The anterior cingulate has been implicated for its role in attentional control and conflict monitoring and has been shown to be involved during adult SWM performance . Diminished anterior cingulate activity during a cognitive task may be related to reorganization of attentional resources as task demands arise . Such cingulate deactivation was observed only in females in this study, suggesting that adolescent females may require greater reallocation of attentional resources than males during SWM. Males consistently perform better than females on visuospatial tasks . Further, recent fMRI studies have demonstrated gender-specific activation patterns during mental rotation, theorizing that females use more detail oriented analytic strategies, while males use more “gestalt” perceptual strategies . Thus, anterior cingulate deactivation among females in this study could represent greater attentional demand to maintain performance. In addition to gender differences in cingulate activation, males in this study evidenced greater activation in right frontopolar cortex. Further, an interaction between age and gender was observed in the frontopolar cluster, with activation in this region decreasing with age in males and increasing with age in females. The right frontopolar cortex has been associated with SWM in adults , and has also received attention for its more general role in subgoal processing and integration during working memory tasks, as well as more efficient retrieval during episodic memory . Such activation among males may indicate a more economical strategy to achieve task demands. This could preclude the need for increased attentional control, and therefore anterior cingulate deactivation, as demonstrated in females. Further, the age-related decrease in frontopolar activity among males may reflect more efficient processing as development progresses,rolling benches for greenhouse while the age-related increase among females could indicate increased ability to reallocate attention from extraneous regions to task-relevant areas, including the frontopolar cortex.

Although it remains unclear when in the course of development the male advantage on spatial tests emerges, meta-analysis has indicated that this gender difference appears some time in early adolescence and increases with age . Similarly, the observed gender differences in brain response in this study could represent the emergence of sexually dimorphic activation patterns and cognitive strategies as neural maturation progresses.It is critical to interpret fMRI results in the context of task performance. We therefore examined whether performance indices mediated the relationship between age or gender and SWM BOLD response. Although vigilance reaction time was negatively associated with age, it did not predict brain response in any region where age and BOLD response were related. This suggests that age-related differences in brain response represent changes in neural utilization and strategy, rather than behavioral alterations. Likewise, boys had faster vigilance reaction times than girls, yet vigilance reaction time was not related to brain response in either region demonstrating a gender difference in SWM BOLD response. This provides evidence that gender differences in brain response are related to gender differences in neurocognitive features other than those manifested behaviorally. The study was also limited by a sample size that may not have been sufficient to detect more subtle variations between the genders. In addition, participants in the current study came from relatively high income families, which may not accurately represent the general population. Motion during scanning is a concern for all functional neuroimaging studies, and constraints of existing motion management programs are a limitation. Further, while this SWM task was used because it has been previously reported on by our group in adolescents and young adults , the high accuracy on both conditions in this study suggests a potential ceiling effect among healthy adolescents. A more difficult task, with greater working memory load and/or more spatial locations could elicit age-related performance differences and elucidate different patterns of functional development. Moreover, the fact that teens performed somewhat faster during the spatial working memory condition than during the vigilance baseline condition warrants consideration. Although this discrepancy has been observed in our previous studies with this task , it is not clear whether reaction time differences may have contributed to fMRI findings.

Therefore, future tasks should be designed in attempt to equate reaction times on experimental and control conditions. Finally, future investigations might attempt to more objectively characterize pubertal development using biological assays as opposed to retrospective self-report measures that can be influenced both by participant recollection of pubertal events and willingness to disclose information.Marijuana is the most commonly used illicit drug among teenagers: almost half of 12 th graders have used cannabinoids, 20% report past-month use, and 5% disclose daily use . During this period of increasing marijuana use, continued neuromaturation includes synaptic refinement, myelination, and improved cognitive and functional efficiency . The potential long-term consequences of marijuana use on the developing adolescentbrain have not been well delineated, but 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 .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 . Functional magnetic resonance imaging evidence suggests that marijuana users show increased and widespread spatial working memory activation after 6 – 36 hours of abstinence, both in anterior cingulate and prefrontal regions normally associated with SWM, as well in additionally recruited brain areas not activated among controls . During verbal working memory, marijuana users had similar fMRI response patterns as controls, yet failed to show practice-related decreases in parietal activation . However, it isunclear whether these neurocognitive abnormalities only represent effects of recent use. Pope and colleagues demonstrated deficits on verbal learning up to 7 days after use among current heavy marijuana users compared to former users and nonusing controls.

