of repetitive transcranial magnetic stimulation targeting the contralesional dorsal premotor versus the ipsilesional primary motor cortex in chronic stroke survivors with severe hand paresis. DESIGN:This assessor-blinded pilot randomized trial enrolled 16 participants ≥6 mos after stroke with severe hand paresis, defined by the absence of either 10° distal extension in wrist/fingers/thumb or motor evoked potentials in paretic muscles. Participants received 5-Hz repetitive transcranial magnetic stimulation to the contralesional dorsal premotor or the ipsilesional primary motor cortex target, combined with upper extremity rehabilitation for 6 wks. Outcomes included Upper Extremity Fugl-Meyer, Wolf Motor Function Test, Stroke Impact Scale-16, and interhemispheric inhibition. RESULTS:Baseline characteristics were similar across groups, although the ipsilesional stimulation group had more participants with motor evoked potentials and ≥10° thumb extension (P = 0.04). Both groups achieved similar gains on Fugl-Meyer, but wrist subscore changes favored the ipsilesional stimulation group (P = 0.011). No differences were observed for other outcomes. CONCLUSIONS:Stimulation of the contralesional dorsal premotor cortex was not superior to stimulation of the ipsilesional primary motor cortex for upper extremity rehabilitation outcomes in chronic stroke survivors with severe hand paresis, though both approaches yielded sustained motor improvements. Future trials should stratify by distal extension and physiology.

Homosynaptic depression (HD) refers to the reduction in the magnitude of the monosynaptic spinal reflex resulting from prior activation of the circuit, often evoked with the H-reflex. Previous literature has reported HD of the soleus H-reflex is reduced post-stroke. However, it remains unclear if HD plays a role in functional impairments. The goal of this study was to characterize HD of the soleus H-reflex in individuals with post-stroke gait impairments and examine the relationship with functional measures of gait. Our results revealed that individuals after stroke experienced reduced depression at longer (8s) interstimulus intervals compared to age-matched neurologically intact individuals. However, we did not observe a difference in the change in HD across interstimulus intervals between groups, contrary to previous reports. This finding could not be explained by age of participants. In addition, we found a strong correlation between faster gait speed and reduced change in depression in individuals after stroke. While the underlying mechanisms linking HD with gait are unclear, this finding represents the first piece of evidence of the potential role of HD in function. Further research is needed to understand the parameters that guide HD and clarify how useful the mechanism is for improving the assessment and treatment of post-stroke impairments.

Background Fatigue, a complex and multidimensional complaint, is highly prevalent after stroke and contributes to adverse outcomes and impaired motor recovery. Here, we focus on post-stroke motor fatigability (PSMF), which refers to objective limitations in continuous motor performance post-stroke. PSMF can impair the performance of activities of daily living and may significantly hinder rehabilitation efforts, limiting progress and recovery. Objectives The purpose of this review is to summarize the current understanding of PSMF and to evaluate various tools used to investigate its underlying mechanisms. Results Prior studies on PMSF differ significantly in their approaches, with some employing neurophysiology and neurostimulation to investigate neural mechanisms, while others focus on functional assessments. Inconsistent terminology and the lack of standardized methodology are key barriers to reaching meaningful conclusions. While there is some consensus that central factors in the neuromuscular pathway limit sustained motor activity more than peripheral factors, additional research is needed to understand the timing and pathophysiology of PSMF including its relationship with other impairments of motor control. We present several specific recommendations for future studies, including the use of proper taxonomy to demystify the patient complaint, consistent paradigms to evoke fatigability, and neurophysiological tools to locate its origin. Conclusion Applying these guidelines to future investigations will help researchers better identify stroke-specific limitations in continuous motor performance and develop tailored interventions to help patients adjust to the persistent, repetitive demands of daily life.

