Deconstructing Arousal Regulation Circuits for Optimal DBS Therapy Design

描述（申请人提供）：中央丘脑深部脑刺激（CT-DBS）是一种很有前途的治疗方法，可以通过改变唤醒状态来恢复昏迷和植物人的意识。早期的实验研究已经建立了中央丘脑脑电刺激和前脑觉醒之间的因果关系。20世纪60年代和70年代的临床研究人员考虑到这些发现的潜在相关性，将其作为一种恢复慢性无意识患者觉醒和意识的方法，并开展了电刺激的试点案例研究。然而，尽管睁眼和自主神经信号与觉醒效应一致，但没有报告描述互动行为的持续恢复。根据这些早期病例报告，开展了一项涉及49名患者的多中心研究。在大多数患者中，脑深部刺激导致觉醒和相关生理反应增加，但不幸的是，行为反应没有变化。最近，一项单一受试者研究首次提供了令人信服的证据，证明一些处于最低意识状态的严重脑损伤患者可能受益于CT/DBS。总体结果表明，行为反应能力的显著提高，既有即时的效果，也有缓慢累积的效果，尽管效果是持久的。然而，这种类型的反应只在单个受试者中观察到，并且很难重现。虽然这些早期的发现提高了使用CT/DBS改善严重创伤性脑损伤患者意识的可能性，但仍有许多关键的挑战摆在面前。其中包括确定作用机制，优化刺激靶点和参数，使CT/DBS成为可靠的临床治疗方法。在这项提议中，我们的目标是克服这些挑战。我们将开发和利用一种新的光遗传功能磁共振成像方法，使我们能够系统地了解CT/DBS治疗的潜在作用机制。阐明CT-DBS治疗的机制将使我们能够优化刺激靶点、刺激参数，甚至有助于将患者分层纳入此类治疗模式。在初步研究中，我们已经确定了mri方法在识别刺激的关键位置以及与CT-DBS相关的功能方面的有效性。我们将首先对正常动物进行mri， EEG和行为研究，以确定涉及急性和长期刺激的回路机制。然后，我们将在TBI动物模型中评估优化后的刺激参数及其在恢复意识中的作用。CT-DBS机制和优化参数的知识对未来的临床试验、觉醒、意识和神经调节治疗机制的理解将是无价的。

DESCRIPTION (provided by applicant): Central thalamic deep brain stimulation (CT-DBS) is a promising therapy for restoring consciousness in patients in coma and vegetative state by changing the arousal state. Early experimental studies have established a causal link between central thalamus electrical brain stimulation and forebrain arousal. Clinical investigators in the 1960s and 1970s considered the potential relevance of the findings as a method for restoration of arousal and consciousness in chronically unconscious patients and carried out pilot case studies of electrical stimulation. However, despite eye opening and autonomic signs consistent with arousal effects, no reports described sustained recovery of interactive behavior. Following on these early case reports, a multicenter study involving a total of 49 patients was carried out. Deep brain stimulation resulted in increases in arousal and associated physiological responses in the majority of these patients but there were unfortunately no changes in behavioral responsiveness. More recently, a single subject study provided the first compelling evidence that some severely brain injured patients in minimally conscious state (MCS) may benefit from CT/DBS. The overall findings indicated significantly improved behavioral responsiveness with a combination of immediate as well as slowly accumulating, though long-lasting effects. However, this type of response has only been observed in a single subject and has been difficult to reproduce. While these earlier findings raise the possibility that using CT/DBS to improve consciousness in severe traumatic brain injury could be efficacious, many critical challenges lay ahead. These include defining the mechanisms of action and optimizing stimulation targets and parameters to make CT/DBS a reliable clinical treatment. In this proposal, we aim to overcome these challenges. We will develop and utilize a novel optogenetic functional magnetic resonance imaging approach that will enable us to systematically understand the underlying mechanism of action of the CT/DBS therapy with unparalleled clarity. Elucidating the mechanism of CT-DBS therapy will allow us to optimize the stimulation target, stimulation parameters, and even help stratify patients for inclusion into such therapeutic modalities. In Preliminary Studies we have established the effectiveness of the ofMRI approach at identifying key locations of stimulation and, importantly, function associated with CT-DBS. We will first conduct ofMRI, EEG, and behavioral studies in normal animals to define circuit mechanisms involved in both acute and long-term stimulation. Then, we will evaluate the optimized parameters of stimulation and their role in restoring consciousness in animal models of TBI. Knowledge of CT-DBS mechanism and optimization parameters will be invaluable for future clinical trials, understanding of mechanisms of arousal, consciousness, and neuromodulation therapy.