Electric Field Navigated 1-Hz rTMS for Poststroke Motor Recovery: The E-FIT Randomized Controlled Trial.

BACKGROUND: To determine if low-frequency repetitive transcranial magnetic stimulation targeting the primary motor cortex contralateral (M1CL) to the affected corticospinal tract in patients with hemiparetic stroke augments intensive training-related clinical improvement; an extension of the NICHE trial (Navigated Inhibitory rTMS to Contralesional Hemisphere Trial) using an alternative sham coil. METHODS: The present E-FIT trial (Electric Field Navigated 1Hz rTMS for Post-stroke Motor Recovery Trial) included 5 of 12 NICHE trial outpatient US rehabilitation centers. The stimulation protocol remained identical (1 Hz repetitive transcranial magnetic stimulation, M1CL, preceding 60-minute therapy, 18 sessions/6 wks; parallel arm randomized clinical trial). The sham coil appearance mimicked the active coil but without the weak electric field in the NICHE trial sham coil. Outcomes measured 1 week, and 1, 3, and 6 months after the end of treatment included the following: upper extremity Fugl-Meyer (primary, 6 months after end of treatment), Action Research Arm Test, National Institutes of Health Stroke Scale, quality of life (EQ-5D), and safety. RESULTS: Of 60 participants randomized, 58 completed treatment and were included for analysis. Bayesian analysis of combined data from the E-FIT and the NICHE trials indicated that active treatment was not superior to sham at the primary end point (posterior mean odds ratio of 1.94 [96% credible interval of 0.61-4.80]). For the E-FIT intent-to-treat population, upper extremity Fugl-Meyer improvement ≥5 pts occurred in 60% (18/30) active group and 50% (14/28) sham group. Participants enrolled 3 to 6 months following stroke had a 67% (31%-91% CI) response rate in the active group at the 6-month end point versus 50% in the sham group (21.5%-78.5% CI). There were significant improvements from baseline to 6 months for both active and sham groups in upper extremity Fugl-Meyer, Action Research Arm Test, and EQ-5D (P<0.05). Improvement in National Institutes of Health Stroke Scale was observed only in the active group (P=0.004). Ten serious unrelated adverse events occurred (4 active group, 6 sham group, P=0.72). CONCLUSIONS: Intensive motor rehabilitation 3 to 12 months after stroke improved clinical impairment, function, and quality of life; however, 1 Hz-repetitive transcranial magnetic stimulation was not an effective treatment adjuvant in the present sample population with mixed lesion location and extent. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03010462.

Central pain syndromes.

The management of pain in persons with neurological injuries is challenging and complex. A holistic view and clinical approach are necessary when addressing pain in patients with neurological impairment because interpreting signs and symptoms and deciphering sources of pain is never a straightforward process. This problem is further magnified with the management of central pain syndromes. The best approach is to have a good understanding of the clinical characteristics commonly found in this patient population, in particular for patients with stroke, multiple sclerosis (MS), or spinal cord injury (SCI), as central pain manifests differently between these groups. This paper will focus on the history, clinical presentation, pathophysiology, assessment, and treatment of central pain in patients with these types of neurological conditions. In addition to being at risk for a decline in quality of life, patients with pain syndromes are also prone to adverse responses to treatments (e.g., opioid addiction). It is therefore important to methodically analyze the similarities and differences between patients with different pain syndromes.

Developing a Wearable Ankle Rehabilitation Robotic Device for in-Bed Acute Stroke Rehabilitation.

Ankle movement training is important in motor recovery post stroke and early intervention is critical to stroke rehabilitation. However, acute stroke survivors receive motor rehabilitation in only a small fraction of time, partly due to the lack of effective devices and protocols suitable for early in-bed rehabilitation. Considering the first few months post stroke is critical in stroke recovery, there is a strong need to start motor rehabilitation early, mobilize the ankle, and conduct movement therapy. This study seeks to address the need and deliver intensive passive and active movement training in acute stroke using a wearable ankle robotic device. Isometric torque generation mode under real-time feedback is used to guide patients in motor relearning. In the passive stretching mode, the wearable robotic device stretches the ankle throughout its range of motion to the extreme dorsiflexion forcefully and safely. In the active movement training mode, a patient is guided and motivated to actively participate in movement training through game playing. Clinical testing of the wearable robotic device on 10 acute stroke survivors over 12 sessions of feedback-facilitated isometric torque generation, and passive and active movement training indicated that the early in-bed rehabilitation could have facilitated neuroplasticity and helped improve motor control ability.

