Reduced functional resting-state connectivity in chronic pain patients with small fiber neuropathy

Chronic neuropathic pain can lead to structural and functional brain reorganization. Neuropathic pain, the main symptom of small fiber neuropathy (SFN), may be linked to specific brain biosignatures. Functional connectivity changes during resting state (RS) have been observed in SFN patients, but little is known about these changes in idiopathic SFN. To explore this, we conducted RS-fMRI in 32 idiopathic SFN patients and 31 healthy controls (HC), focusing on the bilateral caudate nucleus (CN), where reduced gray matter volume (GMV) was previously reported. Functional connectivity analysis revealed that SFN patients had decreased connectivity between the right CN and the left supplementary motor area (SMA) compared to HC. This reduced connectivity correlated positively with both the patients' total pain score (painDETECT) and the GMV of both caudate nuclei, suggesting that decreased RS connectivity is associated with lower GMV and higher pain levels. Exploratory subgroup analyses in patients with rare heterozygous missense variants in voltage-gated sodium channels (Nav) showed distinct connectivity patterns, highlighting potential genetic influences. Our findings suggest that brain functional changes during RS may be linked to a structural basis in chronic pain and might serve as neural signature for SFN patients. Further studies are needed to confirm these results and to investigate the role of genetic factors in SFN-related brain changes. PERSPECTIVE: This study identifies altered resting-state functional connectivity involving the caudate nucleus in idiopathic small fiber neuropathy patients, correlating with pain severity and structural changes. These findings may provide a neural signature for SFN, offering insights into chronic pain mechanisms. Future studies could explore genetic contributions, aiding clinical understanding and personalized treatment approaches.