Cortical Mechanisms Underlying Immersive Interactive Virtual Walking Treatment for Amelioration of Neuropathic Pain after Spinal Cord Injury: Findings from a Preliminary Investigation of Thalamic Inhibitory Function.

BACKGROUND: Neuropathic pain following spinal cord injury (SCI) affects approximately 60% of individuals with SCI. Effective pharmacological and non-pharmacological treatments remain elusive. We recently demonstrated that our immersive virtual reality walking intervention (VRWalk) may be effective for SCI NP. Additionally, we found that SCI NP may result from a decrease in thalamic γ-aminobutyric-acid (GABA), which disturbs central sensorimotor processing. OBJECTIVE: While we identified GABAergic changes associated with SCI NP, a critical outstanding question is whether a decrease in SCI NP generated by our VRWalk intervention causes GABA content to rise. METHOD: A subset of participants (n = 7) of our VRWalk trial underwent magnetic resonance spectroscopy pre- and post-VRWalk intervention to determine if the decrease in SCI NP is associated with an increase in thalamic GABA. RESULTS: The findings revealed a significant increase in thalamic GABA content from pre- to post-VRWalk treatment. CONCLUSION: While the current findings are preliminary and should be interpreted with caution, pre- to post-VRWalk reductions in SCI NP may be mediated by pre- to post-treatment increases in thalamic GABA by targeting and normalizing maladaptive sensorimotor cortex reorganization. Understanding the underlying mechanisms of pain recovery can serve to validate the efficacy of home-based VR walking treatment as a means of managing pain following SCI. Neuromodulatory interventions aimed at increasing thalamic inhibitory function may provide more effective pain relief than currently available treatments.

Can Crossover and Altered Magnitude Estimation in Neglect Be Explained by Contextual Effects?

Three studies that used experimental manipulations of stimulus context and correlational analyses were conducted to examine how contextual effects influence magnitude estimation and the crossover effect on line bisection. Previous work had shown that although orienting attention to one end of a line prior to bisection determines the direction in which crossover occurs, bias in magnitude estimation actually produces the crossover effect. The influence of contextual effects on magnitude estimation, however, was not examined in these previous models of crossover. Consequently, the purpose of the present investigation was to examine these effects. Subjects in the current studies were healthy controls and people who had right and left hemisphere injury due to stroke, both with and without spatial neglect. Study 1 examined the crossover effect for lines bisected with and without a stimulus context. Study 2 examined both stimulus order as well as response order context effects on magnitude estimation. Study 3 examined how much variance in magnitude estimation was accounted for by stimulus contextual effects and how stimulus context influenced the crossover effect. The results showed that contextual bias was ubiquitous but relatively small in the magnitude estimates of normal subjects. Contextual bias was exaggerated to a similar degree in subjects with right or left hemisphere injury due to stroke, but the amount of variance accounted by contextual bias was still quite small. A novel finding of study 2 was that contextual effects can be induced by previous responses to stimuli as well as by the magnitude of preceding stimuli in subjects with unilateral brain injury. This may be a contextual effect related to response perseveration. Finally, studies 1 and 3 indicated that contextual effects strengthened the crossover effect on line bisection, primarily on relatively short lines. Contextual effects, however, cannot fully account for the crossover effect, because crossover bisections were observed also in the absence of a stimulus context. It is concluded that the crossover effect is explained by biases in attentional orientation and magnitude estimation. Contextual effects represent one source of bias in magnitude estimation that influences the crossover effect by promoting contralateral errors on short line lengths (<2 cm).

Functional neurological disorder: Extending the diagnosis to other disorders, and proposing an alternate disease term-Attentionally-modifiable disorder.

