Very Early Initiation Reduces Benefits of Poststroke Rehabilitation Despite Increased Corticospinal Projections

My God, have you got the conclusion wrong. The neuronal cascade of death

is still occurring  during this early rehab. And you didn't know about that or measure its occurrence? 

Very Early Initiation Reduces Benefits of Poststroke Rehabilitation Despite Increased Corticospinal Projections

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Naohiko Okabe, PhD, Naoyuki Himi, PhD, Emi Nakamura-Maruyama, PhD, ...

First Published May 29, 2019 Research Article

https://doi.org/10.1177/1545968319850132

Article information

Abstract

Background. Although the effect of rehabilitation is influenced by aspects of the training protocol, such as initiation time and intensity of training, it is unclear whether training protocol modifications affect the corticospinal projections.
Objective. The present study was designed to investigate how modification of initiation time (time-dependency) and affected forelimb use (use-dependency) influence the effects of rehabilitation on functional recovery and corticospinal projections.  
Methods. The time-dependency of rehabilitation was investigated in rats forced to use their impaired forelimb immediately, at 1 day, and 4 days after photothrombotic stroke. The use-dependency of rehabilitation was investigated by comparing rats with affected forelimb immobilization (forced nonuse), unaffected forelimb immobilization (forced use), and a combination of forced use and skilled forelimb training beginning at 4 days after stroke.  
Results. Although forced use beginning 1 day or 4 days after stroke caused significant functional improvement, immediate forced limb use caused no functional improvement. On the other hand, a combination of forced use and skilled forelimb training boosted functional recovery in multiple tasks compared to simple forced use treatment. Histological examination showed that no treatment caused brain damage. However, a retrograde tracer study revealed that immediate forced use and combination training, including forced use and skilled forelimb training, increased corticospinal projections from the contralesional and ipsilesional motor cortex, respectively.
Conclusions. These results indicate that although both very early initiation time and enhanced skilled forelimb use increased corticospinal projections, premature initiation time hampers the functional improvement induced by poststroke rehabilitation.

Keywords stroke, rehabilitation, constraint-induced movement therapy, corticospinal projection, motor function, time dependency, use dependency

Introduction

Rehabilitation is the most commonly used treatment for chronic stroke patients due to many evidences demonstrating its safety and effectiveness.¹ However, functional recovery is often incomplete even when intensive rehabilitation is carried out. Although preclinical studies showed neurorestorative effects of newly developing therapies such as stem cell therapy² or anti-NogoA immunotherapy,³ none of them has been approved in clinical setting. Thus, improving effectiveness of rehabilitation remains an essential strategy to attain better recovery after stroke.⁴ Since effect of rehabilitation is affected by modification of rehabilitation protocol as well as patient’s age, comorbidity, and size and location of infarct, guideline to design optimal rehabilitation protocol is required to maximize their efficacy. Nevertheless, it has not been accomplished due to lack of sufficient evidences.
Neural plasticity is heightened during the critical period of the early poststroke recovery phase. And the greatest gains in recovery occur in this period through activity-dependent neural network remodeling.⁵ Therefore, there is a general consensus that more intensive rehabilitation initiated in earlier recovery phase would cause better functional outcome, and which was actually supported by many clinical trials.^6,7 For example, a clinical trial that compared the functional improvement after constraint-induced movement therapy (CIMT) initiated in early (3-9 months after stroke) and delayed phase (15-21 months after stroke) demonstrated that early CIMT induces greater functional improvement (EXCITE Stroke Trial).⁸ However, some important questions remain to be clarified. Although it is generally accepted that early rehabilitation caused better functional outcome than later one, how early rehabilitation should begin is still controversial because previous studies demonstrated very early rehabilitation has a potential to increase damage to the ischemic penumbra.⁹ Recent big multicenter randomized controlled trial also reported that the higher dose, very early mobilization protocol was associated with a reduction in the odds of a favorable outcome at 3 months.¹⁰ Similarly, in the regard of training intensity, whereas dose-response relationship has been repeatedly evaluated by comparing total time for therapy,^6,7 a single-blind phase II trial of CIMT (Very Early Constraint-Induced Movement during Stroke Rehabilitation [VECTORS] study) reported that higher intensity CIMT resulted in less motor improvement at 90 days compared to lower intensity CIMT and traditional upper extremity therapy,¹¹ suggesting that too intense training could deteriorate functional recovery. To determine proper rehabilitation regimen, understanding of biological events underlying unfavorable effect induced by too early and intensive training is necessary. However, although previous studies have demonstrated that the integrity and plasticity of corticospinal projections are fundamental for rehabilitation-induced functional recovery after stroke,^12-14 it is not known how modifications of the rehabilitation protocol affect these projections.
The purpose of the present study was to examine how modifications of the rehabilitation protocol, and in particular of time of initiation (time dependency) and affected forelimb use (use dependency), impact functional recovery by rehabilitative training after severe cortical stroke and how corticospinal projections is also affected by these modifications.