Modulating Cortical and Sub-cortical Brain Circuits in Chronic Facial Pain

描述（由申请人提供）：调节慢性面部疼痛的皮质和皮质下脑回路慢性疼痛，特别是面部疼痛是难以治疗的，因为它与神经系统改变的巨大多样性有关。使用动物模型在分子水平上对这些变化进行表征，已经产生了在很大程度上尚未转化为人类的见解，这可能是因为这些变化的分子复杂性确保了在物种之间进行比较时存在显着差异。另一方面，在神经回路水平上，有可能定义与疼痛状态相关的内表型，其可以更好地跨物种（和跨患者）概括，因为它们是许多不同上游分子变化的收敛下游，并且可以因果地与疼痛状态相关联或预测疼痛状态。因此，我们建议研究大鼠模型的疼痛，光学沉默，在时间上精确的方式，候选人的大脑区域的疼痛电路使用新的方法，我们已经开发，并评估疼痛行为的影响，以及疼痛电路使用功能性磁共振成像（fMRI）。通过这种方式，我们将解析出神经回路对疼痛内表型的全脑贡献。通过将我们的研究扩展到疼痛行为之外，我们将更好地了解慢性疼痛的整体行为效应以及特定CNS区域在调节这些行为效应中的作用，并希望更好地模拟人类慢性疼痛。 公共卫生相关性：确定定义慢性面部疼痛状态的神经基质是开发从基础研究推广到人类以及推广到人类患者的治疗方法的关键一步。通过超越分子变化的组合复杂性，了解疼痛如何在大脑中表现，如光学神经控制和功能性脑成像所描述的，我们将开发新的疼痛生物标志物，准确反映疼痛状态，从而推进治疗，诊断和药物发现的状态。

DESCRIPTION (provided by applicant): Modulating Cortical and Sub-cortical Brain Circuits in Chronic Facial Pain Chronic pain, especially facial pain is difficult to treat because it is associated with an enormous diversity of nervous system alterations. Characterizations of these changes at the molecular level, using animal models, have yielded insights that largely have not translated to the human, perhaps because the molecular complexity of the changes insures that significant differences will exist when comparing across species. At a neural circuit level, on the other hand, it may be possible to define endophenotypes that correlate with pain state, that may better generalize across species (and across patients) because they are convergently downstream of many different upstream molecular changes, and may causally be associatable with, or predict, pain state. Accordingly, we propose to study rat models of pain by optically silencing, in a temporally-precise manner, candidate brain regions in the pain circuit using novel methods we have developed, and assessing the impact on pain behavior, as well as on the pain circuit using functional magnetic resonance imaging (fMRI). In this way we will parse out the brainwide contribution of a neural circuit to pain endophenotype. By expanding our investigation beyond pain behaviors we will better understand the global behavioral effects of chronic pain and the role(s) of specific CNS regions in modulating these behavioral effects, and hopefully better model chronic pain in humans. PUBLIC HEALTH RELEVANCE: Determining the neural substrates that define the chronic facial pain state is a key step in developing treatments that generalize from basic research to humans, and also that generalize across human patients. By moving beyond the combinatorial complexity of molecular changes, to the understanding of how pain is represented in the brain, as described by optical neural control and functional brain imaging, we will develop new biomarkers for pain that accurately reflect the pain state, thus advancing the state of therapy, diagnosis, and drug discovery.