Structural Brain Pathways Linking White Matter Hyperintensities to Pain Sensitivity

People differ widely in their sensitivity to pain, and this variability is clinically relevant, yet the underlying structural brain mechanisms remain poorly understood. White matter hyperintensities (WMH), a common imaging marker of cerebral small vessel disease, are associated with microstructural abnormalities in white matter tracts and have also been linked to pain-related outcomes; however, the mechanisms linking WMH to altered pain perception remain unclear. We investigated whether WMH are linked to pain sensitivity through tract-specific microstructural alterations and cortical structural differences.

We analysed data from 1,448 participants (mean age 73 years; 53% women) in the population-based Rotterdam Study and independently replicated the findings in 1,522 participants (mean age 63 years; 52% women) from the population-based Tromsø Study. Pain sensitivity was quantified using the cold pressor test. Multimodal magnetic resonance imaging, including T1-weighted, fluid-attenuated inversion recovery and diffusion tensor imaging, was used to map WMH to predefined white matter tracts, derive tract-specific fractional anisotropy (FA), and estimate cortical measurements. Cox proportional hazards models assessed associations with pain sensitivity, and tract-specific mediation analyses evaluated whether white matter microstructure or tract-connected cortical regions mediated the relationship between white matter hyperintensities and pain sensitivity.

WMH were present in 20 of 27 predefined tracts and were associated with reduced FA in 18 tracts. Higher WMH burden was associated with greater pain sensitivity, particularly in the left anterior thalamic radiation and left superior thalamic radiation, while lower FA in the anterior thalamic radiation, medial lemniscus, superior thalamic radiation and inferior fronto-occipital fasciculus was associated with greater pain sensitivity. Mediation analyses showed that white matter microstructural disruption was the principal pathway linking WMH to pain sensitivity, with the strongest indirect effects observed through the inferior fronto-occipital fasciculus (44.6% mediated) and anterior thalamic radiation (32.6% mediated). Cortical atrophy in the precentral and postcentral gyri provided a smaller secondary pathway, mediating approximately 3–6% of the association between corticospinal or superior thalamic radiation WMH and pain sensitivity. Replication analyses supported these cortical mediation pathways, and meta-analysis strengthened the tract-specific associations.

Together, the results suggest that vascular white matter injury is associated with pain perception through specific structural pathways, with DTI-based markers appearing particularly sensitive to these relationships.