Deconstructing Arousal Regulation Circuits for Optimal DBS Therapy Design

描述（由申请人提供）：中央丘脑脑深部电刺激（CT-DBS）是一种通过改变唤醒状态恢复昏迷和植物人状态患者意识的有前景的治疗方法。早期的实验研究已经建立了中央丘脑脑电刺激和前脑唤醒之间的因果关系。20世纪60年代和70年代的临床研究人员认为，这些发现可能与恢复长期无意识患者的觉醒和意识有关，并进行了电刺激的试点病例研究。然而，尽管眼睛睁开和自主体征与唤醒效应一致，但没有报告描述交互行为的持续恢复。根据这些早期病例报告，进行了一项涉及49例患者的多中心研究。脑深部电刺激导致大多数患者的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提供了第一个令人信服的证据，表明一些处于最低意识状态（MCS）的严重脑损伤患者可能受益于CT/DBS。总体研究结果表明，行为反应性显着改善，具有即时和缓慢积累的组合，但持久的影响。然而，这种类型的反应仅在单个受试者中观察到，并且难以重现。虽然这些早期的发现提高了使用CT/DBS来改善严重创伤性脑损伤的意识可能是有效的，但许多关键的挑战还在前面。这些包括定义作用机制和优化刺激目标和参数，使CT/DBS成为可靠的临床治疗。在本提案中，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学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，具有无与伦比的清晰度。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，甚至有助于对患者进行分层以纳入此类治疗模式。在初步研究中，我们已经确定了ofMRI方法在识别刺激的关键位置方面的有效性，重要的是，与CT-DBS相关的功能。我们将首先在正常动物中进行ofMRI，EEG和行为研究，以确定涉及急性和长期刺激的电路机制。然后，我们将评估刺激的优化参数及其在TBI动物模型中恢复意识的作用。CT-DBS机制和优化参数的知识对于未来的临床试验，唤醒，意识和神经调节治疗机制的理解将是非常宝贵的。

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.