Neuronal and Network Mechanisms of Electrocortical Stimulation

皮层电刺激(ECS)在癫痫或肿瘤手术前已被用于功能定位，以识别大脑中对言语和语言至关重要的区域(即，在受到刺激时会损害功能)。它还用于调节神经活动，例如，在直接治疗癫痫或疼痛时。然而，尽管ECS的临床应用历史悠久，但其确切的机制在神经元和网络层面上都知之甚少。例如，目前尚不清楚不同的大脑皮层和细胞类型对ECS的反应，也不知道ECS对行为的影响是否只影响局部皮质和底层白质。这项研究的长期目标是了解ECS如何与大脑相互作用。这项建议的目的是确定ECS对皮质神经元的局部影响，以及ECS对皮质网络和皮质下白质的影响。我们将检验多重计算模型和间接实验研究的预测。其中之一是ECS优先激活皮质浅层具有广泛投射的细胞，这可能有助于解释局灶性刺激是如何引起广泛影响的。我们假设，大脑皮质部位的解剖和功能连接模式决定了它对语言网络的意义。也就是说，在多个区域之间形成连接的节点更可能是关键节点。我们还假设，ECS通过影响大脑皮层和底层白质而导致行为变化。该项目的具体目标是1)确定ECS对神经元的影响，2)确定ECS的影响与皮质连接模式之间的关系，以及3)调查ECS的影响在多大程度上是由于激活了潜在的白质。该项目的创新之处在于，它使用了纳米网格、µECoG(皮质脑电成像)阵列，以实现神经元反应的同步ECS和双光子钙成像，以及其新颖的动态网络指标，以在毫秒级别分析人类皮质连接。我们已经证明，局灶性皮质降温只影响皮质，而不影响白质，并将利用降温来探索皮质和白质在ECS行为影响中的相对作用。实现我们的目标将具有重要意义，因为它将改善大脑功能图谱和神经调节。我们希望这能为包括癫痫、脑瘤和慢性疼痛在内的各种神经性疾病带来更好的神经外科结果。我们还预计，这项提议将使其他使用刺激来调查因果关系的研究在定义和理解其结果方面更加准确。最后，我们预计这项提议将促进我们对大脑如何编码语言的理解。

Electrocortical stimulation (ECS) has been used for functional mapping for many decades to identify brain areas that are “critical” for speech and language (i.e., that impair function when stimulated) prior to epilepsy or tumor surgery. It also is used to modulate neural activity, e.g., in directly treating epilepsy or pain. However, despite its long history of clinical use, the precise mechanisms of ECS are poorly understood, both on neuronal and network scales. For example, it is not known how different cortical layers and cell types respond to ECS, nor whether ECS’ effects on behavior are due to affecting only the local cortex vs. underlying white matter. The long-term goal of this research is to understand how ECS interacts with the brain. The objectives of this proposal are to determine the local effects of ECS on cortical neurons, and to determine the effects of ECS on the cortical network and subcortical white matter. We will test the predictions of multiple computational modelling and indirect experimental studies. One of these that ECS preferentially activates cells in superficial cortical layers with broad projections, could help explain how focal stimulation causes widespread effects. We hypothesize that the anatomic and functional connectivity patterns of a cortical site determine its significance to the language network. That is, nodes that form connections among multiple regions are more likely to be critical. We also hypothesize that ECS causes behavioral changes by affecting both the cortex and underlying white matter. The specific aims of the project are 1) to determine the effects of ECS on a neuronal scale, 2) to determine the relationship between ECS’ effects and cortical connectivity patterns, and 3) to investigate the extent to which ECS’ effects are due to activating underlying white matter. This project is innovative in its use of nanomesh, µECoG (electrocorticography) arrays to enable simultaneous ECS and two-photon calcium imaging of neuronal responses, as well as its novel dynamic network metrics to analyze human cortical connectivity on a millisecond level. We have shown that focal cortical cooling only affects the cortex, and not the white matter, and will use cooling to probe the relative roles of cortex and white matter in ECS’ behavioral effects. Achieving our objectives will be significant because it will improve functional brain mapping and neuromodulation. We expect this to lead to better neurosurgical outcomes for a variety of neurologic disorders, including epilepsy, brain tumors, and chronic pain. We also expect this proposal will enable other studies using stimulation to investigate causality to be more precise in defining and understanding their outcomes. Finally, we anticipate this proposal will advance our understanding of how the brain encodes language.