BACKGROUND: The term "functional neurological disorder," or "FND," applies to disorders whose occurrence of neurological symptoms fluctuate with the patient's attention to them. However, many other disorders that are not called "FND" nonetheless can also follow this pattern. Consequently, guidelines are unclear for diagnosing "FND." OBJECTIVE: To review the neurological conditions that follow this pattern, but which have not so far been termed "FND," to understand their overlap with conditions that have been termed "FND," and to discuss the rationale for why FND has not been diagnosed for them. METHOD: A systematic review of the PubMed literature registry using the terms "fluctuation," "inconsistency," or "attention" did not yield much in the way of these candidate disorders. Consequently, this review instead relied on the author's personal library of peer-reviewed studies of disorders that have resembled FND but which were not termed this way, due to his longstanding interest in this problem. Consequently, this approach was not systematic and was subjective regarding disease inclusion. RESULTS: This review identified numerous, diverse conditions that generally involve fluctuating neurological symptoms that can vary with the person's attention to them, but which have not been called "FND." The literature was unclear for reasons for not referring to "FND" in these instances. CONCLUSION: Most likely because of historical biases, the use of the term "FND" has been unnecessarily restricted. Because at its core FND is an attentionally-influenced disorder that can respond well to behavioral treatments, the field of neurological rehabilitation could benefit by extending the range of conditions that could be considered as "FND" and referred for similar behavioral treatments. Because the term "FND" has been viewed unfavorably by some patients and clinical practitioners and whose treatment is not implied, the alternative term attentionally-modifiable disorder is proposed.

Perspectives From Persons With Multiple Sclerosis for a Comprehensive Real-World Change Therapy for Mobility.

Objective: To assess the personal perspectives of persons with multiple sclerosis (MS) on the acceptability of a novel physical therapy program that is designed to transfer gains from the clinic to their real-world lower extremity (LE) use, termed LE constraint-induced therapy (CIT). The program includes several behavior change techniques (prescribed home exercises, daily structured therapist interviews and problem solving for LE activities, keeping an activity diary) and a concentrated physical treatment schedule. Design: Anonymous internet survey. Setting: Participants accessed the survey from computers in the community. Participants: Five hundred adults (N=500) were recruited from an MS support organization's registry for having indicated from mild to total limb spasticity because they were anticipated to have markedly impaired LE use in the community. Interventions: Not applicable. Main Outcome Measures: Participants were offered the options on a nonnumerical Likert scale of "Very likely," "Likely," "Neutral," "Unlikely," or "Very unlikely" to indicate their personal acceptability for each of 5 different key treatment procedures after these were explained. Totals for each option within each key procedure were analyzed for their acceptability. Results: Of the 281 persons who responded, 90% expressed interest in participating in LE CIT. A large majority of persons who completed the survey selected either "Very likely" or "Likely" for each key procedure (median=88%, range=65%-90%, P<.01). This indicated strong acceptance for the procedures of LE CIT. In addition, more respondents who already had had previous physical therapy accepted LE CIT than did respondents who had not had physical therapy (P<.01). Conclusions: The results suggest there is strong acceptance of CIT for mobility with preliminary evidence of benefiting community LE use for persons with MS. The results support further clinical trials of LE CIT for persons with MS.

Consistency of inclusion criteria for functional movement disorder clinical research studies: A systematic review.

BACKGROUND: Functional movement disorders (FMDs) are a common cause of disability. With an increasing research interest in FMD, including the emergence of intervention trials, it is crucial that research methodology be examined, and standardized protocols be developed. OBJECTIVE: To characterize the current inclusion criteria used to select patients for FMD research studies and review the consistency and appropriateness of these criteria. METHODS: We identified studies of potential biomarkers for FMD that were published over the last two decades and performed a qualitative analysis on the finally included studies. RESULTS: We identified 79 articles and found inconsistent inclusion criteria. The Fahn-Williams and DSM-IV criteria were the most commonly applied, but neither accounted for the majority (Fahn-Williams 46%, DSM-IV 32% of the total). The selection of the inclusion criteria depended in part on the phenotype of FMD under investigation. We also identified inclusion methodologies that were not appropriate, such as the inclusion of low-certainty diagnoses and diagnosing by excluding specific biomarkers rather than including patients based on clinical characteristics that commonly are thought to suggest FMD. CONCLUSIONS: Significant variability exists with the inclusion criteria for FMD research studies. This variability could limit reproducibility and the appropriate aggregation of data for meta-analysis. Advancing FMD rehabilitation research will need standardized inclusion criteria. We make some suggestions.