Abstract Currently, there is no consensus about how investigators should format their NIBS data for sharing. This presents a barrier to the advancement of big data analyses because it requires time-consuming operations to generate consistent formats across different shared datasets. Recently, we launched ‘Big non-invasive brain stimulation data’ (Big NIBS data), an open-access platform and repository for NIBS data ( https://www.bignibsdata.com/ ), providing a structured mechanism for researchers to share NIBS data. However, the reusability and interoperability of data uploaded to Big NIBS data is restricted by the absence of a common data structure. The current paper addresses this problem by creating the ‘NIBS data analysis structure’ (NIBS-DAS), a template pipeline for the layout, management, and analysis of collated NIBS outcome data. While its primary purpose is to provide a template layout for uploading collated data to the Big NIBS data repository, NIBS-DAS also offers guidelines for the management and analysis of collated NIBS data, thereby forming a data analysis pipeline that can be freely used by the NIBS field in general. We anticipate that NIBS-DAS will serve to facilitate data sharing on the Big NIBS data platform and promote greater standardisation of data management and analytical practices in the NIBS field.

The role of contralesional motor cortices in paretic upper extremity (UE) motor recovery following stroke varies based on available structural reserve. However, an optimal measure of the reserve to stratify patients for different contralesional brain stimulation remains unknown. This study aimed to establish severity criteria distinguishing which patients benefit more from inhibitory contralesional motor cortex (M1) stimulation versus facilitatory contralesional dorsal premotor cortex (cPMd) stimulation. Twenty-four chronic stroke participants underwent three repetitive transcranial magnetic stimulation (rTMS) sessions: inhibitory 1 Hz rTMS to contralesional M1, facilitatory 5 Hz rTMS to cPMd, and sham rTMS. Motor performance on a reaching task (RT) was assessed pre- and post-stimulation. Baseline assessments included UE Fugl-Meyer (UEFM), corticospinal integrity (fractional anisotropy), and motor evoked potentials (MEPs). Classification and Regression Tree (CART) analysis identified UEFM 42 as the threshold distinguishing patients who improved with cM1 inhibition versus cPMd facilitation rTMS, with 91.6 % and 83.3 % accuracy, respectively. Participants with UEFM>42 showed greater RT gains with inhibitory rTMS than more severely impaired individuals (p = 0.06), whereas those with UEFM≤42 demonstrated greater RT gains with facilitatory cPMd rTMS than sham (p = 0.003). Less-severe participants had larger increases in ipsilesional MEPs following inhibitory rTMS (p = 0.007), whereas more-severe (UEFM≤42) MEP-absent participants had larger reductions in interhemispheric inhibition (IHI) following facilitatory cPMd rTMS (p = 0.028). Our findings support the bimodal theory and introduce the START (Stratification Algorithm for rTMS) framework, utilizing clinical impairment and white matter integrity to stratify response. While promising, the START algorithm requires further validation in larger samples to develop targeted and effective neuromodulation treatments.

BACKGROUND:This study compared the effects of contralaterally controlled functional electrical stimulation (CCFES) to cyclic neuromuscular electrical stimulation (cNMES) and task-oriented training (TOT) without electrical stimulation (TOT) on the recovery of hand function in stroke survivors with chronic hand hemiparesis. METHODS:In this assessor-blinded randomized controlled trial conducted at 4 sites in the United States, individuals 6 to 24 months poststroke with moderate-to-severe hand weakness were randomly assigned 1:1:1 to CCFES, cNMES, or TOT and prescribed 10 sessions/week of treatment-specific exercise at home plus 22 sessions of treatment-specific functional task practice in the laboratory over 12 weeks. The primary outcome was the change in the box and blocks test score at 6 months after treatment. Secondary measures included the upper extremity Fugl-Meyer, the action research arm test, and responder rates. Mixed effects analyses and differences of least square means were used to evaluate treatment effects. RESULTS:Between February 15, 2019, and January 24, 2024, 132 patients were randomized; 113 completed the treatment phase (36 CCFES, 39 cNMES, and 38 TOT) and were included in the analysis (modified intention-to-treat). There were no significant between-group differences in the change in the box and blocks test score at 6 months after treatment. CCFES improved upper extremity Fugl-Meyer scores more than cNMES and TOT, CCFES versus cNMES difference of 4.4 (95% CI, 1.5-7.3; P=0.003), and CCFES versus TOT difference of 3.7 (95% CI, 0.8-6.5; P=0.012). CCFES improved action research arm test scores more than TOT, CCFES versus TOT difference of 4.1 (95% CI, 1.1-7.1; P=0.008). The responder rate based on an increase in upper extremity Fugl-Meyer ≥5.25 points at 6 months after treatment was greater for CCFES than cNMES (67% versus 42%; P=0.047) and TOT (67% versus 38%; P=0.020). There were no between-group differences in responder rates based on the box and blocks test (27% CCFES, 32% cNMES, and 21% TOT) or action research arm test (42% CCFES, 32% cNMES, and 26% TOT). There were no serious treatment-related adverse events. CONCLUSIONS:By 6 months after 12 weeks of treatment, CCFES did not improve dexterity more than cNMES or TOT. CCFES reduced upper extremity impairment more than cNMES and TOT and improved upper limb function more than TOT. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03574623.

