Investigation and Modulation of the Mu-Opioid Mechanism in Chronic TMD (in vivo)

 描述（由申请人提供）大约10%的TMD患者的症状不会得到改善，大约75%的保守治疗无效的患者也不适合进行TM关节手术。我们国家卫生研究院的初步研究 NIDCR R56项目使用正电子发射断层扫描（PET）和[11 C]卡芬太尼（μ-阿片受体（μOR）的选择性放射性示踪剂），证明与健康对照组相比，在咬肌疼痛期间，TMD患者大脑中的丘脑μOR可用性（不可替代的结合电位BPND）降低。μ-阿片类神经传递可以说是疼痛调节和体验中最主要的机制之一。此外，丘脑是前脑中（非）伤害性输入的主要中继结构，这些输入随后将分布到多个皮层区域，用于辨别、认知和 情感加工基于MRI的报告发现，这些发现与三叉神经疼痛患者的神经可塑性变化共同定位。传统疗法无法选择性地靶向丘脑和相关区域，并且当可用药物失败时，如何逆转神经可塑性分子机制的数据很少。有趣的是，几项关于运动皮层刺激（MCS）的研究表明，初级运动皮层（M1）中的硬膜外电极可有效地为中枢性疼痛患者提供镇痛，并且通过间接调节丘脑活动进行镇痛。显然，苏查手术的侵入性限制了其对高度严重疼痛疾病的适应症。针对M1的新的非侵入性神经调节方法，如经颅直流电刺激（tDCS），现在可以安全地调节µOR系统，为疼痛患者提供相对持久的疼痛缓解。最近，我们小组创建的一种新的高清tDCS（HD-tDCS）蒙太奇能够完全减少“对侧”感觉辨别性临床疼痛测量（强度/面积）， TMD患者通过精确定位M1区域。因此，我们研究的主要目标是：首先，与健康对照相比，利用TMD患者体内的μ-阿片样物质功能障碍;其次，确定10次每日非侵入性和精确的M1 HD-tDCS是否对TMD患者的临床和实验疼痛测量具有调节作用;第三，研究重复性活动M1 HD-tDCS是否诱导/逆转丘脑和其他疼痛相关区域的μOR BPND变化，以及这些变化是否与TMD疼痛测量相关。上述研究代表了TMD研究范式的变化，因为我们直接研究和调节大脑中最重要的内源性镇痛机制之一。

 DESCRIPTION (provided by applicant) Approximately 10% of TMD patients will not experience an improvement of their symptoms and around 75% of patients who fail to respond to conservative treatments are also not suitable for TM joint surgery. Initial studies from our NIH NIDCR R56 project using positron emission tomography (PET) with [11C] Carfentanil, a selective radiotracer for μ-opioid receptor (μOR), have demonstrated that there is a decrease in thalamic µOR availability (non-displaceable binding potential BPND) in the brains of TMD patients during masseteric pain compared to healthy controls. μ-opioid neurotransmission is arguably one of the mechanisms most centrally involved in pain regulation and experience. Moreover, the thalamus is the major relay structure in the forebrain for (non)-noxious inputs, which will be distributed subsequently to multiple cortical areas for discriminative, cognitive and affective processing. MRI-based reports have found that those findings co-localize with neuroplastic changes in trigeminal pain patients. Conventional therapies are unable to selectively target the thalamus and associated regions, and there is a paucity of data on how to reverse neuroplastic molecular mechanisms when available medications fail. Interestingly, several studies with motor cortex stimulation (MCS) have shown that epidural electrodes in the primary motor cortex (M1) are effective in providing analgesia in patients with central pain, and that it occurs via indirect modulation of thalamic activity. Evidently, the invasive nature of sucha procedure limits its indication to highly severe pain disorders. New non-invasive neuromodulatory methods for M1, such as transcranial direct current stimulation (tDCS), can now safely modulate the µOR system, providing relatively lasting pain relief in pain patients. Recently, a novel high-definition tDCS (HD-tDCS) montage created by our group was able to reduce exclusively "contralateral" sensory- discrimative clinical pain measures (intensity/area) in TMD patients by targeting precisely the M1 region. Therefore, the main goals of our study are: First, to exploit the μ-opioidergic dysfunction in vivo in TMD patients compared to healthy controls; Second, to determine whether 10 daily sessions of non- invasive and precise M1 HD-tDCS have a modulatory effect on clinical and experimental pain measures in TMD patients; and Third, to investigate whether repetitive active M1 HD-tDCS induces/reverts μOR BPND changes in the thalamus and other pain-related regions, and whether those changes are correlated with TMD pain measures. The studies above represent a change in paradigm in TMD research, as we directly investigate and modulate in vivo one of the most important endogenous analgesic mechanisms in the brain.