Video game rehabilitation for outpatient stroke (VIGoROUS): A multi-site randomized controlled trial of in-home, self-managed, upper-extremity therapy.

BACKGROUND: Integrating behavioral intervention into motor rehabilitation is essential for improving paretic arm use in daily life. Demands on therapist time limit adoption of behavioral programs like Constraint-Induced Movement (CI) therapy, however. Self-managed motor practice could free therapist time for behavioral intervention, but there remains insufficient evidence of efficacy for a self-management approach. METHODS: This completed, parallel, five-site, pragmatic, single-blind trial established the comparative effectiveness of using in-home gaming self-management as a vehicle to redirect valuable therapist time towards behavioral intervention. Community-dwelling adults with post-stroke (>6 months) mild/moderate upper extremity hemiparesis were randomized to receive one of 4 different interventions over a 3-week period: 5 h of behaviorally-focused intervention plus gaming self-management (Self-Gaming), the same with additional behaviorally-focused telerehabilitation (Tele-Gaming), 5 h of Traditional motor-focused rehabilitation, or 35 h of CI therapy. Primary outcomes assessed everyday arm use (Motor Activity Log Quality of Movement, MAL) and motor speed/function (Wolf Motor Function Test, WMFT) immediately before treatment, immediately after treatment, and 6 months later. Intent-to-treat analyses were implemented with linear mixed-effects models on data gathered from March 15, 2016 to November 21, 2019. ClinicalTrials.gov, NCT02631850. RESULTS: Of 193 enrolled participants, 167 began treatment and were analyzed, 150 (90%) completed treatment, and 115 (69%) completed follow-up. Tele-Gaming and Self-Gaming produced clinically meaningful MAL gains that were 1·0 points (95% CI 0·8 to 1·3) and 0·8 points (95% CI 0·5 to 1·0) larger than Traditional care, respectively. Self-Gaming was less effective than CI therapy (-0·4 points, 95% CI -0·6 to -0·2), whereas Tele-Gaming was not (-0·2 points, 95% CI -0·4 to 0·1). Six-month retention of MAL gains across all groups was 57%. All had similar clinically-meaningful WMFT gains; six-month retention of WMFT gains was 92%. INTERPRETATION: Self-managed motor-gaming with behavioral telehealth visits has outcomes similar to in-clinic CI therapy. It addresses most access barriers, requiring just one-fifth as much therapist time that is redirected towards behavioral interventions that enhance the paretic arm's involvement in daily life. FUNDING: PCORI, NIH.

Immersive interactive virtual walking reduces neuropathic pain in spinal cord injury: findings from a preliminary investigation of feasibility and clinical efficacy.

ABSTRACT: Chronic neuropathic pain (NP) is a common and often debilitating secondary condition for persons with spinal cord injury (SCI) and is minimally responsive to existing pharmacological and nonpharmacological treatments. The current preliminary investigation describes the feasibility and initial comparative efficacy of an interactive virtual reality walking intervention, which is a novel extension of visual feedback/illusory walking therapies shown to reduce SCI NP. Virtual reality walking intervention builds on previous research by, for the first time, allowing individuals with SCI NP to volitionally control virtual gait to interact with a fully immersive virtual environment. The current pilot study compared this interactive, virtual walking intervention to a passive, noninteractive virtual walking condition (analogous to previous illusory walking interventions) in 27 individuals with complete paraplegia (interactive condition, n = 17; passive condition, n = 10; nonrandomized design). The intervention was delivered over 2 weeks in individuals' homes. Participants in the interactive condition endorsed significantly greater reductions in NP intensity and NP-related activity interference preintervention to postintervention. Notable improvements in mood and affect were also observed both within individual sessions and in response to the full intervention. These results, although preliminary, highlight the potentially potent effects of an interactive virtual walking intervention for SCI NP. The current study results require replication in a larger, randomized clinical trial and may form a valuable basis for future inquiry regarding the mechanisms and clinical applications of virtual walking therapies.