Objective. Ipsilateral motor evoked potentials (iMEPs) are believed to represent cortically evoked excitability of uncrossed brainstem-mediated pathways. In the event of extensive injury to (crossed) corticospinal pathways, which can occur following a stroke, uncrossed ipsilateral pathways may serve as an alternate resource to support the recovery of the paretic limb. However, iMEPs, even in neurally intact people, can be small, infrequent, and noisy, so discerning them in stroke survivors is very challenging. This study aimed to investigate the inter-rater reliability of iMEP features (presence/absence, amplitude, area, onset, and offset) to evaluate the reliability of existing methods for objectively analyzing iMEPs in stroke survivors with chronic upper extremity (UE) motor impairment. Approach. Two investigators subjectively measured iMEP features from thirty-two stroke participants with chronic UE motor impairment. Six objective methods based on standard deviation (SD) and mean consecutive differences (MCD) were used to measure the iMEP features from the same 32 participants. IMEP analysis used both trial-by-trial (individual signal) and average-signal analysis approaches. Inter-rater reliability of iMEP features and agreement between the subjective and objective methods were analyzed (percent agreement-PA and intraclass correlation coefficient-ICC). Main results. Inter-rater reliability was excellent for iMEP detection (PA > 85%), amplitude, and area (ICC > 0.9). Of the six objective methods we tested, the 1SD method was most appropriate for identifying and analyzing iMEP amplitude and area (ICC > 0.9) in both trial-by-trial and average signal analysis approaches. None of the objective methods were reliable for analyzing iMEP onset and offset. Results also support using the average-signal analysis approach over the trial-by-trial analysis approach, as it offers excellent reliability for iMEP analysis in stroke survivors with chronic UE motor impairment. Significance. Findings from our study have relevance for understanding the role of ipsilateral pathways that typically survive unilateral severe white matter injury in people with stroke.

Incomplete spinal cord injury (iSCI) disrupts signal transmission at the level of injury (LOI) and in higher brain structures, weakening intracortical circuits and impairing movement initiation. A potential approach to target intracortical circuits is to deliver transcranial magnetic stimulation (TMS) during motor intention, known as movement-related cortical stimulation (MRCS). We hypothesize that delivering TMS during motor intention will enhance corticospinal excitability (CE) and improve muscle activation below the LOI. One participant with chronic severe iSCI participated in a crossover study followed by five consecutive treatment sessions. First, we investigated the impact of TMS intensity (subthreshold vs. suprathreshold) on CE when delivered 50 ms before movement. The participant then received five consecutive days of MRCS with active subthreshold TMS for 15-20 min. Experiment 1: CE was assessed before and after sham, suprathreshold, and subthreshold MRCS (1-wk washout), targeting the abductor hallucis muscle. Experiment 2: CE and volitional motor unit recruitment were measured at baseline, the start of each session and 3- and 7-day follow-up. Corticomotor maps were assessed at baseline and post 3- and 7-day follow-up. Subthreshold MRCS increased CE compared with sham and suprathreshold MRCS. Five days of subthreshold MRCS increased CE, motor maps, and volitional motor unit recruitment, with improvements lasting up to the 3-day follow-up and remaining above baseline at day 7. These findings suggest that timed cortical stimulation with movement intention may enhance signal transmission in iSCI below the LOI. Future research is needed to determine if MRCS can prime intracortical circuitry before therapy to improve motor function.NEW & NOTEWORTHY We demonstrate that five consecutive days of movement-related cortical stimulation can enhance corticospinal excitability, expand motor maps, and improve volitional motor unit recruitment in a person with severe incomplete spinal cord injury. These results support the brain's adaptive capacity following spinal cord injury, despite limited motor drive to the muscle, and corroborate the potential to improve motor function by targeting higher-order networks during volitional motor intention with noninvasive brain stimulation.

