Research 1-Hogeveen

项目摘要 当前的CoBRE指导PI项目的首要目标是更好地理解， 调节慢性中重度抑郁症患者冷漠的神经计算机制 创伤性脑损伤（msTBI）。以前的研究已经确定，冷漠的特点是失去了 动机-是msTBI的常见和衰弱症状，但引起的潜在神经病理学 msTBI中的冷漠仍是未知的。临床上，msTBI中冷漠的现有治疗方法疗效有限， 或者是由于他们依赖于在msTBI中经常受损的高水平认知能力（例如认知能力）， 行为疗法），或由于缺乏回路，它们可能引起不想要的和有害的副作用， 特异性（例如，调节整个大脑多巴胺能张力的药物疗法）。因此 i）对特定动机行为进行严格的实验性神经科学研究 电路，当损坏时，导致msTBI冷漠，和ii）电路特定方法的发展， 调节冷漠患者的动机回路，而不依赖于高水平的认知功能。在这 项目，PI将使用基于任务的功能磁共振成像（fMRI），以确定是否冷漠 在msTBI中，与参与计算预期脑损伤的功能性神经回路的损伤有关。 环境中刺激的奖励值（即，刺激评估），和/或对参与的电路的损害 确定给定奖励是否值得获得它所需的努力（即，（willingness to engage effort） 此外，PI将利用从该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）是一种可行的方法，用于电路特定的调制， 价值和努力回路。通过建立fMRI引导的rTMS选择性参与价值的有效性， 和努力计算电路，这个项目将形成未来R 01项目完善个性化的基石 rTMS方法用于治疗神经和精神病患者失去动力。 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， 表征和刺激神经回路潜在的异常动机行为，通过独立的 R 01融资目前的指导PI项目为PI提供了一个理想的机会， 研究计划。Mayer博士和Pirio Richardson博士在NIH有良好的记录 基金和丰富的经验，使用功能磁共振成像来阐明TBI引起的功能缺陷（迈耶博士）， 使用rTMS作为神经系统患者的治疗（Pirio Richardson博士）。此外，两位顶尖科学家 (Drs. Husain，Claus和Costa），他们对神经计算基础进行了最先进的研究， 动机行为及其病理学已承诺就拟议的项目进行咨询。因此 指导团队将非常适合在PI领导该项目时指导PI，并将促进其过渡到 成为R 01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.