Tele-rehabilitation of upper-extremity hemiparesis after stroke: Proof-of-concept randomized controlled trial of in-home Constraint-Induced Movement therapy.

BACKGROUND: Although Constraint-Induced Movement therapy (CIMT) has been deemed efficacious for adults with persistent, mild-to-moderate, post-stroke upper-extremity hemiparesis, CIMT is not available on a widespread clinical basis. Impediments include its cost and travel to multiple therapy appointments. To overcome these barriers, we developed an automated, tele-health form of CIMT. OBJECTIVE: Determine whether in-home, tele-health CIMT has outcomes as good as in-clinic, face-to-face CIMT in adults ≥1-year post-stroke with mild-to-moderate upper-extremity hemiparesis. METHODS: Twenty-four stroke patients with chronic upper-arm extremity hemiparesis were randomly assigned to tele-health CIMT (Tele-AutoCITE) or in-lab CIMT. All received 35 hours of treatment. In the tele-health group, an automated, upper-extremity workstation with built-in sensors and video cameras was set-up in participants' homes. Internet-based audio-visual and data links permitted supervision of treatment by a trainer in the lab. RESULTS: Ten patients in each group completed treatment. All twenty, on average, showed very large improvements immediately afterwards in everyday use of the more-affected arm (mean change on Motor Activity Log Arm Use scale = 2.5 points, p < 0.001, d' = 3.1). After one-year, a large improvement from baseline was still present (mean change = 1.8, p < 0.001, d' = 2). Post-treatment outcomes in the tele-health group were not inferior to those in the in-lab group. Neither were participants' perceptions of satisfaction with and difficulty of the interventions. Although everyday arm use was similar in the two groups after one-year (mean difference = -0.1, 95% CI = -1.3-1.0), reductions in the precision of the estimates of this parameter due to drop-out over follow-up did not permit ruling out that the tele-health group had an inferior long-term outcome. CONCLUSIONS: This proof-of-concept study suggests that Tele-AutoCITE produces immediate benefits that are equivalent to those after in-lab CIMT in stroke survivors with chronic upper-arm extremity hemiparesis. Cost savings possible with this tele-health approach remain to be evaluated.

Intermittent Theta Burst Stimulation (iTBS) for Treatment of Chronic Post-Stroke Aphasia: Results of a Pilot Randomized, Double-Blind, Sham-Controlled Trial.

BACKGROUND Research indicates intermittent theta burst stimulation (iTBS) is a potential treatment of post-stroke aphasia. MATERIAL AND METHODS In this double-blind, sham-controlled trial (NCT01512264) participants were randomized to receive 3 weeks of sham (G0), 1 week of iTBS/2 weeks of sham (G1), 2 weeks of iTBS/1 week of sham (G2), or 3 weeks of iTBS (G3). FMRI localized residual language function in the left hemisphere; iTBS was applied to the maximum fMRI activation in the residual language cortex in the left frontal lobe. FMRI and aphasia testing were conducted pre-treatment, at ≤1 week after completing treatment, and at 3 months follow-up. RESULTS 27/36 participants completed the trial. We compared G0 to each of the individual treatment group and to all iTBS treatment groups combined (G1₋3). In individual groups, participants gained (of moderate or large effect sizes; some significant at P<0.05) on the Boston Naming Test (BNT), the Semantic Fluency Test (SFT), and the Aphasia Quotient of the Western Aphasia Battery-Revised (WAB-R AQ). In G1₋3, BNT, and SFT improved immediately after treatment, while the WAB-R AQ improved at 3 months. Compared to G0, the other groups showed greater fMRI activation in both hemispheres and non-significant increases in language lateralization to the left hemisphere. Changes in IFG connectivity were noted with iTBS, showing differences between time-points, with some of them correlating with the behavioral measures. CONCLUSIONS The results of this pilot trial support the hypothesis that iTBS applied to the ipsilesional hemisphere can improve aphasia and result in cortical plasticity.

