Modulating brain plasticity in rehabilitation of stroke and other brain lesions

背景资料： 中风和创伤性脑损伤造成的残疾是成年人长期残疾的主要原因。没有普遍接受的治疗方法可用于治疗这种疾病，这种残疾的经济，个人，家庭和社会成本不可低估。来自不同实验室的初步数据表明，有可能通过药理学、脑刺激和体感刺激技术来调节受损大脑中的可塑性过程。本Z 01的目的是确定中风运动障碍的机制，并表征最有前途的技术，以提高这些患者的皮层可塑性，以增强功能恢复。 今年的发现： 从病理生理学的角度来看，我们发现，在小脑中风患者中，短皮质内抑制（SICI）在对侧病变的初级运动皮层相比，同侧的M1在没有侧到侧的差异，在健康对照组减少。这些结果证明了小脑卒中后慢性期对侧病灶M1的去抑制作用。在皮质下卒中（不涉及小脑）患者中，我们发现在运动准备过程中，同侧M1区SICI异常持续存在，而在年龄匹配的对照组中则不存在。此外，相对于对照组，患者组的静息SICI降低。总而言之，这些研究结果证明了慢性卒中患者同侧M1皮质内抑制的运动前调制不足，这种异常可能导致瘫痪手运动控制的缺陷。 我们还研究了脑卒中患者上肢运动技能训练依赖性改善的神经生理学机制，这些患者大多数是脑卒中幸存者，且有严重的运动障碍。在训练之前，我们发现受影响的三头肌中存在更大的半球间抑制（通过同侧沉默期测量），反映了运动障碍更严重的患者中从非病变到病变的初级运动皮层的抑制。在基线时反应时间较慢的患者中，训练诱导的伸手改善更大。增加运动诱发电位振幅和减少沉默期观察到受影响的三头肌，但不是在训练后的二头肌。这些结果表明，沿着训练诱导的运动改善，训练特异性的半球内和半球间机制的调制发生在手臂严重受损的慢性中风患者达到实践后。 我们合作研究了脑卒中后初级运动皮层的MR波谱学代谢物。结果表明，与对照组相比，卒中幸存者在同侧和对侧病灶M1上显示出较低的N-乙酰天冬氨酸和较高的肌醇。在M1中发现N-乙酰天冬氨酸和谷氨酸/谷氨酰胺之间存在显著相关性。脑卒中后随时间的推移，同侧病变N-乙酰天冬氨酸和谷氨酸/谷氨酰胺与手臂运动障碍和对侧病变N-乙酰天冬氨酸呈正相关。这些结果被解释为初步的，表明在备用M1的神经元-神经胶质细胞相互作用的显着改变，与中风的严重程度和对侧病变的改变中风持续时间的同侧改变。 我们还在中风患者中实施了干预性试验。我们参加了第一个随机平行对照试验，评估使用Wii游戏技术进行虚拟现实在中风康复中的可行性，安全性和有效性，结果可能作为更大的多中心试验的基础。我们确定，对麻痹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，这取决于刺激的强度。有人建议，在设计昂贵的，更大的双盲多中心临床试验之前，需要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卒中残疾机制的理解，并开发了有助于慢性卒中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.