Structural and Molecular Neuroplasticity in Chronic Trigeminal Pain

描述（由申请人提供）：项目总结：Alex DaSilva博士在哈佛大学获得口腔生物学医学博士学位，并接受了三叉神经疼痛的临床培训，随后在马萨诸塞州总医院的Martinos生物医学成像中心获得了偏头痛神经成像的博士后学位。他目前拥有磁共振成像（MRI）方法（例如fMRI，DTI）及其在疼痛研究中的应用的背景。这个K23项目的主要目标是为DaSilva博士提供分子神经成像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，以及与之相关的异常性疼痛机制。事实上，许多治疗方法不能缓解这些治疗抵抗性患者，这增加了这些使人衰弱的疾病的慢性化的原因可能在于大脑本身的可能性，并且可能在特定皮质和皮质下区域（例如SI，导水管周围灰质）和调节机制（例如阿片样物质能机制）的功能障碍中。最近使用选择性μ阿片受体（莫尔）放射性示踪剂的PET研究显示，根据研究的疾病（例如纤维肌痛），莫尔结合电位（BP）降低的模式不同。这些发现代表内源性配体对莫尔的更高占据或阿片受体的丧失。有趣的是，我们最后的结果表明，难治性疼痛的这种分子变化平行皮质厚度和弥散变化的区域相关的疼痛感知和调制在发作性偏头痛患者。因此，我们将通过以下目的来检验偏头痛是由皮层多个水平的适应不良变化所维持的假设：1）研究与健康对照相比，慢性三叉神经痛患者的MOR-BP变化; 2）证明偏头痛患者头痛发作的频率和皮肤异常性疼痛的严重程度与MORBP相关。研究偏头痛患者PAG中MORBP水平是否与疼痛感知和调制相关的皮质区灰质厚度变化相关。相关性：作为一个职业目标，这个多学科的培训项目将有助于建立我的研究作为一个独立的科学家应用PET和MRI为基础的神经成像在偏头痛的细胞和分子神经可塑性相关机制的研究，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了解，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.