Retention of Physical Gains in the Community Following Physical Training for Multiple Sclerosis: A Systematic Review and Implications.

Multiple sclerosis (MS) is a progressive neurological illness whose typically young adult onset results in a nearly entire lifetime of worsening disability. But despite being an unrelenting neurodegenerative disease, numerous clinical trials over the past 40 years for MS have vigorously attempted to improve or at least stabilize declining physical function. Although the vast majority of the studies assessed training effects only within controlled laboratory or clinic settings, in recent years a growing interest has emerged to test whether newer therapies can instead benefit real-life activities in the community. Nonetheless, comparatively little attention has been paid to whether the training gains can be retained for meaningful periods. This review discusses the comparative success of various physical training methods to benefit within-community activities in MS, and whether the gains can be retained long afterward. This review will suggest future research directions toward establishing efficacious treatments that can allow persons with MS to reclaim their physical abilities and maximize functionality for meaningful periods.

Reliability and Validity of the Lower Extremity Motor Activity Log for Measuring Real-World Leg Use in Adults With Multiple Sclerosis.

OBJECTIVES: To determine the test-retest reliability and validity of the Lower Extremity Motor Activity Log (LE-MAL) for assessing LE use in the community in adults with multiple sclerosis (MS). DESIGN: Prospective analysis of measures conducted by trained examiners. SETTING: Participants were evaluated by telephone on several measures of LE use. PARTICIPANTS: Adults with MS (N=43). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The LE-MAL has 3 subscales (Assistance, Functional Performance, and Confidence). It was administered twice, at least 2 weeks apart. The Multiple Sclerosis Walking Scale (MSWS-12), Patient Determined Disease Steps (PDDS), and Mobility Scale were only administered during the first call. RESULTS: The test-retest reliability of the composite and the 3 subscale LE-MAL scores were high (intraclass correlation, >0.94). The composite and subscale LE-MAL scores were strongly correlated with the MSWS-12, PDDS, and Mobility Scale scores (r=-0.56 to -0.77; P<.001). CONCLUSION: This initial study suggests that the LE-MAL reliably and validly measures LE use in the community in adults with MS.

Protocol for a Randomized Controlled Trial of CI Therapy for Rehabilitation of Upper Extremity Motor Deficit: The Bringing Rehabilitation to American Veterans Everywhere Project.

Constraint-induced movement therapy (CI therapy) has been shown to reduce disability for individuals with upper extremity (UE) hemiparesis following different neurologic injuries. This article describes the study design and methodological considerations of the Bringing Rehabilitation to American Veterans Everywhere (BRAVE) Project, a randomized controlled trial of CI therapy to improve the motor deficit of participants with chronic and subacute traumatic brain injury. Our CI therapy protocol comprises 4 major components: (1) intensive training of the more-affected UE for target of 3 hour/day for 10 consecutive weekdays, (2) a behavioral technique termed shaping during training, (3) a "transfer package," 0.5 hour/day, of behavioral techniques to transfer therapeutic gains from the treatment setting to the life situation, and (4) prolonged restraint of use of the UE not being trained. The primary endpoint is posttreatment change on the Motor Activity Log, which assesses the use of the more-affected arm outside the laboratory in everyday life situations. Data from a number of secondary outcome measures are also being collected and can be categorized as physical, genomic, biologic, fitness, cognitive/behavioral, quality of life, and neuroimaging measures.

A feasibility study of combined intermittent theta burst stimulation and modified constraint-induced aphasia therapy in chronic post-stroke aphasia.

