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Background: Stroke remains a major public health concern in the United States and a leading cause of long-term disability in adults. Dynamic body weight support (DBWS) systems are popular technology available for use in clinical settings such inpatient rehabilitation. However, there remains limited studies in such inpatient settings that compare DBWS to standard of care (SOC) using real world outcome measures. For survivors of acute ischemic stroke, we determine if incorporating a dynamic body weight support (DBWS) system into inpatient therapy offers greater improvement than standard of care (SOC)., Methods: A retrospective chart review included 52 individuals with an acute ischemic stroke admitted to an inpatient rehabilitation facility. Functional Independence Measure (FIM) data, specifically changes in FIM at discharge, served as the primary outcome measure. Patient cohorts received either therapies per SOC or therapies incorporating DBWS. Regardless of cohort group, all patients underwent therapies for 3 h per day for 5 days a week., Results: For both groups, a statistically and clinically significant increase in total FIM (P < 0.0001) was observed at discharge compared to at admission. Improvements for the DBWS group were significantly greater than the SOC group as evidenced by higher gains in total FIM (p = 0.04) and this corresponded to a medium effect size (Cohen's d = 0.58). Among FIM subscores, the DBWS group achieved a significant increase in sphincter control while all other subscore changes remained non-significant., Conclusions: This preliminary evidence supports the benefit of using DBWS during inpatient rehabilitation in individuals who have experienced an acute ischemic stroke. This may be due to the greater intensity and repetitions of tasks allowed by DBWS. These preliminary findings warrant further investigations on the use of DBWS in inpatient settings., (© 2023. The Author(s).)

Accumulating evidence suggests that gut microbes modulate brain plasticity via the bidirectional gut-brain axis and play a role in stroke rehabilitation. However, the microbial species alterations associated with stroke and their correlation with functional outcome measures following acute stroke remain unknown. Here we measure post-stroke gut dysbiosis and how it correlates with gut permeability and cognitive functions in 12 stroke participants, 18 controls with risk factors for stroke, and 12 controls without risk factors. Stool samples were used to measure the microbiome with whole genome shotgun sequencing and leaky gut markers. We genotyped APOE status and measured diet composition and motor, cognitive, and emotional status using NIH Toolbox. We used linear regression methods to identify gut microbial associations with cognitive and emotional assessments. We did not find significance differences between the two control groups. In contrast, the bacteria populations of the Stroke group were statistically dissimilar from the control groups. Relative abundance analysis revealed notable decreases in butyrate-producing microbial taxa, secondary bile acid-producing taxa, and equol-producing taxa. The Stroke group had higher levels of the leaky gut marker alpha-1-antitrypsin in the stool than either of the groups and several taxa including Roseburia species (a butyrate producer) were negatively correlated with alpha-1-antitrypsin. Stroke participants scored lower on memory testing than those in the two control groups. Stroke participants with more Roseburia performed better on the picture vocabulary task; more Bacteroides uniformis (a butyrate producer) and less Escherichia coli (a pro-inflammatory species) reported higher levels of self-efficacy. Intakes of fiber, fruit and vegetable were lower, but sweetened beverages were higher, in the Stroke group compared with controls. Vegetable consumption was correlated with many bacterial changes among the participants, but only the species Clostridium bolteae, a pro-inflammatory species, was significantly associated with stroke. Our findings indicate that stroke is associated with a higher abundance of proinflammatory species and a lower abundance of butyrate producers and secondary bile acid producers. These altered microbial communities are associated with poorer functional performances. Future studies targeting the gut microbiome should be developed to elucidate whether its manipulation could optimize rehabilitation and boost recovery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Hammond, Powell, Green, Chlipala, Frank, Yackzan, Yanckello, Chang, Xing, Heil, Springer, Pennypacker, Stromberg, Sawaki and Lin.)

Abstract: Although the physiatric community increasingly embraces evidence-based medicine (EBM), the current state of EBM training for trainees in physiatry is unclear. The purposes of this article are to report the results of the Association of Academic Physiatrists' surveys of physiatry residency programs in the United States, to discuss the implications of their findings, and to better delineate the "baseline" upon which sound and clear recommendations for systematic EBM training can be made. The two Association of Academic Physiatrists surveys of US physiatry residency programs reveal that most survey respondents report that they include EBM training in their programs that covers the five recommended steps of EBM core competencies. However, although most respondents reported using traditional pedagogic methods of training such as journal club, very few reported that their EBM training used a structured and systematic approach. Future work is needed to support and facilitate physiatry residency programs interested in adopting structured EBM training curricula that include recommended EBM core competencies and the evaluation of their impact., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Transcranial direct current stimulation (tDCS) can sometimes cause the opposite of its intended effect. These reverse effects may be related in part to individual differences in personality and neurochemistry. Previous studies have demonstrated that dopamine levels can impact the effects of tDCS. In the present study, 124 healthy participants took the UPPS impulsive behavior scale. Participants then underwent a single, randomized anodal or sham tDCS session on the prefrontal cortex. While the effects of tDCS were still active, they performed the Stop Signal Task, a measure of state impulsivity. tDCS was associated with increased errors on this task in people who had higher scores on the UPPS in two facets of impulsivity that correlate with dopamine levels. tDCS had no effects on people who are low in trait impulsivity. These results suggest that the reverse effects of tDCS could be associated with inter-individual differences in personality and neurochemistry., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Abstract: Rehabilitation strategies after traumatic spinal cord injury aim to maximize functional recovery by applying principles of neuroplasticity via task-specific, repetitive training. Rehabilitation of patients with traumatic spinal cord injury poses unique challenges, including bilateral limb involvement, autonomic dysfunction, loss of proprioception, and potentially spinal precautions/bracing. The purpose of this retrospective case series was to determine whether use of dynamic body weight support would yield greater improvement in functional recovery compared with standard of care in adults with traumatic spinal cord injury. Data were collected from patients with traumatic spinal cord injury who completed inpatient rehabilitation incorporating dynamic body weight support (n = 5) and who completed inpatient rehabilitation without dynamic body weight support (n = 5). The primary outcome measure was the change in Functional Independence Measures. The dynamic body weight support group had a significantly greater improvement in Total Functional Independence Measures and in Functional Independence Measures motor subscale compared with the standard of care group (P = 0.023 and P = 0.033, respectively). This study presents initial evidence that dynamic body weight support therapy during inpatient rehabilitation has the potential to improve functional independence compared with standard of care in patients with traumatic spinal cord injury. Larger prospective randomized studies need to be conducted to expand on these findings., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