Epidural Electrical Stimulation for Stroke Rehabilitation: Results of the Prospective, Multicenter, Randomized, Single-Blinded Everest Trial.

BACKGROUND: This prospective, single-blinded, multicenter study assessed the safety and efficacy of electrical epidural motor cortex stimulation (EECS) in improving upper limb motor function of ischemic stroke patients with moderate to moderately severe hemiparesis. METHODS: Patients ≥ 4 months poststroke were randomized 2:1 to an investigational (n = 104) or control (n = 60) group, respectively. Investigational patients were implanted (n = 94) with an epidural 6-contact lead perpendicular to the primary motor cortex and a pulse generator. Both groups underwent 6 weeks of rehabilitation, but EECS was delivered to investigational patients during rehabilitation. The primary efficacy endpoint (PE) was defined as attaining a minimum improvement of 4.5 points in the upper extremity Fugl-Meyer (UEFM) scale as well as 0.21 points in the Arm Motor Ability Test (AMAT) 4 weeks postrehabilitation. Follow-up assessments were performed 1, 4, 12, and 24 weeks postrehabilitation. Safety was evaluated by monitoring adverse events (AEs) that occurred between enrollment and the end of rehabilitation. RESULTS: Primary intent-to-treat analysis showed no group differences at 4 weeks, with PE being met by 32% and 29% of investigational and control patients, respectively (P = .36). Repeated-measures secondary analyses revealed no significant treatment group differences in mean UEFM or AMAT scores. However, post hoc comparisons showed that a greater proportion of investigational (39%) than control (15%) patients maintained or achieved PE (P = .003) at 24 weeks postrehabilitation. Investigational group mean AMAT scores also improved significantly (P < .05) when compared to the control group at 24 weeks postrehabilitation. Post hoc analyses also showed that 69% (n = 9/13) of the investigational patients who elicited movement thresholds during stimulation testing met PE at 4 weeks, and mean UEFM and AMAT scores was also significantly higher (P < .05) in this subgroup at the 4-, 12-, and 24-week assessments when compared to the control group. Headache (19%), pain (13%), swelling (7%), and infection (7%) were the most commonly observed implant procedure-related AEs. Overall, there were 11 serious AEs in 9 investigational group patients (7 procedure related, 4 anesthesia related). CONCLUSIONS: The primary analysis pertaining to efficacy of EECS during upper limb motor rehabilitation in chronic stroke patients was negative at 4 weeks postrehabilitation. A better treatment response was observed in a subset of patients eliciting stimulation induced upper limb movements during motor threshold assessments performed prior to each rehabilitation session. Post hoc comparisons indicated treatment effect differences at 24 weeks, with the control group showing significant decline in the combined primary outcome measure relative to the investigational group. These results have the potential to inform future chronic stroke rehabilitation trial design.

Cortical stimulation as an adjuvant to upper limb rehabilitation after stroke.

Recovery of upper limb function after stroke remains a clinical challenge in rehabilitation. New insights into the role of activity-dependent motor recovery have guided clinicians to develop novel task-oriented therapies that are effective in reducing functional limitations in hand use after stroke. A number of brain-stimulation techniques have been examined as therapeutic adjuvants applied to enhance functional outcomes. Cortical stimulation with the use of either noninvasive techniques or implanted technology has shown some promise as an adjuvant therapy but has yet to be supported in well-designed clinical trials. In this article, we review the physiology of neural plasticity and of cortical stimulation. Laboratory studies and early clinical trials of repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and epidural cortical stimulation are reported. Cortical stimulation may have a role in facilitating motor recovery after stroke, but a better understanding of the physics of cortical stimulation, biological response to stimulation, effective stimulation protocols, and proper patient selection is needed.

Central poststroke pain syndrome.

Central poststroke pain (CPSP) syndrome is a rare complication of stroke but a common cause of central pain. CPSP is best managed in a well-coordinated interdisciplinary pain management program. Pharmacological options are available but none have proven optimal efficacy. Adequate pain control can be achieved with careful medication adjustment and a willingness to try different options in a stepwise approach. Motor cortex stimulation (MCS) with noninvasive or implanted electrodes is not currently available in the United States but has shown good efficacy in several clinical trials. MCS combined with medication management may be an option for treating CPSP in the future.

