The comorbid use of alcohol and marijuana among teens continues to subtly rise asperception of harm declines.Fifty-eight percent of alcohol drinking adolescents report using alcohol and marijuana simultaneously,45% of youth endorse a lifetime prevalence of marijuana use by the 12th grade,and 22% of these youth endorse use in the past 30 days.The adolescent brain undergoes considerable maturation,including changes in cortical volume and refinement of cortical connections.These neural transformations leave the adolescent brain more susceptible to potential neurotoxic effects of substances.Although overall brain volume remains largely unchanged after puberty,ongoing synaptic refinement and myelination results in reduced gray matter and increased white matter volume by late adolescence.Cortical gray matter follows an inverted U-shaped developmental course,with cortical volume peaking around ages 12–14.The mechanisms underlying the decline in cortical volume and thickness are suggested to involve pruning and elimination of weaker synaptic connections,decreases in neuropil,increases in intra-cortical myelination,or changes in the cellular organization of the cerebral cortex.In contrast,white matter development generally is characterized by linear volume increases driven by progressive axonal myelination.These processes refifine motor functioning,higher-order cognition,and cognitive control.Studies show alterations in white matter integrity in adolescent marijuana users compared to non-users,particularly in fronto-parietal circuitry and pathways connecting the frontal and temporal lobes.Altered cortical morphometry has also been observed in adolescent marijuana users,with marijuana-using adolescents having larger cerebellar volumes than non-users,thinner cortices in prefrontal and insular regions,and thicker cortices in posterior regions when compared to controls.Structural neuroimaging studies have also examined whether structural brain alterations were present before onset of marijuana use.Notably,cannabis square pot orbitofrontal cortex volumes at age 12 predicted initiation of marijuana use at age 16 when controlling for other substance use.
This study builds on previous work by our laboratory examining the acute and longer-term impact of adolescent marijuana use on cortical thickness pre- and post 28-days of monitored abstinence from marijuana.We found increased temporal lobe thickness estimates in adolescent heavy marijuana users,and negative associations with cortical thickness and lifetime marijuana use both acutely and following prolonged abstinence from marijuana.It is unclear if such structural alterations of the cerebral cortex persist into young adulthood.The aim of this prospective study was to identify differences in cortical thickness between adolescent heavy marijuana users and control adolescents with minimal substance use histories assessed at three independent time points.We hypothesized that those individuals who initiated heavy marijuana use during adolescence would show thicker cortices over time compared to our control teens by young adulthood in frontal and temporal brain regions.Adolescents were recruited from local San Diego schools and followed for three years,which included a baseline assessment and subsequent 1.5,and 3-year in-person follow-up visit.Participants underwent neuro imaging and substance use assessment at all three time points.Study design invited individuals back every 18-months in order to capture relationships between substance use and neuro imaging estimates spanning adolescence to young adulthood.Inclusion in the present study required valid neuro imaging data at all three time points to avoid asymmetrical processing in the longitudinal cortical thickness processing approach.All participants underwent written informed consent in accordance with the University of California,San Diego Human Research Protections Program.Marijuana and control groups were selected based on lifetime marijuana use episodes at baseline,and alcohol use was limited to <150 lifetime drinking episodes for both groups at enrollment.Average days of marijuana use per month ranged from 13 to 15 days over the course of three years for the substance users.The vast majority of substance users,MJ +ALC,met criteria for marijuana abuse/dependence over the course of the three-year study and approximately 87% met criteria for alcohol abuse/dependence.Approximately 55% of controls met criteria for alcohol abuse/dependence over the course of the study; six participants in the control group met abuse criteria for marijuana use at 3-year follow-up.
