Abstract
BACKGROUND: An enduring question from cross-sectional clinical studies is whether the structural and functional differences often observed between cocaine users and healthy control subjects result from a history of drug use or instead reflect preexisting differences. To assess causality from drug exposure, true predrug baseline imaging and neurocognitive assessments are needed. METHODS: We addressed this fundamental question of causality using longitudinal anatomical magnetic resonance imaging and neurocognitive assessments in rhesus macaques. Cognitive tasks employed were stimulus reversal learning as a measure of cognitive flexibility/inhibitory control and delayed match to sample as a measure of visual working memory. Time points examined were before and following 12 months of chronic cocaine (n = 8) or water (n = 6) self-administration. A magnetic resonance imaging-only time point was also obtained following 2 years of forced abstinence. RESULTS: We identified localized patterns of gray matter density (GMD) changes that were largely concordant with cross-sectional clinical studies. These included decreases in orbitofrontal cortex, insula, amygdala, and temporal cortex. There was also a prominent increase in GMD in the caudate putamen. GMD decreases were significantly correlated with cognitive impairments across individuals only in select cortical regions. Following abstinence, changes in GMD in some regions, including the orbitofrontal cortex, insula, and amygdala, were persistent and thus may play an important role in risk of relapse following extended abstinence. CONCLUSIONS: Cocaine use is causal in producing regional changes in GMD, and those changes appear to drive cognitive impairments.