Cortical reorganization and plasticity In the Healthy Brain

背景资料： 皮质重组发生在成人中枢神经系统。可塑性有助于各种形式的人类行为，包括运动学习和记忆形成，巩固，再巩固以及短期和长期保持。理解这些不同的行为过程的作用以及这些不同形式的人类可塑性在技能获得过程中的机制是非常重要的。 今年的发现： 在这段时间里，我们对人类运动神经可塑性机制的理解以及在健康受试者中增强运动神经可塑性的策略的发展取得了一些重要进展。最近，我们通过证明人类大脑中的初级皮层处理与预先存在的重新激活的记忆痕迹相互作用，对成功修改现有的相关记忆至关重要，从而推进了我们对人类运动皮层重新巩固的理解。 关于奖励对运动学习的影响，我们发现奖励条件下的训练比惩罚或中性条件下的训练更能有效地激发持久的运动学习，这一优势是由随着时间的推移而持续存在的离线记忆增益驱动的。 这一发现可能会影响训练方案在教育中的设计方式，也会影响脑损伤（如中风或创伤性脑损伤）后的神经康复。 我们还探讨了应用于初级运动皮层（M1）的经颅直流电刺激（tDCS）对运动学习的影响的半球专门化。6组接受3次视觉引导顺序捏力调制任务训练，分别使用右手或左手，并接受右侧M1、左侧M1或假tDCS。运动技能的线性混合模型分析显示，刺激组（左侧M1、右侧M1、假手术组）的主效应显著，但手（右侧、左侧）或其相互作用的主效应不显著。当合并手部数据时，左侧M1 tDCS诱导的技能学习显著高于假手术，这一结果与假设的左半球运动技能学习专业化一致，但也可能增加左侧M1对tDCS的反应性。 单半球蒙太奇效应量是更常见蒙太奇效应量的一半，随后的功效分析表明，每组需要75名受试者才能检测到仅12名受试者采用常规双半球蒙太奇时观察到的差异。有趣的是，尽管其在实验和临床环境中的使用越来越多，但经颅直流电刺激（tDCS）的细胞和分子机制仍然未知。 应用于人类运动皮层（M1）的阳极tDCS改善了运动技能学习，表明了突触可塑性的作用。在一项研究中，我们在小鼠M1切片中证明DCS诱导持久的突触增强（DCS-LTP），这是极性特异性的，NMDA受体依赖性的，需要DCS与重复低频突触激活（LFS）的耦合。BDNF是这种现象的关键介质，因为组合的DCS和LFS增强BDNF分泌和TrkB活化，并且在BDNF和TrkB突变小鼠中不存在DCS-LTP。此外，已知BDNF val 66 met多态性部分影响活动依赖性BDNF分泌，损害人类和小鼠的运动技能获得。只要活动依赖性BDNF分泌到位，运动学习就可以通过阳极tDCS增强。我们认为tDCS可能会通过增强突触可塑性来改善运动技能学习，而突触可塑性需要M1内的脑源性神经营养因子分泌和TrkB激活。 一个重要的研究领域在于确定白色物质的微观结构相关的上级长期技能下获得随机而不是封锁的做法时间表。在一项弥散加权成像与学习相关的研究中，我们证明了随机练习时间表比分组练习时间表更能提高长期内隐技能，更重要的是从机械的角度来看，通过随机练习获得的上级技能可能与感觉运动皮质纹状体网络中的白色物质微观结构有关。

Background: Cortical reorganization occurs in the adult central nervous system. Plasticity contributes to various forms of human behavior including motor learning and memory formation, consolidation, reconsolidation and short and long term retention. It is very important to understand the role of these different behavioral processes and of the mechanisms underlying these various forms of human plasticity during skill acquisition. Findings this year: Several important advances were implemented during this time period on our understanding the mechanisms of human motor neuroplasticity and the development of strategies to enhance it in healthy subjects. Most recently, we advanced our understanding of reconsolidation in the human motor cortex by demonstrating that primary cortical processing in the human brain interacting with pre-existent reactivated memory traces is critical for successful modification of the existing related memory. In relation to the influence of reward on motor learning, we found that training under rewarded conditions is more effective than training under punished or neutral conditions in eliciting lasting motor learning, an advantage driven by offline memory gains that persist over time. This finding may impact the way in which training protocols are designed in education but also in neurorehabilitation after brain lesions such as stroke or traumatic brain injury. We have also probed for hemispheric specialization in the effects of transcranial direct current stimulation (tDCS) applied over the primary motor cortex (M1) on motor learning. Six groups trained for 3 sessions on a visually-guided sequential pinch force modulation task with their right or left hand, and received right M1, left M1, or sham tDCS. A linear mixed model analysis for motor skill showed a significant main effect for the stimulation group (left M1, right M1, sham), but not for hand (right, left) or their interaction. Left M1 tDCS induced significantly greater skill learning than sham when hand data were combined, a result consistent with the hypothesized left hemisphere specialization for motor skill learning, but also with possible increased left M1 responsiveness to tDCS. The unihemispheric montage effect size was half that of the more common montage, and subsequent power analysis indicated that 75 subjects per group would be needed to detect differences seen with only 12 subjects with the customary bihemispheric montage. Interestingly, despite its increasing use in experimental and clinical settings, the cellular and molecular mechanisms underlying transcranial direct current stimulation (tDCS) remain unknown. Anodal tDCS applied to human motor cortex (M1) improves motor skill learning, suggesting a role for synaptic plasticity. In one study, we demonstrated in mouse M1 slices that DCS induces a long-lasting synaptic potentiation (DCS-LTP), which is polarity-specific, NMDA-receptor dependent and requires coupling of DCS with repetitive low-frequency synaptic activation (LFS). BDNF is a key mediator of this phenomenon, as combined DCS and LFS enhance BDNF-secretion and TrkB-activation, and DCS-LTP is absent in BDNF and TrkB mutant mice. Moreover, the BDNF val66met polymorphism known to partially affect activity-dependent BDNF secretion, impairs motor skill acquisition in humans and mice. Motor learning is enhanced by anodal tDCS, as long as activity-dependent BDNF secretion is in place. We proposed that tDCS may improve motor skill learning by augmenting synaptic plasticity that requires BDNF-secretion and TrkB-activation within M1. One important area of research lies in identifying the white matter microstructural correlates of superior long-term skill gained under randomized rather than blocked practice schedules. In one study relating diffusion-weighted imaging with learning, we demonstrated that randomized practice schedules improve long-term implicit skill more than grouped practice schedules, and more importantly from a mechanistic point of view, that the superior skill acquired through randomized practice can be related to white matter microstructure in the sensorimotor corticostriatal network.