PURPOSE: The purpose of this feasibility study was to assess whether combined intermittent theta burst suppression (iTBS) applied to the ipsilesional hemisphere and modified constraint-induced aphasia therapy (mCIAT) are safe and logistically feasible within the time interval associated with iTBS induced long-term potentiation in patients with post-stroke aphasia. We also wanted to determine whether combining priming with iTBS and CIAT improves language functions after treatment. METHODS: Twelve participants received fMRI (semantic decision/tone decision task) and neuropsychological testing of language skills at three time points - before starting the iTBS/mCIAT intervention (T1), immediately after completing 2-week long course of intervention (T2), and at 3-months follow-up (T3). ITBS was applied to the individually determined fMRI language "hot spot" located in the left fronto-temporal regions. RESULTS: There were no serious adverse events, and all mCIAT group therapy sessions (3-4 subjects each) were initiated within 30 minutes of the first group subject receiving iTBS. Neuropsychological assessments of language showed a significant effect of session on Western Aphasia Battery aphasia quotient (WAB-AQ; p = 0.04) and spontaneously correct responses on Boston Naming Test (BNT; p = 0.002), with improvement noted at T2 (p = 0.002) and T3 (p = 0.05) versus T1. FMRI showed significant changes between all timepoints. Post-hoc correlations showed associations between improvements in WAB-AQ from T2 to T3 and decreased BOLD signal in left inferior parietal lobe, and improvements in BNT from T1 to T3 with decreased signal in right inferior frontal gyrus. CONCLUSION: This study shows feasibility and safety for combining behavioral and neurostimulation interventions for chronic post-stroke aphasia. Observed changes in linguistic measures were relatively small. However, they were statistically significant and associated with parallel changes observed in the neuroimaging. Our findings support further development and testing of the combined mCIAT and iTBS protocol and comparisons to either CIAT/mCIAT or iTBS applied alone for the treatment of post-stroke aphasia.

Relation of white matter hyperintensities and motor deficits in chronic stroke.

BACKGROUND: Infarct size and location account for only a relatively small portion of post-stroke motor impairment, suggesting that other less obvious factors may be involved. OBJECTIVE: Examine the relationship between white matter hyperintensity (WMH) load among other factors and upper extremity motor deficit in patients with mild to moderate chronic stroke. METHODS: The magnetic resonance images of 28 patients were studied. WMH load was assessed as total WMH volume and WMH overlap with the corticospinal tract in the centrum semiovale. Hemiparetic arm function was measured using the Motor Activity Log (MAL) and Wolf Motor Function Test (WMFT). RESULTS: Hierarchical multiple regression models found WMH volume predicted motor deficits in both real-world arm use (MAL;ΔR2 = 0.12, F(1, 22) = 4.73, p = 0.04) and in arm motor capacity as measured by a laboratory motor function test (WMFT;ΔR2 = 0.18, F(1, 22) = 6.32, p = 0.02) over and above age and lesion characteristics. However, these models accounted for less than half of the variance in post-stroke motor deficits. CONCLUSION: The results suggest that WMH may be an important factor to consider in stroke-related upper extremity motor impairment. Nonetheless, the basis of the largest part of the post-stroke motor deficit remains unaccounted for by structural CNS factors. This component may be behavioral or learned, involving learned nonuse.

Phase II Randomized Controlled Trial of Constraint-Induced Movement Therapy in Multiple Sclerosis. Part 1: Effects on Real-World Function.

BACKGROUND: Constraint-Induced Movement therapy (CIMT) has controlled evidence of efficacy for improving real-world paretic limb use in non-progressive physically disabling disorders (stroke, cerebral palsy). OBJECTIVE: This study sought to determine whether this therapy can produce comparable results with a progressive disorder such as multiple sclerosis (MS). We conducted a preliminary phase II randomized controlled trial of CIMT versus a program of complementary and alternative medicine (CAM) treatments for persons with MS, to evaluate their effect on real-world disability. METHODS: Twenty adults with hemiparetic MS underwent 35 hours of either CIMT or CAM over 10 consecutive weekdays. The primary clinical outcome was change from pretreatment on the Motor Activity Log (MAL). RESULTS: The CIMT group improved more on the MAL (2.7 points, 95% confidence interval 2.2-3.2) than did the CAM group (0.5 points, 95% confidence interval -0.1 to 1.1; P < .001). These results did not change at 1-year follow-up, indicating long-term retention of functional benefit for CIMT. The treatments were well tolerated and without adverse events. CONCLUSION: These results suggest that CIMT can increase real-world use of the more-affected arm in patients with MS for at least 1 year. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01081275.