See Fig.1 for frequency and cumulative alcohol and marijuana use reported over the course of three years for the sample.Exclusionary criteria at study entry included: history of a lifetime DSM-IV Axis I disorder,history of learning disability; history of neurological disorder or traumatic brain injury with loss of consciousness >2 min; history of a serious physical health problem; complicated or premature birth including prenatal substance use; uncorrectable sensory impairments; left handedness; and use of psychoactive medications.Participants underwent weekly toxicology screening for four weeks prior to their neuro imaging session to confirm abstinence from marijuana at each time point.Decreasing 11-nor-9-carboxytetrahydrocannabinol metabolite ratios confirmed completion of the marijuana abstinence protocol at each visit and helped ensure the longer-term adverse alterations in cortical thickness were being captured,as compared to acute effects of recent use.Compliance at each visit was determined for each positive test result by dividing each THCCOOH normalized collection by the previous collected specimen,per Huestis and Cone recommendations for determining new cannabis use as a function of time.Notably,positive THCCOOH/creatinine ratios ranged from 0.0 to 10.6 ng/mg on the day of the scan session across all three time points,which falls below the commonly used confirmation cutoff <15 ng/mL.The Diagnostic Interview Schedule for Children Predictive Scales was administered to youth and parent at the screening interview to identify and exclude those individuals with Axis-I disorders other than alcohol or cannabis use disorder.The Beck Depression Inventory and Spielberger State Trait Anxiety Inventory assessed depression and state anxiety.The Family History Assessment Module assessed family history of psychiatric and substance use disorders.Parental income and grade point average were collected during a clinical interview prior to the baseline imaging session.The Wechsler Abbreviated Scale of Intelligence Vocabulary subtest was included as an estimate of premorbid intellectual functioning.All scans were acquired on the same 3.0 T CXK4 short bore Excite-2 magnetic resonance system with an eight-channel phase array head coil at the University of California San Diego Center for Functional MRI.Subjects were asked to remain still in the scanner while a high-resolution T1-weighted anatomical spoiled gradient recall scan was acquired.Cortical thickness estimates were extracted using previously published methods by our laboratory.The neuroimaging software FreeSurfer,which is well documented and freely available,was used for cortical surface reconstruction and thickness estimates.
The initial cross-sectional process involves motion correction and averaging of T1 weighted images,removal of non-brain tissue and transformation to standardized space,segmentation of sub-cortical white and deep gray matter structures,intensity normalization,and tessellation of the gray/white matter boundary.Local MRI intensity gradients then guide a surface deformation algorithm to place smooth borders where the greatest shift in intensity defines transition to other tissue classes ; this procedure allows for quantification of sub-millimeter group differences.Cortical thickness was calculated as the closest distance from the gray/white matter boundary to the gray matter/cerebral spinal fluid boundary at each vertex on the cortical surface.Validity of the cortical thickness measurement procedures has been verified using manual measurements and histological analysis.Test–retest reliability across scanners and field strenghts has been shown using these standardized procedures.Following cross-sectional processing of all three time points,data was next fed through the longitudinal processing stream in Free Surfer.This approach extracts reliable volume and thickness estimates by creating an unbiased within-subject template space and image from the three cross sectionally processed time points using a consistent robust inverse registration method.Processing steps such as Talairach transforms,atlas registration,and spherical surface maps and parcellations are initialized with common information from the within-subject template,increasing reliability and statistical power.To identify errors made during cortical reconstruction processing,one rater,blind to participant characteristics,followed the reconstruction and longitudinal edit procedures to correct any errors made during the cortical reconstruction process.This involved verification of the automated skull stripping,and a coronal plane slice-by-slice inspection of the gray/white and gray/cerebral spinal fluid surfaces.Modifications to the surfaces were made as necessary to correct for tissue misclassifications.All longitudinal runs were checked for quality,and no editing was necessary following the longitudinal processing.Following inspection,an automated parcellation procedure divided each hemisphere into 34 independent cortical regions based on gyral and sulcal features.Cortical thickness estimates averaged over each parcellation region were extracted for statistical analyses in SPSS.Repeated measures analysis of covariance examined main effects of group,time,and Group by Time interactions on cortical thickness values for 34 independent standard neuroanatomical cortical regions in each hemisphere.significant between-group and interaction effects were followed-up post hoc to determine what time point was driving the statistically significant between-group differences.Intracranial volume and lifetime alcohol use was included as a covariate given the high rate of alcohol use reported by the marijuana users in this sample.This study looked at cortical thickness estimates at three independent time points in adolescent marijuana and alcohol users compared to controls with limited substance use histories.
