Longitudinal study of cognition among adolescent marijuana users over three weeks of abstinence.

BACKGROUND: Cognitive deficits that persist up to a month have been detected among adult marijuana users, but decrements and their pattern of recovery are less known in adolescent users. Previously, we reported cognitive deficits among adolescent marijuana users after one month of abstinence (Medina, Hanson, Schweinsburg, Cohen-Zion, Nagel, & Tapert, 2007). In this longitudinal study, we characterized neurocognitive changes among marijuana-using adolescents across the first three weeks of abstinence. METHOD: Participants were adolescent marijuana users with limited alcohol and other drug use (n=19) and demographically similar non-using controls (n=21) ages 15-19. Participants completed a brief neuropsychological battery on three occasions, after 3days, 2weeks, and 3weeks of stopping substance use. Abstinence was ascertained by decreasing tetrahydrocannabinol metabolite values on serial urine drug screens. Verbal learning, verbal working memory, attention and vigilance, and time estimation were evaluated. RESULTS: Marijuana users demonstrated poorer verbal learning (p<.01), verbal working memory (p<.05), and attention accuracy (p<.01) compared to controls. Improvements in users were seen on word list learning after 2weeks of abstinence and on verbal working memory after 3weeks. While attention processing speed was similar between groups, attention accuracy remained deficient in users throughout the 3-week abstinence period. CONCLUSIONS: This preliminary study detected poorer verbal learning and verbal working memory among adolescent marijuana users that improved during three weeks of abstinence, while attention deficits persisted. These results implicate possible hippocampal, subcortical, and prefrontal cortex abnormalities.

A preliminary study of functional magnetic resonance imaging response during verbal encoding among adolescent binge drinkers.

Binge alcohol use is common among teenagers with 28% of 12th graders reporting getting drunk in the past month. Chronic heavy drinking has been associated with verbal learning and memory deficits in adolescents and adults, yet verbal encoding in less frequently drinking teens has not yet been studied. Here, we examined functional magnetic resonance imaging (fMRI) response during verbal encoding among adolescent binge drinkers. Participants recruited from local high schools were of ages 16-18 and consisted of 12 binge drinkers and 12 demographically similar nondrinkers. Participants were all nonsmokers, and drinkers were abstinent from alcohol for an average of 33 days at the time of scanning. Participants performed a verbal paired associates learning task during fMRI acquisition. Drinkers recalled marginally fewer words than nondrinkers (P=.07). Compared with nondrinkers, bingers showed more response in right superior frontal and bilateral posterior parietal cortices but less response in occipital cortex during novel encoding (Ps<.05, clusters >1,512microL). In addition, controls showed significant activation in the left hippocampus during novel encoding, whereas binge drinkers did not. Adolescent binge drinkers demonstrated (1) more response than nondrinkers in frontal and parietal regions, which could suggest greater engagement of working memory systems during encoding; (2) no hippocampal activation to novel word pairs; and (3) slightly poorer word pair recall, which could indicate disadvantaged processing of novel verbal information and a slower learning slope. Longitudinal studies will be needed to ascertain the degree to which emergence of binge drinking is linked temporally to these brain response patterns.

Altered white matter microstructure in adolescent substance users.

