Altered cortical maturation in adolescent cannabis users with and without schizophrenia Katherine A. Epstein, Sanjiv Kumra ⁎ Division of Child and Adolescent Psychiatry, University of Minnesota, Minneapolis, MN, United States abstract article info Article history: Received 20 June 2014 Received in revised form 19 November 2014 Accepted 21 November 2014 Available online 15 January 2015 Keywords: Structural imaging Schizophrenia Critical period Endocannabinoid Cortical Gray matter During late adolescence, progressive cortical thinning occurs in heteromodal association cortex (HASC) that is thought to subserve cognitive development. However, the impact of cannabis use disorder (CUD) upon cortical gray matter development in both healthy adolescents and adolescents with early-onset schizophrenia (EOS) is unclear. T1-weighted magnetic resonance images were acquired from 79 adolescents at baseline and after an 18-month follow-up: 17 with EOS, 17 with CUD, 11 with EOS + CUD, and 34 healthy controls (HC). Mean age at baseline was 16.4 years (CUD+) and 17.0 years (CUD-). Using FreeSurfer, measures of cortical thickness for ROIs within HASC were obtained. A 2 (EOS versus no EOS) × 2 (CUD versus no CUD) multivariate analysis of covariance was applied to change scores from baseline to follow-up to test for main effects of EOS and CUD and an interaction effect. After adjusting for covariates, a significant main effect of CUD was observed. Adoles- cents with CUD showed an attenuated loss of cortical thickness in the left and right supramarginal, left and right inferior parietal, right pars triangularis, left pars opercularis, left superior frontal, and left superior temporal regions compared to non-using subjects. Stepwise linear regression analysis indicated that greater cumulative cannabis exposure predicted greater cortical thickness in both the left (p = .008) and right (p = .04) superior frontal gyri at study endpoint after adjusting for baseline cortical thickness for the entire sample. These prelim- inary longitudinal data demonstrate an atypical pattern of cortical development in HASC in adolescents with CUD relative to non-using subjects, across diagnostic groups. Additional studies are needed to replicate these data and to clarify the clinical significance of these findings. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Adolescent brain development is characterized by ongoing mold- ing of cortical gray matter (GM) (Sowell et al., 2001). During typical development, cortical maturation occurs in a back-to-front direction with the heteromodal association cortex (HASC) maturing last, dur- ing late adolescence and into early adulthood (Gogtay et al., 2004). The HASC comprises the prefrontal, superior temporal, and inferior parietal cortices and supports the highest integrative functions of the brain, including attention, language, working memory, and ex- ecutive function (Ross and Pearlson, 1996). Within the HASC, the protracted maturation of the superior frontal cortex during adoles- cence is thought to subserve the development of executive functions (Luciana et al., 2009), including working memory and planning, that are important for the development of self-organized behavior and emotional regulation. Cannabis is one of the most commonly used illicit substances among adolescents and young adults (SAMHSA, 2014). There are increasing data suggesting that the effects of delta-9- tetrahydrocannabinol (THC) may be more deleterious in adolescents, whose cognitive development and brain maturation are still ongoing, than in adults (Lisdahl et al., 2013). Recently, a primate study found that exposure to THC for six months during adolescence selectively impaired development of a spatial working memory task that prefer- entially activates the still-developing superior frontal cortex (Verrico et al., 2014). The primary target of exogenous cannabinoids in the brain is the cannabinoid-1 (CB-1) receptor. CB-1 receptors are located throughout the brain including the HASC and are part of the endocannibinoid system, which regulates synaptic plasticity and other fundamental neuromaturational processes (Harkany et al., 2008). To date, very little is known about the relationship between regular cannabis use during adolescence and cortical GM develop- ment in late-developing brain regions such as the HASC. Data from cross-sectional studies suggest that regular cannabis use during adolescence may disrupt GM pruning processes in both typical Schizophrenia Research 162 (2015) 143–152 ⁎ Corresponding author at: Division of Child and Adolescent Psychiatry, University of Minnesota, F256/2B West, 2450 Riverside Ave., Minneapolis, MN 55454, United States. Tel.: +1 612 273 9775; fax: +1 612 273 9779. E-mail address: kumra002@umn.edu (S. Kumra). http://dx.doi.org/10.1016/j.schres.2014.11.029 0920-9964/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres