Corticospinal inhibition investigated in relation to upper extremity motor function in cervical spinal cord injury.

OBJECTIVE: Corticospinal inhibitory mechanisms are relevant to functional recovery but remain poorly understood after spinal cord injury (SCI). Post-injury characteristics of contralateral silent period (CSP), a measure of corticospinal inhibition evaluated using transcranial magnetic stimulation (TMS), is inconsistent in literature. We envisioned that investigating CSP across muscles with varying degrees of weakness may be a reasonable approach to resolve inconsistencies and elucidate the relevance of corticospinal inhibition for upper extremity function following SCI. METHODS: We studied 27 adults with chronic C1-C8 SCI (age 48.8 ± 16.1 years, 3 females) and 16 able-bodied participants (age 33.2 ± 11.8 years, 9 females). CSP characteristics were assessed across biceps (muscle power = 3-5) and triceps (muscle power = 1-3) representing stronger and weaker muscles, respectively. We assessed functional abilities using the Capabilities of the Upper Extremity Test (CUE-T). RESULTS: Participants with chronic SCI had prolonged CSPs for biceps but delayed and diminished CSPs for triceps compared to able-bodied participants. Early-onset CSPs for biceps and longer, deeper CSPs for triceps correlated with better CUE-T scores. CONCLUSIONS: Corticospinal inhibition is pronounced for stronger biceps but diminished for weaker triceps muscle in SCI indicating innervation relative to the level of injury matters in the study of CSP. SIGNIFICANCE: Nevertheless, corticospinal inhibition or CSP holds relevance for upper extremity function following SCI.

Paired DBS and TMS Reveals Dentato-Cortical Facilitation Underlying Upper Extremity Movement in Chronic Stroke Survivors.

BACKGROUND: Cerebellum shares robust di-synaptic dentato-thalamo-cortical (DTC) connections with the contralateral motor cortex. Preclinical studies have shown that DTC are excitatory in nature. Structural integrity of DTC is associated with better upper extremity (UE) motor function in people with stroke, indicating DTC are important for cerebellar influences on movement. However, there is a lack of understanding of physiologic influence of DTC in humans, largely due to difficulty in accessing the dentate nucleus. OBJECTIVE: Characterize DTC physiology using dentate nucleus deep brain stimulation (DBS) combined with transcranial magnetic stimulation (TMS) in stroke. METHODS: Nine chronic stroke survivors with moderate-to-severe UE impairment (Fugl-Meyer 13-38) underwent a paired DBS-TMS experiment before receiving experimental dentate nucleus DBS in our first-in-human phase I trial (Baker et al., 2023, Nature Medicine). Conditioning DBS pulses were given to dentate nucleus 1 to 10 ms prior to supra-threshold TMS pulses given to ipsilesional motor cortex. Effects were assessed on motor evoked potentials (MEPs). Size of DBS-conditioned MEPs was expressed relative to TMS MEPs, where values >1 indicate facilitation. RESULTS: Dentate nucleus DBS led to facilitation of MEPs at short-latency intervals (3.5 and 5 ms, P = .049 and .021, respectively), a phenomenon we have termed dentato-cortical facilitation (DCF). Higher DCF was observed among patients with more severe UE impairment. Diffusion tensor imaging revealed microstructure of thalamo-cortical portion of DTC was related to higher corticomotor excitability. CONCLUSIONS: Our in vivo investigation reveals for the first time in humans the intrinsic excitatory properties of DTC, which can serve as a novel therapeutic target for post-stroke motor recovery.

Contralaterally controlled functional electrical stimulation video game therapy for hand rehabilitation after stroke: a randomized controlled trial.

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).

Contralaterally controlled functional electrical stimulation (CCFES) is an emerging therapy for upper limb rehabilitation after stroke that is designed, in part, to be self-administered at home.While movement-soliciting video games have shown promise in rehabilitation, this study failed to show a significant added benefit of integrating CCFES with hand therapy video games.For technology-based therapies intended to be self-administered at home, this study brings to light the importance of making every component of rehabilitation technology as user friendly and trouble-free as possible.For technology-based therapies intended to be self-administered at home, this study brings to light the importance of assuring that the home environment is conducive to home-based therapy.

Cerebellar deep brain stimulation for chronic post-stroke motor rehabilitation: a phase I trial.

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 .

Aging-induced alterations in EEG spectral power associated with graded force motor tasks.

