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1.  White Matter Integrity, Substance Use, and Risk Taking in Adolescence 
White matter development is important for efficient communication between brain regions, higher order cognitive functioning, and complex behaviors. Adolescents have a higher propensity for engaging in risky behaviors, yet few studies have explored associations between white matter integrity and risk taking directly. Altered white matter integrity in mid-adolescence was hypothesized to predict subsequent risk taking behaviors 1.5 years later. Adolescent substance users (predominantly alcohol and marijuana, n=47) and demographically similar non-users (n=49) received diffusion tensor imaging at baseline (ages 16–19), and risk taking measures at both baseline and an 18-month follow-up (i.e., at ages 17–20). Brain regions of interest were: fornix, superior corona radiata, superior longitudinal fasciculus, and superior fronto-occipital fasciculus. In substance using youth (n=47), lower white matter integrity at baseline in the fornix and superior corona radiata predicted follow-up substance use (ΔR2 =10–12%, ps < .01), and baseline fornix integrity predicted follow-up delinquent behaviors (ΔR2 = 10%, p < .01) 1.5 years later. Poorer fronto-limbic white matter integrity was linked to a greater propensity for future risk taking behaviors among youth who initiated heavy substance use by mid-adolescence. Most notable were relationships between projection and limbic system fibers and future substance use frequency. Subcortical white matter coherence along with an imbalance between the maturation levels in cognitive control and reward systems may disadvantage the resistance to engage in risk taking behaviors during adolescence.
PMCID: PMC3416962  PMID: 22564204
DTI; risk taking; white matter; marijuana; alcohol; adolescence
2.  The effect of alcohol use on human adolescent brain structures and systems 
Handbook of clinical neurology  2014;125:501-510.
PMCID: PMC4321715  PMID: 25307592
3.  Effects of Cannabis on the Adolescent Brain 
Current pharmaceutical design  2014;20(13):2186-2193.
This article reviews neuroimaging, neurocognitive, and preclinical findings on the effects of cannabis on the adolescent brain. Marijuana is the second most widely used intoxicant in adolescence, and teens who engage in heavy marijuana use often show disadvantages in neurocognitive performance, macrostructural and microstructural brain development, and alterations in brain functioning. It remains unclear whether such disadvantages reflect pre-existing differences that lead to increased substances use and further changes in brain architecture and behavioral outcomes. Future work should focus on prospective investigations to help disentangle dose-dependent effects from pre-existing effects, and to better understand the interactive relationships with other commonly abused substances (e.g., alcohol) to better understand the role of regular cannabis use on neurodevelopmental trajectories.
PMCID: PMC3930618  PMID: 23829363
4.  A longitudinal examination of adolescent response inhibition: Neural differences before and after the initiation of heavy drinking 
Psychopharmacology  2013;230(4):10.1007/s00213-013-3198-2.
Response inhibition abnormalities contribute to several maladaptive behaviors commonly observed during adolescence, including heavy drinking.
The present study aimed to determine whether abnormalities in brain response during response inhibition predate or follow adolescents' transition into heavy drinking, which is pivotal in identifying the neural antecedents and consequences of adolescent alcohol use.
Longitudinal functional magnetic resonance imaging (fMRI) acquired during a response inhibition task was collected on adolescents before the onset of heavy drinking, and then again on the same scanner approximately 3 years later. Adolescents who transitioned into heavy drinking (n=20) were matched to continuously nondrinking adolescents (n=20) on baseline and follow-up demographic and developmental variables.
During no-go relative to go trials, participants showed responses common to inhibitory circuitry: frontal (e.g., pre-supplementary motor area), temporal, and parietal regions. A repeated measures analysis of covariance revealed that adolescents who later transitioned into heavy drinking showed less fMRI response contrast at baseline than continuous nondrinkers in frontal, parietal, subcortical, and cerebellar regions (p < .01, clusters > 756 microliters), then increased activation after the onset of heavy drinking in frontal, parietal, and cerebellar areas.
Future heavy drinkers showed less activation of inhibitory circuitry before the onset of heavy drinking. After transitioning into heavy drinking, they showed more activation during response inhibition than nondrinking controls. These results contribute to the growing literature suggesting that neural vulnerabilities exist prior to the onset of substance use, and the initiation of heavy drinking may lead to additional alterations in brain functioning.