MW01-6-189WH (MW189) is a novel central nervous system-penetrant small-molecule drug candidate that selectively attenuates stressor-induced proinflammatory cytokine overproduction and is efficacious in intracerebral hemorrhage and traumatic brain injury animal models. We report first-in-human, randomized, double-blind, placebo-controlled phase 1 studies to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous doses of MW189 in healthy adult volunteers. MW189 was safe and well tolerated in single and multiple doses up to 0.25 mg/kg, with no clinically significant concerns. The most common drug-related treatment-emergent adverse event was infusion-site reactions, likely related to drug solution acidity. No clinically concerning changes were seen in vital signs, electrocardiograms, physical or neurological examinations, or safety laboratory results. PK analysis showed dose-proportional increases in plasma concentrations of MW189 after single or multiple doses, with approximately linear kinetics and no significant drug accumulation. Steady state was achieved by dose 3 for all dosing cohorts. A pilot pharmacodynamic study administering low-dose endotoxin to induce a systemic inflammatory response was done to evaluate the effects of a single intravenous dose of MW189 on plasma cytokine levels. MW189 treatment resulted in lower levels of the proinflammatory cytokine TNF-α and higher levels of the anti-inflammatory cytokine IL-10 compared with placebo treatment. The outcomes are consistent with the pharmacological mechanism of MW189. Overall, the safety profile, PK properties, and pharmacodynamic effect support further development of MW189 for patients with acute brain injury., (© 2020 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Background: Dynamic body-weight support (DBWS) may play an important role in rehabilitation outcomes, but the potential benefit among disease-specific populations is unclear. In this study, we hypothesize that overground therapy with DBWS during inpatient rehabilitation yields greater functional improvement than standard-of-care in adults with non-traumatic spinal cord injury (NT-SCI)., Methods: This retrospective cohort study included individuals diagnosed with NT-SCI and undergoing inpatient rehabilitation. All participants were recruited at a freestanding inpatient rehabilitation hospital. Individuals who trained with DBWS for at least three sessions were allocated to the experimental group. Participants in the historical control group received standard-of-care (i.e., no DBWS). The primary outcome was change in the Functional Independence Measure scores (FIM gain )., Results: During an inpatient rehabilitation course, participants in the experimental group (n = 11), achieved a mean (SD) FIM gain of 48 (11) points. For the historical control group (n = 11), participants achieved a mean (SD) FIM gain of 36 (12) points. From admission to discharge, both groups demonstrated a statistically significant FIM gain . Between groups analysis revealed no significant difference in FIM gain (p = 0.022; 95% CI 2.0-22) after a post hoc correction for multiple comparisons. In a secondary subscore analysis, the experimental group achieved significantly higher gains in sphincter control (p = 0.011: 95% CI 0.83-5.72) with a large effect size (Cohen's d 1.19). Locomotion subscores were not significantly different (p = 0.026; 95% CI 0.37-5.3) nor were the remaining subscores in self-care, mobility, cognition, and social cognition., Conclusions: This is the first study to explore the impact of overground therapy with DBWS on inpatient rehabilitation outcomes for persons with NT-SCI. Overground therapy with DBWS appears to significantly improve functional gains in sphincter control compared to the standard-of-care. Gains achieved in locomotion, mobility, cognition, and social cognition did not meet significance. Findings from the present study will benefit from future large prospective and randomized studies.

Background: Contemporary goals of rehabilitation after traumatic brain injury (TBI) aim to improve cognitive and motor function by applying concepts of neuroplasticity. This can be challenging to carry out in TBI patients with motor, balance, and cognitive impairments., Objective: To determine whether use of dynamic body-weight support (DBWS) would allow safe administration of intensive motor therapy during inpatient rehabilitation and whether its use would yield greater improvement in functional recovery than standard-of-care (SOC) therapy in adults with TBI., Methods: Data in this retrospective cohort study was collected from patients with TBI who receive inpatient rehabilitation incorporating DBWS (n = 6) and who received inpatient rehabilitation without DBWS (SOC, n = 6). The primary outcome measure was the change in Functional Independence Measures (FIM) scores from admission to discharge., Results: There was significant improvement in total FIM scores at discharge compared to admission for both the DBWS (p = 0.001) and SOC (p = 0.005) groups. Overall, the DBWS group had greater improvement in total FIM score and FIM subscales compared to the SOC group., Conclusions: Our results suggest DBWS has the potential to allow a greater intensity of therapy during inpatient rehabilitation and yield better outcomes compared to SOC in patients with TBI.

Objective: To better understand the role of the presence or absence of motor-evoked potentials (MEPs) in predicting functional outcomes following a severe-moderate stroke., Design: Retrospective exploratory analysis. We compared the effects of the stimulation condition (active or sham), MEP status (+ or -), and a combination of stimulation condition and MEP status on outcome. Within-group and between-group changes were assessed with longitudinal repeated measures analysis of variance and longitudinal repeated measures analysis of covariance, respectively. The proportions of participants who achieved minimal clinically important differences (MCIDs) for the main outcome measures were calculated., Setting: University research laboratory within a rehabilitation hospital., Participants: A total of 129 subjects with severe-moderate stroke-related motor impairments who participated in previous studies combining neuromodulation and motor training., Interventions: Neuromodulation (active or sham) and motor training., Main Outcome Measures: Fugl-Meyer Assessment (FMA) and Action Research Arm Test (ARAT)., Results: When participants were grouped by stimulation condition or MEP status, all groups improved from baseline to immediate postintervention and follow-up evaluations (all P <.05). Analysis by stimulation condition and MEP status found that the MEP-/active group improved by 4.2 points on FMA ( P <.0001) and 1.8 on ARAT ( P =.003) post intervention. The MEP+/active group improved by 5.7 points on FMA ( P <.0001) and 3.9 points on ARAT ( P <.0001) post intervention. There were no between-group differences ( P >.05). Regarding MCIDs, in the MEP-/active group, 14.5% of individuals reached MCID on FMA and 8.3% on ARAT post intervention. In the MEP+/active group, 33.3% of individuals reached MCID on FMA and 27.3% on ARAT post intervention., Conclusion: As expected, the MEP+ group had the greatest improvement in motor function. However, it was shown that individuals without MEPs can also achieve meaningful changes, as reflected by MCID, when neuromodulation is paired with motor training. To our knowledge, this is the first study to differentiate the effects of neuromodulation by MEP status.