BACKGROUND: It has been demonstrated that in young and healthy individuals, there is a strong association between the amplitude of EEG-derived motor activity-related cortical potential or EEG spectral power (ESP) and voluntary muscle force. This association suggests that the motor-related ESP may serve as an index of central nervous system function in controlling voluntary muscle activation Therefore, it may potentially be used as an objective marker to track changes in functional neuroplasticity due to neurological disorders, aging, and following rehabilitation therapies. To this end, the relationship between the band-specific ESP-combined spectral power of EEG oscillatory and aperiodic (noise) components-and voluntary elbow flexion (EF) force has been analyzed in elder and young individuals. METHODS: 20 young (22.6 ± 0.87 year) and 28 elderly (74.79 ± 1.37 year) participants performed EF contractions at 20%, 50%, and 80% of maximum voluntary contraction (MVC) while high-density EEG signals were recorded. Both the absolute and relative ESPs were computed for the EEG frequency bands of interest. RESULTS: The MVC force generated by the elderly was foreseeably lower than that of the young participants. Compared to young, the elderly cohort's (1) total ESP was significantly lower for the high (80% MVC) force task; (2) relative ESP in beta band was significantly elevated for the low and moderate (20% MVC and 50% MVC) force tasks; (3) absolute ESP failed to have a positive trend with force for EEG frequency bands of interest; and (4) beta-band relative ESP did not exhibit a significant decrease with increasing force levels. CONCLUSIONS: As opposed to young subjects, the beta-band relative ESP in elderly did not significantly decrease with increasing EF force values. This observation suggests the use of beta-band relative ESP as a potential biomarker for age-related motor control degeneration.

Stimulation of the Premotor Cortex Enhances Interhemispheric Functional Connectivity in Association with Upper Limb Motor Recovery in Moderate-to-Severe Chronic Stroke.

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.

Efficacy of contralaterally controlled functional electrical stimulation compared to cyclic neuromuscular electrical stimulation and task-oriented training for recovery of hand function after stroke: study protocol for a multi-site randomized controlled trial.

BACKGROUND: Multi-site studies in stroke rehabilitation are important for determining whether a technology and/or treatment can be successfully administered by sites other than the originating site and with similar positive outcomes. This study is the first multi-site clinical trial of a novel intervention for post-stroke upper limb rehabilitation called contralaterally controlled functional electrical stimulation (CCFES). Previous pilot and single-site studies showed positive effects of CCFES on upper limb impairment and hand dexterity in stroke survivors. The main purpose of this study is to confirm and demonstrate the efficacy of CCFES in a larger group of most likely responders across multiple clinical sites. METHODS: Up to 129 stroke survivors with moderate to severe upper extremity hemiparesis at 4 clinical trial sites will be randomized to CCFES, cyclic neuromuscular electrical stimulation (cNMES), or task-oriented-training (TOT). Participants will receive 12 weeks of group-specific therapy. Blinded assessments of upper limb impairment and activity limitation, quality of life, and neurophysiology will be used to compare outcomes at baseline, after treatment, and up to 6 months post-treatment. The primary endpoint is change in dexterity from baseline to 6 months post-treatment. DISCUSSION: Loss of hand function following stroke is a major rehabilitation problem affecting millions of people per year globally. More effective rehabilitation therapies are needed to restore hand function in these individuals. This study will determine whether CCFES therapy produces greater improvements in upper extremity function than cNMES or TOT, and will begin to elucidate the different mechanisms underlying each of the three treatments. This multi-site study is a critical step in advancing a novel method of rehabilitation toward clinical translation and widespread dissemination. TRIAL REGISTRATION: ClinicalTrials.gov NCT03574623 . Registered prior to first enrollment; July 2, 2018.

Contralaterally Controlled Functional Electrical Stimulation Combined With Brain Stimulation for Severe Upper Limb Hemiplegia-Study Protocol for a Randomized Controlled Trial.

Background: Approximately 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. Aim: Here, 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. Methods: In 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. Conclusions: Targeting 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 No: NCT03870672.

Safety and efficacy of transcranial direct current stimulation in upper extremity rehabilitation after tetraplegia: protocol of a multicenter randomized, clinical trial.