PMCID: PMC3840110  PMID: 23832422
Alcohol; inhibition; neuroimaging; heavy drinking
5.  Early Adolescent Cortical Thinning Is Related to Better Neuropsychological Performance 
Adolescence is characterized by significant neuromaturation, including extensive cortical thinning, particularly in frontal regions. The goal of this study was to examine the behavioral correlates of neurostructural development in early adolescence. Participants were 185 healthy 12- to 14-year-olds (44% female) recruited from local schools. Participants completed a comprehensive neuropsychological test battery and magnetic resonance imaging session. Cortical surface reconstruction and thickness estimates were performed via FreeSurfer. Age and cortical thickness were negatively correlated in 10 brain regions, 7 of which were in frontal areas (β = −.15 to −.25, ps ≤.05). Hierarchical linear regressions examined the influence of cortical thickness on working memory, attention, verbal learning and memory, visuospatial functioning, spatial planning and problem solving, and inhibition, controlling for age and intracranial volume. Thinner parietal cortices predicted better performances on tests of verbal learning and memory, visuospatial functioning, and spatial planning and problem solving (β = −.14 to −.24, ps ≤.05). Age, spanning from 12 to 14 years, accounted for up to 6% of cortical thickness, suggesting substantial thinning during early adolescence, with males showing more accelerated thinning than females between ages 12 and 14. For both males and females, thinner parietal association cortices corresponded with better neurocognitive functioning above and beyond age alone.
PMCID: PMC3791607  PMID: 23947395
Adolescence; Cortical thickness; FreeSurfer; Neurocognitive testing; Neuropsychology; Normal development
6.  Spatial Working Memory Performance and fMRI Activation Interactions 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 × 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 × Brain Response interactions in the bilateral temporal lobes, left anterior cingulate, left parahippocampal gyrus, and right thalamus (clusters ≥ 1358 μl; 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.
PMCID: PMC2373252  PMID: 18072830
marijuana; cannabis; adolescence; spatial working memory; functional magnetic resonance imaging
7.  White matter characterization of adolescent binge drinking with and without co-occurring marijuana use: A 3-year investigation 
Psychiatry research  2013;214(3):374-381.
The aims of this study were to investigate the consequences of prolonged patterns of alcohol and marijuana use on white matter integrity and neurocognitive functioning in late adolescence, and examine neurodevelopmental trajectories over three years of regular follow-up visits. Three groups of demographically similar teens received assessments every 1.5 years (controls with consistently minimal substance use, n = 16; teens who gradually increase their heavy episodic drinking n = 17, and continuous binge drinkers with heavy marijuana use, n = 21), including comprehensive neuropsychological evaluations, diffusion tensor imaging, and detailed substance use interviews. One-way ANOVA identified fifteen white matter clusters that significantly differed between groups at 3-year follow-up, ages 19–22; controls consistently demonstrated higher values of tissue integrity across fiber tracts. Repeated measures ANOVA revealed significant declines in white matter integrity from baseline to 3-year follow-up in the subsample of substance users, along with poorer global neurocognitive performance in alcohol users with heavy marijuana use by the 18-month follow-up. Findings suggest healthier brain white matter microstructure and better neurocognitive performance for teens free from heavy alcohol and marijuana use. Long-term engagement in these substances may adversely influence white matter and increase vulnerability for development of neuropathology purported to underlie future risk-taking and addictive behaviors.
PMCID: PMC3900025  PMID: 24139957
Adolescence; Alcohol; Diffusion Tensor Imaging; Cannabis; Brain; Cognition
8.  Gender effects on amygdala morphometry in adolescent marijuana users 
Behavioural brain research  2011;224(1):128-134.
