Cannabis-Associated Psychotic-Like Experiences Are Mediated by Developmental Changes in the Parahippocampal Gyrus

Abstract Objective Cannabis consumption during adolescence has been reported as a risk-factor for psychotic-like experiences (PLEs) and schizophrenia. However, brain developmental processes associated with cannabis-related PLEs are still ill-described. Method 706 adolescents from the general population that were recruited by the IMAGEN consortium had structural MRI scans both at 14 and 19 years-old. We used deformation-based morphometry to map voxel-wise brain changes between the two time points, using the pairwise algorithm in SPM12b. We used an a-priori region of interest (ROI) approach focusing on the hippocampus/parahippocampus to perform voxel-wise linear regressions. Life time cannabis consumption was assessed using the European School Survey Project on Alcohol and other Drugs (ESPAD) and PLEs were assessed with the Comprehensive Assessment Psychotic-like experiences (CAPE). We first tested whether hippocampus/para-hippocampus development was associated with PLEs. Then, we formulated and tested an a-priori simple mediation model where uncus development mediates the association between lifetime cannabis consumption and PLEs. Results We found that PLEs was associated with reduced expansion within a specific region of the right hippocampus/para-hippocampus formation, the uncus (p=0.002 at the cluster level, p=0.018 at the peak-level). The partial simple mediation model revealed a significant total effect from lifetime cannabis consumption to PLEs (b=0.069 95CI [0.04-0.1], p=2 x 10 -16 ), as well as a small yet significant, indirect effect of right uncus development (0.004, 95IC [0.0004-0.01], p=0.026). Conclusion We show here that the uncus development is involved in the cerebral basis of PLEs in a population-based sample of healthy adolescents.