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

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.

Keywords: critical period; neuronal plasticity; stroke; stroke rehabilitation; time factors.

Fig. 1.

CONSORT diagram for the CPASS trial. Seventy-two individuals were adaptively randomized to receive CPASS therapy acute (≤30 d poststroke), subacute (2 to 3 mo), chronic (≥6 mo poststroke), or the control group.

Fig. 2.

Study design. Baseline assessment occurred <30 d from stroke onset, and participants were randomized to one of four groups: acute, received additional 20 h of therapy initiated within 30 d from stroke onset; subacute, received additional 20 h initiated within 2 to 3 mo from stroke onset; chronic, received additional 20 h 6 to 7 mo after onset; controls, received standard rehabilitation. Adapted from ref. , which is licensed under CC BY 4.0.

Fig. 3.

(A–D) Individual trajectories of raw ARAT scores posttroke, by treatment group. Vertical gray bars show average timing of the intervention in each group.

Fig. 4.

Mean total ARAT scores (with SEs) for each group at each time point, from the longitudinal model. (The 6-mo assessment score for the chronic group is their pretreatment assessment.)