Objective: To determine whether chronicity influences outcomes of somatosensory stimulation paired with task-oriented motor training for participants with severe-to-moderate upper extremity hemiparesis., Design: Spearman correlations were used to retrospectively analyze outcomes of a randomized trial., Setting: University research laboratory at a rehabilitation hospital., Participants: Adults, ranging between 3 and 12 months poststroke (N=55)., Interventions: About 18 sessions pairing either 2 hours of active (n=33) or sham (n=22) somatosensory stimulation with 4 hours of intensive task-oriented motor training., Main Outcome Measures: The Wolf Motor Function Test (primary), Action Research Arm Test, Stroke Impact Scale, and Fugl-Meyer Assessment were collected as outcome measures. Analyses evaluated whether within-group chronicity correlated with pre-post changes on primary and secondary outcome measures of motor performance., Results: Both groups exhibited improvements on all outcome measures. No significant correlations between chronicity poststroke and the amount of motor recovery were found., Conclusion: Somatosensory stimulation improved motor recovery compared with sham treatment in cases of severe-to-moderate hemiparesis between 3 and 12 months poststroke; and the extent of recovery did not correlate with baseline levels of stroke chronicity. Future studies should investigate a wider period of inclusion, patterns of corticospinal reorganization, differences between cortical and subcortical strokes, and include long-term follow-up periods., (© 2019 The Authors.)

Objective: The aim of the study was to determine whether somatosensory stimulation affects outcomes of motor training for moderate-to-severe upper limb hemiparesis less than 12 mos before stroke., Design: Fifty-five adults participated in 18 intervention sessions pairing 2 hours of active (n = 33) or sham (n = 22) somatosensory stimulation with 4 hours of intensive task-oriented motor training. Wolf Motor Function Test, Action Research Arm Test, Fugl-Meyer Assessment, and Stroke Impact Scale were administered at baseline, postintervention, and 1- and 4-mo follow-up., Results: Statistically significant between-groups differences favored the active condition on Wolf Motor Function Test at post (P = 0.04) and Action Research Arm Test at post (P = 0.02), 1 mo (P = 0.01), and 4 mos (P = 0.01) but favored the sham condition on Stroke Impact Scale at 1 mo (P = 0.03). There were no significant between-groups differences on Fugl-Meyer Assessment., Conclusions: Somatosensory stimulation can improve objective outcomes of motor training for moderate-to-severe hemiparesis less than 12 mos after stroke, although it needs to be determined whether the magnitude of between-groups differences in this study is clinically relevant. Future studies should investigate the intervention's impact on disability and functional recovery for this population as well as neurophysiological mechanisms underlying intervention effects.

Objective: The aim of the study was to compare functional outcomes of acute inpatient rehabilitation for spinal epidural abscess patients with and without history of intravenous substance abuse., Design: This is a retrospective case series study in freestanding rehabilitation hospital., Methods: Charts of 28 spinal epidural abscess patients admitted from January 2012 to September 2015: 13 with intravenous substance abuse and 15 without intravenous substance abuse were reviewed. Both groups received standard-of-care rehabilitation. Statistical analyses of Functional Independence Measure scores were conducted using individual 2 (substance use) × 2 (rehabilitation status) repeated measures analysis of variance. Functional outcomes were defined by total Functional Independence Measure scores as well as motor and cognitive subsets. Length of stay and morphine equivalents were also compared., Results: There were no significant differences between the two groups. There was a significant main effect of treatment on total Functional Independence Measure scores (P < 0.001), Functional Independence Measure motor scores (P < 0.001), and Functional Independence Measure cognitive scores (P < 0.01) from admission to discharge. Subsequent Student's t tests revealed that the scores of both groups significantly improved on all Functional Independence Measure components. There were no group differences on length of stay and morphine equivalents at discharge., Conclusions: Acute inpatient rehabilitation can effectively improve functional outcomes in spinal epidural abscess patients with or without intravenous substance abuse, even though these two patient groups can vary in clinical factors.

Background: Non-invasive transcranial direct current stimulation has been shown to modulate cortical excitability in various studies. Similarly, recent preliminary studies suggest that transcutaneous spinal direct current stimulation (tsDCS) may engender a modulation effect on spinal and cortical neurons., Objective: The purpose of this study was to evaluate the dose-response effects of tsDCS in healthy subjects and thereby lay groundwork for expanding treatment options for patients with spinal cord injury (SCI)., Methods: Nine healthy subjects received each of the following 2 tsDCS conditions: Anodal and cathodal, in random order with at least 1 week washout period between each session. In order to test safety and dose response, various current intensities were used (2, 2.5 and 3 mA) for 20 minutes. The active electrode was placed vertically over T10-T11, and the reference electrode was placed over the left shoulder. To evaluate corticospinal excitability, motor evoked potentials over soleus muscle elicited by transcranial magnetic stimulation were measured. To assess spinal cord excitability, H- and M- wave over soleus muscle to calculate Hmax/ Mmax ratio were measured., Results: Linear regression showed a dose response with cathodal tsDCS on motor evoked potentials measured from the left leg as well as with anodal tsDCS on Hmax/ Mmax ratio measured from the left leg., Conclusions: These findings indicate tsDCS effects are dose-dependent. These effects should be investigated in a larger sample.

Objectives: This study investigated the feasibility of modulating bilateral corticospinal excitability with different polarities of transcutaneous spinal direct current stimulation (tsDCS) in chronic, incomplete spinal cord injury (SCI)., Methods: Six subjects with chronic incomplete SCI (>12 months post injury) participated in this crossover study. Intervention consisted of 3 sessions, separated by at least 1 week, in which each subject received the conditions cathodal, anodal, and sham tsDCS. Stimulation was delivered at 2.5 mA for 20 minutes with the active electrode positioned over the spinous processes of T10-T11 and the reference electrode over left deltoid. To measure the effects of tsDCS on corticospinal excitability, motor evoked potentials (MEPs) from transcranial magnetic stimulation were measured bilaterally from soleus before and after tsDCS., Results: Five subjects completed all 3 sessions. One subject withdrew after 2 sessions due to complications unrelated to the study. MEPs were measurable in 5 subjects. No significant differences in change of MEP amplitudes were found between the 3 conditions. However, there were trends that indicated laterality of response, particularly with cathodal tsDCS increasing corticospinal excitability contralateral to the reference electrode and decreasing corticospinal excitability ipsilateral to the reference electrode., Conclusion: Corticospinal excitability may be modulated with laterality by tsDCS in individuals with chronic, incomplete SCI. Further research is needed to 1) determine whether different placement of the reference electrode can lead to uniform modulation bilaterally, and 2) reveal whether these alterations in corticospinal excitability can lead to improved movement function in individuals with chronic, incomplete SCI.