However, after 28 days of abstinence, current users performed similarly as former users and controls on all tests, suggesting that neurocognitive decrements may resolve within a month of abstinence . Importantly, fMRI evidence indicates that both abstinent users and active users show brain response abnormalities relative to controls during visual attention , suggesting lasting changes in patterns of neural activity. Together, these studies indicate that neuropsychological decrements observed after one 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 poly substance using youths, marijuana use has been linked to learning and memory and attention . In a longitudinal study, Fried and colleagues assessed cognitive functioning in 9- to 12-yearolds before the initiation of marijuana use, and again when youths were ages 17 – 21. After controlling for baseline performance and demographics, current heavy marijuana users showed poorer immediate and delayed memory, processing speed,and overall IQ. Further, a longitudinal study of ten cannabis-dependent adolescents demonstrated incomplete recovery of learning and memory impairments after six weeks of monitored abstinence , indicating that adolescents may be more susceptible to long-term changes than adults . Together, these studies point to dysfunctional working memory and attention abilities among heavy marijuana using youths 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 to teens with alcohol use disorder alone and non-abusing teens. After an average of eight 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,cannabis grow equipment suggesting compensatory working memory and attention activity associated with heavy marijuana use during youth . Yet it is unclear whether these abnormalities are solely a function of recent use or would present after more abstinence, suggesting persistent effects. A preliminary fMRI study explored verbal working memory among 7 adolescent marijuana, 7 demographically similar tobacco smokers and 7 non-users after a month of abstinence . Compared to other groups, marijuana users demonstrated increased right hippo campal 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 . After at least two weeks of abstinence, marijuana users showed increased parietal activation during nicotine withdrawal and poorer verbal delayed recall, while non-marijuana users did not . 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 a SWM task among marijuana using teens and non-abusing controls after 28 days of monitored abstinence. Blood oxygen level-dependent fMRI was collected during a SWM task that typically activates bilateral prefrontal and posterior parietal networks in adolescents , and has been associated with neural dysfunction among youths with alcohol use disorders as well as comorbid alcohol and marijuana use disorders .

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, based on prior findings in recently using and abstinent adolescent marijuana users.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 , approved by the University of California San Diego Human Research Protection Program. Each adolescent and a parent were separately administered detailed screening interviews . The computerized NIMH Diagnostic Interview Schedule for Children Predictive Scales  excluded adolescents with a psychiatric disorder based on youth or parent report. Teens in the marijuana group who met DSM-IV criteria for alcohol use disorder were not excluded due to high comorbidity with marijuana use disorder . Additional exclusionary criteria included prenatal substance exposure, psychotropic medication use, neurological dysfunction, head injury, family history of bipolar I or psychotic disorder as ascertained by the Family History Assessment Module screener , left-handedness, learning disorder, MRI contraindications, or substance use in the 28 days before scanning. Eligible teens were 15 heavy marijuana users and 17 demographically similar non-using controls . While most MJ teens were current users, five reported no use in the month before the monitored abstinence period. Groups were similar in gender and ethnic composition. Importantly, both MJ and control teens demonstrated similar levels of estimated premorbid IQ, as assessed by the Wechsler Abbreviated Scale of Intelligence Vocabulary subtest and socioeconomic status . MJ teens showed higher levels of depressive symptoms on the Hamilton Depression Rating Scale and Beck Depression Inventory , and higher levels of anxiety on the Hamilton Anxiety Rating Scale . MJ teens had more lifetime and recent experience with alcohol than controls , yet five MJ teens reported no alcohol use in the month before the abstinence period. Among current alcohol users, most were weekend binge drinkers. Both groups had low rates of nicotine use, but, MJ teens had used cigarettes more recently than controls, and four MJ teens smoked cigarettes on the day of the scan. Although MJ teens divulged more use of other drugs than controls , such use was limited to 25 lifetime experiences, most commonly oral opiates or hallucinogens.Substance use was characterized with the Customary Drinking and Drug Use Record , which collected lifetime and past 3-month information on marijuana, alcohol, nicotine, and other drug use, withdrawal symptoms, and DSM-IV abuse and dependence criteria. Based on CDDR reports, typical blood alcohol concentration achieved during drinking episodes was calculated using the Widmark method, based on amount and duration of drinking, height, weight, and gender . The Fagerstrom Test for Nicotine Dependence assessed degree of nicotine dependence on a scale of 0 – 10. The Timeline Follow back assessed substance use for 28 days before starting monitored abstinence, and for the 28 days of the abstinence period. Teens were asked to indicate for each day whether they used or drank, and if so, how many hits of marijuana, standard drinks of alcohol, or amount of other substances were used. The Hamilton Depression Rating Scale , Beck Depression Inventory , Hamilton Anxiety Rating Scale , and state scale of the Spielberger State Trait Anxiety Inventory assessed mood at the time of scanning.