STUDY DESIGN: A multisite, randomized, controlled, double-blinded phase I/II clinical trial. OBJECTIVE: The purpose of this clinical trial is to evaluate the safety, feasibility and efficacy of pairing noninvasive transcranial direct current stimulation (tDCS) with rehabilitation to promote paretic upper extremity recovery and functional independence in persons living with chronic cervical spinal cord injury (SCI). SETTING: Four-site trial conducted across Cleveland Clinic, Louis Stokes Veterans Affairs Medical Center of Cleveland and MetroHealth Rehabilitation Rehabilitation Institute of Ohio, and Kessler Foundation of New Jersey. METHODS: Forty-four adults (age ≥18 years) with tetraplegia following cervical SCI that occurred ≥1-year ago will participate. Participants will be randomly assigned to receive anodal tDCS or sham tDCS given in combination with upper extremity rehabilitation for 15 sessions each over 3-5 weeks. Assessments will be made twice at baseline separated by at least a 3-week interval, once at end-of-intervention, and once at 3-month follow-up. PRIMARY OUTCOME MEASURE(S): Primary outcome measure is upper extremity motor impairment assessed using the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) scale. Functional abilities will be assessed using Capabilities of Upper Extremity-Test (CUE-T), while functional independence and participation restrictions will be evaluated using the self-care domain of Spinal Cord Independent Measure (SCIM), and Canadian Occupational Performance Measure (COPM). SECONDARY OUTCOME MEASURES: Treatment-associated change in corticospinal excitability and output will also be studied using transcranial magnetic stimulation (TMS) and safety (reports of adverse events) and feasibility (attrition, adherence etc.) will also be evaluated. TRIAL REGISTRATION: ClincalTrials.gov identifier NCT03892746. This clinical trial is being performed at four sites within the United States: Cleveland Clinic (lead site), Louis Stokes Cleveland Veterans Affairs Medical Center (VAMC) and MetroHealth Rehabilitation Institute in Ohio, and Kessler Foundation in New Jersey. The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office.

Repetitive Transcranial Magnetic Stimulation of the Contralesional Dorsal Premotor Cortex for Upper Extremity Motor Improvement in Severe Stroke: Study Protocol for a Pilot Randomized Clinical Trial.

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.

Repetitive Peripheral Sensory Stimulation as an Add-On Intervention for Upper Limb Rehabilitation in Stroke: A Randomized Trial.

INTRODUCTION: Repetitive peripheral sensory stimulation (RPSS) followed by 4-hour task-specific training (TST) improves upper limb motor function in subjects with stroke who experience moderate to severe motor upper limb impairments. Here, we compared effects of RPSS vs sham followed by a shorter duration of training in subjects with moderate to severe motor impairments in the chronic phase after stroke. METHODS: This single-center, randomized, placebo-controlled, parallel-group clinical trial compared effects of 18 sessions of either 1.5 h of active RPSS or sham followed by a supervised session that included 45 min of TST of the paretic upper limb. In both groups, subjects were instructed to perform functional tasks at home, without supervision. The primary outcome measure was the Wolf Motor Function Test (WMFT) after 6 weeks of treatment. Grasp and pinch strength were secondary outcomes. RESULTS: In intention-to-treat analysis, WMFT improved significantly in both active and sham groups at 3 and 6 weeks of treatment. Grasp strength improved significantly in the active, but not in the sham group, at 3 and 6 weeks. Pinch strength improved significantly in both groups at 3 weeks, and only in the active group at 6 weeks. CONCLUSIONS: The between-group difference in changes in WMFT was not statistically significant. Despite the short duration of supervised treatment, WMFT improved significantly in subjects treated with RPSS or sham. These findings are relevant to settings that impose constraints in duration of direct contact between therapists and patients. In addition, RPSS led to significant gains in hand strength.Trial Registry Name: Peripheral Nerve Stimulation and Motor Training in Stroke Clinical Trials.gov identifier: NCT0265878 https://clinicaltrials.gov/ct2/show/NCT02658578.

Measurement error and reliability of TMS metrics collected from biceps and triceps in individuals with chronic incomplete tetraplegia.

