Completing the Pain Circuit: Recent Advances in Imaging Pain and Inflammation beyond the Central Nervous System

摘要

This review describes some of the recent developments in imaging aspects of pain in the periphery. It is now possible to image nerves in the cornea non-invasively, to image receptor level expression and inflammatory processes in injured tissue, to image nerves and alterations in nerve properties, to image astrocyte and glial roles in neuroinflammatory processes, and to image pain conduction functionally in the trigeminal ganglion. These advances will ultimately allow us to describe the pain pathway, from injury site to behavioral consequence, in a quantitative manner. Such a development could lead to diagnostics determining the source of pain (peripheral or central), objective monitoring of treatment progression, and, hopefully, objective biomarkers of pain.Keywords: Astrocytes, inflammation, microglia, MRI, pain, PETINTRODUCTIONEarly work in the fields of neuroanatomy, neurophysiology, and clinical observations has provided a robust description of pain pathways. These pathways can now be evaluated with imaging to contribute to a more objective view of pain, where both the sensory and emotional experience may be assessed in health and disease. This review describes some recent advances in imaging of pain and inflammation-related processes below the level of the brain, that is, at the level of 1) the periphery; 2) the nerve; and 3) the nerve root. We discuss methods to measure neuroinflammation and future lines of inquiry linking peripheral markers to spine, brainstem, and brain functional imaging. An ultimate goal is a more mechanistic definition than the one currently offered by the International Association for the Study of Pain: “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”1IMAGING PERIPHERAL NEUROPATHY AND INFLAMMATIONIdentifying active inflammatory pathology may be critical for adequate treatment. Further, precise measurement of inflammation may allow assessment of disease activity and assess the effect of therapeutic measures. Structural imaging methods such as computerized tomography (CT), magnetic resonance imaging (MRI), and ultrasound may detect large anatomical lesions and subtle swelling, but differentiating active disease from anatomical changes in healed tissue and/or normal variations is difficult. Two non-invasive imaging techniques, corneal confocal microscopy (CCM) and positron emission tomography (PET), may, however, provide insights into peripheral nerve function.Corneal Confocal MicroscopyThe cornea is a window into free nerve fiber endings.2 Burning neuropathic pain and small fiber sensory loss involving the limbs, trunk, and face is characterized by abnormal skin biopsies as non-length-dependent small fiber neuropathy. A novel non-invasive technique to quantify small fiber pathology is corneal confocal microscopy (CCM). As the cornea contains C and A delta sensory fibers arising from branches of the trigeminal nerve, it offers a window for evaluating neuropathy in diabetic peripheral neuropathy,3 Crohn’s disease,4 Sj?gren’s syndrome,4 idiopathic neuropathy,4 and Fabry’s disease.5 Future studies relating CCM findings to individual variations in pain and disability and central nervous system (CNS) function are warranted.Peripheral Positron Emission TomographyAlthough it is not currently possible to image nociceptors in vivo with PET ligands directly, the technique may still inform us on the functional state of the inflammatory milieu and levels of receptor expression/occupancy. Due to changes in blood flow, vascular permeability, metabolism, white blood cell influx, and changes in the local chemical environment, many PET ligands accumulate at sites of peripheral inflammation.Infection and inflammation may be visualized by scintigraphy and 67Gallium citrate, or autologous leukocytes labeled with indium-111 or technetium-99m.6 By far the most commonly used PET ligands 18F-fluorodeoxyglucose (FDG), thanks to its availa