Background and Purpose: Robot-assisted locomotor training on a bodyweight-supported treadmill is a rehabilitation intervention that compels repetitive practice of gait movements. Standard treadmill speed may elicit rhythmic movements generated primarily by spinal circuits. Slower-than-standard treadmill speed may elicit discrete movements, which are more complex than rhythmic movements and involve cortical areas., Objective: Compare effects of fast (i.e., rhythmic) versus slow (i.e., discrete) robot-assisted locomotor training on a bodyweight-supported treadmill in subjects with chronic, severe gait deficit after stroke., Methods: Subjects (N = 18) were randomized to receive 30 sessions (5 d/wk) of either fast or slow robot-assisted locomotor training on a bodyweight-supported treadmill in an inpatient setting. Functional ambulation category, time up and go, 6-min walk test, 10-m walk test, Berg Balance Scale, and Fugl-Meyer Assessment were administered at baseline and postintervention., Results: The slow group had statistically significant improvement on functional ambulation category (first quartile-third quartile, P = 0.004), 6-min walk test (95% confidence interval [CI] = 1.8 to 49.0, P = 0.040), Berg Balance Scale (95% CI = 7.4 to 14.8, P < 0.0001), time up and go (95% CI = -79.1 to 5.0, P < 0.0030), and Fugl-Meyer Assessment (95% CI = 24.1 to 45.1, P < 0.0001). The fast group had statistically significant improvement on Berg Balance Scale (95% CI = 1.5 to 10.5, P = 0.02)., Conclusions: In initial stages of robot-assisted locomotor training on a bodyweight-supported treadmill after severe stroke, slow training targeting discrete movement may yield greater benefit than fast training.

Background: Intensive, task-oriented motor training has been associated with neuroplastic reorganization and improved upper extremity movement function after stroke. However, to optimize such training for people with moderate-to-severe movement impairment, pharmacological modulation of neuroplasticity may be needed as an adjuvant intervention., Objective: Evaluate safety, as well as improvement in movement function, associated with motor training paired with a drug to upregulate neuroplasticity after stroke., Methods: In this double-blind, randomized, placebo-controlled study, 12 subjects with chronic stroke received either atomoxetine or placebo paired with motor training. Safety was assessed using vital signs. Upper extremity movement function was assessed using Fugl-Meyer Assessment, Wolf Motor Function Test, and Action Research Arm Test at baseline, post-intervention, and 1-month follow-up., Results: No significant between-groups differences were found in mean heart rate (95% CI, -12.4-22.6; p = 0.23), mean systolic blood pressure (95% CI, -1.7-29.6; p = 0.21), or mean diastolic blood pressure (95% CI, -10.4-13.3; p = 0.08). A statistically significant between-groups difference on Fugl-Meyer at post-intervention favored the atomoxetine group (95% CI, 1.6-12.7; p = 0.016)., Conclusion: Atomoxetine combined with motor training appears safe and may optimize motor training outcomes after stroke.

Afferent electrical stimulation is known to augment the effect of rehabilitative therapy through use-dependent cortical plasticity. Experiments pairing transcranial magnetic stimulation (TMS) with peripheral nerve stimulation (PNS) have shown a timing-dependent effect on motor evoked potential (MEP) amplitude suggesting that PNS applied in closed-loop (CL) mode could augment this effect through positive reinforcement. We present early results from a clinical trial in which an EEG brain-machine interface (BMI) was used to apply PNS to two subjects in response to motor intent detected from sensorimotor cortex in a cue-driven hand grip task. Both subjects had stable incomplete cervical spinal cord injury (SCI) with impaired upper limb function commensurate with the injury level. Twelve sessions of CL-PNS applied over a 4-6 week period yielded results suggesting improved hand grip strength and increased task-related modulation of the EEG in one hand of both subjects, and increased TMS-measured motor map area in one. These observations suggest that rehabilitation using such interactive therapies could benefit affected individuals.

Background: Intensive motor training is a therapeutic intervention that supports recovery of movement function after stroke by capitalizing on the brain's capacity for neuroplastic change. Peripheral nerve stimulation and transcranial direct current stimulation are neuromodulation techniques that can upregulate neuroplasticity and, in turn, enhance outcomes of motor training after stroke. Few studies have investigated possible adjuvant effects between peripheral nerve stimulation, transcranial direct current stimulation, and intensive motor training., Objective: This proof-of-concept study investigated whether timing variations in neuromodulation paired with robot-assisted motor training effect differential outcomes for subjects with chronic, moderate-to-severe upper extremity impairment after stroke., Methods: Ten subjects in the chronic phase (>12 months after stroke) of recovery completed the study. Subjects received 10 daily sessions of transcranial direct current stimulation either at the start (n = 4) or at the end (n = 6) of peripheral nerve stimulation preceding intensive motor training. Pre-post changes in motor function (Fugl-Meyer Assessment; Stroke Impact Scale) and neuroplasticity (transcranial magnetic stimulation) were assessed by condition., Results: Significant improvement in Stroke Impact Scale (p = 0.02) and no change in Fugl-Meyer Assessment were associated with the start condition. No changes in Stroke Impact Scale and Fugl-Meyer Assessment were associated with the end condition. Only 1 subject in the start group had measurable neuroplastic responses and demonstrated an increase in ipsilesional cortical map volume. Only 1 subject in the end group had measurable neuroplastic responses and demonstrated a decrease in ipsilesional cortical map volume. Opposite shifts in ipsilesional cortical centers of gravity occurred relative to condition., Conclusion: In cases of moderate-to-severe impairment after stroke, transcranial direct current stimulation at the start, rather than the end, of peripheral nerve stimulation prior to motor training may effect better functional outcomes. Future research with a larger sample size is needed to validate the findings of this proof-of-concept study.

Background and Purpose: A sensory-based intervention called peripheral nerve stimulation can enhance outcomes of motor training for stroke survivors with mild-to-moderate hemiparesis. Further research is needed to establish whether this paired intervention can have benefit in cases of severe impairment (almost no active movement)., Methods: Subjects with chronic, severe poststroke hemiparesis (n=36) were randomized to receive 10 daily sessions of either active or sham stimulation (2 hours) immediately preceding intensive task-oriented training (4 hours). Upper extremity movement function was assessed using Fugl-Meyer Assessment (primary outcome measure), Wolf Motor Function Test, and Action Research Arm Test at baseline, immediately post intervention and at 1-month follow-up., Results: Statistically significant difference between groups favored the active stimulation group on Fugl-Meyer at postintervention (95% confidence interval [CI], 1.1-6.9; P=0.008) and 1-month follow-up (95% CI, 0.6-8.3; P=0.025), Wolf Motor Function Test at postintervention (95% CI, -0.21 to -0.02; P=0.020), and Action Research Arm Test at postintervention (95% CI, 0.8-7.3; P=0.015) and 1-month follow-up (95% CI, 0.6-8.4; P=0.025). Only the active stimulation condition was associated with (1) statistically significant within-group benefit on all outcomes at 1-month follow-up and (2) improvement exceeding minimal detectable change, as well as minimal clinically significant difference, on ≥1 outcomes at ≥1 time points after intervention., Conclusions: After stroke, active peripheral nerve stimulation paired with intensive task-oriented training can effect significant improvement in severely impaired upper extremity movement function. Further confirmatory studies that consider a larger group, as well as longer follow-up, are needed., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02633215., (© 2016 American Heart Association, Inc.)