Transcranial magnetic stimulation (TMS) is used to investigate corticomotor neurophysiology associated with functional recovery in individuals with spinal cord injury (SCI). There is insufficient evidence about test-retest measurement properties of TMS in SCI. Therefore, we investigated test-retest agreement and reliability of TMS metrics representing corticomotor excitability, output, gain, map (representation), and inhibition in individuals with cervical SCI. We collected TMS metrics from biceps and triceps muscles because of the relevance of this proximal muscle pair to the cervical SCI population. Twelve individuals with chronic C3-C6 SCI participated in two TMS sessions separated by ≥ 2 weeks. Measurement agreement was evaluated using t tests, Bland-Altman limits of agreement and relative standard error of measurement (SEM%), while reliability was investigated using intra-class correlation coefficient (ICC) and concordance correlation coefficient (CCC). We calculated the smallest detectable change for all TMS metrics. All TMS metrics except antero-posterior map coordinates and corticomotor inhibition were in agreement upon repeated measurement though limits of agreement were generally large. Measures of corticomotor excitability, output and medio-lateral map coordinates had superior agreement (SEM% < 10). Metrics representing corticomotor excitability, output, and inhibition had good-to-excellent reliability (ICC/CCC > 0.75). The smallest detectable change for TMS metrics was generally high for a single individual, but this value reduced substantially with increase in sample size. We recommend use of corticomotor excitability and recruitment curve area owing to their superior measurement properties. A modest group size (20 or above) yields more stable measurements, which may favor use of TMS metrics in group level modulation after SCI.

Contralesional Cathodal Transcranial Direct Current Stimulation Does Not Enhance Upper Limb Function in Subacute Stroke: A Pilot Randomized Clinical Trial.

Transcranial direct current stimulation (tDCS) has the potential to improve upper limb motor outcomes after stroke. According to the assumption of interhemispheric inhibition, excessive inhibition from the motor cortex of the unaffected hemisphere to the motor cortex of the affected hemisphere may worsen upper limb motor recovery after stroke. We evaluated the effects of active cathodal tDCS of the primary motor cortex of the unaffected hemisphere (ctDCSM1UH) compared to sham, in subjects within 72 hours to 6 weeks post ischemic stroke. Cathodal tDCS was intended to inhibit the motor cortex of the unaffected hemisphere and hence decrease the inhibition from the unaffected to the affected hemisphere and enhance motor recovery. We hypothesized that motor recovery would be greater in the active than in the sham group. In addition, greater motor recovery in the active group might be associated with bigger improvements in measures in activity and participation in the active than in the sham group. We also explored, for the first time, changes in cognition and sleep after ctDCSM1UH. Thirty subjects were randomized to six sessions of either active or sham ctDCSM1UH as add-on interventions to rehabilitation. The NIH Stroke Scale (NIHSS), Fugl-Meyer Assessment of Motor Recovery after Stroke (FMA), Barthel Index (BI), Stroke Impact Scale (SIS), and Montreal Cognitive Assessment (MoCA) were assessed before, after treatment, and three months later. In the intent-to-treat (ITT) analysis, there were significant GROUP∗TIME interactions reflecting stronger gains in the sham group for scores in NIHSS, FMA, BI, MoCA, and four SIS domains. At three months post intervention, the sham group improved significantly compared to posttreatment in FMA, NIHSS, BI, and three SIS domains while no significant changes occurred in the active group. Also at three months, NIHSS improved significantly in the sham group and worsened significantly in the active group. FMA scores at baseline were higher in the active than in the sham group. After adjustment of analysis according to baseline scores, the between-group differences in FMA changes were no longer statistically significant. Finally, none of the between-group differences in changes in outcomes after treatment were considered clinically relevant. In conclusion, active CtDCSM1UH did not have beneficial effects, compared to sham. These results were consistent with other studies that applied comparable tDCS intensities/current densities or treated subjects with severe upper limb motor impairments during the first weeks post stroke. Dose-finding studies early after stroke are necessary before planning larger clinical trials.

Proprioceptive Augmentation With Illusory Kinaesthetic Sensation in Stroke Patients Improves Movement Quality in an Active Upper Limb Reach-and-Point Task.