Adolescent developments in limbic structures and the endogenous cannabinoid system suggest that teenagers may be more vulnerable to the negative consequences of marijuana use. This study examined the relationships between amygdala volume and internalizing symptoms in teenaged chronic marijuana users. Participants were 35 marijuana users and 47 controls ages 16–19 years. Exclusions included psychiatric (e.g., mood and anxiety) or neurologic disorders. Substance use, internalizing (anxiety/depression) symptoms and brain scans were collected after 28 days of monitored abstinence. Reliable raters manually traced amygdala and intracranial volumes on high-resolution magnetic resonance images. Female marijuana users had larger right amygdala volumes and more internalizing symptoms than female controls, after covarying head size, alcohol, nicotine and other substance use (p<0.05), while male users had similar volumes as male controls. For female controls and males, worse mood/anxiety was linked to smaller right amygdala volume (p<0.05), whereas more internalizing problems was associated with bigger right amygdala in female marijuana users. Gender interactions may reflect marijuana-related interruptions to sex-specific neuromaturational processes and staging. Subtle amygdala development abnormalities may underlie particular vulnerabilities to sub-diagnostic depression and anxiety in teenage female marijuana users.
PMCID: PMC3139567  PMID: 21664935
Adolescence; Anxiety; Depression; Development; Gender; Marijuana; Structural MRI
9.  Adolescent Binge Drinking Linked to Abnormal Spatial Working Memory Brain Activation: Differential Gender Effects 
Binge drinking is prevalent during adolescence, and its effect on neurocognitive development is of concern. In adult and adolescent populations, heavy substance use has been associated with decrements in cognitive functioning, particularly on tasks of spatial working memory (SWM). Characterizing the gender-specific influences of heavy episodic drinking on SWM may help elucidate the early functional consequences of drinking on adolescent brain functioning.
40 binge drinkers (13 females, 27 males) and 55 controls (24 females, 31 males) ages 16 to 19, completed neuropsychological testing, substance use interviews, and a spatial working memory task (SWM) during functional magnetic resonance imaging (fMRI).
Significant binge drinking status x gender interactions were found (p<.05) in 8 brain regions spanning bilateral frontal, anterior cingulate, temporal, and cerebellar cortices. In all regions, female binge drinkers showed less SWM activation than female controls, while male bingers exhibited greater SWM response than male controls. For female binge drinkers, less activation was associated with poorer sustained attention and working memory performances (ps<.025). For male binge drinkers, greater activation was linked to better spatial performance (p<.025).
Binge drinking during adolescence is associated with gender-specific differences in frontal, temporal, and cerebellar brain activation during a SWM task, which in turn relate to cognitive performance. Activation correlates with neuropsychological performance, strengthening the argument that BOLD activation is both affected by alcohol use and is an important indicator of behavioral functioning. Females may be more vulnerable to the neurotoxic effects of heavy alcohol use during adolescence, while males may be more resilient to the deleterious effects of binge drinking. Future longitudinal research will examine the significance of SWM brain activation as an early neurocognitive marker of alcohol impact to the brain on future behaviors such as driving safety, academic performance, and neuropsychological performance.
PMCID: PMC3183294  PMID: 21762178
adolescence; alcohol; binge; gender; fMRI
10.  Neural Correlates of Verbal Learning in Adolescent Alcohol and Marijuana Users 
Addiction (Abingdon, England)  2010;106(3):564-573.
Alcohol and marijuana are the most widely used intoxicants among adolescents, yet their potential unique and interactive influences on the developing brain are not well established. Brain regions subserving learning and memory undergo continued maturation during adolescence, and may be particularly susceptible to substance-related neurotoxic damage. Here, we characterize brain response during verbal learning among adolescent users of alcohol and marijuana.
Participants performed a verbal paired associates encoding task during fMRI scanning.
Adolescent subjects were recruited from local public schools and imaged at a University-based fMRI Center.
Participants were 74 16- to 18-year-olds, divided into four groups: (1) 22 controls with limited alcohol and marijuana experience, (2) 16 binge drinkers, (3) 8 marijuana users, and (4) 28 binge drinking marijuana users.
Diagnostic interview assured that all teens were free from neurologic or psychiatric disorders; urine toxicology and breathalyzer verified abstinence for 22–28 days before scanning; a verbal paired associates task was administered during fMRI.
Groups demonstrated no differences in performance on the verbal encoding task, yet exhibited different brain response patterns. A main effect of drinking pointed to decreased inferior frontal but increased dorsal frontal and parietal fMRI response among binge drinkers (corrected p < .05). There was no main effect of marijuana use. Binge drinking × marijuana interactions were found in bilateral frontal regions (corrected p < .05), where users of either alcohol or marijuana showed greater response than non-users, but users of both substances resembled non-users.