Design for the everest randomized trial of cortical stimulation and rehabilitation for arm function following stroke.

BACKGROUND: Cortical stimulation (CS) combined with rehabilitation may improve upper limb motor function after stroke. OBJECTIVE: Describe the study design for the Everest Clinical Trial, a randomized single-blinded pivotal device trial, testing safety and efficacy of epidural CS delivered during rehabilitation for upper limb motor function in patients with ischemic stroke. METHOD: A total of 174 participants from 21 centers with hemiplegia at least 4 months after acute ischemic stroke are randomized in a 2:1 ratio to investigational or control groups. Investigational patients undergo implantation of cortical electrode and pulse generator and receive 6 weeks of upper limb rehabilitation with subthreshold CS delivered only during therapy. Control group patients receive the same therapy without device implantation or stimulation. Primary outcome measures include the upper extremity Fugl-Meyer (UEFM) score and the arm motor ability test (AMAT) measured at baseline and 1, 4, 12, and 24 weeks following rehabilitation treatment with primary endpoint at 4 weeks following treatment. A successful outcome is defined as an improvement in UEFM of at least 4.5 points and in AMAT of at least 0.21 points from baseline to primary endpoint. A 20% better success rate between investigational and control groups will be considered clinically meaningful. Adverse events occurring during the study will be identified. RESULTS: Not applicable. CONCLUSIONS: The Everest Clinical Trial is the first randomized pivotal trial on the safety and efficacy of direct CS delivered during rehabilitation for recovery of upper limb motor function in patients with ischemic stroke.

Cortical stimulation for upper limb recovery following ischemic stroke: a small phase II pilot study of a fully implanted stimulator.

OBJECTIVE: To evaluate the feasibility of a fully implanted cortical stimulator for improving hand and arm function in patients following ischemic stroke. METHOD: Twenty-four chronic stroke patients with hemiplegia were randomized to targeted implanted cortical electrical stimulation of the motor cortex with upper limb rehabilitation therapy or rehabilitation therapy alone. RESULTS: Using repeated measures regression models, we estimated and compared treatment effects between groups over the study follow-up period. The investigational group had significantly greater mean improvements in Upper Extremity Fugl-Meyer (UEFM) scores during the 6-month follow-up period (weeks 1-24 following therapy), as compared to the control group (difference in estimated means = 3.8, p = .042). Box and Block (B & B) test improvement from baseline scores were also significantly better in the investigational group across the 6-month follow-up assessments (difference in estimated means = 3.8, p = .046). There was one report of seizure after device implant but prior to cortical stimulation and rehabilitation therapy, but no reports of neurologic decline. There were no improvements seen in the other measures assessed. CONCLUSION: Evidence suggests that cortical stimulation with rehabilitation therapy produces a lasting treatment effect in upper extremity motor control and is not associated with serious neurological complications. A larger multicenter study is underway.

Intramuscular electrical stimulation for shoulder pain in hemiplegia: does time from stroke onset predict treatment success?

BACKGROUND: A randomized clinical has shown the effectiveness of intramuscular electrical stimulation for the treatment of poststroke shoulder pain. OBJECTIVE: Identify predictors of treatment success and assess the impact of the strongest predictor on outcomes. METHOD: This is a secondary analysis of a multisite randomized clinical trial of intramuscular electrical stimulation for poststroke shoulder pain. The study included 61 chronic stroke survivors with shoulder pain randomized to a 6-week course of intramuscular electrical stimulation (n = 32) versus a hemisling (n = 29). The primary outcome measure was Brief Pain Inventory Question 12. Treatment success was defined as > or = 2-point reduction in this measure at end of treatment and at 3, 6, and 12 months posttreatment. Forward stepwise regression was used to identify factors predictive of treatment success among participants assigned to the electrical stimulation group. The factor most predictive of treatment success was used as an explanatory variable, and the clinical trials data were reanalyzed. RESULTS: Time from stroke onset was most predictive of treatment success. Subjects were divided according to the median value of stroke onset: early (<77 weeks) versus late (> 77 weeks). Electrical stimulation was effective in reducing poststroke shoulder pain for the early group (94% vs 7%, P < .001) but not for the late group (31% vs 33%). Repeated-measure analysis of variance revealed significant treatment (P < .001), time from stroke onset (P = .032), and treatment by time from stroke onset interaction (P < .001) effects. CONCLUSIONS: Stroke survivors who are treated early after stroke onset may experience greater benefit from intramuscular electrical stimulation for poststroke shoulder pain. However, the relative importance of time from stroke onset versus duration of pain is not known.