Background: Constraint-based therapy and peripheral nerve stimulation can significantly enhance movement function after stroke. No studies have investigated combining these interventions for cases of chronic, mild-to-moderate hemiparesis following stroke., Objective: This study aims to determine the effects of peripheral nerve stimulation paired with a modified form of constraint-induced therapy on upper extremity movement function after stroke. Nineteen adult stroke survivors with mild-to-moderate hemiparesis more than 12 mo after stroke received 2 hours of either active (n = 10) or sham (n = 9) peripheral nerve stimulation preceding 4 hours of modified constraint-induced therapy (10 sessions)., Results: Active peripheral nerve stimulation enhanced modified constraint-induced therapy more than sham peripheral nerve stimulation (significance at P < 0.05), both immediately after intervention (Wolf Motor Function Test: P = 0.006 (timed score); P = 0.001 (lift score); Fugl-Meyer Assessment: P = 0.022; Action Research Arm Test: P = 0.007) and at 1-mo follow-up (Wolf Motor Function Test: P = 0.025 (timed score); P = 0.007 (lift score); Fugl-Meyer Assessment: P = 0.056; Action Research Arm Test: P = 0.028)., Conclusion: Pairing peripheral nerve stimulation with modified constraint-induced therapy can lead to significantly more improvement in upper extremity movement function than modified constraint-induced therapy alone. Future research is recommended to help establish longitudinal effects of this paired intervention, particularly as it affects movement function and daily life participation., To Claim Cme Credits: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES:: Upon completion of this article, the reader should be able to: (1) Understand the role that afferent input plays with regard to movement function; (2) Understand general concepts of delivering modified constraint-based therapy in stroke rehabilitation research; and (3) Understand the rationale for applying an adjuvant intervention to optimize outcomes of constraint-based therapy following stroke., Level: Advanced, Accreditation: : The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Association of Academic Physiatrists designates this activity for a maximum of 1.5 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity.

Study Design: This double-blind, sham-controlled, crossover case study combined transvertebral direct current stimulation (tvDCS) and locomotor training on a robot-assisted gait orthosis (LT-RGO)., Objective: Determine whether cathodal tvDCS paired with LT-RGO leads to greater changes in function and neuroplasticity than sham tvDCS paired with LT-RGO., Setting: University of Kentucky (UK) HealthCare Stroke and Spinal Cord Neurorehabilitation Research at HealthSouth Cardinal Hill Hospital., Methods: A single subject with motor incomplete spinal cord injury (SCI) participated in 24 sessions of sham tvDCS paired with LT-RGO before crossover to 24 sessions of cathodal tvDCS paired with LT-RGO. Functional outcomes were measured with 10 Meter Walk Test (10MWT), 6 Minute Walk Test (6MWT), Spinal Cord Independence Measure-III (SCIM-III) mobility component, lower extremity manual muscle test (MMT), and Berg Balance Scale (BBS). Corticospinal changes were assessed using transcranial magnetic stimulation., Results: Improvement in 10MWT speed, SCIM-III mobility component, and BBS occurred with both conditions. 6MWT worsened after sham tvDCS and improved after cathodal tvDCS. MMT scores for both lower extremities improved following sham tvDCS but decreased following cathodal tvDCS. Corticospinal excitability increased following cathodal tvDCS but not sham tvDCS., Conclusion: These results suggest that combining cathodal tvDCS and LT-RGO may improve functional outcomes, increase corticospinal excitability, and possibly decrease spasticity. Randomized controlled trials are needed to confirm these conclusions., Sponsorship: This publication was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR000117, and the HealthSouth Cardinal Hill Stroke and Spinal Cord Endowment (1215375670).

Background: Locomotor training with a robot-assisted gait orthosis (LT-RGO) and transcranial direct current stimulation (tDCS) are interventions that can significantly enhance motor performance after spinal cord injury (SCI). No studies have investigated whether combining these interventions enhances lower extremity motor function following SCI., Objective: Determine whether active tDCS paired with LT-RGO improves lower extremity motor function more than a sham condition, in subjects with motor incomplete SCI., Methods: Fifteen adults with SCI received 36 sessions of either active (n = 9) or sham (n = 6) tDCS (20 minutes) preceding LT-RGO (1 hour). Outcome measures included manual muscle testing (MMT; primary outcome measure); 6-Minute Walk Test (6MinWT); 10-Meter Walk Test (10MWT); Timed Up and Go Test (TUG); Berg Balance Scale (BBS); and Spinal Cord Independence Measure-III (SCIM-III)., Results: MMT showed significant improvements after active tDCS, with the most pronounced improvement in the right lower extremity. 10MWT, 6MinWT, and BBS showed improvement for both groups. TUG and SCIM-III showed improvement only for the sham tDCS group., Conclusion: Pairing tDCS with LT-RGO can improve lower extremity motor function more than LT-RGO alone. Future research with a larger sample size is recommended to determine longer-term effects on motor function and activities of daily living.

Objective: Constraint-induced movement therapy (CIMT) has been shown to improve upper extremity voluntary movement and change cortical movement representation after stroke. Direct comparison of the differential degree of cortical reorganization according to chronicity in stroke subjects receiving CIMT has not been performed and was the purpose of this study. We hypothesized that a higher degree of cortical reorganization would occur in the early (less than 9 months post-stroke) compared to the late group (more than 12 months post-stroke)., Methods: 17 early and 9 late subjects were enrolled. Each subject was evaluated using transcranial magnetic stimulation (TMS) and the Wolf Motor Function Test (WMFT) and received CIMT for 2 weeks., Results: The early group showed greater improvement in WMFT compared with the late group. TMS motor maps showed persistent enlargement in both groups but the late group trended toward more enlargement. The map shifted posteriorly in the late stroke group. The main limitation was the small number of TMS measures that could be acquired due to high motor thresholds, particularly in the late group., Conclusion: CIMT appears to lead to greater improvement in motor function in the early phase after stroke. Greater cortical reorganization in map size and position occurred in the late group in comparison., Significance: The contrast between larger functional gains in the early group vs larger map changes in the late group may indicate that mechanisms of recovery change over the several months following stroke or that map changes are a time-dependent epiphenomenon.

