Deconstructing Arousal Regulation Circuits for Optimal DBS Therapy Design

解构唤醒调节电路以实现最佳 DBS 治疗设计

• 批准号: 9344706
• 负责人: Jin Hyung Lee
• 金额: $ 37.6万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9344706
• 关键词: Acute; Anatomy; Animal Model; Animals; Anterior; Arousal; Behavior; Behavioral; Brain; Brain Injuries; Brain Stem; Case Study; Cell Nucleus; Central Lateral Nucleus; Central Medial Thalamic Nucleus; Chronic; Clinical; Clinical Investigator; Clinical Treatment; Clinical Trials; Cognitive; Coma; Conscious; Deep Brain Stimulation; Dependency; Effectiveness; Electric Stimulation; Electrical Stimulation of the Brain; Electroencephalography; Evaluation; Eye; Frequencies; Functional Magnetic Resonance Imaging; Future; Imaging technology; Individual; Intralaminar Nuclear Group; Investigation; Knowledge; Link; Location; Long-Term Effects; Longitudinal Studies; Maps; Measures; Mediating; Methodology; Methods; Minimally Conscious States; Modality; Multicenter Studies; Neurons; Outcome; Paracentral Nucleus; Patients; Physiological; Pontine structure; Prosencephalon; Recovery; Regulation; Reporting; Reticular Formation; Role; Seizures; Signal Pathway; Sleep; Spottings; Study Subject; System; Testing; Thalamic Nuclei; Thalamic structure; Therapeutic; Therapeutic Effect; Time; Tracer; Translating; Trauma; Traumatic Brain Injury; Unconscious State; Vegetative States; awake; basal forebrain; base; behavior measurement; behavioral outcome; behavioral study; brain cell; cingulate gyrus; cognitive recovery; experimental study; human study; human subject; imaging approach; improved; man; neuroregulation; new technology; novel; optogenetics; patient stratification; public health relevance; putamen; response; restoration; therapy design

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.

描述（由申请人提供）：中央丘脑深脑刺激（CT-DBS）是一种有希望的疗法，可通过改变唤醒状态来恢复昏迷和营养状态患者的意识。早期的实验研究已经建立了丘脑中部电脑刺激与唤醒前脑之间的因果关系。 1960年代和1970年代的临床研究人员认为，调查结果的潜在相关性是一种恢复长期无意识的患者的唤醒和意识的方法，并进行了电刺激的试点案例研究。然而，尽管开眼界和自主迹象与唤醒效应一致，但尚无报告描述了互动行为的持续恢复。在这些早期病例报告之后，进行了一项涉及49例患者的多中心研究。大脑刺激导致大多数患者的唤醒和相关生理反应增加，但不幸的是，行为反应性没有变化。最近，一项单一主题研究提供了第一个令人信服的证据，表明一些严重的大脑受伤的患者（MCS）可能会受益于CT/DBS。总体发现表明，与立即积累和缓慢积累但持久的效果相结合的组合可以显着提高行为反应能力。但是，这种类型的反应仅在单个受试者中观察到，并且很难繁殖。尽管这些较早的发现提出了一种可能性，即使用CT/DBS提高严重创伤性脑损伤的意识可能是有效的，但前方的许多关键挑战。这些包括定义作用机理以及优化刺激靶标和参数，使CT/DBS成为可靠的临床治疗方法。在此提案中，我们旨在克服这些挑战。我们将开发和利用一种新型的光遗传功能磁共振成像方法，该方法将使我们能够系统地了解CT/DBS治疗的基本作用机理，并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标，刺激参数，甚至有助于将患者分层纳入这种治疗方式。在初步研究中，我们确定了OFMRI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。我们将首先在正常动物中进行MRI，EEG和行为研究，以定义参与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恢复TBI动物模型中意识中的作用。 CT-DBS机制和优化参数的知识对于将来的临床试验，对唤醒，意识和神经调节疗法的机制的理解将是无价的。