Critical Period After Stroke Study (CPASS): A phase II clinical trial testing an optimal time for motor recovery after stroke in humans

Significance

Restoration of postinjury brain function is a signal neuroscience challenge. Animal models of stroke recovery demonstrate time-limited windows of heightened motor recovery, similar to developmental neuroplasticity. However, no equivalent windows have been demonstrated in humans. We report a randomized controlled trial applying essential elements of animal motor training paradigms to humans, to determine the existence of an analogous sensitive period in adults. We found a similar sensitive or optimal period 60 to 90 d after stroke, with lesser effects ≤30 d and no effect 6 mo or later after stroke. These findings prospectively demonstrated the existence of a sensitive period in adult humans. We urge the provision of more intensive motor rehabilitation within 60 to 90 d after stroke onset.

Abstract

Restoration of human brain function after injury is a signal challenge for translational neuroscience. Rodent stroke recovery studies identify an optimal or sensitive period for intensive motor training after stroke: near-full recovery is attained if task-specific motor training occurs during this sensitive window. We extended these findings to adult humans with stroke in a randomized controlled trial applying the essential elements of rodent motor training paradigms to humans. Stroke patients were adaptively randomized to begin 20 extra hours of self-selected, task-specific motor therapy at ≤30 d (acute), 2 to 3 mo (subacute), or ≥6 mo (chronic) after stroke, compared with controls receiving standard motor rehabilitation. Upper extremity (UE) impairment assessed by the Action Research Arm Test (ARAT) was measured at up to five time points. The primary outcome measure was ARAT recovery over 1 y after stroke. By 1 y we found significantly increased UE motor function in the subacute group compared with controls (ARAT difference = +6.87 ± 2.63, P = 0.009). The acute group compared with controls showed smaller but significant improvement (ARAT difference = +5.25 ± 2.59 points, P = 0.043). The chronic group showed no significant improvement compared with controls (ARAT = +2.41 ± 2.25, P = 0.29). Thus task-specific motor intervention was most effective within the first 2 to 3 mo after stroke. The similarity to rodent model treatment outcomes suggests that other rodent findings may be translatable to human brain recovery. These results provide empirical evidence of a sensitive period for motor recovery in humans.