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Background and Purpose: The brain changes that underlie therapy-induced improvement in motor function after stroke remain obscure. This study sought to demonstrate the feasibility and utility of measuring motor system physiology in a clinical trial of intensive upper extremity rehabilitation in chronic stroke-related hemiparesis. Methods: This was a substudy of two multi-center clinical trials of intensive robotic and intensive conventional therapy arm therapy in chronic, significantly hemiparetic, stroke patients. Transcranial magnetic stimulation was used to measure motor cortical output to the biceps and extensor digitorum communus muscles. Magnetic resonance imaging (MRI) was used to determine the cortical anatomy, as well as to measure fractional anisotropy, and blood oxygenation (BOLD) during an eyes-closed rest state. Region-of-interest time-series correlation analysis was performed on the BOLD signal to determine interregional connectivity. Functional status was measured with the upper extremity Fugl-Meyer and Wolf Motor Function Test. Results: Motor evoked potential (MEP) presence was associated with better functional outcomes, but the effect was not significant when considering baseline impairment. Affected side internal capsule fractional anisotropy was associated with better function at baseline. Affected side primary motor cortex (M1) activity became more correlated with other frontal motor regions after treatment. Resting state connectivity between affected hemisphere M1 and dorsal premotor area (PMAd) predicted recovery. Conclusions: Presence of motor evoked potentials in the affected motor cortex and its functional connectivity with PMAd may be useful in predicting recovery. Functional connectivity in the motor network shows a trends towards increasing after intensive robotic or non-robotic arm therapy. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00372411 \& NCT00333983.

Goal-directed reaching is important for activities of daily living. Populations of neurons in the primary motor cortex (M1) that project to spinal motor circuits are known to represent kinematics of reaching movements. We investigated whether repetitive practice of goal-directed reaching movements induces use-dependent plasticity of those kinematic characteristics, in a manner similar to finger movements, as had been shown previously. Transcranial magnetic stimulation (TMS) was used over the scalp to evoke upper extremity movements while the forearm was resting in a robotic cradle. Plasticity was measured by the change in kinematics of these evoked movements following goal-directed reaching practice. Baseline direction of TMS-evoked arm movements was determined for each subject. Subjects then practiced 3 blocks of 160 goal-directed reaching movements in a direction opposite to the baseline direction (14 cm reach 180° from baseline direction) against a 75 N·m spring field. Changes in TMS-evoked whole arm movements were assessed after each practice block and after 5 minutes following the end of practice. Direction and the position of the point of peak velocity of TMS-evoked movements were significantly altered following training and at a 5-minute interval following training, while amplitude did not show significant changes. This was accompanied by changes in the motor evoked potentials (MEPs) of the shoulder and elbow agonist muscles that partly explained the change in direction, mainly by increase in agonist MEP, without significant changes in antagonists. These findings demonstrate that the arm representation accessible by motor cortical stimulation demonstrates rapid plasticity induced by goal-directed robotic reach training in healthy subjects.

Background and Purpose: The brain changes that underlie therapy-induced improvement in motor function after stroke remain obscure. This study sought to demonstrate the feasibility and utility of measuring motor system physiology in a clinical trial of intensive upper extremity rehabilitation in chronic stroke-related hemiparesis. Methods: This was a substudy of two multi-center clinical trials of intensive robotic and intensive conventional therapy arm therapy in chronic, significantly hemiparetic, stroke patients. Transcranial magnetic stimulation was used to measure motor cortical output to the biceps and extensor digitorum communus muscles. Magnetic resonance imaging (MRI) was used to determine the cortical anatomy, as well as to measure fractional anisotropy, and blood oxygenation (BOLD) during an eyes-closed rest state. Region-of-interest time-series correlation analysis was performed on the BOLD signal to determine interregional connectivity. Functional status was measured with the upper extremity Fugl-Meyer and Wolf Motor Function Test. Results: Motor evoked potential (MEP) presence was associated with better functional outcomes, but the effect was not significant when considering baseline impairment. Affected side internal capsule fractional anisotropy was associated with better function at baseline. Affected side primary motor cortex (M1) activity became more correlated with other frontal motor regions after treatment. Resting state connectivity between affected hemisphere M1 and dorsal premotor area (PMAd) predicted recovery. Conclusions: Presence of motor evoked potentials in the affected motor cortex and its functional connectivity with PMAd may be useful in predicting recovery. Functional connectivity in the motor network shows a trends towards increasing after intensive robotic or non-robotic arm therapy. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00372411 \& NCT00333983.