We found significant between group differences in cortical thickness estimates after controlling for lifetime alcohol use.MJ +ALC demonstrated increased cortical thickness estimates in all four lobes of the brain,bilaterally.Notably,18 of 23 regions in which differences were observed were in the frontal and parietal cortex.Positive dose-dependent associations were identified in temporal brain regions,trim tray as cumulative marijuana use from ages 16 to 22 was associated with thicker cortices in inferior temporal and entorhinal cortex.Several negative associations were observed with lifetime alcohol use,as more alcohol use reported was associated with thinner cortical estimates in all four lobes.It is important to detail how these findings compare to our previous work with a similar sample,as we found both similarities and differences from our cortical thickness study in which adolescent marijuana users were observed pre- and post 28-days of monitored abstinence.In Jacobus et al.,increased thickness estimates in our marijuana users was found in the entorhinal cortex compared to matched controls.Similarly,the present study found increased thickness estimates in our user group compared to our controls,and findings were more widespread and noted in all four lobes of the brain.The present study also found more lifetime marijuana use was associated with increased thickness in the entorhinal cortex,a region rich in cannabinoid 1 receptors and important for learning and memory.However,dose-dependent bivariate correlations were different in that previously we saw increased marijuana use associated with thinner cortices and increased alcohol use associated with thicker cortical estimates at age 17,pre- and post monitored abstinence.Our dose-dependent associations in the present study suggest otherwise.We found increased lifetime marijuana use reported associated with thicker cortical estimates and increased lifetime alcohol use reported associated with thinner cortices.This may reflect several points recently discussed by Filbey and colleagues in the literature,including methodological issues,the present study assessed substance independently over the course of three years compared to 28-days at age 17; age and maturational bias,correlations in the present study reflect associations following many years of substance use and potential for interference with complex neuro developmental processes; changes in marijuana and alcohol use patterns,as individuals in the present study remain relatively chronic in their marijuana use over time but subtly increase in their alcohol use; and possible interactions with pre-existing vulnerabilities that are present at age 17,but likely changes as the individual continues to chronically use substances and increase in age Lopez-Larson and colleagues cross-sectionally investigated cortical thickness in adolescents ages 16–19 years,with heavy marijuana use histories.They found decreased thickness in frontal regions and the insula,along with increased thickness in lingual,temporal,and parietal regions.The present study found increases in thickness in parietal,temporal,and occipital cortices,consistent with work by this team.The mechanism by which marijuana may alter the neural architecture and plasticity of the brain is undetermined.The endocannabinoid system plays a role in neuromaturational processes and modulates neurotransmission for several neurotransmitter systems.Interference with this system due to marijuana,or tetrahydrocannabinol administration,likely causes a cascade of neuronal events that changes brain structure and function,and thereby neurocognitive processing,emotional regulation and reward processing,and propensity for psychiatric comorbidities and addiction.It is unclear how associations with marijuana use and cortical thickness remodeling may be unique compared to alterations in macrostructural volume.Studies suggest that volume changes are driven by changes in surface area whereas others suggest thickness as one ages,however relationships between these metrics are likely dynamic across the lifespan and represent different neuromaturational mechanisms at different stages of life and disease.Changes in regional brain volume associated with marijuana use have varied,as some have observed decreased volume and others have identified macrostructural volume increases in CB1-dense brain regions such as neocortex,amygdala,striatum,hippocampus,and cerebellum.In reward-network regions specifically,such as the orbitofrontal cortex,a recent examination by Filbey and colleauges,found decreased orbitofrontal cortex volume in heavy marijuana users compared to controls,and increased structural and functional connectivity within the OFC network.Lorenzetti and collages,did not find OFC differences in their sample of heavy marijuana users,but did see smaller hippocampus and amygdala volumes.Cheetham et al.found that smaller OFC volume pre-initiation of marijuana use predicted progression into use four years later.