Chronic marijuana use during adolescence is frequently comorbid with heavy alcohol consumption and associated with CNS alterations, yet the influence of early cannabis and alcohol use on microstructural white matter integrity is unclear. Building on evidence that cannabinoid receptors are present in myelin precursors and affect glial cell processing, and that excessive ethanol exposure is associated with persistently impaired myelination, we used diffusion tensor imaging (DTI) to characterize white matter integrity in heavy substance using and non-using adolescents. We evaluated 36 marijuana and alcohol-using (MJ+ALC) adolescents (ages 16-19) and 36 demographically similar non-using controls with DTI. The diffusion parameters fractional anisotropy (FA) and mean diffusivity (MD) were subjected to whole-brain voxelwise group comparisons using tract-based spatial statistics (Smith, S.M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T.E., Mackay, C.E., Watkins, K.E., Ciccarelli, O., Cader, M.Z., Matthews, P.M., Behrens, T.E., 2006. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31, 1487-1505). MJ+ALC teens had significantly lower FA than controls in 10 regions, including left superior longitudinal fasciculus (SLF), left postcentral gyrus, bilateral crus cerebri, and inferior frontal and temporal white matter tracts. These diminutions occurred in the context of increased FA in right occipital, internal capsule, and SLF regions. Changes in MD were less distributed, but increased MD was evident in the right occipital lobe, whereas the left inferior longitudinal fasciculus showed lower MD in MJ+ALC users. Findings suggest that fronto-parietal circuitry may be particularly impacted in adolescent users of the most prevalent intoxicants: marijuana and alcohol. Disruptions to white matter in this young group could indicate aberrant axonal and myelin maturation with resultant compromise of fiber integrity. Findings of increased anisotropic diffusion in alternate brain regions suggest possible neuroadaptive processes and can be examined in future studies of connectivity to determine how aberrancies in specific tracts might influence efficient cognitive processing.

Altered white matter integrity in adolescent binge drinkers.

BACKGROUND: White matter integrity has been found to be compromised in adult alcoholics, but it is unclear when in the course of alcohol exposure white matter abnormalities become apparent. This study assessed microstructural white matter integrity among adolescent binge drinkers with no history of an alcohol use disorder. METHODS: We used diffusion tensor imaging to examine fractional anisotropy (FA), a measure of directional coherence of white matter tracts, among teens with (n = 14) and without (n = 14) histories of binge drinking but no history of alcohol use disorder, matched on age, gender, and education. RESULTS: Binge drinkers had lower FA than controls in 18 white matter areas (clusters > or =27 contiguous voxels, each with p < 0.01) throughout the brain, including the corpus callosum, superior longitudinal fasciculus, corona radiata, internal and external capsules, and commissural, limbic, brainstem, and cortical projection fibers, while exhibiting no areas of higher FA. Among binge drinkers, lower FA in 6 of these regions was linked to significantly greater lifetime hangover symptoms and/or higher estimated peak blood alcohol concentrations. CONCLUSIONS: Binge drinking adolescents demonstrated widespread reductions of FA in major white matter pathways. Although preliminary, these results could indicate that infrequent exposure to large doses of alcohol during youth may compromise white matter fiber coherence.

Effects of family history of alcohol use disorders on spatial working memory BOLD response in adolescents.

BACKGROUND: A positive family history (FH) of alcohol use disorders (AUD) has been linked to increased risk for the development of AUD, and neurocognitive factors have been postulated as important underlying mechanisms of familial alcoholism transmission. METHODS: We used functional magnetic resonance imaging (fMRI) during a spatial working memory (SWM) and vigilance paradigm to investigate potential neurodevelopmental differences linked to familial density of AUD in 72 adolescents aged 12 to 14 years. RESULTS: Youth with denser family histories of AUD showed less activation during a simple vigilance condition relative to SWM in cingulate and medial frontal gyri (beta = 0.28, p = 0.03), and a trend for more relative activity during rest (beta = -0.25, p = 0.07) in this cluster. CONCLUSIONS: Youth with greater familial densities of AUD may be less successful at modulating activity of the default network, potentially indicating a greater propensity for task-independent thought or reduced inhibition of task-irrelevant processing. Failure to moderate activation of the default network may have implications for cognitive efficiency and goal directed behavior in youth with dense FH. Further, aberrant activation in cingulate regions may be linked to genetic variation in GABA receptor units, suggesting a useful endophenotype for risk associated with alcohol dependence.

Abstinent adolescent marijuana users show altered fMRI response during spatial working memory.

