Structural and Molecular Neuroplasticity in Chronic Trigeminal Pain

项目概述：Alex DaSilva博士在哈佛大学获得口腔生物学医学博士学位，并接受了三叉神经痛临床培训，随后在马萨诸塞州总医院马蒂诺斯生物医学成像中心获得偏头痛神经影像学博士后学位。他目前拥有磁共振成像（MRI）方法（如fMRI， DTI）及其在疼痛研究中的应用的背景。K23项目的主要目标是为DaSilva博士提供分子神经影像学方面的高级指导和培训，该技术仅在选定的机构中提供，以建立坚实的独立科学和学术生涯。在这个项目中，我们将结合解剖MRI技术和正电子发射断层扫描（PET）来研究偏头痛的结构和分子皮质神经可塑性，以及与之相关的变动力机制。许多治疗方式不能缓解这些治疗抵抗性患者，这一事实提出了这样一种可能性，即这些衰弱性疾病的慢性原因可能在于大脑本身，也可能在于特定皮层和皮层下区域（如SI，导水管周围灰质）和调节机制（如阿片能机制）的功能障碍。最近使用选择性多阿片受体（MOR）放射性示踪剂的PET研究显示，根据所研究的疾病（如纤维肌痛），MOR结合电位（BP）降低的模式各不相同。这些发现表明内源性配体或阿片受体丧失对MOR的更高占据。有趣的是，我们最近的研究结果表明，这种难治性疼痛的分子变化与发作性偏头痛患者疼痛感知和调节相关区域的皮质厚度和弥漫性变化平行。因此，我们将通过以下目的来验证偏头痛是由多水平皮层的不良适应变化所持续的假设：1)研究慢性三叉神经痛患者与健康对照组的more - bp变化；2)研究偏头痛患者的头痛发作频率和皮肤异常性疼痛的严重程度是否与病态相关。3)探讨偏头痛患者PAG中MORBP水平是否与疼痛感知和调节相关皮质区灰质厚度变化有关。相关性：作为一个职业目标，这个多学科的培训项目将帮助我建立一个独立的科学家的研究，应用PET和mri为基础的神经成像在细胞和分子神经可塑性相关的机制研究偏头痛，以及皮肤异常性疼痛。该项目有望扩大我们对皮质偏头痛病理生理学的认识，并可能在大脑中找到新的治疗靶点。

DESCRIPTION (provided by applicant): PROJECT SUMMARY: Dr. Alex DaSilva has received his Doctor in Medical Science degree in Oral Biology with clinical training in Trigeminal Pain at Harvard University, which was followed by a post-doctoral on Migraine Neuroimaging at the Martinos Center for Biomedical Imaging, Massachusetts General Hospital. He currently has a background in magnetic resonance imaging (MRI) methods (e.g. fMRI, DTI), and their application in pain research. The main goal of this K23 project is to provide Dr. DaSilva advanced mentoring and training on molecular neuroimaging, technology only available in selected institutions, to establish a solid independent scientific and academic career. In this project, we will integrate anatomical MRI techniques with positron emission tomography (PET) for the study of structural and molecular cortical neuroplasticity in migraine, as well as the allodynic mechanisms associated with it. The fact that many therapeutic modalities do not provide relief for these treatment-resistant patients raises the possibility that the cause for the chronicity of these debilitating disorders may lie in the brain itself, and possibly in the dysfunction of specific cortical and subcortical areas (e.g. SI, periaqueductal gray matter) and modulatory mechanisms (e.g. opioidergic mechanisms). Recent studies with PET using a selective mu-opioid receptor (MOR) radiotracer, have shown varied pattern of reduced MOR binding potential (BP) depending on the disorders investigated (e.g. fibromyalgia). These findings represent either higher occupation of MOR by endogenous ligands or loss of opioid receptors. Interestingly, our last results suggest that such molecular changes in refractory pain parallel cortical thickness and diffusional changes in areas related to pain perception and modulation in episodic migraine patients. Therefore, we will test the hypothesis that migraine is sustained by mal-adaptive changes at multiple levels of the cortex by pursuing the following Aims: 1) To investigate MOR-BP changes in chronic trigeminal pain patients compared to healthy controls; 2) To demonstrate that frequency of the headache attacks and severity of cutaneous allodynia levels in migraineurs are correlated with MORBP.3) To investigate whether MORBP levels in the PAG of migraineurs are associated with changes in the gray matter thickness changes in cortical areas associated with pain perception and modulation. RELEVANCE: As a career goal, this multidisciplinary training project will help to establish my research as an independent scientist applying PET and MRI-based neuroimaging in the study of cellular and molecular neuroplastic- ssocited mechanisms in migraine, as well as cutaneous allodynia. This project is expected to expand our knowlegde on cortical migraine pathophysiology, and possibly novel therapeutic targets in the brain.