fMRI and DTI of Cerebellar Responses to Pain in the Human Trigeminal System

描述（由申请人提供）：此K01申请旨在为申请人准备必要的技能，以建立小脑疼痛相关处理的独立研究计划。尽管使用人类功能成像的疼痛研究一直发现小脑激活，但该结构在疼痛中的作用尚不清楚。在这些研究中，关于小脑在疼痛事件中的功能的推测通常受到小脑作为运动功能协调者的声誉的影响，尽管动物研究表明，小脑也可能调节有害刺激的神经编码。该候选人已发表的研究表明，在健康受试者和神经性疼痛患者中，小脑对实验性疼痛的反应方式存在功能二分法。这表明小脑作为一个潜在的疼痛处理区域被忽视了，对这一区域的研究可以为了解与疼痛及其调节有关的基本生理回路提供宝贵的见解。该项目的假设是，小脑作为厌恶刺激和适应性运动行为的整合者，并可能调节区分疼痛感知和无害感觉刺激欣赏的情绪和认知体验。实验将使用人类三叉神经疼痛模型，因为所有与疼痛相关的回路都可以与小脑同时成像。具体目的是：(1)利用功能性磁共振成像（fMRI）和弥散张量成像（DTI）绘制与有害刺激的感觉编码相关的小脑激活图，并将功能活动与解剖连接联系起来；(2)根据小脑反应和连通性区分疼痛和预期；(3)确定身体疼痛和厌恶的图像是否在小脑中有类似的回路。为了实现这些目标，候选人将需要扩展他在皮质和脑干疼痛处理的fMRI背景，以涵盖小脑生理学，精通DTI分析，并学习与小脑的白质连接。麦克莱恩医院和哈佛医学院系统的其他附属机构的研究环境将为候选人提供在4年内实现其目标的资源。加强对小脑疼痛处理的理解可能会导致慢性神经性疼痛的新治疗方法，这可能会改变小脑的功能。

DESCRIPTION (provided by applicant): This K01 application is designed to prepare the applicant with the skills necessary to establish an independent research program on pain-related processing in the cerebellum. Although pain studies using functional imaging in humans consistently find cerebellar activation, the role of this structure during pain is unknown. In such studies, speculation regarding the cerebellum's function during a painful event is often influenced by its reputation as a coordinator of motor function, though animal studies have indicated that it may also modulate the neural encoding of noxious stimuli. The candidate has published work that indicates a functional dichotomy in the way the cerebellum responds to experimental pain in healthy subjects and neuropathic pain patients. This suggests that the cerebellum has been overlooked as a potential pain processing area, and research into this area could lend invaluable insight into the basic physiological circuitry involved with pain and its modulation. The hypothesis of this project is that the cerebellum serves as an integrator of aversive stimuli and adaptive motor behavior, and may modulate the emotional and cognitive experience that distinguishes the perception of pain from the appreciation of innocuous sensory stimulation. A human trigeminal model of experimental pain will be used, as all the pain-related circuitry involved can be imaged along with the cerebellum at the same time. The specific aims are (1) to map cerebellar activations related to sensory coding of noxious stimuli and to correlate functional activity with anatomical connectivity using functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI); (2) to distinguish between pain and its anticipation based on cerebellar responses and connectivity; and (3) to determine whether physical pain and aversive images engage similar circuitry in the cerebellum. To accomplish these aims, the candidate will need to expand his background in fMRI of cortical and brainstem pain processing to encompass cerebellar physiology, become proficient in DTI analysis, and learn the white matter connectivity to and from the cerebellum. The research environment at McLean Hospital and the other affiliates of the Harvard Medical School system will provide the candidate with the resources to reach his aims within 4 years. Enhanced understanding of cerebellar pain processing may lead to new treatments for chronic neuropathic pain conditions, which can have altered cerebellar functionality.