Widespread reductions in white matter-gray matter functional connectivity in long-term fibromyalgia syndrome patients

Long-term fibromyalgia syndrome (FMS) patients experience chronic pain, emotional disturbances, and poor treatment responses, yet the neural mechanisms underlying disease chronicity remain unclear. This study aimed to investigate the white matter-gray matter functional connectivity (WM-GM FC) in long-term FMS patients to explore changes in brain network communication associated with chronicity and their relationship with clinical symptoms. A total of 52 FMS patients (30 long-term, 22 short-term) and 49 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (fMRI). WM-GM FC was analyzed by calculating Pearson correlation coefficients between 48 predefined white matter tracts and 82 gray matter regions. Clinical evaluations included the Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), Visual Analogue Scale (VAS), and pain duration. The results revealed that long-term FMS patients had 64 significantly reduced WM-GM FCs compared to HCs, 44 of which involved the left uncinate fasciculus (UF) and multiple gray matter regions. No significant differences in WM-GM FC were observed between short-term FMS patients and HCs. In long-term FMS patients, FC between the left UF and several gray matter regions showed negative correlations with HAMD, HAMA, VAS, and pain duration. These findings suggest that widespread reductions in WM-GM FC in long-term FMS, particularly involving the left UF, may play a crucial role in pain modulation and emotional regulation. The study provides new insights into the neural mechanisms underlying FMS chronicity and supports the potential of WM-GM FC as a biomarker for identifying pathophysiological processes and therapeutic targets in FMS. PERSPECTIVE: Fibromyalgia syndrome (FMS) patients with prolonged symptoms often face treatment resistance and worsening emotional-pain comorbidities, yet the neural basis of chronicity remains unclear. This study explored white matter-gray matter functional connectivity (WM-GM FC) in 30 long-term FMS patients, 22 short-term patients, and 49 healthy controls. Long-term patients exhibited 64 reduced WM-GM FCs, predominantly between the left uncinate fasciculus (UF)-a tract linking emotion and pain networks-and limbic/cortical regions. These disruptions correlated with higher depression, anxiety, pain severity, and duration, while short-term patients showed no significant FC differences. The findings identify left UF dysfunction as a potential neural marker of FMS chronicity, offering insights into how prolonged pain reshapes brain connectivity. Clinically, WM-GM FC could guide early interventions to prevent progression or serve as a therapeutic target, addressing the unmet need for biomarkers in managing this debilitating disorder. This advances understanding of FMS pathophysiology and highlights pathways to mitigate its long-term societal and individual burden.