Finding an optimal rehabilitation paradigm after stroke: enhancing fiber growth and training of the brain at the right moment

Abstract

After stroke the central nervous system reveals a spectrum of intrinsic capacities to react as a highly dynamic system which can change the properties of its circuits, form new contacts, erase others, and remap related cortical and spinal cord regions. This plasticity can lead to a surprising degree of spontaneous recovery. It includes the activation of neuronal molecular mechanisms of growth and of extrinsic growth promoting factors and guidance signals in the tissue. Rehabilitative training and pharmacological interventions may modify and boost these neuronal processes, but almost nothing is known on the optimal timing of the different processes and therapeutic interventions and on their detailed interactions. Finding optimal rehabilitation paradigms requires an optimal orchestration of the internal processes of re-organization and the therapeutic interventions in accordance with defined plastic time windows. In this review we summarize the mechanisms of spontaneous plasticity after stroke and experimental interventions to enhance growth and plasticity, with an emphasis on anti-Nogo-A immunotherapy. We highlight critical time windows of growth and of rehabilitative training and consider different approaches of combinatorial rehabilitative schedules. Finally, we discuss potential future strategies for designing repair and rehabilitation paradigms by introducing a "3 step model": determination of the metabolic and plastic status of the brain, pharmacological enhancement of its plastic mechanisms, and stabilization of newly formed functional connections by rehabilitative training.

Keywords: Nogo-A; critical time window; plasticity; rehabilitation; stroke; training.

Figure 1

Schematic overview of the “3 step model”—as a possible roadmap for designing future rehabilitation schedules: (1) determination of the metabolic and plastic status of the brain by using state- of the art imaging technologies (image taken by the Akashi Municipal Hospital, Japan) and biomarker profiles in the blood and CSF; (2) enhancement of intrinsic repair and plasticity mechanisms in the ispi- and contralesional hemisphere as well as the spinal cord by application of growth and plasticity-promoting factors such as anti-Nogo-A antibody or Chondroitinase ABC; and (3) selection and stabilization of newly formed functional connections and pruning of non-functional ones by rehabilitative training.