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.

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.

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.

Gender differences in ergonomics during simulated ureteroscopy.

BACKGROUND: Female urologists report higher rates of work-related physical discomfort compared to male urologists. We compared ergonomics during simulated ureteroscopy, the most common surgery for kidney stones, between male and female urologists. METHODS: Surface electromyography was used to measure muscle activation during common ureteroscopic tasks in urology trainees and staff with different surgeon positions and ureteroscopes. Subjective workload was assessed using the NASA Task Load Index (NASA-TLX). Paired t-tests, Wilcoxon rank-sum tests, and multivariate regressions were used to compare muscle activation by gender for each trial condition. RESULTS: There was no difference in age or distribution of training level between genders, though men had larger glove sizes. Across all conditions, women required greater muscle activation in multiple muscle groups and had greater NASA-TLX scores compared to men. CONCLUSIONS: There may be gender differences in ergonomics during ureteroscopy based on muscle activation and subjective workload, suggesting potential for personalizing surgical ecosystems.

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.

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.

Ergonomics in the OR: An Electromyographic Evaluation of Common Muscle Groups Used During Simulated Flexible Ureteroscopy - a Pilot Study.

OBJECTIVE: To assess the effects of different surgeon positions and ureteroscope types on muscle activation as measured by surface electromyography (sEMG) during simulated ureteroscopy in an endourology box-trainer model and the kidney phantom. METHODS: For this exploratory study, sEMG was used to quantify muscle activation of 3 endourology fellows during various ureteroscopic tasks. Electrodes were placed on the ureteroscope-holding side of the following muscles: thenar, forearm flexor, forearm extensor, biceps, triceps, deltoid, and trapezius. Subjects wore fitted lead aprons in an operating room and used a cystoscopy table with surgical drapes and an endoscopic video tower. Trials were completed with a disposable and reusable ureteroscope, both in the standing and sitting positions. Each subject performed an identical set of tasks in a phantom silicone kidney and ureteroscopy box trainer to recreate the procedural components of basketing, navigating a renal collecting system, and dusting. Raw EMG data for each task was processed and normalized as a percent of each subject's maximum voluntary contraction to allow comparison. RESULTS: The forearm extensor was the most heavily utilized muscle. The trapezius and deltoid muscles were activated more during sitting whereas the forearm flexors had increased activity during standing. The heavier reusable ureteroscope had increased forearm extensor activation compared to the disposable ureteroscope. CONCLUSION: Preliminary data show measurable differences in muscle activation based on both surgical posture and type of ureteroscope used. This highlights the need for more extensive EMG studies to identify techniques and equipment to optimize ergonomics and potentially minimize injury during flexible ureteroscopy.

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.