Adolescent substance users demonstrated altered fMRI response relative to nonusing controls, yet binge drinking appeared associated with more differences in activation than marijuana use. Alcohol and marijuana may have interactive effects that alter these differences, particularly in prefrontal brain regions.
PMCID: PMC3423457  PMID: 21134014
adolescence; functional magnetic resonance imaging; verbal learning; cannabis; alcohol; binge drinking
11.  Resting-State Functional Connectivity of Subgenual Anterior Cingulate Cortex in Depressed Adolescents 
Biological psychiatry  2013;74(12):898-907.
Very few studies have been performed to understand the underlying neural substrates of adolescent major depressive disorder (MDD). Studies in depressed adults have demonstrated that the subgenual anterior cingulate cortex (sgACC) plays a pivotal role in depression and have revealed aberrant patterns of resting-state functional connectivity (RSFC). Here, we examine the RSFC of the sgACC in medication-naïve first-episode adolescents with MDD.
Twenty-three adolescents with MDD and 36 well-matched control subjects underwent functional magnetic resonance imaging to assess the RSFC of the sgACC.
We observed elevated connectivity between the sgACC and the insula and between the sgACC and the amygdala in the MDD group compared with the control subjects. Decreased connectivity between the sgACC and the precuneus was also found in the MDD group relative to the control subjects. Within the MDD group, higher levels of depression significantly correlated with decreased connectivity between the sgACC and left precuneus. Increased rumination was significantly associated with reduced connectivity between sgACC and the middle and inferior frontal gyri in the MDD group.
Our study is the first to examine sgACC connectivity in medication-naïve first-episode adolescents with MDD compared with well-matched control participants. Our results suggest aberrant functional connectivity among the brain networks responsible for salience attribution, executive control, and the resting-state in the MDD group compared with the control participants. Our findings raise the possibility that therapeutic interventions that can restore the functional connectivity among these networks to that typical of healthy adolescents might be a fruitful avenue for future research.
PMCID: PMC4103629  PMID: 23910949
Adolescent major depression; amygdala; default mode network; insula; resting-state; subgenual anterior cingulate
12.  What do you feel? Adolescent Drug and Alcohol Users Show Altered Brain Response to Pleasant Interoceptive Stimuli* 
Drug and alcohol dependence  2013;133(2):10.1016/j.drugalcdep.2013.08.015.
Altered interoception, i.e., processing of stimuli from inside the body, has been considered an important component of drug-taking behavior. However, approaches to examine interoceptive sensitivity in humans have been limited. This study examined the hypothesis that adolescents with substance use disorder show altered interoceptive processing, measured by stimulating mechanoreceptive C-fibers (MR-CF) via soft touch.
Adolescents with substance use disorders (SUD, n=15) and comparison youth (CON, n=17) underwent functional magnetic resonance imaging (fMRI) during anticipation or reception of a positively valenced “Soft Touch” consisting of MR-CF stimulation to the palm or forearm. Visual analog scales (VAS) indexed subjective interoceptive experience (e.g., pleasantness, intensity).
Across all conditions, SUD displayed attenuated left posterior insula activation compared to CON . Greater left anterior insula and right lentiform nucleus activation was evident during the application of soft touch for SUD but not for CON. Whereas for CON, greater left anterior insula activation was associated with higher pleasantness ratings, pleasantness was linked to less anterior insula activation in SUD. Finally, within SUD, attenuated posterior insula activation was related to more recent cannabis use.
SUD adolescents exhibit blunted somatovisceral processing of pleasant stimulation, heightened sensitivity in regions responsible for processing reward value, and altered relationships between interoceptive processing and subjective experience.
