Research 1-Hogeveen

项目总结 当前Cobre指导的PI项目的首要目标是更好地理解和准确地 调节，慢性中重度患者冷漠的神经计算机制 创伤性脑损伤(MsTBI)。之前的研究已经证实，冷漠--其特征是失去 动机-是msTBI的一种常见和令人衰弱的症状，但潜在的神经病理导致 MsTBI的冷漠仍不为人所知。在临床上，现有的治疗msTBI冷漠的方法疗效有限， 要么是因为他们依赖于在msTBI中经常受损的高级认知能力(例如认知能力 行为疗法)，或它们由于缺乏回路而可能引起不想要的有害副作用- 特异性(例如，调节整个大脑的多巴胺能张力的药物疗法)。因此，在那里 对于i)对特定动机行为的严格的实验神经科学研究是重要的需求 电路--当损坏时--在msTBI中造成冷漠，以及ii)开发针对电路的方法 调节麻木患者的动机回路，不依赖于高水平的认知功能。在这 项目中，PI将使用基于任务的功能磁共振成像(FMRI)来确定是否冷漠 在msTBI中，与功能神经回路的损害有关，这些神经回路参与计算预期的 环境中刺激物的奖赏价值(即刺激物价值)，和/或对涉及的电路的损害 确定某一报酬是否值得付出获得它所需的努力(即，愿意投入努力)。 此外，PI将利用从此msTBI项目中获得的见解来确定任务fMRI- 引导重复经颅磁刺激(RTMS)是一种可行的电路特异性调制方法 价值和努力电路。通过建立fMRI引导的rTMS对选择性接合价值的有效性 和努力计算电路，该项目将为未来R01项目的个性化精炼奠定基础 RTMS治疗失去动力的神经科和精神科患者的方法。 PI的目标是建立一个世界级的人类神经科学实验室，开发创新的方法 通过独立的行为表征和刺激异常动机行为的神经回路 R01基金。目前被指导的PI项目为PI提供了一个理想的机会来启动这一点 研究计划。资深导师梅耶尔博士和皮里奥·理查森博士在美国国立卫生研究院有良好的履历。 资金和丰富的使用功能磁共振成像来阐明脑外伤引起的功能缺陷的经验(迈耶博士)和 使用rTMS作为神经科患者的治疗方法(Pirio Richardson博士)。此外，两位领先的科学家 (侯赛因博士、克劳斯博士和科斯塔博士)，他们对大脑的神经计算基础进行了最先进的研究 动机行为及其病理已经承诺就拟议的项目进行咨询。因此， 指导团队将非常适合指导PI领导此项目，并将促进他过渡到 成为R01资助的独立调查员。

PROJECT SUMMARY The overarching goals of the current CoBRE mentored PI project are to better understand, and precisely modulate, the neurocomputational mechanisms underlying apathy in patients with chronic moderate-to-severe traumatic brain injury (msTBI). Previous studies have established that apathy–characterized by a loss of motivation–is a common and debilitating symptom of msTBI, but the underlying neural pathologies causing apathy in msTBI remain unknown. Clinically, existing treatments for apathy in msTBI have limited efficacy, either due to their reliance on high-level cognitive abilities that are often impaired in msTBI (e.g. cognitive behavioral therapy), or their potential to induce unwanted and deleterious side effects due to a lack of circuit- specificity (e.g. pharmacotherapies that modulate dopaminergic tone throughout the brain). Therefore, there are significant needs for i) rigorous experimental neuroscience studies on the specific motivated behavior circuits that–when damaged–cause apathy in msTBI, and ii) the development of circuit-specific approaches for modulating motivation circuits in apathetic patients, not reliant on high-level cognitive functioning. In this project, the PI will use task-based functional magnetic resonance imaging (fMRI) to determine whether apathy in msTBI is associated with damage to the functional neural circuits involved in computing the anticipated reward value of stimuli in the environment (i.e., stimulus valuation), and/or damage to the circuits involved in determining whether a given reward is worth the effort required to obtain it (i.e., willingness-to-engage effort). Additionally, the PI will leverage the insights derived from this msTBI project to determine whether task fMRI- guided repetitive transcranial magnetic stimulation (rTMS) is a viable approach for circuit-specific modulation of value and effort circuits. By establishing the effectiveness of fMRI-guided rTMS for selectively engaging value and effort computation circuits, this project will form the bedrock for future R01 projects refining personalized rTMS approaches for treating neurological and psychiatric patients experiencing a loss of motivation. The PI’s goal is to build a world-class human neuroscience laboratory that develops innovative methods for characterizing and stimulating the neural circuits underlying aberrant motivated behavior through independent R01 funding. The current mentored PI project provides an ideal opportunity for the PI to jump-start this research program. The senior mentors Drs. Mayer and Pirio Richardson have proven track records with NIH funding and extensive experience using fMRI to elucidate the functional deficits caused by TBI (Dr. Mayer) and using rTMS as a treatment for neurological patients (Dr. Pirio Richardson). Additionally, two leading scientists (Drs. Husain, Claus, and Costa) who conduct state-of-the-art research on the neurocomputational bases of motivated behavior and its pathologies have committed to consult on the proposed project. Therefore, the mentoring team will be well-suited to guide the PI as he leads this project, and will facilitate his transition to becoming an independent R01-funded investigator.