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)是一种很有前途的疗法，可以通过改变唤醒状态来恢复昏迷和植物状态的患者的意识。早期的实验研究已经确定了中央丘脑电刺激和前脑唤醒之间的因果联系。20世纪60年代和70年代的临床研究人员考虑了这些发现作为恢复慢性昏迷患者觉醒和意识的一种方法的潜在相关性，并开展了电刺激的试点案例研究。然而，尽管睁开眼睛和自主神经的迹象与唤醒效应相一致，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。脑深部刺激导致大多数患者的觉醒和相关的生理反应增加，但不幸的是，行为反应没有改变。最近，一项单一受试者的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(MCS)的严重脑损伤患者可能从CT/DBS中受益。总体结果表明，行为反应性显著改善，既有即时的，也有缓慢积累的，尽管是长期的影响。然而，这种类型的反应只在单个受试者中观察到，而且很难重现。虽然这些早期的发现提出了使用CT/DBS来改善严重创伤性脑损伤患者意识的可能性，但前方仍有许多关键挑战。这些措施包括明确作用机制，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功能磁共振成像方法，使我们能够以无与伦比的清晰度系统地了解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目标、刺激参数，甚至有助于将患者分层纳入此类治疗方案。在初步研究中，我们已经确定了ofMRI方法在确定关键刺激位置以及重要的与CT-DBS相关的功能方面的有效性。我们将首先在正常动物身上进行MRI、EEG和行为学研究，以确定急性和长期刺激所涉及的回路机制。然后，我们将评估优化的刺激参数及其在脑外伤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未来的临床试验、了解觉醒、意识和神经调节治疗的机制将是非常有价值的。

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.