Stroke patients often have difficulty completing motor tasks even after substantive rehabilitation. Poor recovery of motor function can often be linked to stroke-induced damage to motor pathways. However, stroke damage in pathways that impact effective integration of sensory feedback with motor control may represent an unappreciated obstacle to smooth motor coordination. In this study we investigated the effects of augmenting movement proprioception during a reaching task in six stroke patients as a proof of concept. We used a wearable neurorobotic proprioceptive feedback system to induce illusory kinaesthetic sensation by vibrating participants' upper arm muscles over active limb movements. Participants were instructed to extend their elbow to reach-and-point to targets of differing sizes at various distances, while illusion-inducing vibration (90 Hz), sham vibration (25 Hz), or no vibration was applied to the distal tendons of either their biceps brachii or their triceps brachii. To assess the impact of augmented kinaesthetic feedback on motor function we compared the results of vibrating the biceps or triceps during arm extension in the affected arm of stroke patients and able-bodied participants. We quantified performance across conditions and participants by tracking limb/hand kinematics with motion capture, and through Fitts' law analysis of reaching target acquisition. Kinematic analyses revealed that injecting 90 Hz illusory kinaesthetic sensation into the actively contracting (agonist) triceps muscle during reaching increased movement smoothness, movement directness, and elbow extension. Conversely, injecting 90 Hz illusory kinaesthetic sensation into the antagonistic biceps during reaching negatively impacted those same parameters. The Fitts' law analyses reflected similar effects with a trend toward increased throughput with triceps vibration during reaching. Across all analyses, able-bodied participants were largely unresponsive to illusory vibrational augmentation. These findings provide evidence that vibration-induced movement illusions delivered to the primary agonist muscle involved in active movement may be integrated into rehabilitative approaches to help promote functional motor recovery in stroke patients.

Does rTMS Targeting Contralesional S1 Enhance Upper Limb Somatosensory Function in Chronic Stroke? A Proof-of-Principle Study.

BACKGROUND: Somatosensory deficits are prevalent after stroke, but effective interventions are limited. Brain stimulation of the contralesional primary somatosensory cortex (S1) is a promising adjunct to peripherally administered rehabilitation therapies. OBJECTIVE: To assess short-term effects of repetitive transcranial magnetic stimulation (rTMS) targeting contralesional (S1) of the upper extremity. METHODS: Using a single-session randomized crossover design, stroke survivors with upper extremity somatosensory loss participated in 3 rTMS treatments targeting contralesional S1: Sham, 5 Hz, and 1 Hz. rTMS was delivered concurrently with peripheral of sensory electrical stimulation and vibration of the affected hand. Outcomes included 2-point discrimination (2PD), proprioception, vibration perception threshold, monofilament threshold (size), and somatosensory evoked potential (SEP). Measures were collected before, immediately after treatment, and 1 hour after treatment. Mixed models were fit to analyze the effects of the 3 interventions. RESULTS: Subjects were 59.8 ± 8.1 years old and 45 ± 39 months poststroke. There was improvement in 2PD after 5-Hz rTMS for the stroke-affected (F(2, 76.163) = 3.5, P = .035) and unaffected arm (F(2, 192.786) = 10.6, P < .0001). Peak-to-peak SEP amplitudes were greater after 5-Hz rTMS for N33-P45 (F(2, 133.027) = 3.518, P = .032) and N45-P60 (F(2, 67.353) = 3.212, P = .047). Latencies shortened after 5-Hz rTMS for N20 (F(2, 69.64) = 3.37, P = .04), N60 (F(2, 47.343) = 4.375, P = .018), and P100 (F(2, 37.608) = 3.537, P = .039) peaks. There were no differences between changes immediately after the intervention and an hour later. CONCLUSIONS: Short-term application of facilitatory high-frequency rTMS (5Hz) to contralesional S1 combined with peripheral somatosensory stimulation may promote somatosensory function. This intervention may serve as a useful adjunct in somatosensory rehabilitation after stroke.

TMS over the posterior cerebellum modulates motor cortical excitability in response to facial emotional expressions.

Evidence suggests that the posterior cerebellum is involved in emotional processing. Specific mechanisms by which the cerebellum contributes to the perception of and reaction to the emotional state of others are not well-known. It is likely that perceived emotions trigger anticipatory/preparatory motor changes. However, the extent to which the cerebellum modulates the activity of the motor cortex to contribute to emotional processing has not been directly investigated. In this study, we assessed whether the activity of the posterior cerebellum influences the modulation of motor cortical excitability in response to emotional stimuli. To this end, we transiently disrupted the neural activity of the left posterior cerebellum using 1 Hz repetitive transcranial magnetic stimulation (rTMS) and examined its effect on motor cortical excitability witnessed during emotional face processing (in comparison to the effects of sham rTMS). Motor excitability was measured as TMS-based motor evoked potentials (MEPs) recorded from bilateral first dorsal interosseous (FDI) muscles during the viewing of negative emotional (i.e. fearful) and neutral facial expressions. In line with previous evidence, we found that MEP amplitude was increased during the viewing of fearful compared to neutral faces. Critically, when left posterior cerebellar activity was transiently inhibited with 1 Hz rTMS, we observed a reduction in amplitude of MEPs recorded from the contralateral (right) motor cortex during the viewing of emotional (but not neutral) faces. In turn, inhibition of the left posterior cerebellum did not affect the amplitude of MEPs recorded from the ipsilateral motor cortex. Our findings suggest that the posterolateral (left) cerebellum modulates motor cortical response to negative emotional stimuli and may serve as an interface between limbic, cognitive, and motor systems.