Background: After stroke, impaired bimanual coordination reduces quality of life, where precise coordination of force between arms is essential for daily activities. Effective coordination relies on balanced interhemispheric communication, which induces crossed facilitation between primary motor cortices (M1). Intracortical inhibition influences both crossed facilitation and bimanual coordination in neurologically intact individuals. This study examines whether GABAB-mediated inhibition in ipsilesional M1 influences crossed facilitation from contralesional M1 and its relationship with bimanual coordination post-stroke.Methods: Thirteen chronic stroke participants performed dynamic and isometric bimanual force grip task. In the dynamic task, the paretic hand maintained 30% of maximal voluntary contraction while the non-paretic hand varied force levels (low-mid-high). Cross-covariance coefficient between hands measured interference from non-paretic hand to paretic hand. In the isometric task, transcranial magnetic stimulation assessed crossed facilitation via motor evoked potential (MEP) and intracortical inhibition via cortical silent period (CSP) in ipsilesional M1 under varying bimanual force conditions (paretic: rest, 5%, 30%; non-paretic: rest, 10%, 30%, 70%).Results: Results showed variable bimanual interference post-stroke, with greater interference in less impaired individuals and under high non-paretic force. Crossed facilitation increased with higher force asymmetry and lower paretic effort, particularly in less impaired participants, but became more variable as paretic effort increased (during PH 30%: NPH 70%). Under the high asymmetry condition, GABAB-mediated disinhibition was most pronounced and greater crossed facilitation was associated with increased bimanual interference.Conclusion: These findings suggest that reduced inhibitory tone may contribute to the regulation of crossed facilitation, and bimanual coordination deficits may be driven by excessive crossed facilitation. Future work will examine other ipsilesional factors regulating crossed facilitation, as targeted asymmetric training and neuromodulation may help improve bimanual coordination in individuals with moderate-to-mild motor impairment.

Following spinal cord injury (SCI), intact neural resources undergo widespread reorganization within the brain. Animal models reveal motor cortical representations devoted to spared muscles above injury expand at the expense of territories occupied by weaker muscles. In this study, we investigated whether motor representations are similarly reorganized between a relatively spared biceps muscle and a weakened triceps muscle in persons with chronic tetraplegia following traumatic cervical SCI in association with upper limb motor function. Twenty-four adults with cervical SCI and 15 able-bodied participants underwent motor mapping using transcranial magnetic stimulation. We determined following map characteristics: area, amplitude (maximal motor evoked potential and volume), and center of gravity. Maximal voluntary contraction (MVC) and motor function (Capabilities of the Upper Extremity Test or CUE-T) were also assessed. Findings reveal that participants with SCI had hyper-excitable biceps maps than triceps, and hyper-excitable biceps maps also compared to biceps maps in able-bodied participants. Higher amplitude of biceps and triceps maps was associated with better motor function (higher CUE-T) and more distal injury (i.e., more spared segments) in persons with SCI. Amplitudes of biceps but not the triceps maps were associated with higher muscle MVCs. In conclusion, over-excitable biceps than triceps map in SCI may represent deafferentation plasticity. For the first time, we demonstrate how map reorganization of spared and weaker muscles in persons with chronic cervical SCI is associated with upper limb motor status. Use-dependent mechanisms may shift neural balance in favor of spared muscles, supporting potential use as response biomarkers in rehabilitation studies. New & Noteworthy Our study reports evidence in humans with cervical SCI that motor representation for the relatively spared muscle becomes hyper-excitable compared to that for the weaker muscle to the extent that hyper-excitability is even higher compared to biceps maps in uninjured individuals. Use-dependent mechanisms likely favor such heightened excitability of spared maps. For the first time, we demonstrate clinical relevance of map excitability in humans with SCI, supporting potential use as a biomarker of recovery. ### Competing Interest Statement The authors have declared no competing interest.