Marijuana is the most widely used illicit substance among teenagers, yet little is known about the possible neural influence of heavy marijuana use during adolescence. We previously demonstrated an altered functional magnetic resonance imaging (fMRI) activity related to spatial working memory (SWM) among adolescents who were heavy users of after an average of 8 days of abstinence, but the persisting neural effects remain unclear. To characterize the potentially persisting neurocognitive effects of heavy marijuana use in adolescence, we examined fMRI response during SWM among abstinent marijuana-using teens. Participants were 15 MJ teens and 17 demographically similar non-using controls, ages 16-18. Teens underwent biweekly urine toxicology screens to ensure abstinence for 28 days before fMRI acquisition. Groups performed similarly on the SWM task, but MJ teens demonstrated lower activity in right dorsolateral prefrontal and occipital cortices, yet significantly more activation in right posterior parietal cortex. MJ teens showed abnormalities in brain response during a SWM task compared with controls, even after 1 month of abstinence. The activation pattern among MJ teens may reflect different patterns of utilization of spatial rehearsal and attention strategies, and could indicate altered neurodevelopment or persisting abnormalities associated with heavy marijuana use in adolescence.

Microstructural integrity of the corpus callosum linked with neuropsychological performance in adolescents.

BACKGROUND: Diffusion tensor imaging (DTI) has revealed microstructural aspects of adolescent brain development, the cognitive correlates of which remain relatively uncharacterized. METHODS: DTI was used to assess white matter microstructure in 18 typically developing adolescents (ages 16-18). Fractional anisotropy (FA) and mean diffusion (MD) were evaluated within the splenium and body of the corpus callosum in relation to cognitive performance. RESULTS: Visuospatial construction abilities were associated with white matter integrity in both the splenium and body of the corpus callosum, while only splenium integrity was associated with language and psychomotor function. CONCLUSION: Results suggest that, for typically developing adolescents, white matter coherence positively relates to visuospatial, psychomotor, and language skills. These findings may have implications for the cognitive functioning of clinical populations in which typical white matter development is altered.

Prefrontal cortex volumes in adolescents with alcohol use disorders: unique gender effects.

BACKGROUND: Adolescents with alcohol use disorders (AUD) have shown smaller prefrontal cortex (PFC) volumes compared with healthy controls; however, differences may have been due to comorbid disorders. This study examined PFC volumes in male and female adolescents with AUD who did not meet criteria for comorbid mood or attention disorders. METHODS: Participants were adolescents aged 15 to 17 who met criteria for AUD (n = 14), and demographically similar healthy controls (n = 17). Exclusions included any history of a psychiatric or neurologic disorder other than AUD or conduct disorder. Magnetic resonance imaging scans occurred after at least 5 days of abstinence from alcohol or drugs. Overall PFC volumes and white matter PFC volumes were compared between groups. RESULTS: After controlling for conduct disorder, gender, and intracranial volume, AUD teens demonstrated marginally smaller anterior ventral PFC volumes (p = 0.09) than controls, and significant interactions between group and gender were observed (p < 0.001 to p < 0.03). Compared with same-gender controls, females with AUD demonstrated smaller PFC volumes, while males with AUD had larger PFC volumes. The same pattern was observed for PFC white matter volumes. CONCLUSIONS: Consistent with adult literature, alcohol use during adolescence is associated with prefrontal volume abnormalities, including white matter differences. However, adolescents with AUD demonstrated gender-specific morphometric patterns. Thus, it is possible that gender may moderate the impact of adolescent alcohol use on prefrontal neurodevelopment, and the neurodevelopmental trajectories of heavy drinking boys and girls should be evaluated separately in longitudinal studies.

The influence of marijuana use on neurocognitive functioning in adolescents.

Marijuana use is common in adolescence, yet neural consequences have not been well delineated. This review seeks to ascertain whether heavy marijuana use in adolescence is associated with persistent neurocognitive abnormalities, and whether adolescents are more vulnerable to the impact of chronic marijuana use than adults. Among heavy marijuana using adults, neurocognitive deficits are apparent for several days following use, but may disappear after one month of abstinence. Studies of adolescent heavy users have identified impairments in learning and working memory up to six weeks after cessation, suggesting persisting effects, yet raise the possibility that abnormalities may remit with a longer duration of abstinence. Given ongoing neuromaturation during youth, adolescents may be more vulnerable to potential consequences of marijuana use than adults. This is supported by rodent models, which show greater memory impairments in animals exposed to cannabinoids as adolescents relative to those exposed as adults. Further, adult humans who initiated use in early adolescence show greater dysfunction than those who began use later. Together, these results suggest that adolescents are more vulnerable than adults to neurocognitive abnormalities associated with chronic heavy marijuana use; however, the impact of preexisting risk factors is unknown. Adolescents demonstrate persisting deficits related to heavy marijuana use for at least six weeks following discontinuation, particularly in the domains of learning, memory, and working memory. Further, adolescents appear more adversely affected by heavy use than adults. Longitudinal studies will help ascertain whether preexisting differences contribute to these abnormalities.