The aim of this study was to determine the relationship between motor skill and attentional reserve. Participants practiced a reaching task with the dominant upper extremity, to which a distortion of the visual feedback was applied, while a control group performed the same task without distortion. Event-related brain potentials (ERPs), elicited by auditory stimuli were recorded throughout practice. Performance, as measured by initial directional error, was initially worse relative to controls and improved over trials. Analyses of the ERPs revealed that exogenous components, N1 and P2, were undifferentiated between the groups and did not change with practice. Notably, amplitude of the novelty P3 component, an index of the involuntary orienting of attention, was initially attenuated relative to controls, but progressively increased in amplitude over trials in the learning group only. The results provide psychophysiological evidence that attentional reserve increases as a function of motor skill acquisition.

Background and Purpose: The brain changes that underlie therapy-induced improvement in motor function after stroke remain obscure. This study sought to demonstrate the feasibility and utility of measuring motor system physiology in a clinical trial of intensive upper extremity rehabilitation in chronic stroke-related hemiparesis. Methods: This was a substudy of two multi-center clinical trials of intensive robotic arm therapy in chronic, significantly hemiparetic, stroke patients. Transcranial magnetic stimulation was used to measure motor cortical output to the biceps and extensor digitorum communus muscles. Magnetic resonance imaging (MRI) was used to determine the cortical anatomy, as well as to measure fractional anisotropy, and blood oxygenation (BOLD) during an eyes-closed rest state. Region-of-interest time-series correlation analysis was performed on the BOLD signal to determine interregional connectivity. Functional status was measured with the upper extremity Fugl-Meyer and Wolf Motor Function Test. Results: Motor evoked potential (MEP) presence was associated with better functional outcomes, but the effect was not significant when considering baseline impairment. Affected side internal capsule fractional anisotropy was associated with better function at baseline. Affected side primary motor cortex (M1) activity became more correlated with other frontal motor regions after treatment. Resting state connectivity between affected hemisphere M1 and dorsal premotor area (PMAd) predicted recovery. Conclusions: Presence of motor evoked potentials in the affected motor cortex and its functional connectivity with PMAd may be useful in predicting recovery. Functional connectivity in the motor network shows a trends towards increasing after intensive robotic or non-robotic arm therapy. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifiers: CT00372411 & NCT00333983.

Introduction: Intensive task practice assisted by robots is a promising treatment for hemiparesis after stroke. However, not all respond to the treatment, so a better patient selection method is needed. Previous studies have shown that motor cortical responsiveness to transcranial magnetic stimulation (TMS) may predict gains from practice and may change with those gains. Hypotheses: In the first study, we hypothesized that more intact motor cortical pathways would predict better response to treatment, and that motor cortical excitability would increase when motor function improved. In the second study we had the same hypotheses, and: Motor cortical excitability would increase during a single session of intensive therapy, and that this increase would itself predict gains in motor function. Methods: Study 1: participants in trials of upper extremity robotic rehabilitation in chronic stroke were recruited to have TMS measures for extensor digitorum communis (EDC) and biceps muscles before and after the therapeutic intervention, which consisted of 6-12 wks. of intensive rehabilitation for 3 hr. each wk., using either robotics or more conventional methods. TMS measures included motor maps, threshold, recruitment curves, and ipsilateral silent period. Study 2: all participants received 12 wks. of a newly optimized robotic training, with or without functional task practice. In addition to TMS measures before and after the intervention, participants had the same measures before and after one of the first sessions of therapy using a particular robot. Results: Study 1: (N=13) TMS thresholds in the EDC was lowered in 6/8 and recruitment curve threshold increased in 5 /8 with measurable responses after treatment, particularly in one participant with an 18 point increase in upper extremity Fugl-Meyer (FM) score. MEP presence showed a non-significant trend towards prediction of functional response (3.3 higher FM gain) even when baseline FM was included in the analysis. Study 2: While this is an ongoing study and outcome data are not available, motor threshold fell in the EDC after 1 hr. of robotic therapy for one participant and an MEP was present only after a therapy session for another. Conclusion: TMS measures in multiple muscles in moderately impaired stroke patients are feasible for rehabilitation trials and may be valuable both for prediction of response to therapy as well as demonstrating mechanisms of motor function improvement.

