Sex-Specific White Matter Abnormalities Across the Dynamic Pain Connectome in Neuropathic Pain: A Fixel-Based Analysis Study

A fundamental issue in neuroscience is a lack of understanding regarding the relationship between brain function and the white matter architecture that supports it. Individuals with chronic neuropathic pain (NP) exhibit functional abnormalities throughout brain networks collectively termed the "dynamic pain connectome" (DPC), including the default mode network (DMN), salience network, and ascending nociceptive and descending pain modulation systems. These functional abnormalities are often observed in a sex-dependent fashion. However, the enigmatic white matter structural features underpinning these functional networks and the relationship between structure and function/dysfunction in NP remain poorly understood. Here we used fixel-based analysis of diffusion weighted imaging data in 80 individuals (40 with NP [21 female, 19 male] and 40 sex- and age-matched healthy controls [HCs]) to evaluate white matter microstructure (fiber density [FD]), macrostructure (fiber bundle cross section) and combined microstructure and macrostructure (fiber density and cross section) within anatomical connections that support the DPC. We additionally examined whether there are sex-specific abnormalities in NP white matter structure. We performed fixel-wise and connection-specific mean analyses and found three main ways in which individuals with NP differed from HCs: (1) people with NP exhibited abnormally low FD and FDC within the corona radiata consistent with the ascending nociceptive pathway between the sensory thalamus and primary somatosensory cortex (S1). Furthermore, the entire sensory thalamus-S1 pathway exhibited abnormally low FD and FDC in people with NP, and this effect was driven by the females with NP; (2) females, but not males, with NP had abnormally low FD within the cingulum consistent with the right medial prefrontal cortex-posterior cingulate cortex DMN pathway; and (3) individuals with NP had higher connection-specific mean FDC than HCs in the anterior insula-temporoparietal junction and sensory thalamus-posterior insula pathways. However, sex-specific analyses did not corroborate these connection-specific findings in either females or males with NP. Our findings suggest that females with NP exhibit microstructural and macrostructural white matter abnormalities within the DPC networks including the ascending nociceptive system and DMN. We propose that aberrant white matter structure contributes to or is driven by functional abnormalities associated with NP. Our sex-specific findings highlight the utility and importance of using sex-disaggregated analyses to identify white matter abnormalities in clinical conditions such as chronic pain.