Background Heroin and other opioid use disorders (HUD and OUD) cause massive public health morbidity and mortality. Although standard-of-care medication assisted treatment (MAT) exists, little is known about potential predictors of change during recovery. Recovery can include normalization of the brain’s white matter (WM) microstructure, which is sensitive to cytokine and immune signaling. Here we aimed to determine whether blood-based cytokine/immune markers can predict WM microstructure recovery following medication-assisted treatment.

Methods Inpatient Individuals with HUD (iHUD; n=21) and healthy controls (HC; n=24) underwent magnetic resonance scans with diffusion tensor imaging (DTI) and provided ratings of drug cue-induced craving, arousal and valence twice, earlier in treatment and ≈14 weeks of inpatient MAT (with methadone or buprenorphine) thereafter. At this second session (MRI2), they also provided a peripheral blood sample for multiplex relative quantification of serum cytokine/immune proteins (with a proximity extension assay, Olink). We explored the correlation of a multi-target cytokine biomarker score (based on principal component analysis of 19 proteins that differed significantly between iHUD and HC) with change in whole-brain DTI (ΔDTI; MRI2 - MRI1) metrics (fractional anisotropy, mean diffusivity, and axial diffusivity) across the 14 weeks of MAT.

Results The cytokine biomarker score, obtained at the MRI2 stage, was correlated with ΔDTI metrics in frontal, fronto-parietal, and cortico-limbic WM tracts (e.g., including the genu of the corpus callosum, anterior corona radiata, and others). In a follow-up analysis, specific cytokines represented in the multi-target biomarker score, such as the interleukin oncostatin M (OSM), colony stimulating factor (CSF21), and the chemokine CCL7 were correlated with similar ΔDTI metrics in iHUD, but not in HC. Levels of other specific cytokines (i.e., CCL19 and CCL2) were negatively correlated with change in cue-induced craving or arousal. Thus, lower levels of the aforementioned cytokines were correlated with an increase in cue-induced craving or arousal across the two stages (MRI2 - MRI1).

Conclusions Studied as a multi-target biomarker score, or as individual targets, peripheral serum cytokines are highly accessible biomarkers of WM microstructure recovery in iHUD undergoing inpatient MAT.

The authors have declared no competing interest.

This work was supported by NIDA U01DA053625 (ERB), R01DA049547 (NAK), R01DA047880 (PR), NCCIH R01AT010627 (RZG), NIMH R01MH104559 (SJR), R01MH127820 (SJR), and NIA R01AG067025 (PR).

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