Re-wiring the human brain

项目摘要/摘要 行为和心理功能是大规模神经元网络的紧急属性，其中连接 节点之间的优势决定了网络。相应地，许多神经和精神症状 产生于特定大脑区域之间的结构和/或功能连接的网络级不平衡 已经改变(例如，皮质下中风、创伤性脑损伤)。对于结构性损伤，而成人的大脑 几乎没有能力重新生长受损的远程轴突，通过训练恢复连接是可能的 大脑使用备用路径重新连接这些区域和/或抵消不适应连接的变化， 目的是改善运动/行为/认知功能。这也适用于无结构性障碍 受伤，但有获得性病理连接变化(例如，成瘾、抑郁)。恢复网络的步骤 以一种受控的方式，迫切需要开发能够有选择地与目标交战的技术 连接并增加或减少其有效连接强度。此外，还应应用这些技术。 电缆连接到人脑，理想情况下是非侵入性的。为此，大脑皮层-大脑皮层配对联想刺激 (CCPAS)协议已被提出，推测涉及尖峰时间相关塑性(STDP)机制-- 语无伦次。然而，在将CCPAS应用于人类方面的进展有限。这是因为毫秒级精度 颅内传导延迟，这是选择CCPAS参数的先决条件 想要的效果，还不得而知。此外，捕捉颅内CCPAS效应的神经生理学结果指标- 缺乏效果，这使得很难评估刺激是否达到了它的目标--事实上，它甚至没有 已经令人信服地表明，如果CCPAS与STDP接洽。因此，该提案的总体目标是克服 这些障碍通过(A)制作能够测量所需的快速颅内传导延迟的新技术， (B)制定准确捕捉CCPAS神经生理效应的结果衡量标准，以及(C)证明 CCPAS机制。具体地说，受到之前的动物和人类研究以及我们自己的初步研究的启发 CCPAS数据，我们将用毫秒级的异步刺激两个相互连接的大脑皮层区域 独立的经颅磁刺激器(TMS)线圈。我们的初步数据显示源-空间皮质-心-心- 皮层诱发电位(CCEP)，捕捉所需的传导延迟并作为CCPAS的结果 在生理上相关的快速(&lt；10毫秒)时间尺度上的效果。此外，我们的初步数据表明，参数 操纵CCPAS的异步性符合该机制确实是STDP。如果成功，这将是 这项研究将使我们的能力转变为非侵入性地操纵大脑区域间的有效连接 人类大脑，因此为一类新的强大的网络级治疗疾病奠定了基础 在广泛的神经和精神障碍中涉及大脑连通性的变化。

PROJECT SUMMARY / ABSTRACT Behaviors and mental functions are emergent properties of large-scale neuronal networks where connectivity strengths between nodes define the network. Correspondingly, many neurological and psychiatric symptoms arise from network-level imbalances where structural and/or functional connectivity between specific brain areas has been altered (e.g., sub-cortical stroke, traumatic brain injury TBI). For structural injury, while the adult brain has little capacity to re-grow damaged long-range axons, it may be possible to restore connectivity by training the brain to use alternate routes reconnecting the areas and/or counteracting maladaptive connectivity changes, with the goal of improving motor/behavioral/cognitive function. This also applies to disorders without structural injury but with acquired pathological connectivity changes (e.g., addictions, depression). To restore the network in a controlled fashion, there is a critical need to develop techniques that can selectively engage the targeted connection and increase or reduce its effective connectivity strength. Moreover, the techniques should be appli- cable to the human brain and ideally be non-invasive. To this aim, cortico-cortical paired associative stimulation (ccPAS) protocols have been proposed, presumably engaging spike timing-dependent plasticity (STDP) mech- anisms. However, progress in applying ccPAS in humans has been limited. This is because millisecond-precision intracranial conduction delays, which are a prerequisite for choosing ccPAS parameters that would have the desired effect, are not known. Further, neurophysiological outcome measures to capture intracranial ccPAS ef- fects are lacking, which makes it difficult to assess if the stimulation achieved its goals – in fact, it has not even been convincingly shown if ccPAS engages STDP. The overall goal of the proposal, therefore, is to overcome these barriers by (a) crafting novel techniques that can measure the required fast intracranial conduction delays, (b) developing outcome measures that capture ccPAS neurophysiological effects accurately, and (c) proving ccPAS mechanisms. Specifically, inspired by previous animal and human studies, as well as our own preliminary ccPAS data, we will stimulate two interconnected cortical regions with millisecond-level asynchronies with two independent transcranial magnetic stimulator (TMS) coils. Our preliminary data show source-space cortico-cor- tical evoked potentials (ccEP) that capture both the required conduction delays and serve as outcomes of ccPAS effects at the physiologically relevant fast (<10 ms) timescales. Further, our preliminary data that parametrically manipulates ccPAS asynchronies are in accord with that the mechanism is indeed STDP. If successful, this study will transform our capability to non-invasively manipulate brain interregional effective connectivity in the human brain, therefore laying the foundation for a new class of robust network-level therapies in disorders that involve brain connectivity changes in a broad range of neurological and psychiatric disorders.