Structural and Molecular Neuroplasticity in Chronic Trigeminal Pain

描述(申请人提供)：项目摘要：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三叉神经疼痛临床培训，之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成像博士后学位。他目前在磁共振成像(MRI)方法(如功能磁共振成像、DTI)及其在疼痛研究中的应用方面拥有背景。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，这项技术仅在选定的机构提供，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，以及与之相关的痛觉异常机制。许多治疗方法都不能缓解这些耐药患者的事实，这增加了这样一种可能性，即这些衰弱疾病的慢性化可能存在于大脑本身，也可能存在于特定皮质和皮质下区域的功能障碍(例如，SI，中脑导水管周围灰质)和调节机制(例如，阿片能机制)。最近使用选择性mU-阿片受体(MOR)放射性示踪剂进行的PET研究显示，根据所研究的疾病(如纤维肌痛)，MOR结合电位(BP)降低的模式不同。这些发现要么表明内源性配体对MOR的占有率更高，要么表明阿片受体丢失。有趣的是，我们的最新结果表明，在发作性偏头痛患者中，这种顽固性疼痛的分子变化与与疼痛感知和调制相关的区域的皮质厚度和弥漫性变化平行。因此，我们将通过追求以下目标来检验偏头痛持续存在的假设：1)与健康对照组相比，慢性三叉神经痛患者的MOR-BP变化；2)证明偏头痛发作的频率和皮肤异位痛的严重程度与MORBP相关。3)探讨偏头痛患者PAG中MORBP水平是否与与疼痛感知和调制相关的皮质区域灰质厚度的变化有关。相关性：作为一个职业目标，这个多学科培训项目将有助于建立我作为一名独立科学家的研究，将基于PET和MRI的神经成像应用于偏头痛以及皮肤异常痛症的细胞和分子神经可塑性机制的研究。这个项目有望扩大我们对皮质偏头痛病理生理学的了解，并可能在大脑中建立新的治疗靶点。

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.