*C. W. BRADBERRY1,6, D. TUDORASCU2, D. MINHAS3, L. SHEU4, H. P. JEDEMA5, P. J. GIANAROS4, J. C. PRICE3, H. AIZENSTEIN3; 1Psychiatry, Univ. of Pittsburgh, PITTSBURGH, PA; 2Med., Univ. of Pittsburgh, Pittsburgh, PA; 3Radiology, 4Psychology, 5Psychiatry, Univ. of Pittsburgh, Pittsburgh, PA, PA; 6VA Pittsburgh Hlth. Services, Pittsburgh, PA
Abstract Body: Structural deficits in brains of cocaine users are seen in cross-sectional studies, including reduced gray matter density and volume in subregions of prefrontal, insular, and temporal cortex. While some studies have linked the magnitude of differences with duration of use to infer a causal link between cocaine use and altered brain structure, direct longitudinal studies in clinical populations do not exist. To determine causality of changes to cocaine use, we conducted longitudinal structural MR imaging in control (n=6) and experimental (n=8) rhesus monkeys before and after approx. one year of cocaine self-administration. Sessions occurred Tues-Fri, with up to six infusions of 0.5 mg/kg. The cumulative dose of i.v. self-administered cocaine was 513 + 19 mg/kg. Time between scans for all animals was 868 days + 21, and time from end of cocaine to scan for the experimental group was 56 + 9 days. An initial whole brain approach to evaluate longitudinal changes used tensor-based morphometry. A flexible factorial design performed in SPM8 revealed no main effects of group or group x time interactions. However, within group comparisons showed contraction in ventromedial prefrontal cortex in the cocaine group, but not in the control group (p < 0.05 uncorrected and a 100 voxel extent threshold). Based on this and a priori hypotheses of prefrontal deficits in the cocaine group, a targeted region of interest (ROI) approach was employed. We used an atlas based segmentation method to transform anatomic ROIs on a reference macaque template to fit each individual’s image. Wilcoxon’s rank sum was used to test if there were any differences between groups. We collapsed time to one factor, post-pre gray matter volume, and used that as our outcome variable. Significant differences across groups were found for Area 45 bilateral (p=0.019) and Area 45 right (p=0.019). Areas 45 and 46 bilateral combined (p=0.052) was marginal, and Area 45 left and Area 46 bilateral were not significant (both p=0.107). These results demonstrate a causal link between cocaine use and structural deficits in cocaine users. Because of our previous report of executive control deficits in these same animals (Porter et al., 2011), structural changes likely contribute to cognitive deficits in cocaine users.
Lay Language Summary:: In monkeys that self-administer cocaine, we show that cocaine use leads to decreased gray matter volume in a restricted region of the prefrontal cortex, and that these structural changes are directly related to cognitive deficits in these animals. Human cocaine users show similar structural and cognitive deficits compared to non-users, but what cannot be controlled for in clinical studies is the extent to which pre-existing traits, lifestyle, etc. are responsible for the deficits. These results demonstrate conclusively the impact of cocaine on brain structure and cognitive function, and will help guide future research on the mechanisms involved. Our work involved a longitudinal study of cognitive assessments in cocaine-exposed monkeys and matched controls. We measured cognitive performance before any cocaine exposure, and then observed specific types of deficits following one year of regular exposure. We also conducted baseline structural magnetic resonance imaging for comparison with later images after cocaine exposure. The before and after brain images from each animal were compared. We observed decreased volume in the lateral prefrontal cortex in the experimental group that self-administered cocaine. Most importantly, across individuals in the cocaine group, the amount of gray matter lost was significantly correlated with the change in cognitive performance. The control group showed no significant tissue loss as a group, and no relationship between tissue volume changes and cognitive performance changes across individuals. The next step for this project is to explore potential mechanisms whereby cocaine is changing structure and function. This knowledge may be critical for helping to design treatment strategies that ameliorate the negative impact of cocaine on cognition. This is especially important because impaired cognition is a risk for poor treatment outcomes.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit