Brain as a Research and Therapeutic Target in Chronic TMD

描述(由申请人提供)：慢性颞下颌关节紊乱病(TMD)代表临床问题，其中经验性治疗为大量患者提供不确定的缓解。许多传统疗法是无效的，导致持续的治疗失败和/或医源性不良的结果；这增加了疼痛耐受性的可能性也在于大脑环境。尽管基于MRI的技术已经为人类TMD的一些神经再生机制提供了深入的见解，但关于其在体内的分子机制的许多问题仍然没有答案。首先，大脑中已知参与疼痛调节的内源性阿片机制如何受到急性和慢性TMD疼痛的影响？第二，如何直接调节它们以在疼痛措施中提供止痛效果？最后，在这些分子机制的持续调节后，大脑中的神经再生效应是什么？对这些过程的理解对于确定TMD的持久性以及最重要的是缓解TMD的机制至关重要。本中心的初步研究表明，慢性三叉神经痛患者大脑中与疼痛相关的关键结构的非置换结合势(BPND)减少，这与他们的临床疼痛措施有关。有趣的是，一种非侵入性的神经调节工具，即经颅直流电刺激(TDC)，可以通过改变关键结构的活动，包括激活内源性阿片类神经传递，对急性和慢性面部疼痛措施提供后效调制结果。这项拟议的研究采用了一个三步过程：首先，我们将确定在急性(实验)和慢性(临床)TMD疼痛状态下调节个体经验的Mu阿片类药物机制；其次，我们将研究在初级运动皮质(M1)上重复进行10次活跃的和安慰剂tDCS会话对急性和慢性TMD疼痛措施的调制作用；第三，我们将研究重复的M1-tDCS是否诱导或逆转丘脑和其他疼痛相关结构的Mu-ORBPND变化，以及这些变化是否与调节急性和慢性TMD疼痛措施有关。这代表着范式的改变，因为我们建议通过应用新的分子神经成像和神经调节方案来直接针对正在研究的相同的神经再生机制，远远超出传统的翻译模型。

DESCRIPTION (provided by applicant): Chronic temporomandibular joint disorders (TMD) represent clinical problems in which empirical treatments offer uncertain relief for a large number of patients. Many conventional therapies are ineffectual, leading to persistent treatment failure and/or poor iatrogenic-induced results; which raises the possibility that the cause for ther pain endurance may also lie in the brain milieu. Although MRI-based techniques have provided insights into some neuroplastic mechanisms of TMD in humans, many questions regarding its molecular mechanisms in vivo are still unanswered. First, how are endogenous mu-opioid mechanisms in the brain, known to be centrally involved in pain regulation, affected by acute and chronic TMD pain? Second, how can they be directly modulated to provide analgesic effect on pain measures? Finally, what are the neuroplastic effects in the brain after continuous modulation of those molecular mechanisms? The understanding of these processes is crucial to determine the mechanisms engaged in the persistence and, most important, the alleviation of TMD. Preliminary studies from our center, using positron emission tomography (PET) with [11C] carfentanil, a selective radiotracer for mu-opioid receptor (mu-OR), have demonstrated that there is a decrease in mu-OR availability (non-displaceable binding potential -BPND) in key pain-related structures in the brains of chronic trigeminal pain patients, which correlated with their clinical pain measures. Interestingly, a non-invasive and neuromodulatory tool, namely transcranial direct current stimulation (tDCS), can provide after-effect modulatory results on acute and chronic facial pain measures by changing activity of those key structures, including the activation of the endogenous mu-opioid neurotransmission. This proposed research utilizes a 3-step process: First, we will determine mu-opioid mechanisms mediating individual experiences in acute (experimental) and chronic (clinical) TMD pain states; Second, we will investigate the modulatory effect of 10 repetitive active and placebo tDCS sessions over the primary motor cortex (M1) on acute and chronic TMD pain measures; and Third, we will study whether repetitive M1-tDCS induces or reverts mu-ORBPND changes in the thalamus, and other pain-related structures, and if those changes are associated with modulation on acute and chronic TMD pain measures. This represents a change of paradigm, as we propose to directly target the same neuroplastic mechanisms under study by applying novel molecular neuroimaging and neuromodulatory protocols, reaching far beyond the traditional translational model.