Cortical brain stimulation: a potential therapeutic agent for upper limb motor recovery following stroke.

There is emerging interest in the use of cortical electrical stimulation as a novel physical agent for the treatment of upper limb motor impairment after stroke. Evidence from animal models suggests that both motor learning and cortical stimulation alter intracortical inhibitory circuits and can facilitate long-term potentiation and cortical remodeling. This article reviews current research on the physiology and use of cortical stimulation animal models and in humans with stroke related hemiplegia. Both transcranial cortical stimulation techniques and targeted epidural cortical stimulation are discussed in detail.

Intramuscular electrical stimulation for hemiplegic shoulder pain: a 12-month follow-up of a multiple-center, randomized clinical trial.

OBJECTIVE: Assess the effectiveness of intramuscular electrical stimulation in reducing hemiplegic shoulder pain at 12 mos posttreatment. DESIGN: A total of 61 chronic stroke survivors with shoulder pain and subluxation participated in this multiple-center, single-blinded, randomized clinical trial. Treatment subjects received intramuscular electrical stimulation to the supraspinatus, posterior deltoid, middle deltoid, and upper trapezius for 6 hrs/day for 6 wks. Control subjects were treated with a cuff-type sling for 6 wks. Brief Pain Inventory question 12, an 11-point numeric rating scale was administered in a blinded manner at baseline, end of treatment, and at 3, 6, and 12 mos posttreatment. Treatment success was defined as a minimum 2-point reduction in Brief Pain Inventory question 12 at all posttreatment assessments. Secondary measures included pain-related quality of life (Brief Pain Inventory question 23), subluxation, motor impairment, range of motion, spasticity, and activity limitation. RESULTS: The electrical stimulation group exhibited a significantly higher success rate than controls (63% vs. 21%, P = 0.001). Repeated-measure analysis of variance revealed significant treatment effects on posttreatment Brief Pain Inventory question 12 (F = 21.2, P < 0.001) and Brief Pain Inventory question 23 (F = 8.3, P < 0.001). Treatment effects on other secondary measures were not significant. CONCLUSIONS: Intramuscular electrical stimulation reduces hemiplegic shoulder pain, and the effect is maintained for > or =12 mos posttreatment.

Intramuscular neuromuscular electric stimulation for poststroke shoulder pain: a multicenter randomized clinical trial.

OBJECTIVE: To assess the effectiveness of intramuscular neuromuscular electric stimulation (NMES) in reducing poststroke shoulder pain. DESIGN: Multicenter, single-blinded, randomized clinical trial. SETTING: Ambulatory centers of 7 academic rehabilitation centers in the United States. PARTICIPANTS: Volunteer sample of 61 chronic stroke survivors with shoulder pain and subluxation. INTERVENTION: Treatment subjects received intramuscular NMES to the supraspinatus, posterior deltoid, middle deltoid, and trapezius for 6 hours a day for 6 weeks. Control subjects were treated with a cuff-type sling for 6 weeks. Main outcome measure Brief Pain Inventory question 12 (BPI 12), an 11-point numeric rating scale administered in a blinded manner at the end of treatment, and at 3 and 6 months posttreatment. RESULTS: The NMES group exhibited significantly higher proportions of success based on the 3-point or more reduction in BPI 12 success criterion at the end of treatment (65.6% vs 24.1%, P<.01), at 3 months (59.4% vs 20.7%, P<.01), and at 6 months (59.4% vs 27.6%, P<.05). By using the most stringent "no pain" criterion, the NMES group also exhibited significantly higher proportions of success at the end of treatment (34.4% vs 3.4%, P<.01), at 3 months (34.4% vs 0.0%, P<.001), and at 6 months (34.4% vs 10.3%, P<.05). CONCLUSIONS: Intramuscular NMES reduces poststroke shoulder pain among those with shoulder subluxation and the effect is maintained for at least 6 months posttreatment.