PMCID: PMC3880189  PMID: 24071571
alcohol; cannabis; interoception; reward; fMRI
13.  Changes in Neuropsychological Functioning over 10 Years Following Adolescent Substance Abuse Treatment 
Previously, Anderson, Ramo, Cummins, and Brown (2010) described six distinct patterns of alcohol and other drug (AOD) use during the decade following adolescents’ treatment for alcohol and other substance use disorders (A/SUD). This time period represents a phase of significant neurodevelopment and the influence of substance use on the brain is a concern. In the present study we examined patterns of neuropsychological function over these 10 years in relation to the AOD trajectories identified for youth as they transition into their twenties. Participants were part of a longitudinal research project following adolescents with and without A/SUD who received neuropsychological examinations at baseline and up to 7 times thereafter spanning 10 years (N=213; 46% female at baseline). Neuropsychological trajectories were significantly related to substance involvement patterns over time on measures of verbal learning and memory (ps=.011 to <.0001), visuospatial memory (p=.0002), and verbal attention/working memory (p=.020), with heavier use patterns generally followed by poorer cognition. Heavy use of alcohol alone was independently associated with poorer verbal memory over time. Further, substance withdrawal symptoms during each follow-up time point were related to poorer verbal learning and memory scores (ps<.05), while substance abuse/dependence diagnostic criteria were not related to neuropsychological performance levels. These findings suggest that AOD use during adolescence and young adulthood may primarily influence performance that relies on later maturing brain structures, although further research is needed. Higher levels of AOD withdrawal symptoms may signify greater neuropsychological impairment, reflecting potential neurotoxic effects of AOD use.
PMCID: PMC3066459  PMID: 21443308
Adolescence; alcohol abuse; drug abuse; neuropsychological assessment; longitudinal
14.  BOLD Response to Working Memory Not Related to Cortical Thickness during Early Adolescence 
Brain research  2013;1537:10.1016/j.brainres.2013.08.053.
Significant cortical thinning and neural resource allocation changes emerge during adolescence; however, little is known of how morphometric changes influence neural response to cognitive demands. This study used a novel multimodal imaging registration technique to examine the relationship between brain structure and function during adolescence.
156 healthy 12–14 year-olds (44% female) participants underwent structural and functional magnetic resonance imaging. Cortical surface reconstruction was performed via FreeSurfer, and neural activation was measured from a blood oxygen level dependent (BOLD) contrast during visual working memory (VWM) via AFNI. AFNI Surface Mapper aligned segmented volumetric and functional datasets to a common template space. Hierarchical linear regressions determined the effect of cortical thickness on VWM BOLD contrast in brain regions that activated during the VWM task, controlling for age, pubertal development, gender, IQ, and intracranial volume.
Power analyses suggest this study was able to detect small effect sizes. However, in no region was cortical thickness related to BOLD activation (ps > .01; R2Δ < .02). Gender did not moderate effects.
Cortical thickness, although variable across individuals, was not related to BOLD response, suggesting that structural and functional maturation do not have the same developmental trajectory during early adolescence. These findings are important, as imaging studies that report group differences in regards to cortical thickness should not necessarily assume co-occurring behavioral or functional changes. The methodology used in this study could be of interest to other developmental neuroimaging researchers using multimodal imaging to understand adolescent brain development.
PMCID: PMC3833275  PMID: 24012876
adolescence; cortical thickness; brain activation; BOLD response; normal development; visual working memory
15.  Altered Cerebral Perfusion in Executive, Affective, and Motor Networks During Adolescent Depression 
While substantial literature has reported regional cerebral blood flow (rCBF) abnormalities in adults with depression, these studies commonly necessitated the injection of radioisotopes into subjects. The recent development of arterial spin labeling (ASL), however, allows for noninvasive measurements of rCBF. Currently, no published ASL studies have examined cerebral perfusion in adolescents with depression. Thus, the aim of the present study was to examine baseline cerebral perfusion in adolescent depression using a newly developed ASL technique: pseudocontinuous arterial spin labeling (PCASL).
25 medication-naive adolescents (ages 13–17 years) diagnosed with major depressive disorder (MDD) and 26 well-matched controls underwent functional magnetic resonance imaging. Baseline rCBF was measured via a novel PCASL method that optimizes tagging efficiency.
Voxel-based whole brain analyses revealed significant frontal, limbic, paralimbic, and cingulate hypoperfusion in the group with depression (p<0.05, corrected). Hyperperfusion was also observed within the subcallosal cingulate, putamen, and fusiform gyrus (p<0.05, corrected). Similarly, region-of-interest analyses revealed amygdalar and insular hypoperfusion in the group with depression, as well as hyperperfusion in the putamen and superior insula (p<0.05, corrected).