Spatial working memory performance and fMRI activation interaction in abstinent adolescent marijuana users.

Previous studies have suggested neural disruption and reorganization in adult marijuana users. However, it remains unclear whether these effects persist in adolescents after 28 days of abstinence and, if they do, what Performance x Brain Response interactions occur. Adolescent marijuana users (n=17) and controls (n=17) aged 16-18 years were recruited from local schools. Functional magnetic resonance imaging data were collected after 28 days' monitored abstinence as participants performed a spatial working memory task. Marijuana users show Performance x Brain Response interactions in the bilateral temporal lobes, left anterior cingulate, left parahippocampal gyrus, and right thalamus (clusters >/=1358 microl; p<.05), although groups do not differ on behavioral measures of task performance. Marijuana users show differences in brain response to a spatial working memory task despite adequate performance, suggesting a different approach to the task via altered neural pathways.

Neuropsychological functioning in adolescent marijuana users: subtle deficits detectable after a month of abstinence.

In adults, studies examining the long-lasting cognitive effects of marijuana use demonstrate subtle deficits in attention, executive function, and memory. Because neuromaturation continues through adolescence, these results cannot necessarily generalize to adolescent marijuana users. The goal of this study was to examine neuropsychological functioning in abstinent marijuana using and demographically similar control adolescents. Data were collected from 65 adolescent marijuana users (n=31, 26% females) and controls (n=34, 26% females) 16-18 years of age. Extensive exclusionary criteria included independent psychiatric, medical, and neurologic disorders. Neuropsychological assessments were conducted after>23 days of monitored abstinence. After controlling for lifetime alcohol use and depressive symptoms, adolescent marijuana users demonstrated slower psychomotor speed (p<.05), and poorer complex attention (p<.04), story memory (p<.04), and planning and sequencing ability (p<.001) compared with controls. Post hoc analysis revealed that the number of lifetime marijuana use episodes was associated with poorer cognitive function, even after controlling for lifetime alcohol use. The general pattern of results suggested that, even after a month of monitored abstinence, adolescent marijuana users demonstrate subtle neuropsychological deficits compared with nonusers. It is possible that frequent marijuana use during adolescence may negatively influence neuromaturation and cognitive development.

Functional MRI of inhibitory processing in abstinent adolescent marijuana users.

BACKGROUND: Marijuana intoxication appears to impair response inhibition, but it is unclear if impaired inhibition and associated brain abnormalities persist after prolonged abstinence among adolescent users. We hypothesized that brain activation during a go/no-go task would show persistent abnormalities in adolescent marijuana users after 28 days of abstinence. METHODS: Adolescents with (n = 16) and without (n = 17) histories of marijuana use were compared on blood oxygen level dependent (BOLD) response to a go/no-go task during functional magnetic resonance imaging (fMRI) after 28 days of monitored abstinence. Participants had no neurological problems or Axis I diagnoses other than cannabis abuse/dependence. RESULTS: Marijuana users did not differ from non-users on task performance but showed more BOLD response than non-users during inhibition trials in right dorsolateral prefrontal, bilateral medial frontal, bilateral inferior and superior parietal lobules, and right occipital gyri, as well as during "go" trials in right prefrontal, insular, and parietal cortices (p < 0.05, clusters > 943 microl). Differences remained significant even after controlling for lifetime and recent alcohol use. CONCLUSIONS: Adolescent marijuana users relative to non-users showed increased brain processing effort during an inhibition task in the presence of similar task performance, even after 28 days of abstinence. Thus, increased brain processing effort to achieve inhibition may predate the onset of regular use or result from it. Future investigations will need to determine whether increased brain processing effort is associated with risk to use.

