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.

Impaired brain network architecture as neuroimaging evidence of pain in diabetic neuropathy.

AIMS: To investigate alterations in structural brain networks due to chronic diabetic neuropathic pain. METHODS: The current study recruited 24 patients with painful diabetic neuropathy (PDN) to investigate the influences of chronic pain on the brain. Thirteen patients with painless diabetic neuropathy (PLDN) and 24 healthy adults were recruited as disease and healthy controls. White matter connectivity of the brain networks constructed by diffusion tractography was compared across groups using the Network-based statistic (NBS) method. Graph theoretical analysis was further applied to assess topological changes of the brain networks. RESULTS: The PDN patients had a significant reduction in white matter connectivity compared with PLDN and controls in the limbic and temporal regions, particularly the insula, hippocampus and parahippocampus, the amygdala, and the middle temporal gyrus. The PDN patients also exhibited an altered topology of the brain networks with reduced global efficiency and betweenness centrality. CONCLUSION: The current findings indicate that topological alterations of brain networks may serve as a biomarker for pain-induced maladaptive reorganization of the brain in PDN. Given the high prevalence of diabetes worldwide, novel insights from network sciences to investigate the central mechanisms of diabetic neuropathic pain are warranted.