Use it and/or lose it-experience effects on brain remodeling across time after stroke

Abstract

The process of brain remodeling after stroke is time- and neural activity-dependent, and the latter makes it inherently sensitive to behavioral experiences. This generally supports targeting early dynamic periods of post-stroke neural remodeling with rehabilitative training (RT). However, the specific neural events that optimize RT effects are unclear and, as such, cannot be precisely targeted. Here we review evidence for, potential mechanisms of, and ongoing knowledge gaps surrounding time-sensitivities in RT efficacy, with a focus on findings from animal models of upper extremity RT. The reorganization of neural connectivity after stroke is a complex multiphasic process interacting with glial and vascular changes. Behavioral manipulations can impact numerous elements of this process to affect function. RT efficacy varies both with onset time and its timing relative to the development of compensatory strategies with the less-affected (nonparetic) hand. Earlier RT may not only capitalize on a dynamic period of brain remodeling but also counter a tendency for compensatory strategies to stamp-in suboptimal reorganization patterns. However, there is considerable variability across injuries and individuals in brain remodeling responses, and some early behavioral manipulations worsen function. The optimal timing of RT may remain unpredictable without clarification of the cellular events underlying time-sensitivities in its effects.

Keywords: learned non-use; motor cortex; motor skill learning; restorative plasticity; upper extremity function.

Figure 1

Rodent models of upper extremity impairments after stroke used to study forelimb experience effects on brain and behavioral outcomes. Examples of behavioral manipulations in rats and mice include (A) forelimb constraint, used to force greater use of the paretic limb, (B,C) skilled reaching tasks, used to model both rehabilitative training (RT) focused on the paretic limb and compensatory skill learning with the nonparetic limb and, (D,E) pasta handling tasks, used to provide coordinated bimanual experience. (F) Approximate motor cortical infarct location (dark oval) used in several studies, as shown relative to head (yellow) and forelimb (green) movement representation regions of motor cortex. The caudal forelimb area (CFA) is in primary motor cortex and the rostral forelimb area (RFA) is in premotor/supplementary motor cortex. Motor cortical samples showing (G) vasculature (collagen IV immunolabeled), (H) a pyramidal neuron dendritic arbor (Golgi stained) and (I) synapses surrounded by peri-synaptic astrocytic processes (yellow highlights). The functional efficacy of motor RT has been linked with the reorganization of movement representations in peri-infarct motor cortex, but the influence of RT over time on the remodeling of surviving neurons, glia and vasculature has not yet been well examined.