Conroy SS, Whitall J, Dipietro L, Jones-Lush LM, Zhan M, Finley MA, Wittenberg GF, Krebs HI, Bever CT. Effect of gravity on robot-assisted motor training after chronic stroke: a randomized trial. Objectives To determine the efficacy of 2 distinct 6-week robot-assisted reaching programs compared with an intensive conventional arm exercise program (ICAE) for chronic, stroke-related upper-extremity (UE) impairment. To examine whether the addition of robot-assisted training out of the horizontal plane leads to improved outcomes. Design Randomized controlled trial, single-blinded, with 12-week follow-up. Setting Research setting in a large medical center. Participants Adults (N=62) with chronic, stroke-related arm weakness stratified by impairment severity using baseline UE motor assessments. Interventions Sixty minutes, 3 times a week for 6 weeks of robot-assisted planar reaching (gravity compensated), combined planar with vertical robot-assisted reaching, or intensive conventional arm exercise program. Main Outcome Measure UE Fugl-Meyer Assessment (FMA) mean change from baseline to final training. Results All groups showed modest gains in the FMA from baseline to final with no significant between group differences. Most change occurred in the planar robot group (mean change ± SD, 2.94±0.77; 95% confidence interval [CI], 1.40–4.47). Participants with greater motor impairment (n=41) demonstrated a larger difference in response (mean change ± SD, 2.29±0.72; 95% CI, 0.85–3.72) for planar robot-assisted exercise compared with the intensive conventional arm exercise program (mean change ± SD, 0.43±0.72; 95% CI, –1.00 to 1.86). Conclusions Chronic UE deficits because of stroke are responsive to intensive motor task training. However, training outside the horizontal plane in a gravity present environment using a combination of vertical with planar robots was not superior to training with the planar robot alone.

Cortical rhythms in the alpha/mu frequency range (7-12 Hz) have been variously related to "idling," anticipation, seizure, and short-term or working memory. This overabundance of interpretations suggests that sensory cortex may be able to produce more than one (and even more than two) distinct alpha/mu rhythms. Here we describe simultaneous local field potential and single-neuron recordings made from primary sensory (gustatory) cortex of awake rats and reveal three distinct 7-12 Hz de novo network rhythms within single sessions: an "early," taste-induced approximately 11 Hz rhythm, the first peak of which was a short-latency gustatory evoked potential; a "late," significantly lower-frequency (approximately 7 Hz) rhythm that replaced this first rhythm at approximately 750-850 ms after stimulus onset (consistently timed with a previously described shift in taste temporal codes); and a "spontaneous" spike-and-wave rhythm of intermediate peak frequency (approximately 9 Hz) that appeared late in the session, as part of a oft-described reduction in arousal/attention. These rhythms proved dissociable on many grounds: in addition to having different peak frequencies, amplitudes, and shapes and appearing at different time points (although often within single 3 s snippets of activity), the early and late rhythms proved to have completely uncorrelated session-to-session variability, and the spontaneous rhythm affected the early rhythm only (having no impact on the late rhythm). Analysis of spike-to-wave coupling suggested that the early and late rhythms are a unified part of discriminative taste process: the identity of phase-coupled single-neuron ensembles differed from taste to taste, and coupling typically lasted across the change in frequency. These data reveal that even rhythms confined to a narrow frequency band may still have distinct properties.

Many neurological diseases result in a severe inability to reach for which there is no proven therapy. Promising new interventions to address reaching rehabilitation using robotic training devices are currently under investigation in clinical trials but the neural mechanisms that underlie these interventions are not understood. Transcranial magnetic stimulation (TMS) may be used to probe such mechanisms quickly and non-invasively, by mapping muscle and movement representations in the primary motor cortex (M1). Here we investigate movement maps in healthy young subjects at rest using TMS in the robotic environment, with the goal of determining the range of TMS accessible movements, as a starting point for the study of cortical plasticity in combination with robotic therapy. We systematically stimulated the left motor cortex of 14 normal volunteers while the right hand and forearm rested in the cradle of a two degree-of-freedom planar rehabilitation robot (IMT). Maps were created by applying 10 stimuli at each of nine locations (3x3 cm(2) grid) centered on the M1 movement hotspot for each subject, defined as the stimulation location that elicited robot cradle movements of the greatest distance. TMS-evoked movement kinematics were measured by the robotic encoders and ranged in magnitude from 0 to 3 cm. Movement maps varied by subject and by location within a subject. However, movements were very consistent within a single stimulation location for a given subject. Movement vectors remained relatively constant (limited to