Adolescents with depression and healthy adolescents appear to differ on rCBF in executive, affective, and motor networks. Dysfunction in these regions may contribute to the cognitive, emotional, and psychomotor symptoms commonly present in adolescent depression. These findings point to possible biomarkers for adolescent depression that could inform early interventions and treatments and establishes a methodology for using PCASL to noninvasively measure rCBF in clinical and healthy adolescent populations.
PMCID: PMC3825460  PMID: 24074474
cerebral blood flow; functional magnetic resonance imaging (fMRI); major depressive disorder (MDD); pseudocontinuous arterial spin labeling (PCASL)
16.  Altered Neural Processing of the Need to Stop in Young Adults at Risk for Stimulant Dependence 
The Journal of Neuroscience  2014;34(13):4567-4580.
Identification of neurocognitive predictors of substance dependence is an important step in developing approaches to prevent addiction. Given evidence of inhibitory control deficits in substance abusers (Monterosso et al., 2005; Fu et al., 2008; Lawrence et al., 2009; Tabibnia et al., 2011), we examined neural processing characteristics in human occasional stimulant users (OSU), a population at risk for dependence. A total of 158 nondependent OSU and 47 stimulant-naive control subjects (CS) were recruited and completed a stop signal task while undergoing functional magnetic resonance imaging (fMRI). A Bayesian ideal observer model was used to predict probabilistic expectations of inhibitory demand, P(stop), on a trial-to-trial basis, based on experienced trial history. Compared with CS, OSU showed attenuated neural activation related to P(stop) magnitude in several areas, including left prefrontal cortex and left caudate. OSU also showed reduced neural activation in the dorsal anterior cingulate cortex (dACC) and right insula in response to an unsigned Bayesian prediction error representing the discrepancy between stimulus outcome and the predicted probability of a stop trial. These results indicate that, despite minimal overt behavioral manifestations, OSU use fewer brain processing resources to predict and update the need for response inhibition, processes that are critical for adjusting and optimizing behavioral performance, which may provide a biomarker for the development of substance dependence.
PMCID: PMC3965782  PMID: 24672002
Bayesian model; cognitive control; ideal observer model; inhibitory control; stimulants
17.  The Influence of Recency of Use on fMRI Response During Spatial Working Memory in Adolescent Marijuana Users 
Journal of psychoactive drugs  2010;42(3):401-412.
Some neurocognitive recovery occurs within a month of abstinence from heavy marijuana use, yet functional magnetic resonance imaging (fMRI) has revealed altered activation among recent and abstinent adult users. Here, we compared fMRI response during a spatial working memory (SWM) task between adolescent marijuana users with brief and sustained durations of abstinence.
Participants were 13 recent users (2 – 7 days abstinent), 13 abstinent users (27 – 60 days abstinent), and 18 non-using controls, all ages 15 – 18. Groups were similar on demographics, had no psychiatric or medical disorders, and user groups were similar on substance histories. Teens performed a 2-back SWM task during fMRI.
Groups performed similarly on the task, but recent users showed greater fMRI response in medial and left superior prefrontal cortices, as well as bilateral insula. Abstinent users had increased response in the right precentral gyrus (clusters ≥1328 μl, p<.05).
This cross-sectional study did not examine changes in brain response among the same participants over time. Yet results suggests that adolescents who recently used marijuana show increased brain activity in regions associated with working memory updating and inhibition, compared to users with weeks to months of abstinence. This study preliminarily suggests that (1) recent marijuana use may disrupt neural connections associated with SWM and result in compensatory brain response, and (2) sustained abstinence from marijuana may be associated with improvements in SWM response among adolescents.
PMCID: PMC3016644  PMID: 21053763
18.  Sleep Architecture in Adolescent Marijuana and Alcohol Users during Acute and Extended Abstinence 
Addictive behaviors  2009;34(11):976-979.
