An Interpretable and Predictive Connectivity-Based Neural Signature for Chronic Cannabis Use

Background: Cannabis is one of the most widely used substances in the world, with usage trending upward in recent years. However, although the psychiatric burden associated with maladaptive cannabis use has been well established, reliable and interpretable biomarkers associated with chronic use remain elusive. In this study, we combine large-scale functional magnetic resonance imaging with machine learning and network analysis and develop an interpretable decoding model that offers both accurate prediction and novel insights into chronic cannabis use. Methods: Chronic cannabis users (n = 166) and nonusing healthy control subjects (n = 124) completed a cue-elicited craving task during functional magnetic resonance imaging. Linear machine learning methods were used to classify individuals into chronic users and nonusers based on whole-brain functional connectivity. Network analysis was used to identify the most predictive regions and communities. Results: We obtained high (∼80% out-of-sample) accuracy across 4 different classification models, demonstrating that task-evoked connectivity can successfully differentiate chronic cannabis users from nonusers. We also identified key predictive regions implicating motor, sensory, attention, and craving-related areas, as well as a core set of brain networks that contributed to successful classification. The most predictive networks also strongly correlated with cannabis craving within the chronic user group. CONCLUSIONS: This novel approach produced a neural signature of chronic cannabis use that is both accurate in terms of out-of-sample prediction and interpretable in terms of predictive networks and their relation to cannabis craving.