The effects of treadmill training intensities on rehabilitation outcomes in subacute stroke : a focal ischemic rat model

Abstract

Stroke increases risk of mortality and is a major cause of disability. The growing elderly population vulnerable to stroke has substantially increased the burden of medical care in China and other developing countries. Effective rehabilitation is essential to help stroke survivors regain impaired motor function to improve quality of life and to reduce the pressure on current healthcare system. Early intervention of physical training is necessary for effective rehabilitation after stroke. Treadmill is a conventional intervention after stroke in both clinical and animal studies; however, overloaded treadmill training increases stress level during treatment, which may affect the recovery. Effective treadmill training protocols should be further optimized. Animal studies commonly use fixed training intensity throughout rehabilitation period and without adapting the training intensity with their recovered motor ability. This study used a standardized focal ischemic stroke rat model induced by intraluminal suture middle cerebral artery occlusion and reperfusion (MCAo/r) to explore the correlation between training intensity and rehabilitation efficacy in the early stage after stroke. Forty male Sprague-Dawley (SD) rats (between 2 and 3 months) were used in a pilot study to evaluate neural and motor function assessment tools, and to investigate the effects of treadmill training on motor function recovery, brain infarct, and stress levels. Longa's test and De Ryck's test were selected for post-stroke functional evaluations after comparison. Treadmill training after stroke induced significantly (p<0.05) high stress level than control but still significantly improved motor function recovery. A separate cohort of 94 male SD rats (between 2 and 3 months) was then used to investigate the effects of differing treadmill training intensities on stroke recovery during 7 early consecutive intervention days. Among the 94 rats, 7 did not meet screening requirements after accommodation, while 10 exhibited no stroke and 17 died within 24 hours after MCAo/r surgery. The rest 60 rats with successful stroke were assigned into four groups: control (CG, n=15), low intensity (LG, n=15), gradually increased intensity (GIG, n=15) and high intensity (HG, n=15). Rats in LG and HG ran at fixed velocities of 5 m/min and 26 m/min, respectively. Rats in GIG ran from 5 m/min on the first treatment day to 26 m/min on the last day, with a gradually increased running speed matching the average recovery rate of the stroke rat. De Ryck's tests were conducted daily to evaluate motor function recovery. Stress level and neural recovery were evaluated via plasma corticosterone and brain-derived neurotrophic factor (BDNF) concentrations in the brain tissues (hippocampus, striatum, and cortex), respectively. Results showed that GIG rats significantly (p<0.05) recovered motor function and produced higher hippocampal BDNF (112.87±25.18 ng/g). GIG and LG rats exhibited similar stress levels (540.63±117.40 nM/L and 508.07±161.30 nM/L, respectively), which were significantly lower than that (716.90±156.48 nM/L) of HG rats. Training with higher intensity did not result in better motor function recovery and resulted in high stress levels. Training with gradually increased intensity achieved a better recovery outcome with lower stress. These observations indicate that training intensity influences stroke recovery. This study firstly systematically investigated the relationship of training intensity and rehabilitation after stroke. Gradually increased training intensity was firstly proposed and investigated in this study, suggesting a better improvement of rehabilitation after stroke than fixed training intensities by upregulating cerebral BDNF levels and downregulating stress levels. A training protocol that includes gradually increasing training intensity should be considered in both animal and clinical human studies for better stroke recovery.