The role of neuroinflammation in human peripheral neuropathic pain

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In this proposal, we will investigate the role of neuroinflammation in neuropathic pain by evaluating patients suffering from a common entrapment neuropathy, carpal tunnel syndrome (CTS). We will clinically evaluate and then scan a total of 100 participants: 80 patients suffering from CTS and 20 healthy volunteers. All participants will be evaluated clinically, and receive brain and spinal cord imaging with integrated Positron Emission Tomography / Magnetic Resonance (PET/MR) imaging and [11C]PBR28, a second-generation radioligand for the 18 kDa translocator protein (TSPO), which we have previously used to demonstrate glial activation in chronic pain patients and neurodegenerative disorders. Patients will be re-scanned and evaluated clinically a second time, after carpal tunnel release surgery. The first Aim is to investigate the presence of neuroinflammation in CTS patients. We hypothesize that, compared to healthy adults, CTS patients will demonstrate higher [11C]PBR28 PET signal in the brain (thalamus and the hand representation of the primary somatosensory cortex, S1) and in the lower cervical spinal cord (corresponding to the territory of innervation of the median nerve in dermatomes C6-C7). We further hypothesize that higher brain/cord [11C]PBR28 PET signal will be associated with higher clinical pain, increased median nerve conduction latency, more severe functional deficits (i.e., worse finger agnosia and fine motor performance) and more severe neuroplastic changes (i.e., a smaller separation between S1 cortical representations for digits 2 and 3). The second Aim is to assess the effect of surgery on neuroinflammation and neuroplastic alterations in CTS patients. We hypothesize that 3 months after surgery, CTS patients will, on average, demonstrate reduced brain/cord [11C]PBR28 PET signal and increased D2/D3 S1 separation, compared to before the surgery. We also hypothesize that these brain changes will be correlated with each other, and with the reduction in pain and functional deficits. The final Aim is to evaluate neuroinflammation and neuroplastic alterations as predictors of response to surgery. We hypothesize that higher pre-surgical brain/cord [11C]PBR28 PET signal and reduced D2/D3 S1 separation will predict poorer response to surgery. While this project is purposely focused on neuropathic pain due to nerve compression at the wrist, identifying the role of brain and spinal cord 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 providing rationale for the development of tailored interventions focused on glial modulation.