Brain imaging signature of neuropathic pain phenotypes in small-fiber neuropathy: altered thalamic connectome and its associations with skin nerve degeneration

Abstract Small-fiber neuropathy (SFN) has been traditionally considered as a pure disorder of the peripheral nervous system, characterized by neuropathic pain and degeneration of small-diameter nerve fibers in the skin. Previous functional magnetic resonance imaging studies revealed abnormal activations of pain networks, but the structural basis underlying such maladaptive functional alterations remains elusive. We applied diffusion tensor imaging to explore the influences of SFN on brain microstructures. Forty-one patients with pathology-proven SFN with reduced skin innervation were recruited. White matter connectivity with the thalamus as the seed was assessed using probabilistic tractography of diffusion tensor imaging. Patients with SFN had reduced thalamic connectivity with the insular cortex and the sensorimotor areas, including the postcentral and precentral gyri. Furthermore, the degree of skin nerve degeneration, measured by intraepidermal nerve fiber density, was associated with the reduction of connectivity between the thalamus and pain-related areas according to different neuropathic pain phenotypes, specifically, the frontal, cingulate, motor, and limbic areas for burning, electrical shocks, tingling, mechanical allodynia, and numbness. Despite altered white matter connectivity, there was no change in white matter integrity assessed with fractional anisotropy. Our findings indicate that alterations in structural connectivity may serve as a biomarker of maladaptive brain plasticity that contributes to neuropathic pain after peripheral nerve degeneration.