Abstinent adolescent marijuana users show altered fMRI response during spatial working memory☆
Introduction
Marijuana is the most commonly used illicit drug among teenagers: almost half of 12th graders have used cannabinoids, 20% report past-month use, and 5% disclose daily use (Johnston et al., 2006). During this period of increasing marijuana use, continued neuromaturation includes synaptic refinement, myelination, and improved cognitive and functional efficiency (Huttenlocher and Dabholkar, 1997, Giedd et al., 1999, Casey et al., 2000, Paus et al., 2001, Gogtay et al., 2004). The potential long-term consequences of marijuana use on the developing adolescent brain have not been well delineated, but they could have major implications for academic, occupational and social achievement.
Neuropsychological studies in adults have indicated that within a few days of abstinence, heavy users demonstrate impairments in learning and memory, attention, visuospatial skills, processing speed, and executive functioning (Varma et al., 1988, Pope and Yurgelun-Todd, 1996, Pope et al., 1997, Croft et al., 2001, Bolla et al., 2002, Solowij et al., 2002, Lyons et al., 2004). Event-related potential studies suggest slowed information processing and difficulty focusing attention (Solowij et al., 1991, Solowij et al., 1995). Heavy marijuana users have demonstrated reduced cerebellar and frontal blood flow both at rest and during verbal learning and memory, while also showing poorer verbal learning abilities (Loeber and Yurgelun-Todd, 1999, Block et al., 2000, Lundqvist et al., 2001, Block et al., 2002). Functional magnetic resonance imaging (fMRI) evidence suggests that marijuana users show increased and widespread spatial working memory (SWM) activation after 6–36 h of abstinence, both in anterior cingulate and prefrontal regions normally associated with SWM, as well as in additionally recruited brain areas not activated among controls (Kanayama et al., 2004). During verbal working memory, marijuana users had similar fMRI response patterns as controls, yet failed to show practice-related decreases in parietal activation (Jager et al., 2006). However, it is unclear whether these neurocognitive findings only represent effects of recent use.
Pope et al. (2001) demonstrated deficits on verbal learning up to 7 days after use among current heavy marijuana users compared with former users and non-using controls. However, after 28 days of abstinence, current users performed similarly to former users and controls on all tests, suggesting that neurocognitive decrements may resolve within a month of abstinence (Pope et al., 2001). Importantly, fMRI evidence indicates that both abstinent users and active users show brain response abnormalities relative to controls during visual attention (Chang et al., 2006), suggesting lasting changes in patterns of neural activity. Together, these studies indicate that neuropsychological decrements observed after 1 week of use may not persist, and highlight the importance of examining neural responding after several weeks of abstinence.
Few studies have examined neurocognitive functioning among adolescent marijuana users. Among polysubstance using youths, marijuana use has been linked to poorer learning and memory (Millsaps et al., 1994) and attention (Tapert et al., 2002). In a longitudinal study, Fried and colleagues (Fried et al., 2005) assessed cognitive functioning in 9- to 12-year-olds before the initiation of marijuana use, and again when youths were ages 17–21. After controlling for baseline performance and demographics, they found that current heavy marijuana users showed deficits in immediate and delayed memory, processing speed, and overall IQ. Further, a longitudinal study of 10 cannabis-dependent adolescents demonstrated incomplete recovery of learning and memory impairments after 6 weeks of monitored abstinence (Schwartz et al., 1989), indicating that adolescents may be more susceptible to long-term changes than adults (Pope et al., 2001). Together, these studies point to dysfunctional working memory and attention abilities among adolescents who are heavy marijuana users that may persist after several weeks of abstinence.
We previously investigated fMRI response to a SWM task among adolescents with comorbid marijuana and alcohol use disorders compared with teens with alcohol use disorder alone and non-abusing teens. After an average of 8 days of abstinence, adolescents with comorbid marijuana and alcohol use disorders showed brain response abnormalities not evidenced by those with alcohol use disorders alone, including increased dorsolateral prefrontal activation and reduced inferior frontal response, suggesting compensatory working memory and attention activity associated with heavy marijuana use during youth (Schweinsburg et al., 2005b). Yet it is unclear whether these abnormalities are solely a function of recent use or would be present after a longer period of abstinence, suggesting persistent effects. A preliminary fMRI study explored verbal working memory among seven adolescent marijuana, seven demographically similar tobacco smokers, and seven non-users after a month of abstinence (Jacobsen et al., 2004). Compared with other groups, marijuana users demonstrated increased right hippocampal activity and poorer attention and verbal working memory performance. Recently, these researchers evaluated verbal working memory among abstinent adolescent marijuana users and non-users during nicotine withdrawal (Jacobsen et al., 2007). After at least 2 weeks of abstinence, marijuana users showed increased parietal activation during nicotine withdrawal and poorer verbal delayed recall, while non-marijuana users did not (Jacobsen et al., 2007). Together, these studies suggest persisting brain response abnormalities during working memory among adolescent marijuana users.
To investigate the potentially enduring neurocognitive effects of chronic marijuana use during adolescence, we examined fMRI response during an SWM task among marijuana-using teens and non-abusing controls after 28 days of monitored abstinence. Blood-oxygen-level-dependent (BOLD) fMRI was obtained during an SWM task that typically activates bilateral prefrontal and posterior parietal networks in adolescents (Schweinsburg et al., 2005a), and has been associated with neural dysfunction among youths with alcohol use disorders (Tapert et al., 2004) as well as comorbid alcohol and marijuana use disorders (Schweinsburg et al., 2005b). We predicted that after 28 days of monitored abstinence, marijuana-using teens would demonstrate intact performance on the SWM task yet increased brain response in frontal and parietal regions.
Section snippets
Participants
Flyers were distributed at high schools in San Diego County to recruit adolescent participants ages 16–18. Interested teens and a parent provided informed assent and consent (for 18-year-olds, the youth provided consent and the parent consented to a collateral informant interview), approved by the University of California San Diego Human Research Protection Program. Each adolescent and a parent were separately administered detailed screening interviews (Tapert et al., 2003, Schweinsburg et al.,
Task performance
Task accuracy was similar between groups, with MJ teens performing correctly on 96.43 ± 1.74% trials of vigilance and 93.43 ± 5.64% trials of SWM, and controls performing correctly on 95.73 ± 2.53% trials of vigilance and 93.20 ± 5.49% trials of SWM. A repeated measures ANOVA revealed a main effect for better accuracy on vigilance than on SWM [F(1,27) = 6.30, P = 0.018], but no main effect for group or a group × task condition interaction. Groups had similar reaction times, with 625.36 ± 41.01 ms for vigilance
Discussion
This study examined fMRI brain activation during a spatial working memory task among marijuana-using teens and controls after 28 days of monitored abstinence, verified by biweekly urine toxicology screens. Despite similar overall patterns of brain response to SWM, group differences were observed in right dorsolateral prefrontal cortex, right posterior parietal cortex, medial superior occipital cortex, and medial inferior occipital cortex.
MJ teens displayed reduced SWM BOLD response relative to
Acknowledgments
This research was supported by National Institute on Drug Abuse grants DA15228 and DA021182 to S. F. Tapert. We thank Valerie Barlett, Christina Burke, Lisa Caldwell, Tim McQueeny and Dr. M.J. Meloy for their assistance with this project.
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Portions of this study were presented at the annual meeting of the International Neuropsychological Society, February 2–5, 2005, St. Louis, Missouri.