Painful trigeminal neuropathy (PTN) is defined as facial pain in the distribution(s) of one or more branches of the trigeminal nerve, associated with neural damage induced by trauma, viral infection, or other causes. PTN is very unresponsive to medical and surgical treatments. Clearly, a more in-depth knowledge of the molecular pathomechanisms of PTN are in urgent need to improve the management of this disorder. In the last six years our group has demonstrated the presence of increased levels of the 18kDa translocator protein (TSPO, using positron emission tomography) and/or myo-inositol (mIns, using magnetic resonance spectroscopy), in the brains of patients with various chronic pain conditions. Because both TSPO and mIns are overexpressed by glial cells, our results suggest that neuroinflammation might be a pervasive phenomenon that can be observed across multiple, etiologically heterogeneous human pain disorders, but in a disorder-specific spatial distribution within the central nervous system. Despite these advances, the clinical significance of these brain inflammatory signals (e.g., whether neuroinflammation imaging could be used to identify patients more likely to respond to anti-inflammatory therapies) remains to be evaluated. In this exploratory project, we will recruit PTN patients scheduled to receive oral steroid therapy. All participants will be evaluated clinically by an experienced neurologist and, prior to commencing their treatment, receive brain imaging with integrated (i.e., simultaneous) positron emission tomography / magnetic resonance imaging (PET/MRI) and [11C]PBR28, a second-generation radioligand for TSPO, which we have used to demonstrate glial activation in patients with pain or neurodegenerative disorders. After the scan, participants will undergo a 3-week treatment with the steroid prednisone, followed by another clinical/behavioral visit. Clinical characterization will include quantitative sensory testing and questionnaires. Patients’ imaging data will be compared to an existing dataset of healthy controls and chronic pain patients with a different etiology (chronic low back pain) to assess the specificity of our findings to PTN. For Aim 1, we will assess in-vivo neuroinflammation in painful trigeminal neuropathy, using multimodal brain imaging. For Aim 2 we will test the brain neuroinflammatory signals’ ability to predict response to steroid treatment. This work will advance our understanding of the clinical significance of neuroinflammation in chronic pain conditions. While this project is focused on neuropathic pain, identifying the role of glia in the development and maintenance of persistent neuropathic pain and pain-related disability in humans will have important practical implications for the management of a wide range of pain disorders. For instance, it will provide crucial human evidence contributing to rationale for the development of tailored interventions focused on glial modulation.