Effects of alcohol and combined marijuana and alcohol use during adolescence on hippocampal volume and asymmetry.

BACKGROUND: Converging lines of evidence suggest that the hippocampus may be particularly vulnerable to deleterious effects of alcohol and marijuana use, especially during adolescence. The goal of this study was to examine hippocampal volume and asymmetry in adolescent users of alcohol and marijuana. METHODS: Participants were adolescent (aged 15-18) alcohol (ALC) users (n=16), marijuana and alcohol (MJ+ALC) users (n=26), and demographically similar controls (n=21). Extensive exclusionary criteria included prenatal toxic exposure, left handedness, and psychiatric and neurologic disorders. Substance use, cognitive, and anatomical measures were collected after at least 2 days of abstinence from all substances. RESULTS: Adolescent ALC users demonstrated a significantly different pattern of hippocampal asymmetry (p<.05) and reduced left hippocampal volume (p<.05) compared to MJ+ALC users and non-using controls. Increased alcohol abuse/dependence severity was associated with increased right>left (R>L) asymmetry and smaller left hippocampal volumes while marijuana abuse/dependence was associated with increased L>R asymmetry and larger left hippocampal volumes. Although MJ+ALC users did not differ from controls in asymmetry, functional relationships with verbal learning were found only among controls, among whom greater right than left hippocampal volume was associated with superior performance (p<.05). CONCLUSIONS: Aberrations in hippocampal asymmetry and left hippocampal volumes were found for adolescent heavy drinkers. Further, the functional relationship between hippocampal asymmetry and verbal learning was abnormal among adolescent substance users compared to healthy controls. These findings suggest differential effects of alcohol and combined marijuana and alcohol use on hippocampal morphometry and the relationship between hippocampal asymmetry and verbal learning performance among adolescents.

Age-related changes in prefrontal white matter volume across adolescence.

Past research has suggested that white matter volume increases from childhood to adulthood; however, during adolescence, there is somewhat limited data to support this finding. In the present study, 65 typically developing adolescents underwent structural magnetic resonance imaging. Using magnetic resonance imaging, prefrontal white matter volumes were examined in relation to adolescent age and sex. Surprisingly, results suggested that prefrontal white matter volume decreased during late adolescence, particularly among the female sex. These findings are inconsistent with past research and suggest that perhaps some developmental processes in late adolescence are not yet fully explained. Possible methodological contributions and implications for the current findings are discussed.

fMRI reveals alteration of spatial working memory networks across adolescence.

Recent studies have described neuromaturation and cognitive development across the lifespan, yet few neuroimaging studies have investigated task-related alterations in brain activity during adolescence. We used functional magnetic resonance imaging (fMRI) to examine brain response to a spatial working memory (SWM) task in 49 typically developing adolescents (25 females and 24 males; ages 12-17). No gender or age differences were found for task performance during SWM. However, age was positively associated with SWM brain response in left prefrontal and bilateral inferior posterior parietal regions. Age was negatively associated with SWM activation in bilateral superior parietal cortex. Gender was significantly associated with SWM response; females demonstrated diminished anterior cingulate activation and males demonstrated greater response in frontopolar cortex than females. Our findings indicate that the frontal and parietal neural networks involved in spatial working memory change over the adolescent age range and are further influenced by gender. These changes may represent evolving mnemonic strategies subserved by ongoing adolescent brain development.

Neuropsychological predictors of BOLD response during a spatial working memory task in adolescents: what can performance tell us about fMRI response patterns?

