Modulating brain plasticity in rehabilitation of stroke and other brain lesions

背景： 中风和创伤性脑损伤导致的残疾是成年人长期残疾的主要原因。目前还没有普遍接受的治疗方法来治疗这种疾病，这种残疾在经济、个人、熟悉和社会方面的代价也不能低估。来自不同实验室的初步数据表明，通过药理学、脑刺激和体感刺激技术来调节受损大脑的可塑性过程是可能的。Z01的目的是确定中风运动障碍的机制，并确定最有希望改善这些患者皮质可塑性的技术，以促进功能恢复。 今年的调查结果： 从病理生理学的角度来看，我们发现在小脑中风患者中，在健康对照组中，与患侧M1相比，对侧初级运动皮质的短皮质内抑制(SICI)减少。这些结果证明，在小脑中风后的慢性期，对侧M1的抑制解除。在皮质下卒中患者(未累及小脑)中，我们发现在运动准备期间，患侧M1的SICI异常持续，而在年龄匹配的对照组中则没有。此外，与对照组相比，患者组的静息SICI减少。综上所述，这些发现证明了慢性中风患者患侧M1皮质内抑制的运动前调节不足，这一异常可能导致偏瘫手的运动控制缺陷。 我们还研究了中风患者上肢运动技能依赖训练改善的神经生理学机制，这些患者大多是中风幸存者。在训练前，我们发现在受累的三头肌中有更大的大脑半球间抑制(以同侧静默期衡量)，反映出在更严重的运动障碍患者中，非受损者对受损的初级运动皮质的抑制。在基线反应时间较慢的患者中，训练导致的REACH改善更大。训练后，患侧三头肌的运动诱发电位波幅增加，静息时间缩短，而二头肌则未见明显变化。这些结果表明，伴随着训练诱导的运动改善，训练对大脑半球内和大脑间机制的特定调制发生在具有实质性手臂损伤的慢性中风患者的实践之后。 我们合作对中风后初级运动皮质的代谢产物进行了磁共振波谱研究。结果表明，与对照组相比，卒中幸存者患侧和对侧M1的N-乙酰天冬氨酸水平降低，肌醇水平升高。在M1中，N-乙酰天冬氨酸与谷氨酸/谷氨酰胺显著相关。卒中后患侧N-乙酰天冬氨酸和谷氨酸/谷氨酰胺比值与上肢运动功能障碍呈正相关，而与N-乙酰天冬氨酸的对侧呈正相关。这些结果被解释为初步的，表明备用M1中神经元-神经胶质细胞的相互作用发生了显著的变化，与中风严重程度相关的自身改变和与中风持续时间相关的对照改变。 我们还在中风患者中进行了干预试验。我们参与了第一个使用Wii游戏技术评估虚拟现实在中风康复中的可行性、安全性和有效性的随机平行对照试验，结果可能作为更大规模的多中心试验的基础。根据刺激强度的不同，我们确定对偏瘫肢体进行多次体感刺激可以促进亚急性卒中后运动功能的训练效果。有人建议，在设计昂贵的、更大规模的双盲多中心临床试验之前，需要进行仔细的剂量-反应研究，以优化体感刺激的参数。 我们共同推进了对运动性中风致残机制的理解，并开发了可促进慢性中风后功能恢复的干预措施。

Background: Disability resulting from stroke and traumatic brain injury represent the main cause of long-term disability among adults. There are no universally accepted treatments available for the treatment of this condition and the financial, personal, familiar and social cost of this disability cannot be underestimated. Preliminary data from different laboratories has shown that it is possible to modulate plastic processes in the lesioned brain by pharmacological, brain stimulation and somatosensory stimulation techniques. The purpose of this Z01 is to identify mechanisms of stroke motor disability and characterize the most promising techniques to improve cortical plasticity in these patients in order to enhance functional recovery. Findings this year: From a pathophysiological point of view, we found in cerebellar stroke patients that short intracortical inhibition (SICI) was decreased in the contralesional primary motor cortex compared to ipsilesional M1 in the absence of side-to-side differences in healthy controls. These results document disinhibition of contralesional M1 in the chronic phase after cerebellar stroke. In patients with subcortical strokes (not involving the cerebellum), we found an abnormal persistence of SICI in the ipsilesional M1 during movement preparation that was absent in age-matched controls. Additionally, resting SICI was reduced in the patient group relative to controls. Alltogether, these findings document deficient premovement modulation of intracortical inhibition in the ipsilesional M1 of patients with chronic stroke, an abnormality that might contribute to deficits in motor control of the paretic hand. We also investigated the neurophysiological mechanisms underlying training-dependent improvements in upper-extremity motor skills in stroke patients with substantial motor disability, the majority of stroke survivors. Preceding training, we found greater interhemispheric inhibition (measured by ipsilateral silent periods) in the affected triceps muscle, reflecting inhibition from the nonlesioned to the lesioned primary motor cortex in patients with more severe motor impairment. Training-induced improvements in reaching were greater in patients with slower response times at baseline. Increased motor evoked potential amplitudes and decreased silent periods were observed in the affected triceps but not in the biceps muscle after training. These results indicate that along with training-induced motor improvements, training-specific modulation of intrahemispheric and interhemispheric mechanisms occurs after reaching practice in chronic stroke patients with substantial arm impairment. We collaborated in an investigation on metabolites studied with MR spectroscopy in the primary motor cortex after stroke. It was shown that stroke survivors showed lower N-acetylaspartate and higher myo-inositol across ipsilesional and contralesional M1 compared with control subjects. Significant correlations between N-acetylaspartate and glutamate/glutamine were found in M1. Ipsilesional N-acetylaspartate and glutamate/glutamine were positively correlated with arm motor impairment and contralesional N-acetylaspartate with time after stroke. The results were interpreted as preliminary, suggesting significant alterations of neuronal-glial interactions in spared M1 with the ipsilesional alterations related to stroke severity and contralesional alterations to stroke duration. We have also implemented interventional trials in stroke patients. We participated in the first randomized parallel controlled trial assessing the feasibility, safety, and efficacy of virtual reality using Wii gaming technology in stroke rehabilitation and the results may serve as the basis for a larger multicentre trial. We determined that application of multiple sessions of somatosensory stimulation to the paretic limb could facilitate training effects on motor function after subacute stroke depending on the intensity of stimulation. It was proposed that careful dose-response studies are needed to optimize parameters of somatosensory stimulation before designing costly, larger double-blind multicenter clinical trials. All together we advanced our understanding of the mechanisms underlying motor stroke disability and in the development of interventions that could facilitate functional recovery after chronic stroke.