Objectives: 1) To investigate the feasibility of combining transcranial direct current stimulation (tDCS) to the lower extremity (LE) motor cortex with novel locomotor training to facilitate gait in subjects with chronic stroke and low ambulatory status, and 2) to obtain insight from study subjects and their caregivers to inform future trial design., Methods: Double-blind, randomized controlled study with additional qualitative exploratory descriptive design. One-month follow-up.10 subjects with stroke were recruited and randomized to active tDCS or sham tDCS for 12 sessions. Both groups participated in identical locomotor training with a robotic gait orthosis (RGO) following each tDCS session. RGO training protocol was designed to harness cortical neuroplasticity. Data analysis included assessment of functional and participation outcome measures and qualitative thematic analysis., Results: Eight subjects completed the study. Both groups demonstrated trends toward improvement, but the active tDCS group showed greater improvement than the sham group. Qualitative analyses indicated beneficial effects of this combined intervention., Conclusions: It is feasible to combine tDCS targeting the LE motor cortex with our novel locomotor training. It appears that tDCS has the potential to enhance the effectiveness of gait training in chronic stroke. Insights from participants provide additional guidance in designing future trials.

Background: Stroke continues to be a major public health concern in the United States. Motor recovery in the post-acute stages of stroke is possible due to neuroplasticity, or the capacity of the brain to reorganize., Objective: This case study tracks neuroplastic and motor change in a subject with severe hemiparesis following an extensive middle cerebral artery stroke. He had absence of ipsilesional motor evoked potentials in early evaluations. This report is unique in that the duration of follow-up evaluation extends nearly 2 years, with evaluations being performed at 7, 9, 10, 13, 20, and 21 months post-stroke., Methods: At each evaluation we used transcranial magnetic stimulation to track neuroplastic change and the Fugl-Meyer Assessment and the Wolf Motor Function Test to evaluate upper extremity motor performance., Results: The contralesional hemisphere showed dynamic change throughout the study period. In contrast, the ipsilesional hemisphere demonstrated notable change only between 13 and 21 months post-stroke, with the most dramatic change occurring between 20 and 21 months post-stroke. Motor performance generally improved throughout the study period., Conclusions: Our findings demonstrate that substantial neuroplasticity-mediated motor recovery can occur nearly 2 years after stroke in an individual with severe post-stroke motor impairment.

Objective: We evaluated the effects of occupation-based intervention on poststroke upper-extremity (UE) motor recovery, neuroplastic change, and occupational performance in 1 research participant., Method: A 55-yr-old man with chronic stroke and moderately impaired UE motor function participated in 15 sessions of occupation-based intervention in a hospital setting designed to simulate a home environment. We tested behavioral motor function (Fugl-Meyer Assessment, Stroke Impact Scale, Canadian Occupational Performance Measure) and neuroplasticity (transcranial magnetic stimulation [TMS]) at baseline and at completion of intervention. We collected descriptive data on occupational participation throughout the study., Results: All behavioral outcomes indicated clinically relevant improvement. TMS revealed bihemispheric corticomotor reorganization. Descriptive data revealed enhanced occupational performance., Conclusion: Occupation-based intervention delivered in a hospital-based, homelike environment can lead to poststroke neuroplastic change, increased functional use of the affected UE, and improved occupational performance., (Copyright © 2012 by the American Occupational Therapy Association, Inc.)

Cerebral cortical activity is heavily influenced by interactions with the basal ganglia. These interactions occur via cortico-basal ganglia-thalamo-cortical loops. The putamen is one of the major sites of cortical input into basal ganglia loops and is frequently activated during pain. This activity has been typically associated with the processing of pain-related motor responses. However, the potential contribution of putamen to the processing of sensory aspects of pain remains poorly characterized. In order to more directly determine if the putamen can contribute to sensory aspects of pain, nine individuals with lesions involving the putamen underwent both psychophysical and functional imaging assessment of perceived pain and pain-related brain activation. These individuals exhibited intact tactile thresholds, but reduced heat pain sensitivity and widespread reductions in pain-related cortical activity in comparison with 14 age-matched healthy subjects. Using magnetic resonance imaging to assess structural connectivity in healthy subjects, we show that portions of the putamen activated during pain are connected not only with cortical regions involved in sensory-motor processing, but also regions involved in attention, memory and affect. Such a framework may allow cognitive information to flow from these brain areas to the putamen where it may be used to influence how nociceptive information is processed. Taken together, these findings indicate that the putamen and the basal ganglia may contribute importantly to the shaping of an individual subjective sensory experience by utilizing internal cognitive information to influence activity of large areas of the cerebral cortex.

Background: A goal of stroke rehabilitation is to harness the capacity of the brain to reorganize following neurological damage and enable restoration of function., Objective: To understand how neural oscillatory motor responses change following a therapeutic intervention and to illuminate whether these neurophysiological alterations correlate with improvements on behavioral measurements., Methods: Magnetoencephalography (MEG) was used to evaluate plasticity in motor networks following 2 weeks of intensive task-oriented therapy, which was paired with sham or peripheral nerve stimulation (PNS). Patients completed unilateral finger tapping before and 3 weeks after therapy as whole-head MEG data were acquired. MEG data were imaged using beamforming, and the resulting event-related synchronizations and desynchronizations (ERSs/ERDs) were subjected to region-of-interest (ROI) analyses. For each ROI, the authors compared the baseline and postintervention MEG response amplitude, volume, and peak location for premovement β ERD, movement-onset γ ERS, and postmovement β ERS., Results: Following therapy, all patients showed reduced postmovement β ERS response amplitudes in bilateral precentral gyri and reduced γ ERS amplitudes in the precentral gyrus of the affected hemisphere. This latter response also distinguished treatment groups, as the posttherapy γ reduction was greater in patients who received PNS. Finally, both β and γ response amplitudes were significantly correlated with improvement on several behavioral indices of motor function., Discussion: These case-series data indicate that oscillatory MEG responses may be useful in gauging plasticity in motor cortices following therapy in stroke patients.

Background and Purpose: Although constraint-induced movement therapy (CIMT) has been shown to improve upper extremity function in stroke survivors at both early and late stages after stroke, the comparison between participants within the same cohort but receiving the intervention at different time points has not been undertaken. Therefore, the purpose of this study was to compare functional improvements between stroke participants randomized to receive this intervention within 3 to 9 months (early group) to participants randomized on recruitment to receive the identical intervention 15 to 21 months after stroke (delayed group)., Methods: Two weeks of CIMT was delivered to participants immediately after randomization (early group) or 1 year later (delayed group). Evaluators blinded to group designation administered primary (Wolf Motor Function Test, Motor Activity Log) and secondary (Stroke Impact Scale) outcome measures among the 106 early participants and 86 delayed participants before delivery of CIMT, 2 weeks thereafter, and 4, 8, and 12 months later., Results: Although both groups showed significant improvements from pretreatment to 12 months after treatment, the earlier CIMT group showed greater improvement than the delayed CIMT group in Wolf Motor Function Test Performance Time and the Motor Activity Log (P<0.0001), as well as in Stroke Impact Scale Hand and Activities domains (P<0.0009 and 0.0214, respectively). Early and delayed group comparison of scores on these measures 24 months after enrollment showed no statistically significant differences between groups., Conclusions: CIMT can be delivered to eligible patients 3 to 9 months or 15 to 21 months after stroke. Both patient groups achieved approximately the same level of significant arm motor function 24 months after enrollment. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00057018.

