Substance use patterns in 9-10 year olds: Baseline findings from the adolescent brain cognitive development (ABCD) study.

BACKGROUND: The Adolescent Brain Cognitive Development ™ Study (ABCD Study®) is an open-science, multi-site, prospective, longitudinal study following over 11,800 9- and 10-year-old youth into early adulthood. The ABCD Study aims to prospectively examine the impact of substance use (SU) on neurocognitive and health outcomes. Although SU initiation typically occurs during teen years, relatively little is known about patterns of SU in children younger than 12. METHODS: This study aims to report the detailed ABCD Study® SU patterns at baseline (n = 11,875) in order to inform the greater scientific community about cohort's early SU. Along with a detailed description of SU, we ran mixed effects regression models to examine the association between early caffeine and alcohol sipping with demographic factors, externalizing symptoms and parental history of alcohol and substance use disorders (AUD/SUD). PRIMARY RESULTS: At baseline, the majority of youth had used caffeine (67.6 %) and 22.5 % reported sipping alcohol (22.5 %). There was little to no reported use of other drug categories (0.2 % full alcohol drink, 0.7 % used nicotine, <0.1 % used any other drug of abuse). Analyses revealed that total caffeine use and early alcohol sipping were associated with demographic variables (p's<.05), externalizing symptoms (caffeine p = 0002; sipping p = .0003), and parental history of AUD (sipping p = .03). CONCLUSIONS: ABCD Study participants aged 9-10 years old reported caffeine use and alcohol sipping experimentation, but very rare other SU. Variables linked with early childhood alcohol sipping and caffeine use should be examined as contributing factors in future longitudinal analyses examining escalating trajectories of SU in the ABCD Study cohort.

Baseline brain function in the preadolescents of the ABCD Study.

The Adolescent Brain Cognitive Development (ABCD) Study® is a 10-year longitudinal study of children recruited at ages 9 and 10. A battery of neuroimaging tasks are administered biennially to track neurodevelopment and identify individual differences in brain function. This study reports activation patterns from functional MRI (fMRI) tasks completed at baseline, which were designed to measure cognitive impulse control with a stop signal task (SST; N = 5,547), reward anticipation and receipt with a monetary incentive delay (MID) task (N = 6,657) and working memory and emotion reactivity with an emotional N-back (EN-back) task (N = 6,009). Further, we report the spatial reproducibility of activation patterns by assessing between-group vertex/voxelwise correlations of blood oxygen level-dependent (BOLD) activation. Analyses reveal robust brain activations that are consistent with the published literature, vary across fMRI tasks/contrasts and slightly correlate with individual behavioral performance on the tasks. These results establish the preadolescent brain function baseline, guide interpretation of cross-sectional analyses and will enable the investigation of longitudinal changes during adolescent development.

Altered neurometabolites and motor integration in children exposed to methamphetamine in utero.

Methamphetamine (METH) is a neurotoxic drug. This study aimed to evaluate brain metabolite levels and cognitive function in young children with prenatal METH exposure. 101 children ages 3-4 years were evaluated with neuropsychological tests and underwent proton magnetic resonance spectroscopy ((1)H-MRS) without sedation. Complete datasets from 49 METH-exposed and 49 controls who completed the neuropsychological test battery, and 38 METH-exposed and 37 controls with high-quality MR spectra are reported here. Despite similar physical characteristics (including head circumference), global cognitive function (on Stanford-Binet), parental education, intelligence, mood, and socioeconomic status, METH-exposed children had higher total creatine (tCr: +7%, p=0.003), N-acetyl compounds (NA: +4.3%, p=0.004) and glutamate+glutamine (GLX: +9.6%, p=0.02) concentrations in the frontal white matter, but lower myoinositol (MI: -7%, p=0.01) and MI/tCr (-7.5%, p=0.03) in the thalamus, than control children. The higher frontal white matter NA in the METH-exposed children was due to the higher NA in the METH-exposed girls (+10.2%, p=0.003), but not the boys (+0.8%) compared to sex-matched controls. Furthermore, the METH-exposed children had poorer performance on a visual motor integration (VMI) task, which correlated with lower MI in the thalamus (r=0.26, p=0.03). The higher NA, tCr and GLX concentrations suggest higher neuronal density or cellular compactness in the white matter, especially in the girls, whereas the lower MI suggests lower glial content in the thalamus of these METH-expose children. These findings combined with their poorer performance on VMI also suggest accelerated but aberrant neuronal and glial development in these brain regions.

Lower diffusion in white matter of children with prenatal methamphetamine exposure.

BACKGROUND: Methamphetamine use is a common problem among women of childbearing age, leading to an increasing number of children with prenatal methamphetamine exposure. Whether microstructural brain changes associated with prenatal methamphetamine exposure can be detected with diffusion tensor imaging (DTI) is unknown. METHOD: Twelve-direction DTI was performed in 29 methamphetamine-exposed and 37 unexposed children ages 3-4 years on a 3-T MRI scanner. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were determined in the corpus callosum (genu and splenium) and bilaterally in the frontal and parietal white matter (WM), basal ganglia (caudate, putamen, globus pallidus), and thalamus. RESULTS: Children with prenatal methamphetamine exposure had lower ADC in the frontal (right: -2.1%, p = 0.04; left: -2.0%, p = 0.09) and parietal WM (right: -3.9%, p = 0.002; left: -3.3%, p = 0.02) compared to unexposed children. The methamphetamine-exposed children also showed a trend for higher FA in the left frontal WM (+4.9%, p = 0.06) compared to the unexposed children. CONCLUSION: Since less myelination and higher dendritic or spine density have been reported in animals exposed to methamphetamine, lower diffusion in our children may reflect more compact axons or greater dendritic or spine density associated with prenatal methamphetamine exposure. These findings suggest alterations in white matter maturation in these children exposed to methamphetamine in utero.

