Joanna Jacobus

The Influence of Substance Use on Adolescent Brain Development

Adolescence is a unique period in neurodevelopment. Alcohol and marijuana use are common. Recent research has indicated that adolescent substance users show abnormalities on measures of brain functioning, which is linked to changes in neurocognition over time. Abnormalities have been seen in brain structure volume, white matter quality, and activation to cognitive tasks, even in youth with as little as 1–2 years of heavy drinking and consumption levels of 20 drinks per month, especially if >4–5 drinks are consumed on a single occasion. Heavy marijuana users show some subtle anomalies too, but generally not the same degree of divergence from demographically similar non-using adolescents. This article reviews the extant literature on neurocognition, brain structure, and brain function in adolescent substance users with an emphasis on the most commonly used substances, and in the context of ongoing neuromaturational processes. Methodological and treatment implications are provided.

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.

Longitudinal characterization of white matter maturation during adolescence.

BACKGROUND Late adolescence is comprised of considerable developmental transitions, though brain maturational changes during this period are subtle and difficult to quantitatively evaluate from standard brain imaging acquisitions. To date, primarily cross-sectional studies have characterized typical developmental changes during adolescence, but these processes need further description within a longitudinal framework. METHOD To assess the developmental trajectory of typical white matter development, we examined 22 healthy adolescents with serial diffusion tensor images (DTI) collected at a mean age of 17.8 years and 16-months later. Diffusion parameters fractional anisotropy, and mean, radial, and axial diffusivity were subjected to whole-brain voxelwise time point comparisons using tract-based spatial statistics. RESULTS At follow-up, adolescents showed a significant change (>or=153 contiguous voxels each at p<0.01) in diffusion properties, including in bilateral superior longitudinal fasciculi, superior corona radiata, anterior thalamic radiations, and posterior limb of the internal capsule. Overall, correlations with cognitive performances suggested behavioral improvement corresponding with white matter changes. CONCLUSION These longitudinal DTI findings support continued microstructural change in white matter during late adolescence, and suggest ongoing refinement of projection and association fibers into early adulthood.

Neurotoxic Effects of Alcohol in Adolescence

This review examines neuroimaging and neurocognitive findings on alcohol-related toxicity in adolescents. Teens who meet criteria for alcohol use disorders, as well as those who engage in subdiagnostic binge drinking behaviors, often show poorer neurocognitive performance, alterations in gray and white matter brain structure, and discrepant functional brain activation patterns when compared to nonusing and demographically matched controls. Abnormalities are also observed in teens with a family history of alcoholism, and such differences in neuromaturation may leave youths at increased risk for the development of an alcohol use disorder or increased substance use severity. More prospective investigations are needed, and future work should focus on disentangling preexisting differences from dose-dependent effects of alcohol on neurodevelopment. Intervention strategies that utilize neuroimaging findings (e.g., identified weaknesses in particular neural substrates and behavioral correlates) may be helpful in both prevention and intervention campaigns for teens both pre- and postinitiation of alcohol use.

White matter tract injury and cognitive impairment in human immunodeficiency virus–infected individuals

Approximately half of those infected with the human immunodeficiency virus (HIV) exhibit cognitive impairment, which has been related to cerebral white matter damage. Despite the effectiveness of antiretroviral treatment, cognitive impairment remains common even in individuals with undetectable viral loads. One explanation for this may be subtherapeutic concentrations of some antiretrovirals in the central nervous system (CNS). We utilized diffusion tensor imaging and a comprehensive neuropsychological evaluation to investigate the relationship of white matter integrity to cognitive impairment and antiretroviral treatment variables. Participants included 39 HIV-infected individuals (49% with acquired immunodeficiency syndrome [AIDS]; mean CD4=529) and 25 seronegative subjects. Diffusion tensor imaging indices were mapped onto a common whole-brain white matter tract skeleton, allowing between-subject voxelwise comparisons. The total HIV-infected group exhibited abnormal white matter in the internal capsule, inferior longitudinal fasciculus, and optic radiation; whereas those with AIDS exhibited more widespread damage, including in the internal capsule and the corpus callosum. Cognitive impairment in the HIV-infected group was related to white matter injury in the internal capsule, corpus callosum, and superior longitudinal fasciculus. White matter injury was not found to be associated with HIV viral load or estimated CNS penetration of antiretrovirals. Diffusion tensor imaging was useful in identifying changes in white matter tracts associated with more advanced HIV infection. Relationships between diffusion alterations in specific white matter tracts and cognitive impairment support the potential utility of diffusion tensor imaging in examining the anatomical underpinnings of HIV-related cognitive impairment. The study also confirms that CNS injury is evident in persons infected with HIV despite effective antiretroviral treatment.

