Brain as a Research and Therapeutic Target in Chronic TMD

描述（由申请人提供）：慢性颞下颌关节疾病（TMD）是一种临床问题，经验性治疗对大量患者的缓解效果不确定。许多传统疗法无效，导致持续治疗失败和/或不良的医源性结果；这就提出了一种可能性，即他们忍受疼痛的原因也可能与大脑环境有关。尽管基于mri的技术已经为人类TMD的神经可塑性机制提供了一些见解，但关于其体内分子机制的许多问题仍未得到解答。首先，已知在疼痛调节中起核心作用的大脑内源性mu-阿片机制如何受到急性和慢性TMD疼痛的影响？其次，如何直接调节它们以对疼痛测量提供镇痛效果？最后，在连续调节这些分子机制后，大脑中的神经可塑性效应是什么？了解这些过程对于确定持续存在的机制至关重要，最重要的是减轻TMD。我们中心使用正电子发射断层扫描（PET）和[11C]卡芬太尼（一种选择性的阿片受体（mu-OR）放射性示踪剂）进行的初步研究表明，慢性三叉神经痛患者大脑中关键疼痛相关结构的mu-OR可用性（非可置换结合电位-BPND）降低，这与他们的临床疼痛测量相关。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（tDCS），可以通过改变这些关键结构的活性，包括内源性mu-阿片类神经传递的激活，对急性和慢性面部疼痛措施提供后效调节结果。本研究采用三步流程：首先，我们将确定在急性（实验）和慢性（临床）TMD疼痛状态下，μ -阿片类药物介导个体体验的机制；其次，我们将研究10次重复活动和安慰剂tDCS对初级运动皮层（M1）对急性和慢性TMD疼痛测量的调节作用；第三，我们将研究重复性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急性和慢性TMD疼痛测量的调节有关。这代表了范式的变化，因为我们建议通过应用新的分子神经成像和神经调节协议直接针对正在研究的相同神经可塑性机制，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.