Phase II Randomized Controlled Trial of Constraint-Induced Movement Therapy in Multiple Sclerosis. Part 2: Effect on White Matter Integrity.

BACKGROUND: Constraint-induced movement therapy (CIMT) is a method of physical rehabilitation that has demonstrated clinical efficacy in patients with chronic stroke, cerebral palsy, and multiple sclerosis (MS). OBJECTIVE: This pilot randomized controlled trial tested whether CIMT can also induce increases in white matter integrity in patients with MS. METHODS: Twenty adults with chronic hemiparetic MS were randomized to receive either CIMT or complementary and alternative medicine (CAM) treatment (reported in the first article of this pair). Structural white matter change was assessed by tract-based spatial statistics (TBSS); measures included fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). RESULTS: CIMT and CAM groups did not differ in pretreatment disability or expectancy to benefit. As noted in the companion paper, the motor activity log (MAL) improved more after CIMT than CAM ( P < .001); the within-group effect size for CIMT was 3.7 (large d' = 0.57), while for CAM it was just 0.7. Improvements in white matter integrity followed CIMT and were observed in the contralateral corpus callosum (FA, P < .05), ipsilateral superior occipital gyrus (AD, P < .05), ipsilateral superior temporal gyrus (FA, P < .05), and contralateral corticospinal tract (MD and RD, P < .05). CONCLUSION: CIMT produced a very large improvement in real-world limb use and induced white matter changes in patients with hemiparetic MS when compared with CAM. The findings suggest in preliminary fashion that the adverse changes in white matter integrity induced by MS might be reversed by CIMT. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT01081275).

Rehabilitation of stroke patients with plegic hands: Randomized controlled trial of expanded Constraint-Induced Movement therapy.

PURPOSE: To evaluate the efficacy of an expanded form of Constraint-Induced Movement Therapy (eCIMT) that renders CIMT, originally designed for treating mild-to-moderate upper-extremity hemiparesis, suitable for treating severe hemiparesis. METHODS: Twenty-one adults ≥1 year after stroke with severe upper-extremity hemiparesis (with little or no capacity to make movements with the more-affected hand) were randomly assigned to eCIMT (n = 10), a placebo-control procedure (n = 4), or usual care (n = 7). The participants who received usual care were crossed over to eCIMT four months after enrollment. The CIMT protocol was altered to include fitting of orthotics and adaptive equipment, selected neurodevelopmental techniques, and electromyography-triggered functional electrical stimulation. Treatment was given for 15 consecutive weekdays with 6 hours of therapy scheduled daily for the immediate eCIMT group and 3.5 hours daily for the cross-over eCIMT group. RESULTS: At post-treatment, the immediate eCIMT group showed significant gains relative to the combination of the control groups on the Grade-4/5 Motor Activity Log (MAL; mean = 1.5 points, P < 0.001, f = 4.2) and a convergent measure, the Canadian Occupational Performance Measure (COPM; mean = 2.3, P = 0.014, f = 1.1; f values ≥0.4 are considered large, on the COPM changes ≥2 are considered clinically meaningful). At 1-year follow-up, the MAL gains in the immediate eCIMT group were only 13% less than at post-treatment. The short and long-term outcomes of the crossover eCIMT group were similar to those of the immediate eCIMT group. CONCLUSIONS: This small, randomized controlled trial (RCT) suggests that eCIMT produces a large, meaningful, and persistent improvement in everyday use of the more-affected arm in adults with severe upper-extremity hemiparesis long after stroke. These promising findings warrant confirmation by a large RCT.