Stratifying chronic stroke patients based on the influence of contralesional motor cortices: An inter-hemispheric inhibition study.

OBJECTIVE: A recent "bimodal-balance recovery" model suggests that contralesional influence varies based on the amount of ipsilesional reserve: inhibitory when there is a large reserve, but supportive when there is a low reserve. Here, we investigated the relationships between contralesional influence (inter-hemispheric inhibition, IHI) and ipsilesional reserve (corticospinal damage/impairment), and also defined a criterion separating subgroups based on the relationships. METHODS: Twenty-four patients underwent assessment of IHI using Transcranial Magnetic Stimulation (ipsilateral silent period method), motor impairment using Upper Extremity Fugl-Meyer (UEFM), and corticospinal damage using Diffusion Tensor Imaging and active motor threshold. Assessments of UEFM and IHI were repeated after 5-week rehabilitation (n = 21). RESULTS: Relationship between IHI and baseline UEFM was quadratic with criterion at UEFM 43 (95%conference interval: 40-46). Patients less impaired than UEFM = 43 showed stronger IHI with more impairment, whereas patients more impaired than UEFM = 43 showed lower IHI with more impairment. Of those made clinically-meaningful functional gains in rehabilitation (n = 14), more-impaired patients showed further IHI reduction. CONCLUSIONS: A criterion impairment-level can be derived to stratify patient-subgroups based on the bimodal influence of contralesional cortex. Contralesional influence also evolves differently across subgroups following rehabilitation. SIGNIFICANCE: The criterion may be used to stratify patients to design targeted, precision treatments.

Treatment of Upper Limb Paresis With Repetitive Peripheral Nerve Sensory Stimulation and Motor Training: Study Protocol for a Randomized Controlled Trial.

Background: Repetitive peripheral nerve sensory stimulation (RPSS) has emerged as a potential adjuvant strategy to motor training in stroke rehabilitation. The aim of this study is to test the hypothesis that 3 h sessions of active RPSS associated with functional electrical stimulation (FES) and task-specific training (TST) distributed three times a week, over 6 weeks, is more beneficial to improve upper limb motor function than sham RPSS in addition to FES and TST, in subjects with moderate to severe hand motor impairments in the chronic phase (>6 months) after stroke. Methods: In this single-center, randomized, placebo controlled, parallel-group, double-blind study we compare the effects of 18 sessions of active and sham RPSS as add-on interventions to FES and task-specific training of the paretic upper limb, in 40 subjects in the chronic phase after ischemic or hemorrhagic stroke, with Fugl-Meyer upper limb scores ranging from 7 to 50 and able to voluntarily activate any active range of wrist extension. The primary outcome measure is the Wolf Motor Function Test (WMFT) after 6 weeks of treatment. The secondary outcomes are the WMFT at 3, 10, and 18 weeks after beginning of treatment, as well as the following outcomes measured at 3, 6, 10, and 18 weeks: Motor Activity Log; active range of motion of wrist extension and flexion; grasp and pinch strength in the paretic and non-paretic sides (the order of testing is randomized within and across subjects); Modified Ashworth Scale; Fugl-Meyer Assessment-Upper Limb in the paretic arm; Barthel Index; Stroke Impact Scale. Discussion: This project represents a major step in developing a rehabilitation strategy with potential to have impact on the treatment of stroke patients with poor motor recovery in developing countries worldwide. The study preliminarily evaluates a straightforward, non-invasive, inexpensive intervention. If feasibility and preliminary efficacy are demonstrated, further investigations of the proposed intervention (underlying mechanisms/ effects in larger numbers of patients) should be performed. Trial Registration: NCT02658578.