While ipsilesional cortical electroencephalography has been associated with poststroke recovery mechanisms and outcomes, the role of the cerebellum and its interaction with the ipsilesional cortex is still largely unknown. We have previously shown that poststroke motor control relies on increased corticocerebellar coherence (CCC) in the low beta band to maintain motor task accuracy and to compensate for decreased excitability of the ipsilesional cortex. We now extend our work to investigate corticocerebellar network changes associated with chronic stimulation of the dentato-thalamo-cortical pathway aimed at promoting poststroke motor rehabilitation. We investigated the excitability of the ipsilesional cortex, the dentate (DN), and their interaction as a function of treatment outcome measures. Relative to baseline, 10 human participants (two women) at the end of 4–8 months of DN deep brain stimulation (DBS) showed (1) significantly improved motor control indexed by computerized motor tasks; (2) significant increase in ipsilesional premotor cortex event-related desynchronization that correlated with improvements in motor function; and (3) significant decrease in CCC, including causal interactions between the DN and ipsilesional cortex, which also correlated with motor function improvements. Furthermore, we show that the functional state of the DN in the poststroke state and its connectivity with the ipsilesional cortex were predictive of motor outcomes associated with DN-DBS. The findings suggest that as participants recovered, the ipsilesional cortex became more involved in motor control, with less demand on the cerebellum to support task planning and execution. Our data provide unique mechanistic insights into the functional state of corticocerebellar-cortical network after stroke and its modulation by DN-DBS.

PURPOSE To estimate the effect of integrating custom-designed hand therapy video games (HTVG) with contralaterally controlled functional electrical stimulation (CCFES) therapy. METHODS Fifty-two stroke survivors with chronic (>6 months) upper limb hemiplegia were randomized to 12 weeks of CCFES or CCFES + HTVG. Treatment involved self-administration of technology-mediated therapy at home plus therapist-administered CCFES-assisted task practice in the lab. Pre- and post-treatment assessments were made of hand dexterity, upper limb impairment and activity limitation, and cognitive function. RESULTS No significant between-group differences were found on any outcome measure, and the average magnitudes of improvement within both groups were small. The incidence of technical problems with study devices at home was greater for the CCFES + HTVG group. This negatively affected adherence and may partially explain the absence of effect of HTVG. At end-of-treatment, large majorities of both treatment groups had positive perceptions of treatment efficacy and expressed enthusiasm for the treatments. CONCLUSION This study makes an important contribution to the research literature on the importance of environmental factors, concomitant impairments, and technology simplification when designing technology-based therapies intended to be self-administered at home. This study failed to show any added benefit of HTVG to CCFES therapy.Clinicaltrials.gov (NCT03058796).

Upper-extremity impairment after stroke remains a major therapeutic challenge and a target of neuromodulation treatment efforts. In this open-label, non-randomized phase I trial, we applied deep brain stimulation to the cerebellar dentate nucleus combined with renewed physical rehabilitation to promote functional reorganization of ipsilesional cortex in 12 individuals with persistent (1-3 years), moderate-to-severe upper-extremity impairment. No serious perioperative or stimulation-related adverse events were encountered, with participants demonstrating a seven-point median improvement on the Upper-Extremity Fugl-Meyer Assessment. All individuals who enrolled with partial preservation of distal motor function exceeded minimal clinically important difference regardless of time since stroke, with a median improvement of 15 Upper-Extremity Fugl-Meyer Assessment points. These robust functional gains were directly correlated with cortical reorganization evidenced by increased ipsilesional metabolism. Our findings support the safety and feasibility of deep brain stimulation to the cerebellar dentate nucleus as a promising tool for modulation of late-stage neuroplasticity for functional recovery and the need for larger clinical trials. ClinicalTrials.gov registration: NCT02835443 .

