Cortical reorganization and plasticity In the Healthy Brain

背景： 皮质重组发生在成年中枢神经系统中。可塑性有助于人类行为的各种形式，包括运动学习和记忆的形成、巩固、再巩固和短期和长期保持。理解这些不同的行为过程的作用，以及在技能获得过程中这些不同形式的人类可塑性背后的机制是非常重要的。 今年的调查结果： 在这一时期，在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其可塑性的策略的发展方面，已经取得了一些重要的进展。最近，我们通过证明人脑中的初级皮质处理与先前存在的重新激活的记忆痕迹相互作用是成功修改现有相关记忆的关键，从而推进了对人类运动皮质重新巩固的理解。 关于奖赏对运动学习的影响，我们发现，在奖赏条件下的训练比在惩罚或中性条件下的训练更有效地引发持久的运动学习，这一优势是由随着时间的推移而获得的离线记忆所驱动的。这一发现可能会影响教育中训练方案的设计方式，也会影响中风或创伤性脑损伤等脑损伤后的神经康复。 我们还探讨了对初级运动皮质(M1)施加经颅直流电刺激(TDC)对运动学习的影响，以实现大脑半球的特化。6组受试者分别用右手或左手进行3次视觉引导的顺序夹力调制任务训练，分别接受右手M1、左手M1或假TDCs训练。运动技能的线性混合模型分析显示，刺激组(左M1、右M1、假刺激)的主效应显著，而手(右、左)及其交互作用的主效应不显著。当结合手部数据时，左侧M1 tDCs诱导的技能学习显著高于Sham，这一结果与假设的左侧大脑半球运动技能学习专门化一致，但也可能与左侧M1对tDCs的反应性增加一致。单半球蒙太奇效应的大小是更常见的蒙太奇的一半，随后的能量分析表明，每组需要75名受试者才能检测到与通常的双半球蒙太奇只有12名受试者所看到的差异。有趣的是，尽管它在实验和临床环境中越来越多地使用，但经颅直流电刺激(TDC)背后的细胞和分子机制仍然未知。 应用于人类运动皮质(M1)的阳极tdcs改善了运动技能的学习，暗示了突触可塑性的作用。在一项研究中，我们在小鼠的M1脑片上证明了DC诱导长时间突触增强(DC-LTP)，这是极性特定的，NMDA受体依赖的，需要将DC与重复的低频突触激活(LFS)耦合。BDNF是这一现象的关键介质，因为联合使用DCs和LFS可促进BDNF的分泌和TrkB的激活，而DCSLTP在BDNF和TrkB突变小鼠中缺失。此外，已知的部分影响依赖活动的BDNF分泌的BDNF Val66Met多态会损害人类和小鼠的运动技能获得。只要依赖活动的脑源性神经营养因子分泌到位，阳极tDDC就能促进运动学习。我们认为，tDCs可能通过增强突触的可塑性来改善运动技能的学习，突触可塑性需要M1内BDNF的分泌和TrkB的激活。 一个重要的研究领域在于识别在随机而不是阻塞的练习时间表下获得的卓越长期技能的脑白质微结构相关性。在一项将弥散加权成像与学习联系在一起的研究中，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，从机械学的角度来看，通过随机练习获得的优越技能可能与感觉运动皮质纹状体网络中的白质微结构有关。

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 have been implemented in this period on our understanding of mechanisms of human motor neuroplasticity and in the development of strategies to enhance it in healthy subjects. Most recently we advanced out 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 like 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. 6 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 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 through augmentation of synaptic plasticity that requires BDNF-secretion and TrkB-activation within M1. One important area of research lies in the identification of 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.