Evan Chan

Critical periods after stroke study: translating animal stroke recovery experiments into a clinical trial

Introduction: Seven hundred ninety-five thousand Americans will have a stroke this year, and half will have a chronic hemiparesis. Substantial animal literature suggests that the mammalian brain has much potential to recover from acute injury using mechanisms of neuroplasticity, and that these mechanisms can be accessed using training paradigms and neurotransmitter manipulation. However, most of these findings have not been tested or confirmed in the rehabilitation setting, in large part because of the challenges in translating a conceptually straightforward laboratory experiment into a meaningful and rigorous clinical trial in humans. Through presentation of methods for a Phase II trial, we discuss these issues and describe our approach. Methods: In rodents there is compelling evidence for timing effects in rehabilitation; motor training delivered at certain times after stroke may be more effective than the same training delivered earlier or later, suggesting that there is a critical or sensitive period for strongest rehabilitation training effects. If analogous critical/sensitive periods can be identified after human stroke, then existing clinical resources can be better utilized to promote recovery. The Critical Periods after Stroke Study (CPASS) is a phase II randomized, controlled trial designed to explore whether such a sensitive period exists. We will randomize 64 persons to receive an additional 20 h of upper extremity therapy either immediately upon rehab admission, 2–3 months after stroke onset, 6 months after onset, or to an observation-only control group. The primary outcome measure will be the Action Research Arm Test (ARAT) at 1 year. Blood will be drawn at up to 3 time points for later biomarker studies. Conclusion: CPASS is an example of the translation of rodent motor recovery experiments into the clinical setting; data obtained from this single site randomized controlled trial will be used to finalize the design of a Phase III trial.

Neural Substrates of Motor Recovery in Severely Impaired Stroke Patients With Hand Paralysis

In well-recovered stroke patients with preserved hand movement, motor dysfunction relates to interhemispheric and intracortical inhibition in affected hand muscles. In less fully recovered patients unable to move their hand, the neural substrates of recovered arm movements, crucial for performance of daily living tasks, are not well understood. Here, we evaluated interhemispheric and intracortical inhibition in paretic arm muscles of patients with no recovery of hand movement (n = 16, upper extremity Fugl-Meyer Assessment = 27.0 ± 8.6). We recorded silent periods (contralateral and ipsilateral) induced by transcranial magnetic stimulation during voluntary isometric contraction of the paretic biceps and triceps brachii muscles (correlates of intracortical and interhemispheric inhibition, respectively) and investigated links between the silent periods and motor recovery, an issue that has not been previously explored. We report that interhemispheric inhibition, stronger in the paretic triceps than biceps brachii muscles, significantly correlated with the magnitude of residual impairment (lower Fugl-Meyer scores). In contrast, intracortical inhibition in the paretic biceps brachii, but not in the triceps, correlated positively with motor recovery (Fugl-Meyer scores) and negatively with spasticity (lower Modified Ashworth scores). Our results suggest that interhemispheric inhibition and intracortical inhibition of paretic upper arm muscles relate to motor recovery in different ways. While interhemispheric inhibition may contribute to poorer recovery, muscle-specific intracortical inhibition may relate to successful motor recovery and lesser spasticity.

Cortical effects of repetitive finger flexion- vs. extension-resisted tracking movements: a TMS study

While the cortical effects of repetitive motor activity are generally believed to be task specific, the task parameters that modulate these effects are incompletely understood. Since there are differences in the neural control of flexor vs. extensor muscles, the type of muscles involved in the motor task of interest may be one important parameter. In addition, the role each muscle plays in the task, such as whether or not it is the prime mover, is another potentially important task parameter. In the present study, use-dependent cortical plasticity was examined in healthy volunteers performing a robotic waveform tracking task with either the extensor digitorum communis (EDC) or flexor digitorum superficialis (FDS) acting as the prime mover. Transcranial magnetic stimulation was used to measure corticospinal excitability (CE) and short-interval intracortical inhibition of lower and higher threshold corticospinal neurons (SICI(L) and SICI(H), respectively) before and after a flexion- or extension-resisted finger tracking task. After repetitive performance of the tracking task, there was a significant decrease in SICI(L) targeting the EDC, while no change in CE targeting EDC was observed. In contrast, the reverse pattern was observed in the FDS: a significant increase in CE with no change in SICI(L). There was also a tendency toward increased SICI(H) targeting whichever muscle was acting as the prime mover, although this effect did not reach statistical significance. We conclude that there is a difference in patterns of use-dependent plasticity between extrinsic finger flexor and extensor muscles performing the same task.

Role of Non-Lesioned Hemisphere in Affected Arm Reaching Movements After Severe Stroke: A Pilot Study

measures. Rehabilitation therapists completed FIM ratings at discharge from the IRF. Results: A principal components analysis (PCA) of the discharge FIM scores (nZ337) identified three distinct factors accounting for 75% of the total variance: an ADL/mobility factor (factor 1), a cognitive-linguistic factor (factor 2), and a wheelchair factor (factor 3). In stepwise regression analyses, 36% of FIM factor 1 variance was predicted by age and NIHSS only.Factor 2 was predicted by the presence of aphasia, SBT and BNT scores (34% of the variance). No significant variance in factor 3 (wheelchair use) was predicted by acute measures. The presence of neglect did not account for any factor variance. Conclusions: Beyond age, early NIHSS score predicts IRF discharge FIM scores that involve ADLs and mobility, but cognitive-linguistic performance does not. About a third of the variance in cognitive and languagerelated FIM items is explained by the presence of acute aphasia and cognitive impairment (as measured by the SBT). We conclude that early post-stroke rehabilitation assessments can predict discharge independence weeks later in an impairment-specific fashion.