Functional connectivity of the nucleus accumbens predicts clinical course in treated and non-responder adult ADHD

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental condition that often persists into adulthood, contributing to a challenging trajectory characterised by increased rates of psychiatric comorbidity. Contrary to previous assumptions, the clinical course of ADHD in adulthood is characterised by dynamic changes influenced by stimulant treatment. To improve the precision of treatment, the identification of a predictive neuroimaging biomarker would be of great clinical importance. In this study, we explore the potential of seed-based functional connectivity (FC) as a predictive tool for assessing the clinical course of ADHD symptoms. We conducted a longitudinal follow-up study of 54 adult ADHD patients who underwent magnetic resonance imaging (MRI) using a 3 Tesla scanner. All patients received stimulant treatment during an initial run-in period. After an average of three years, only subjective responders continued treatment (n=34), while subjective non-responders discontinued medication (n=20). We reassessed patients after three years of treatment to 1) evaluate the prediction of individual outcome by baseline fMRI and 2) to investigate differences in prediction by baseline fMRI depending on long-term treatment vs. discontinuation. Our investigation focused on determining whether a relationship could be established between resting-state FC of the nucleus accumbens (NAc) and the trajectory of symptom development, as well as identifying possible differences in FC between individuals who had been on long-term stimulant treatment and those who had not used stimulants at the time of follow-up. In general, reduced FC between the NAc and the default mode network (DMN) was associated with initially higher symptom burden, whereas patterns of improvement correlated with reduced FC between the NAc and the salience network (SN). Comparatively, higher FC between the NAc and the SN was associated with better symptom outcomes in patients receiving long-term stimulant medication, whereas lower FC between the NAc and the SN was correlated with a more favourable prognosis in non-responders. Our prospective fMRI study suggests that functional connectivity between the dopaminergic reward circuitry and the SN, especially the insula, is predictive of better ADHD symptom outcomes. This work highlights the potential of dopaminergic functional connectivity as a prognostic factor in ADHD. While future research with larger samples and longer follow-up is warranted, our study highlights the role of the NAc in the prognosis of ADHD.