This study examined sleep changes following cessation of marijuana and alcohol use during late adolescence. Twenty-nine heavy marijuana and alcohol users and 20 matched controls were studied during a 28-day monitored abstinence period. Sleep as examined as a function of prior substance use during Nights 1–2 and Nights 27–28. On Night 2, percent Rapid Eye Movement sleep was predicted by past month alcohol use, whereas percent Slow Wave Sleep was predicted by marijuana intake. By Night 28, neither alcohol no marijuana use predicted any sleep architecture measure. However, on Night 28, indices of period limb movements (PLMs) in sleep were predicted by marijuana and alcohol intake. Results indicate that in adolescents: (1) cessation of heavy marijuana and alcohol use may influence sleep; (2) most sleep abnormalities abate within several weeks of abstinence; and (3) PLMs may increase following abstinence.
PMCID: PMC2727851  PMID: 19505769
Polysomnography; Adolescence; Alcohol; Marijuana; Withdrawal; Sleep
19.  Altered white matter microstructure in adolescent substance users 
Psychiatry research  2009;173(3):228-237.
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. Diffusion parameters fractional anisotropy (FA) and mean diffusivity (MD) were subjected to whole-brain voxelwise group comparisons using tract-based spatial statistics (Smith et al., 2006). 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 suggests possible neuroadaptive processes and can be examined in future studies of connectivity to determine how aberrancies in specific tracts might influence efficient cognitive processing.
PMCID: PMC2734872  PMID: 19699064
Marijuana; Alcohol; DTI; Adolescence; White matter
20.  Prefrontal cortex morphometry in abstinent adolescent marijuana users: Subtle gender effects 
Addiction biology  2009;14(4):457-468.
Adult human studies suggest frontal dysfunction associated with chronic marijuana (MJ) use, but due to continued neuromaturation, adult studies may not generalize to adolescents. This study characterized prefrontal cortex (PFC) morphometry in chronic MJ-using adolescents following one month of monitored abstinence.
Data were collected from MJ users (n=16) and controls (n=16) aged 16-18. Extensive exclusionary criteria included comorbid psychiatric and neurologic disorders. Substance use and anatomical measures were collected after 28 days of monitored abstinence. PFC volumes were ascertained from manual tracing by reliable raters on high-resolution magnetic resonance images.
After controlling for lifetime alcohol use, gender, and intracranial volume, MJ users did not differ from controls in PFC volume. However, marginal group-by-gender interactions were observed (p<.09): female MJ users demonstrated comparatively larger PFC volumes while male MJ users had smaller volumes compared to same-gender controls. Further, group status and total PFC volume interacted in predicting executive functioning (p<.05). Among MJ users, smaller PFC total volume was associated with better executive functioning while the opposite pattern was seen among the controls.
These preliminary results indicate that gender may moderate the relationship between MJ use and PFC morphometry. Given the relationship between larger PFC total volumes and poorer executive functioning among MJ users, female MJ users may be at increased risk for neurocognitive consequences. Future research will measure PFC gray and white matter separately and follow boys and girls over adolescence to examine the influence of MJ use on neurodevelopment.
PMCID: PMC2741544  PMID: 19650817
Adolescents; Cannabis; Drug Effects; Executive Functioning; Gender; MRI
21.  Methamphetamine Dependent Individuals show Attenuated Brain Response to Pleasant Interoceptive Stimuli* 
Drug and alcohol dependence  2013;131(3):238-246.
Mechano-receptive C-fiber (MR-CF) stimulation via slow stroking of C-fiber rich skin areas can be used to probe the relationship between reward and interoception. Individuals with substance use disorders show impaired reward processing, and dysfunctional interoceptive processing of MR-CF may contribute to this dysfunction. This study predicted that methamphetamine dependent (MD) individuals would exhibit altered responses to MR-CF stimulation in brain regions important for interoception.
Recently abstinent MD (n=25) and comparison (CTL, n=17) subjects received a pleasant interoceptive stimulus (“Soft Touch” consisting of a slow brush stroke) to the palm or forearm during functional magnetic resonance imaging. Subjects were provided with cues signaling stimulation to examine anticipatory and stimulus-related processing. Subjective responses were measured using visual analog scales (VAS).
Groups were similar on behavioral performance and ratings of the interoceptive stimuli, yet MD exhibited lower anterior insula, dorsal striatum, and thalamus activation than CTL, across anticipation and soft touch conditions. The lower the anterior insula activation, the faster the reaction time across conditions in MD, whereas the opposite pattern was evident in CTL. Striatal activation in MD was greater than CTL during anticipation, but lower during soft touch. Greater striatal attenuation was associated with higher VAS pleasantness ratings of soft touch.
