Widespread and prolonged pain may reduce brain clearance capacity only via sleep impairment: Evidence from participants with knee pain.

The brain is key in the pain-sleep relationship, and sleep is needed for glymphatic clearance. However, no studies have examined how pain relates to the glymphatic system (GS). Characterizing the GS alongside sleep quality in well-characterized pain samples is essential for advancing this understanding. Non-invasive MRI techniques, such as Diffusion Tensor Imaging-Analysis aLong the Perivascular Space (DTI-ALPS), are particularly valuable as they are approved for humans. Although the relationship between the DTI-ALPS index and the GS is primarily deductive, the index may be a proxy for waste clearance capacity in deep white matter. Its sensitivity to interstitial space changes-known to be modulated by norepinephrine-offers a unique opportunity to investigate how sleep impairment and chronic pain regulation affect specific components of brain waste clearance. We thus fitted two longitudinal models linking pain, sleep quality and the DTI-ALPS index. We hypothesized that variations in pain characteristics would predict DTI-ALPS index changes, either directly or mediated by sleep quality changes. Alternatively, we hypothesized that variations in sleep quality would predict changes in pain characteristics via DTI-ALPS index modifications. Knee pain participants (n=87) completed an MRI and self-reported measures of pain and sleep impairment at baseline and two years later. We only found evidence supporting that more widespread and longer pain at baseline significantly influenced decreases in the DTI-ALPS index in the left hemisphere through increased sleep impairment two years later (p=0.039, corrected). PERSPECTIVE: Findings highlight the need for research on the relationship between pain and sleep quality and its implications for brain health.