Transl Psychiatry. 2026 Feb 3. doi: 10.1038/s41398-026-03845-6. Online ahead of print.
ABSTRACT
One approach to addressing the immense unmet need for treatments of severe opioid use disorder (sOUD) is to understand more about associated changes in the brain's reward circuitry. It has been shown that during reward anticipation in the Monetary Incentive Delay (MID) task, people with severe substance use disorder (SUD) show blunted responses in reward neural circuitry compared with healthy controls (HC). Conversely, drug-related cues result in heightened responses in the same neural reward circuitry in those with SUD compared with HC. However, it is unclear how such dysfunctional reward processing is related to neural correlates of other processes commonly dysregulated in addiction, such as attention and cognition. The aim of this work was to evaluate whether people with sOUD show different relationships between reward networks to networks that regulate cognition, attention, sensory processes, and more. Then, we evaluated whether there is a spatial relationship between differences in brain function and atlases of μ-opioid receptor (MOR) and dopamine D2 receptor (DRD2) availability. We collected fMRI data while people with sOUD receiving methadone (MD; n = 25) and HC (n = 22) completed the MID and cue reactivity tasks. We evaluated differences in functional connectivity (FC) and measures of brain state dynamics. Partial least squared (PLS) analysis computed the spatial relationship between FC metrics to MOR and D2DR availability. We found that MD participants generally exhibited weaker miFC compared to HC in both tasks except when comparing the difference in miFC during anticipation of monetary reward or drug related stimuli vs neutral stimuli. Contrasts between rewarding or drug-related to neutral stimuli showed MD participants had stronger miFC between reward/anti-reward networks to regions in the control network and default mode Network (DMN) in both tasks. Analysis of brain state dynamics showed the DMN was more prevalent in MD participants during the MID task. PLS analysis showed spatial autocorrelation between MOR and D2DR availability and connectivity metrics during the MID task. These findings reveal distinct patterns of neural network interactions in individuals with sOUD, characterized by generally reduced FC but enhanced connections between reward-related networks and cognitive control regions in response to either monetary or drug-related cues vs neutral cues. We observed spatial correspondence between receptor availability and altered connectivity and dynamics in MD vs HC. These results provide new insights into the neural basis of reward processing dysfunction in sOUD and may inform the development of targeted neuromodulation therapeutic approaches. Clinical trial registration: This study is not a clinical trial and therefore was not registered as a clinical trial. The study design and planned analytical approach for the primary analyses was pre-registered [1]. This paper consists of secondary analyses which were not primary considerations when designing the research study that collected the data.
PMID:41633966 | DOI:10.1038/s41398-026-03845-6