MD expend fewer brain processing resources during soft touch, a form of positively-valenced interoceptive stimuli, in brain areas that are important for both interoception and reward. Future studies will ascertain if sustained abstinence from methamphetamine use can normalize aberrant neural interoceptive processing.
PMCID: PMC3760794  PMID: 23806873
methamphetamine; interoception; reward; fMRI
22.  Adolescent Heavy Episodic Drinking: Neurocognitive Functioning during Early Abstinence 
The present study investigated the rate and pattern of neuropsychological recovery in heavy episodic drinking teens during the initial days to weeks of abstinence from alcohol.
Adolescents (ages 16–18) with histories of heavy episodic drinking (HED; N=39) and socio-demographically similar control teens (CON; N=26) were recruited from San Diego area schools. HED and CON were comparable on 5th grade standardized math and language arts test performance to ensure similar functioning prior to onset of substance use. Participants were administered three neuropsychological test batteries with 2-week intervals during a 4-week monitored abstinence period.
HED teens performed worse overall than CON on tests of prospective memory (p=.005), cognitive switching (p=.039), inhibition task accuracy (p=.001), verbal memory (p's<.045), visuospatial construction (p’s<.043), and language and achievement (p’s<.008). The statistically significant group × time interaction for block design demonstrated normalization within the four weeks of abstinence for the HED (p=.009).
This study identified cognitive performance deficits associated with heavy episodic drinking in adolescence during early abstinence and with sustained 4-week abstention. These findings suggest alcohol-related influences on several underlying brain systems that may predate the onset of alcohol abuse or dependence or take longer than four weeks to recover.
PMCID: PMC4117934  PMID: 24512674
Adolescence; Neuropsychological Tests; Alcohol Consumption; Memory Deficits; Achievement; Adolescent Development
23.  Abnormal cerebellar morphometry in abstinent adolescent marijuana users 
Psychiatry research  2010;182(2):152-159.
Functional neuroimaging data from adults have, in general, found frontocerebellar dysfunction associated with acute and chronic marijuana (MJ) use (Loeber & Yurgelun-Todd, 1999). One structural neuroimaging study found reduced cerebellar vermis volume in young adult MJ users with a history of heavy polysubstance use (Aasly et al., 1993). The goal of this study was to characterize cerebellar volume in adolescent chronic MJ users following one month of monitored abstinence.
Participants were MJ users (n=16) and controls (n=16) aged 16-18 years. Extensive exclusionary criteria included history of psychiatric or neurologic disorders. Drug use history, neuropsychological data, and structural brain scans were collected after 28 days of monitored abstinence. Trained research staff defined cerebellar volumes (including three cerebellar vermis lobes and both cerebellar hemispheres) on high-resolution T1-weighted magnetic resonance images.
Adolescent MJ users demonstrated significantly larger inferior posterior (lobules VIII-X) vermis volume (p<.009) than controls, above and beyond effects of lifetime alcohol and other drug use, gender, and intracranial volume. Larger vermis volumes were associated with poorer executive functioning (p’s<.05).
Following one month of abstinence, adolescent MJ users had significantly larger posterior cerebellar vermis volumes than non-using controls. These greater volumes are suggested to be pathological based on linkage to poorer executive functioning. Longitudinal studies are needed to examine typical cerebellar development during adolescence and the influence of marijuana use.
PMCID: PMC2866789  PMID: 20413277
Adolescents; MRI; Cerebellum; Vermis; Cannabis; Alcohol; Drug Effects
24.  Altered White Matter Integrity in Adolescent Binge Drinkers 
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.
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.
Binge drinkers had lower FA than controls in 18 white matter areas (clusters ≥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.
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.
PMCID: PMC2825379  PMID: 19389185
Diffusion Tensor Imaging; Alcohol; Binge Drinking; Adolescence; Brain Imaging; Hangover
25.  Prefrontal Cortex Volumes in Adolescents With Alcohol Use Disorders: Unique Gender Effects 
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.
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.
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.
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.
PMCID: PMC2825148  PMID: 18302722
Adolescence; Brain Imaging; Magnetic Resonance Imaging; Alcohol Abuse; White Matter; Prefrontal Cortex

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