Background: Transcranial direct current stimulation (tDCS) targeting the primary motor cortex is modestly effective for promoting upper-limb motor function following stroke. The premotor cortex (PMC) represents an alternative target based on its higher likelihood of survival and dense motor-network connections.Objective: The objective of this study was to determine whether ipsilesional PMC tDCS affects motor network functional connectivity (FC) in association with reduction in motor impairment, and to determine whether this relationship is influenced by baseline motor severity.Methods: Participants with chronic stroke were randomly assigned to receive active-PMC or sham-tDCS with rehabilitation for 5 weeks. Resting-state functional magnetic resonance imaging was acquired to characterize change in FC across motor-cortical regions.Results: Our results indicated that moderate-to-severe participants who received active-tDCS had greater increases in PMC-to-PMC interhemispheric FC compared to those who received sham; this increase was correlated with reduction in proximal motor impairment. There was also an increase in intrahemispheric dorsal premotor cortex-primary motor cortex FC across participants regardless of severity or tDCS group assignment; this increase was correlated with a reduction in proximal motor impairment in only the mild participants.Conclusions: Our findings have significance for developing targeted brain stimulation approaches. While participants with milder impairments may inherently recruit viable substrates within the ipsilesional hemisphere, stimulation of PMC may enhance interhemispheric FC in association with recovery in more impaired participants.Trial Registration: ClinicalTrials.gov Identifier: NCT01539096; Registration date: February 21, 2012. Impact statementThis study reports that improved post-stroke proximal motor impairment following constraint induced movement therapy is associated with increases (a) inter-hemispheric connectivity in participants with moderate-to-severe impairments, and (b) intra-hemispheric connectivity in participants with mild impairments. As non-invasive brain stimulation of the ipsilesional premotor cortex was shown to enhance inter-hemispheric connectivity between homologous premotor cortex in participants with more severe impairments, we suggest that future studies of non-invasive brain stimulation should aim to personalize stimulation targets based on intrinsic mechanisms of recovery available to patients within different impairment ranges.

Neural stimulation technology aids stroke survivors in regaining lost motor functions. This article explores its applications in upper and lower limb stroke rehabilitation. The authors review various methods to target the corticomotor system, including transcranial direct current stimulation, repetitive transcranial magnetic stimulation, and vagus nerve stimulation. In addition, the authors review the use of peripheral neuromuscular electrical stimulation for therapeutic and assistive purposes, including transcutaneous electrical nerve stimulation, neuromuscular electrical stimulation, and functional electrical stimulation. For each, the authors examine the potential benefits, limitations, safety considerations, and FDA status.

The robust, reciprocal anatomic connections between the cerebellum and contralateral sensorimotor cerebral hemisphere underscore the strong physiological interdependence between these two regions in relation to human behavior. Previous studies have shown that damage to sensorimotor cortex can result in a lasting reduction of cerebellar metabolism, the magnitude of which has been linked to poor rehabilitative outcomes. A better understanding of movement-related cerebellar physiology as well as cortico-cerebellar coherence (CCC) in the chronic, poststroke state may be key to developing novel neuromodulatory techniques that promote upper limb motor rehabilitation. As a part of the first in-human phase I trial investigating the effects of deep brain stimulation of the cerebellar dentate nucleus (DN) on chronic poststroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG in participants (both sexes) with middle cerebral artery stroke during a visuo-motor tracking task. We investigated the excitability of ipsilesional cortex, DN, and their interaction as a function of motor impairment and performance. Our results indicate the following: (1) event-related oscillations in the ipsilesional cortex and DN were significantly correlated at movement onset in the low beta band, with moderately and severely impaired participants showing desynchronization and synchronization, respectively; and (2) significant CCC was observed during the isometric hold period in the low beta band, which was critical for maintaining task accuracy. Our findings support a strong coupling between ipsilesional cortex and DN in the low beta band during motor control across all impairment levels, which encourages the exploitation of the cerebello–thalamo–cortical pathway as a neuromodulation target to promote rehabilitation. SIGNIFICANCE STATEMENT Cerebral infarct because of stroke can lead to lasting reduction in cerebellar metabolism, resulting in poor rehabilitative outcomes. Thorough investigation of the cerebellar electrophysiology, as well as cortico-cerebellar connectivity in humans that could provide key insights to facilitate the development of novel neuromodulatory technologies, has been lacking. As a part of the first in-human phase I trial investigating deep brain stimulation of the cerebellar dentate nucleus (DN) for chronic, poststroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG while stroke survivors performed a motor task. Our data indicate strong coupling between ipsilesional sensorimotor cortex and DN in the low beta band across all impairment levels encouraging the exploration of electrical stimulation of the DN.

