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

Abstract

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.

Stroke Lesions in a Large Upper Limb Rehabilitation Trial Cohort Rarely Match Lesions in Common Preclinical Models

“…One path towards resolution of the controversies is to study both animal and human models of stroke recovery, often in analogous interspecies studies 57 . This approach may be strengthened by aligning the models as much as possible to resolve whether lesion location, size, timing and other variables are determinants of recovery or treatment response.…”

Motor compensation and its effects on neural reorganization after stroke

“…However, there has been much interest in initiating rehabilitative interventions earlier after stroke, to capitalize on the pro-growth environment of the early remodelling period 13–15,108 . Training the paretic forelimb in skilled motor tasks can promote new dendrite and synapse formation in peri-infarct motor cortex in rats 117 and can induce the reorganization of surviving movement representations of the paretic forelimb in residual motor cortex of rodents and monkeys 116,130–133 (FIG.…”

“…There is currently much interest in the potential to optimize functional outcome after CNS damage by capitalizing on early endogenous mechanisms of neural repair and remodelling after stroke, which are sensitive to behavioural manipulation and could facilitate the efficacy of motor rehabilitation 12–15 . Behavioural compensation is often a major contributor to the functional improvements that result from motor rehabilitative training 16,17 .…”

Moving Rehabilitation Research Forward: Developing Consensus Statements for Rehabilitation and Recovery Research

“…Based on similar analyses from traumatic brain injury (21) and Alzheimer's Disease (22), there is an expectation of identifying molecular signatures of recovery post-stroke in humans (23).…”