Limbic Connectivity Underlies Pain Treatment Response in Small‐Fiber Neuropathy

Objective Small‐fiber neuropathy (SFN) is characterized by neuropathic pain due to degeneration of small‐diameter nerves in the skin. Given that brain reorganization occurs following chronic neuropathic pain, this study investigated the structural and functional basis of pain‐related brain changes after skin nerve degeneration. Methods Diffusion‐weighted and resting‐state functional MRI data were acquired from 53 pathologically confirmed SFN patients, and the structural and functional connectivity of the pain‐related network was assessed using network‐based statistic (NBS) analysis. Results Compared with age‐ and sex‐matched controls, the SFN patients exhibited a robust and global reduction of functional connectivity, mainly across the limbic and somatosensory systems. Furthermore, lower functional connectivity was associated with skin nerve degeneration measured by reduced intraepidermal nerve fiber density and better therapeutic response to anti‐neuralgia medications, particularly for the connectivity between the insula and the limbic areas including the anterior and middle cingulate cortices. Similar to the patterns of functional connectivity changes, the structural connectivity was robustly reduced among the limbic and somatosensory areas, and the cognition‐integration areas including the inferior parietal lobule. There was shared reduction of structural and functional connectivity among the limbic, somatosensory, striatal, and cognition‐integration systems: (1) between the middle cingulate cortex and inferior parietal lobule and (2) between the thalamus and putamen. These observations indicate the structural basis underlying altered functional connectivity in SFN. Interpretation Our findings provide imaging evidence linking structural and functional brain dysconnectivity to sensory deafferentation caused by peripheral nerve degeneration and therapeutic responses for neuropathic pain in SFN. ANN NEUROL 2023;93:655–667