Up to 50% of stroke survivors have persistent, severe upper extremity paresis even after receiving rehabilitation. Repetitive transcranial magnetic stimulation (rTMS) can augment the effects of rehabilitation by modulating corticomotor excitability, but the conventional approach of facilitating excitability of the ipsilesional primary motor cortex (iM1) fails to produce motor improvement in stroke survivors with severe loss of ipsilesional substrate. Instead, the undamaged, contralesional dorsal premotor cortex (cPMd) may be a more suitable target. CPMd can offer alternate, bi-hemispheric and ipsilateral connections in support of paretic limb movement. This pilot, randomized clinical trial seeks to investigate whether rTMS delivered to facilitate cPMd in conjunction with rehabilitation produces greater gains in motor function than conventional rTMS delivered to facilitate iM1 in conjunction with rehabilitation in severely impaired stroke survivors. Twenty-four chronic (≥6 months) stroke survivors with severe loss of ipsilesional substrate (defined by the absence of physiologic evidence of excitable residual pathways tested using TMS) will be included. Participants will be randomized to receive rTMS to facilitate cPMd or iM1 in conjunction with task-oriented upper limb rehabilitation given for 2 sessions/week for 6 weeks. Assessments of primary outcome related to motor impairment (upper extremity Fugl-Meyer [UEFM]), motor function, neurophysiology, and functional neuroimaging will be made at baseline and at 6-week end-of-treatment. An additional assessment of motor outcomes will be repeated at 3-month follow-up to evaluate retention. The primary endpoint is 6-week change in UEFM. This pilot trial will provide preliminary evidence on the effects and mechanisms associated with facilitating intact cPMd in chronic severe stroke survivors. The trial is registered on clinicaltrials.gov, NCT03868410.

BackgroundApproximately two-thirds of stroke survivors experience chronic upper limb paresis, and of them, 50% experience severe paresis. Treatment options for severely impaired survivors are often limited. Rehabilitation involves intensively engaging the paretic upper limb, and disincentivizing use of the non-paretic upper limb, with the goal to increase excitability of the ipsilesional primary motor cortex (iM1) and suppress excitability of the undamaged (contralesional) motor cortices, presumed to have an inhibitory effect on iM1. Accordingly, brain stimulation approaches, such as repetitive transcranial magnetic stimulation (rTMS), are also given to excite iM1 and/or suppress contralesional motor cortices. But such approaches aimed at ultimately increasing iM1 excitability yield limited functional benefit in severely impaired survivors who lack sufficient ipsilesional substrate.AimHere, we test the premise that combining Contralaterally Controlled Functional Electrical Stimulation (CCFES), a rehabilitation technique that engages the non-paretic upper limb in delivery of neuromuscular electrical stimulation to the paretic upper limb, and a new rTMS approach that excites intact, contralesional higher motor cortices (cHMC), may have more favorable effect on paretic upper limb function in severely impaired survivors based on recruitment of spared, transcallosal and (alternate) ipsilateral substrate.MethodsIn a prospective, double-blind, placebo-controlled RCT, 72 chronic stroke survivors with severe distal hand impairment receive CCFES plus cHMC rTMS, iM1 rTMS, or sham rTMS, 2X/wk for 12wks. Measures of upper limb motor impairment (Upper Extremity Fugl Meyer, UEFM), functional ability (Wolf Motor-Function Test, WMFT) and perceived disability are collected at 0, 6, 12 (end-of-treatment), 24, and 36 wks (follow-up). TMS is performed at 0, 12 (end-of-treatment), and 36 wks (follow-up) to evaluate inter-hemispheric and ipsilateral mechanisms. Influence of baseline severity is also characterized with imaging.ConclusionsTargeting of spared neural substrates and rehabilitation which engages the unimpaired limb in movement of the impaired limb may serve as a suitable combinatorial treatment option for severely impaired stroke survivors.ClinicalTrials NoNCT03870672.

Loss of muscle mass is a major concern for long duration spaceflight. However, due to the need for specialized equipment, muscle size has only been assessed before and after spaceflight where ~20% loss is observed. Here, we demonstrate the utility of teleguided self-ultrasound scanning (Tele-SUS) to accurately monitor leg muscle size in astronauts during spaceflight. Over an average of 168 ± 57 days of spaceflight, 74 Tele-SUS sessions were performed. There were no significant differences between panoramic ultrasound images obtained by astronauts seven days prior to landing and expert sonographer after flight or between change in muscle size assessed by ultrasound and magnetic resonance imaging. These findings extend the current capabilities of ultrasound imaging to allow self-monitoring of muscle size with remote guidance.