Reinforcement Learning Neuropathologies Underlying Psychiatric Sequelae in Traumatic Brain Injury

霍格文研究项目项目总结 目前Cobre指导的PI项目的首要目标是更好地了解并精确调节慢性中重度创伤性脑损伤(MsTBI)患者冷漠背后的神经计算机制。先前的研究已经证实，冷漠--以动力丧失为特征--是msTbi的一种常见且令人衰弱的症状，但导致msTBI冷漠的潜在神经病理仍不清楚。在临床上，现有的治疗msTbi冷漠的方法疗效有限，要么是因为它们依赖于经常在msTBI中受损的高水平认知能力(例如认知行为疗法)，要么是由于缺乏电路特异性而可能导致有害的副作用(例如调节整个大脑的多巴胺能张力的药物疗法)。因此，有必要对特定的动机行为回路进行严格的实验神经科学研究，这些回路在受损时会导致msTBI患者的冷漠，以及ii)开发电路特有的方法来调节冷漠患者的动机回路，而不是依赖于高级认知功能。在这个项目中，PI将使用基于任务的功能磁共振成像(FMRI)来确定msTBI中的冷漠是否与涉及计算环境中刺激的预期奖赏价值的功能神经回路的损害(即刺激估值)有关，和/或涉及确定给定的奖赏是否值得获得它所需的努力(即参与努力的意愿)的回路受损。此外，PI将利用来自此msTBI项目的洞察力来确定任务功能磁共振引导的重复经颅磁刺激(RTMS)是否是对价值和努力电路进行特定电路调制的可行方法。通过建立fMRI引导的rTMS选择性参与价值和努力计算电路的有效性，该项目将为未来的R01项目奠定基础，精炼个性化的rTMS方法，用于治疗经历动力丧失的神经科和精神科患者。 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R01资助来表征和刺激异常动机行为背后的神经回路。目前的指导PI项目为PI启动这一研究计划提供了一个理想的机会。资深导师Mayer博士和Pierio Richardson博士拥有美国国立卫生研究院资助的TRACH记录和丰富的经验，他们使用功能磁共振来阐明脑外伤(Mayer博士)造成的功能缺陷，并将rTMS用于治疗神经科患者(Pirio Richardson博士)。此外，两位顶尖科学家(侯赛因博士、克劳斯博士和科斯塔博士)对动机行为的神经计算基础及其病理学进行了最先进的研究，他们已承诺为拟议的项目提供咨询。因此，咨询委员会将非常适合指导PI领导这一项目，并将促进他过渡到R01资助的独立调查员。

Project Summary for Hogeveen Research Project 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 Pierio Richardson have proven trach 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 advisory committee 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.