Subjective sensory experiences are constructed by the integration of afferent sensory information with information about the uniquely personal internal cognitive state. The insular cortex is anatomically positioned to serve as one potential interface between afferent processing mechanisms and more cognitively oriented modulatory systems. However, the role of the insular cortex in such modulatory processes remains poorly understood. Two individuals with extensive lesions to the insula were examined to better understand the contribution of this brain region to the generation of subjective sensory experiences. Despite substantial differences in the extent of the damage to the insular cortex, three findings were common to both individuals. First, both subjects had substantially higher pain intensity ratings of acute experimental noxious stimuli than age-matched control subjects. Second, when pain-related activation of the primary somatosensory cortex was examined during left- and right-sided stimulation, both individuals exhibited dramatically elevated activity of the primary somatosensory cortex ipsilateral to the lesioned insula in relation to healthy control subjects. Finally, both individuals retained the ability to evaluate pain despite substantial insular damage and no evidence of detectable insular activity. Together, these results indicate that the insula may be importantly involved in tuning cortical regions to appropriately use previous cognitive information during afferent processing. Finally, these data suggest that a subjectively available experience of pain can be instantiated by brain mechanisms that do not require the insular cortex.

Background: Constraint-induced movement therapy (CIMT) has received considerable attention as an intervention to enhance motor recovery and cortical reorganization after stroke., Objective: The present study represents the first multi-center effort to measure cortical reorganization induced by CIMT in subjects who are in the subacute stage of recovery., Methods: A total of 30 stroke subjects in the subacute phase (>3 and <9 months poststroke) were recruited and randomized into experimental (receiving CIMT immediately after baseline evaluation) and control (receiving CIMT after 4 months) groups. Each subject was evaluated using transcranial magnetic stimulation (TMS) at baseline, 2 weeks after baseline, and at 4-month follow-up (ie, after CIMT in the experimental groups and before CIMT in the control groups). The primary clinical outcome measure was the Wolf Motor Function Test., Results: Both experimental and control groups demonstrated improved hand motor function 2 weeks after baseline. The experimental group showed significantly greater improvement in grip force after the intervention and at follow-up (P = .049). After adjusting for the baseline measures, the experimental group had an increase in the TMS motor map area compared with the control group over a 4-month period; this increase was of borderline significance (P = .053)., Conclusions: Among subjects who had a stroke within the previous 3 to 9 months, CIMT produced statistically significant and clinically relevant improvements in arm motor function that persisted for at least 4 months. The corresponding enlargement of TMS motor maps, similar to that found in earlier studies of chronic stroke subjects, appears to play an important role in CIMT-dependent plasticity.

Objective: To evaluate the role of 2 noradrenergic drugs in modulating use-dependent plasticity in humans., Design: Double-blind, randomized, and placebo-controlled crossover design., Setting: A laboratory in a hospital., Participants: A convenience sample of 10 healthy subjects., Intervention: An established paradigm that measures motor memory as a short-term model of use-dependent plasticity. Subjects attended 3 sessions, separated by at least 1 week to allow drug washout. Subjects received atomoxetine (Strattera), venlafaxine (Effexor), or placebo., Main Outcome Measure: Increase in the proportion of movements into the training target zone (TTZ), an indicator of enhanced plasticity., Results: Atomoxetine, but not venlafaxine, significantly increased movements into the TTZ., Conclusions: These results support a role for norepinephrine in enhancing cortical plasticity and suggest potential benefits in using these drugs for improving motor recovery after stroke.

Background and Purpose: There is a need to develop strategies to enhance the beneficial effects of motor training, including use-dependent plasticity (UDP), in neurorehabilitation. Peripheral nerve stimulation (PNS) modulates motor cortical excitability in healthy humans and could influence training effects in stroke patients., Methods: We compared the ability of PNS applied to the (1) arm, (2) leg, and (3) idle time to influence training effects in the paretic hand in 7 chronic stroke patients. The end point measure was the magnitude of UDP., Results: UDP was more prominent with arm stimulation (increased by 22.8%) than with idle time (by 2.9%) or leg stimulation (by 6.4%)., Conclusions: PNS applied to the paretic limb paired with motor training enhances training effects on cortical plasticity in stroke patients.

Mirror neurons discharge with both action observation and action execution. It has been proposed that the mirror neuron system is instrumental in motor learning. The human primary motor cortex (M1) displays mirror activity in response to movement observation, is capable of forming motor memories, and is involved in motor learning. However, it is not known whether movement observation can lead directly to the formation of motor memories in the M1, which is considered a likely physiological step in motor learning. Here, we used transcranial magnetic stimulation (TMS) to show that observation of another individual performing simple repetitive thumb movements gives rise to a kinematically specific memory trace of the observed motions in M1. An extended period of observation of thumb movements that were oriented oppositely to the previously determined habitual directional bias increased the probability of TMS-evoked thumb movements to fall within the observed direction. Furthermore, the acceleration of TMS-evoked thumb movements along the principal movement axis and the balance of excitability of muscle representations active in the observed movements were altered in favor of the observed movement direction. These findings support a role for the mirror neuron system in memory formation and possibly human motor learning.

The ability of the central nervous system to form motor memories, a process contributing to motor learning and skill acquisition, decreases with age. Dopaminergic activity, one of the mechanisms implicated in memory formation, experiences a similar decline with aging. It is possible that restoring dopaminergic function in elderly adults could lead to improved formation of motor memories with training. We studied the influence of a single oral dose of levodopa (100mg) administered preceding training on the ability to encode an elementary motor memory in the primary motor cortex of elderly and young healthy volunteers in a randomized, double-blind, placebo-controlled design. Attention to the task and motor training kinematics were comparable across age groups and sessions. In young subjects, encoding a motor memory under placebo was more prominent than in older subjects, and the encoding process was accelerated by intake of levodopa. In the elderly group, diminished motor memory encoding under placebo was enhanced by intake of levodopa to levels present in younger subjects. Therefore, upregulation of dopaminergic activity accelerated memory formation in young subjects and restored the ability to form a motor memory in elderly subjects; possible mechanisms underlying the beneficial effects of dopaminergic agents on motor learning in neurorehabilitation.

