Crosstalk of peripheral cytokine-white matter alteration-insomnia during methadone maintenance treatment

Insomnia is commonly seen in opioid use disorder (OUD) patients receiving methadone maintenance treatment (MMT) and might be related to high heroin relapse risk. This study aims to identify potential mediation pathways among peripheral cytokines, neuroimaging characteristics, and insomnia in MMT patients, and explore diagnostic markers and therapeutic targets for MMT-related insomnia.

A total of 121 OUD individuals (OUDs) and 109 healthy controls were recruited, including MMT individuals (MMT group, N = 53), short-term abstinent (median: 30 days) heroin users at baseline (OUD1, N = 68), and around 10-month follow-up (OUD2, N = 61) without MMT, healthy controls-cohort 1 (HC1, N = 53, age/gender/education match MMT), and healthy controls-cohort 2 (HC2, N = 56, age/gender match OUD1). Multimodal datasets, including cerebral diffusion tensor imaging (DTI), peripheral hematologic indicators, and neuropsychological assessments, were collected from the MMT group and HC1. Within the MMT group, we revealed relationships among cytokines, DTI metrics, and neuropsychological assessments via partial correlation and mediation analyses. Mendelian randomization (MR) analyses between OUD and white matter (WM)-related imaging-derived phenotypes were used to further confirm Tract-Based Spatial Statistics (TBSS) results. Besides, the results of TBSS among OUD1, OUD2, and HC2 hypothetically served as baseline WM alteration before MMT.

Through comparisons among OUD1, OUD2, and HC2, WM aberrances could return to normal after 10-month abstinence, and we used the results as baseline alterations before MMT. MMT patients exhibited a broad imbalance in peripheral immune cells and cytokines, as well as presented insomnia, anxiety, and depression symptoms. After Bonferroni correction, mean diffusivity and radial diffusivity in extensive WM regions were higher in MMT patients than those of HC1. Ultimately, through multimodal correlation analysis, the ‘Interferon-γ (IFN-γ)-WM aberrance-insomnia’ axis was discovered in the MMT group.

Together, these results primarily link cytokines and WM injury for OUDs with MMT to insomnia, implicating pharmacological IFN-γ target as a latent strategy to improve the insomnia of MMT patients.