The relationship between standardized neuropsychological test performance and functional magnetic resonance imaging (fMRI) response during cognitive tasks is largely unknown. This exploratory investigation examined the relationship between neuropsychological test performance and fMRI response to a spatial working memory (SWM) task among 49 typically developing adolescents. Participants were administered a variety of neuropsychological tests in the domains of working memory, visuospatial skills, executive functioning, attention, learning and memory, visuomotor skills and processing speed, and language functioning. Neuropsychological domain scores were used to predict fMRI response during a SWM task. Results suggest that in many brain regions, neuropsychological performance negatively predicts fMRI response, suggesting that those teens with better neuropsychological abilities required fewer neural resources to adequately perform the task. This study provides further understanding of how neuropsychological abilities relate to neural activity during fMRI tasks, and provides an important link between neuropsychological and fMRI research.

Reduced hippocampal volume among adolescents with alcohol use disorders without psychiatric comorbidity.

Studies have suggested that teens with alcohol use disorder (AUD) can demonstrate memory deficits, but the underlying neuroanatomical substrates are unclear. The hippocampus is crucial to intact memory functioning, and it actively develops during adolescence. The current study attempted to replicate and extend previous findings suggesting that adolescents with AUD show smaller hippocampal volumes than healthy adolescents. Manual tracings of bilateral hippocampi were performed on structural magnetic resonance images of 14 adolescents (ages 15 to 17 years) with AUD and 17 healthy comparison teens. Intracranial, white, and gray matter volumes, as well as memory abilities, were also measured. Results revealed that adolescents with AUD had significantly smaller left hippocampal volumes than healthy teens, even after removal of teens with comorbid conduct disorder from the analyses. In contrast the groups did not differ in right hippocampal, intracranial, gray or white matter volumes, or memory performance. Hippocampal volumes were not related to alcohol-consumption rates. These findings indicate that adolescents with AUD, but free from other psychiatric comorbidities, have reduced left hippocampal volume. Because hippocampal volume did not relate to alcohol use characteristics, it is possible that premorbid volumetric differences could account for some of the observed group differences in hippocampal volume.

fMRI response to spatial working memory in adolescents with comorbid marijuana and alcohol use disorders.

Alcohol and marijuana use are prevalent in adolescence, yet the neural impact of concomitant use remains unclear. We previously demonstrated functional magnetic resonance imaging (fMRI) response to spatial working memory (SWM) among teens with alcohol use disorders (AUD) compared to controls, and predicted that adolescents with marijuana and alcohol use disorders would show additional abnormalities. Participants were three groups of 15-17-year-olds: 19 non-abusing controls, 15 AUD teens with limited exposure to drugs, and 15 teens with comorbid marijuana and alcohol use disorders (MAUD) and minimal other drug experience. After >2 days' abstinence, participants performed a SWM task during fMRI acquisition. fMRI brain response patterns differed between groups, despite similar performance on the task. MAUD youths showed less activation in inferior frontal and temporal regions than controls, and more response in other prefrontal regions. Compared to AUD teens, MAUD youths also showed less inferior frontal and temporal activation, but more medial frontal response. Overall, MAUD youths showed different brain response abnormalities than teens with AUD alone, despite relatively short histories of substance involvement. This pattern could suggest compensation for marijuana-related attention and working memory deficits. However, relatively recent use and premorbid features may influence results, and should be examined in future studies.

Gender and adolescent alcohol use disorders on BOLD (blood oxygen level dependent) response to spatial working memory.

AIMS: To determine how alcohol use differentially affects brain functioning in male and female adolescents. METHODS: Adolescents with alcohol use disorders (AUDs; 7 female, 11 male) and control adolescents without AUDs (9 female, 12 male), aged 14-17 years, performed spatial working memory and vigilance tasks during functional magnetic resonance imaging. RESULTS: Gender, AUD and their interaction were significantly associated with brain activation patterns to the tasks. There were interactions in the superior frontal, superior temporal, cingulate and fusiform regions, in which female and male adolescents with AUDs showed a different brain response from each other and control subjects. Overall, female adolescents with AUDs showed a greater departure from normal activation patterns than male adolescents with AUD. CONCLUSIONS: Adolescent alcohol involvement may affect male and female brains differently, and adolescent females may be somewhat more vulnerable to adverse alcohol effects. With continued drinking, these adolescents may be at an increased risk for behavioural deficits.