Investigation and Modulation of the Mu-opioid Mechanisms in TMD (in Vivo)

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 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 such a 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 this research 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 this 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 noninvasive 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 this research group directly investigates and modulates in vivo one of the most important endogenous analgesic mechanisms in the brain.

The IRB approved study protocol also includes secondary data sets to be used for analysis in study objective #6 only. The data sets are not part of the clinical trial as they were collected during a previous study (NIDCR-R56-DE022637 project [IRBMED #HUM00080911; Dr. Alexandre DaSilva, Principal Investigator]). Participants in HUM00080911 (both Healthy and TMD patients) received no intervention, but underwent the same Baseline, MRI and PET protocol. This secondary data will not be represented in the Adverse Event or final enrollment total for this clinical trial. However, the data will be analyzed in a meta-analysis addressing secondary objective #6 only. These data sets will not be used to analyze any primary study objectives, nor change the terms of the clinical trial. Manuscripts that include these secondary data sets will clearly indicate the use of this data and clarify that the data was collected separate from the clinical trial data.