Motor training consisting of repetitive thumb movements results in encoding of motor memories in the primary motor cortex. It is not known if proprioceptive input originating in the training movements is sufficient to produce this effect. In this study, we compared the ability of training consisting of voluntary (active) and passively-elicited (passive) movements to induce this form of plasticity. Active training led to successful encoding accompanied by characteristic changes in corticomotor excitability, while passive training did not. These results support a pivotal role for voluntary motor drive in coding motor memories in the primary motor cortex.

Cortical reorganization has been demonstrated in the motor network that mediates performance of a motor task in patients with multiple sclerosis. How this network responds to motor training is not known. This study examined functional MRI (fMRI) activation patterns associated with performance of a motor task, consisting of repetition of directionally specific voluntary thumb movements, before and after motor training in a group of multiple sclerosis patients with mild motor impairment of the right upper extremity. Patients and healthy subjects were scanned in one session before, during and after a 30 min training period. fMRI data obtained during rest, thumb flexion (trained movement) and thumb extension (untrained movement) were analysed using random effects analysis (SPM99). Motor kinematics of training motions and EMG from the resting hand were monitored with an accelerometer and surface EMG electrodes. Kinematics of thumb movements before, during and after training were comparable in the absence of mirror EMG activity in the resting hand. Before training, thumb movements elicited more prominent activation of the contralateral dorsal premotor cortex [PMd, Brodmann area (BA) 6] in multiple sclerosis patients than in controls. After training, unlike the control group, multiple sclerosis patients did not exhibit task-specific reductions in activation in the contralateral primary somatosensory (S1), motor (M1) and adjacent parietal association (BA 40) cortices. These results indicate that patients engage the contralateral PMd more than controls in order to perform directionally specific movements before training. The absence of training-dependent reductions in activation in S1, M1 and BA 40 is consistent with a decreased capacity to optimize recruitment of the motor network with practice.

Motor training consisting of repetition of directionally specific voluntary thumb movements elicits a short-term memory trace that encodes the kinematic details of the practiced motions in the primary motor cortex. Here, we studied activation patterns associated with this form of training using functional magnetic resonance imaging under careful monitoring of motor training kinematics and electromyography. We identified task-specific reductions in activation in contralateral motor cortex, a region that controls executive motor output, as well as somatosensory cortex and inferior parietal lobule, regions in charge of monitoring motor training kinematics. Our findings are consistent with the hypothesis that a short training period consisting of repetition of finger motions leads to cortical reorganization characterized by a smaller and more efficient network that is specific for the trained movement direction.

In healthy individuals, motor training elicits cortical plasticity that encodes the kinematic details of the practiced movements and is thought to underlie recovery of function after stroke. The influence of age on this form of plasticity is incompletely understood. We studied 55 healthy subjects and identified a substantial decrease in training-dependent plasticity as a function of age in the absence of differences in training kinematics. These results suggest that the ability of the healthy aging motor cortex to reorganize in response to training decreases with age.

An internal model of the dynamics of a tool or an object is part of the motor memory acquired when learning to use the tool or to manipulate the object. Changes in synaptic efficacy may underlie acquisition and storage of memories. Here we studied the effect of pharmacological agents that interfere with synaptic plasticity on acquisition of new motor memories and on recall of a previously learned internal model. Forty-nine subjects, divided into six groups, made reaching movements while holding a robotic arm that applied forces to the hand. On day 1, all subjects learned to move in force field A. On day 2, each group of subjects was tested on their ability to recall field A and their ability to learn a new internal model in field B. Four groups participated in the experiments of day 2 under the effects of lorazepam (LZ; a GABA type A receptor-positive allosteric modulator), dextromethorphan [DM; an N-methyl-D-aspartate (NMDA) receptor blocker], lamotrigine (LG, a drug that blocks voltage-gated Na(+) and Ca(2+) channel), or scopolamine (SP; muscarinic receptor antagonist). Two control groups were tested in a drug-free condition: one group that was not exposed to additional experimental protocols (NP) and another group was tested under ~24 h of sleep deprivation between completion of learning on day 1 and start of testing on day 2 (SD). Recall of field A was normal in all groups. Learning of field B was reduced by LZ and DM but not by SP, LG, SD or in the NP condition. These results suggest that a 24-h sleep-deprivation period may have little or no effect on consolidation of this motor memory and that NMDA receptor activation and GABAergic inhibition are mechanisms operating in the acquisition but not recall of new motor memories in humans.

In humans, somatosensory stimulation results in increased corticomotoneuronal excitability to the stimulated body parts. The purpose of this study was to investigate the underlying mechanisms. We recorded motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) from abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM) muscles. MEP amplitudes, recruitment curves (RC), intracortical inhibition (ICI), intracortical facilitation (ICF), resting (rMT) and active motor thresholds (aMT) were recorded before and after a 2-h period of ulnar nerve electrical stimulation at the wrist. Somatosensory input was monitored by recording somatosensory evoked potentials. To differentiate excitability changes at cortical vs. subcortical sites, we recorded supramaximal peripheral M-responses and MEPs to brainstem electrical stimulation (BES). In order to investigate the involvement of GABAergic mechanisms, we studied the influence of lorazepam (LZ) (a GABA(A) receptor agonist) relative to that of dextromethorphan (DM) (an NMDA receptor antagonist) and placebo in a double-blind design. We found that somatosensory stimulation increased MEP amplitudes to TMS only in the ADM, confirming a previous report. This effect was blocked by LZ but not by either DM or placebo and lasted between 8 and 20 min in the absence of (i) changes in MEPs elicited by BES, (ii) amplitudes of early somatosensory-evoked potentials or (iii) M-responses. We conclude that somatosensory stimulation elicited a focal increase in corticomotoneuronal excitability that outlasts the stimulation period and probably occurs at cortical sites. The antagonistic effect of LZ supports the hypothesis of GABAergic involvement as an operating mechanism.

Use-dependent plasticity, thought to contribute to functional recovery after brain injury, is elicited by motor training. The purpose of this study was to determine if administration of d-amphetamine facilitates the effects of motor training on use-dependent plasticity. Healthy human volunteers underwent a training period of voluntary thumb movements under the effects of placebo or d-amphetamine in different sessions in a randomized double-blind, counterbalanced design. Previous work in a drug-naive condition showed that such training causes changes in the direction of thumb movements evoked by transcranial magnetic stimulation and in transcranial magnetic stimulation-evoked electromyographic responses. The endpoint measure of the study was the magnitude of training-induced changes in transcranial magnetic stimulation-evoked kinematic and electromyographic responses in the d-amphetamine and in the placebo conditions. Motor training resulted in increased magnitude, faster development and longer lasting duration of use-dependent plasticity under d-amphetamine compared to the placebo session. These results document a facilitatory effect of d-amphetamine on use-dependent plasticity, a possible mechanism mediating the beneficial effect of this drug on functional recovery after cortical lesions.