Diffusion Tensor Imaging Reveals Altered Centrality of Pain-Related Regions in SCN9A-Associated Small Fiber Neuropathy

Background and Purpose: Small fiber neuropathy (SFN) is a neuropathic disorder that is associated with chronic pain. While most SFN cases are idiopathic, SFN can also have hereditary causes. For example, rare SCN9A gene mutations can impair the Na_V1.7 sodium channel, which leads to dorsal root ganglion neuron hyperexcitability, causing SFN. Although chronic pain may induce cerebral changes, the specific structural brain alterations in SCN9A-associated SFN (SFN-SCN9A) remain insufficiently characterized. Therefore, potential alterations in the structural brain network of idiopathic SFN and SFN-SCN9A were explored. Methods: Ten SFN-SCN9A patients, 20 idiopathic SFN patients, and 20 controls were included. All participants underwent 3-Tesla diffusion MRI (66 gradient directions, b-value = 1200 s/mm²), and the brain network was quantified using nodal importance, which describes the influence of a group of regions on the whole network. Results: The nodal importance of pain-associated regions (postcentral gyrus, insular cortex, anterior cingulate cortex, and thalamus) was increased in SFN-SCN9A patients compared to controls (β = 0.43, p = 0.02) and idiopathic SFN patients (β = 0.43, p = 0.02). Moreover, higher self-reported pain was associated with higher nodal importance of pain-associated regions in the SFN-SCN9A group (r = 0.67, p = 0.03), while this effect was not observed in the idiopathic SFN patients (r = −0.22, p = 0.34). As self-reported pain did not differ between the SFN groups, it is likely specific to the SCN9A-mutation and not to differences in pain intensity. Conclusion: Combined, these results suggest the potential involvement of a distinct structural pathway related to pain processing in SFN-SCN9A.