Longitudinal changes in white matter integrity among adolescent substance users

BACKGROUND The influence of repeated substance use during adolescent neurodevelopment remains unclear as there have been few prospective investigations. The aims of this study were to identify longitudinal changes in fiber tract integrity associated with alcohol- and marijuana-use severity over the course of 1.5 years. METHODS Adolescents with extensive marijuana- and alcohol-use histories by mid-adolescence (n = 41) and youth with consistently minimal if any substance use (n = 51) were followed over 18 months. Teens received diffusion tensor imaging and detailed substance-use assessments with toxicology screening at baseline and 18-month follow-ups (i.e., 182 scans in all), as well as interim substance-use interviews each 6 months. RESULTS At an 18-month follow-up, substance users showed poorer white matter integrity in 7 tracts: (i) right superior longitudinal fasciculus, (ii) left superior longitudinal fasciculus, (iii) right posterior thalamic radiations, (iv) right prefrontal thalamic fibers, (v) right superior temporal gyrus white matter, (vi) right inferior longitudinal fasciculus, and (vii) left posterior corona radiata (ps < 0.01). More alcohol use during the interscan interval predicted higher mean diffusivity (i.e., worsened integrity) in right (p < 0.05) and left (p = 0.06) superior longitudinal fasciculi, above and beyond baseline values in these bundles. Marijuana use during the interscan interval did not predict change over time. More externalizing behaviors at Time 1 predicted lower fractional anisotropy and higher radial diffusivity (i.e., poorer integrity) of the right prefrontal thalamic fibers (p < 0.025). CONCLUSIONS Findings add to previous cross-sectional studies reporting white matter disadvantages in youth with substance-use histories. In particular, alcohol use during adolescent neurodevelopment may be linked to reductions in white matter quality in association fiber tracts with frontal connections. In contrast, youth who engage in a variety of risk-taking behaviors may have unique neurodevelopmental trajectories characterized by truncated development in fronto-thalamic tracts, which could have functional and clinical consequences in young adulthood.

Brain development in heavy-drinking adolescents

OBJECTIVE Heavy alcohol use during adolescence may alter the trajectory of normal brain development. The authors measured within-subject changes in regional brain morphometry over longer intervals and in larger samples of adolescents than previously reported and assessed differences between adolescents who remained nondrinkers and those who drank heavily during adolescence as well as differences between the sexes. METHOD The authors examined gray and white matter volume trajectories in 134 adolescents, of whom 75 transitioned to heavy drinking and 59 remained light drinkers or nondrinkers over roughly 3.5 years. Each underwent MRI scanning two to six times between ages 12 and 24 and was followed for up to 8 years. The volumes of the neocortex, allocortex, and white matter structures were measured using atlas-based parcellation with longitudinal registration. Linear mixed-effects models described differences in trajectories of heavy drinkers and nondrinkers over age; secondary analyses considered the contribution of other drug use to identified alcohol use effects. RESULTS Heavy-drinking adolescents showed accelerated gray matter reduction in cortical lateral frontal and temporal volumes and attenuated white matter growth of the corpus callosum and pons relative to nondrinkers. These results were largely unchanged when use of marijuana and other drugs was examined. Male and female drinkers showed similar patterns of development trajectory abnormalities. CONCLUSIONS Longitudinal analysis enabled detection of accelerated typical volume decline in frontal and temporal cortical volumes and attenuated growth in principal white matter structures in adolescents who started to drink heavily. These results provide a call for caution regarding heavy alcohol use during adolescence, whether heavy drinking is the sole cause or one of several in these alterations in brain development.

Neurocognitive correlates of white matter quality in adolescent substance users

BACKGROUND Progressive myelination during adolescence implicates an increased vulnerability to neurotoxic substances and enduring neurocognitive consequences. This study examined the cognitive manifestations of altered white matter microstructure in chronic marijuana and alcohol-using (MJ+ALC) adolescents. METHODS Thirty-six MJ+ALC adolescents (ages 16-19) and 36 demographically similar controls were evaluated with diffusion tensor imaging (Bava et al., 2009) and neurocognitive tests. Regions of group difference in fractional anisotropy (FA) and mean diffusivity (MD) were analyzed in relation to cognitive performance. RESULTS In users, lower FA in temporal areas related to poorer performance on attention, working memory, and speeded processing tasks. Among regions where users had higher FA than controls, occipital FA was positively associated with working memory and complex visuomotor sequencing, whereas FA in anterior regions was negatively associated with verbal memory performance. CONCLUSIONS Findings suggest differential influences of white matter development on cognition in MJ+ALC using adolescents than in non-using peers. Neuroadaptation may reflect additive and subtractive responses to substance use that are complicated by competing maturational processes.

Characteristics of prospective memory deficits in HIV-seropositive substance-dependent individuals: preliminary observations.

The construct of “prospective memory” (PM) refers to a type of episodic memory for a future intention or “remembering what one must do.” This function has been proposed as a candidate mechanism underlying behaviors of critical importance in HIV disease, including adherence with medication regimens and continued engagement in risk behavior. We administered tasks of time-based and event-based prospective memory and control tasks of retrospective and working memory to 31 HIV-seropositive and 35 HIV-seronegative substance-dependent individuals (SDIs). We found that compared with HIV− controls HIV+ participants showed deficits in time-based but not event-based PM. Retrospective, but not working, memory performance correlated significantly with time-based PM performance. In addition, performance on the time-based PM task was a significant predictor of scores on a self-report measure of risky sexual and injection practices. These preliminary data provide new and unique findings regarding the components of executive function mediated by prefrontal cortical systems that are impaired among HIV+ SDIs and their relevance to “real-world” behaviors.

White matter characterization of adolescent binge drinking with and without co-occurring marijuana use: A 3-year investigation

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.