Marijuana use is associated with a reorganized visual-attention network and cerebellar hypoactivation.

Attention and memory deficits have been reported in heavy marijuana users, but these effects may be reversible after prolonged abstinence. It remains unclear whether the reversibility of these cognitive deficits indicates that chronic marijuana use does not alter cortical networks, or that such changes occur but the brain adapts to the drug-induced changes. Blood oxygenation-level dependent (BOLD) functional MRI (fMRI) was performed in 24 chronic marijuana users (12 abstinent and 12 active) and 19 age-, sex- and education-matched control subjects during a set of visual-attention tasks with graded levels of difficulty. Neuropsychological tests were also administered on each subject. The two marijuana user groups showed no significant difference in usage pattern (frequency or duration of use, age of first use, cumulative joints used, averaged >2000 joints) or estimated cumulative lifetime exposure of Delta-9-tetrahydrocannabinol (THC) (mean 168 +/- 45 versus 244 +/- 135 g). Despite similar task and cognitive test performance compared with control subjects, active and abstinent marijuana users showed decreased activation in the right prefrontal, medial and dorsal parietal, and medial cerebellar regions, but greater activation in various frontal, parietal and occipital brain regions during the visual-attention tasks (all with P < or = 0.001, corrected, cluster level). However, the BOLD signals in the right frontal and medial cerebellar regions normalized with duration of abstinence in the abstinent users. Active marijuana users, with positive urine tests for THC, showed greater activation in the frontal and medial cerebellar regions than abstinent marijuana users and greater usage of the reserve network (regions with load effect), suggesting a neuroadaptive state. Both earlier age of first use and greater estimated cumulative dose of THC exposure were related to lower BOLD signals in the right prefrontal region and medial cerebellum. The altered BOLD activation pattern in the attention network and hypoactivation of the cerebellum suggest neuroadaptive processes or alteration of brain development in chronic marijuana users. These changes also may be related to marijuana-induced alteration in resting cerebral blood volume/flow or downregulation of cannabinoid (CB1) receptors. The greater activation in the active compared with abstinent marijuana users demonstrates a neuroadaptive state in the setting of active marijuana use, while the long-term chronic effect of marijuana on the altered brain network may be reversible with prolonged abstinence.

Combined and independent effects of chronic marijuana use and HIV on brain metabolites.

The effects of chronic marijuana (MJ) use on brain function remain controversial. Because MJ is often used by human immunodeficiency virus (HIV) patients, the aim of this study was to evaluate whether chronic MJ use and HIV infection are associated with interactive or additive effects on brain chemistry and cognitive function. We evaluated 96 subjects (30 seronegative nondrug users, 24 MJ users, 21 HIV without MJ use, 21 HIV + MJ) using proton magnetic resonance spectroscopy and a battery of neuropsychological tests. The two primarily abstinent MJ user groups showed no significant differences on calculated estimates of lifetime grams of delta9-tetrahydrocannabinol exposure, despite some differences in usage pattern. The two HIV groups also had similar HIV disease severity (CD4 cell count, plasma viral load, HIV dementia staging, Karnofsky score). On two-way analyses of covariance, HIV infection (independent of MJ) was associated with trends for reduced N-acetyl aspartate (NA) in the parietal white matter and increased choline compounds (CHO) in the basal ganglia. In contrast, MJ (independent of HIV) was associated with decreased basal ganglia NA (-5.5%, p = 0.05), CHO (-10.6%, p = 0.04), and glutamate (-9.5%, p = 0.05), with increased thalamic creatine (+6.1%, p = 0.05). HIV + MJ was associated with normalization of the reduced glutamate in frontal white matter (interaction p = 0.01). After correction for age, education, or mood differences, MJ users had no significant abnormalities on neuropsychological test performance, and HIV subjects only had slower reaction times. These findings suggest chronic MJ use may lead to decreased neuronal and glial metabolites, but may normalize the decreased glutamate in HIV patients.

Increased frontal white matter diffusion is associated with glial metabolites and psychomotor slowing in HIV.

Diffusion-weighted imaging (DWI) measures brain water diffusion that is sensitive to microscopic brain injury. A total of 11 HIV seropositive patients were compared to 14 seronegative subjects using DWI, proton magnetic resonance spectroscopy (1H MRS), and neuropsychological tests. The apparent diffusion coefficient (ADC) was significantly increased in the HIV patients, primarily in the frontal white matter (FWM; +5%, p=0.01). Diffusivity correlated positively with the glial marker myo-inositol (r=0.5, p=0.008) and negatively with cognitive performance (NPZ-8 composite score; r=-0.43, p=0.05). These findings suggest increased brain water diffusion may reflect increased glial activation or inflammation, which in turn, may contribute to the cognitive deficits in HIV patients.

Methamphetamine and AIDS: 1HMRS studies in a feline model of human disease.

Potential interactions between psychostimulant drugs and infection with feline immunodeficiency virus (FIV) on brain metabolism were evaluated. Four groups of cats were studied: control, FIV positive, methamphetamine (MA) exposed, and FIV positive plus MA exposed. Frontal gray matter, frontal white matter, and caudate brain extracts were studied with proton magnetic resonance spectroscopy (1HMRS). In the frontal white matter, FIV-infected cats showed decreases in creatine and choline, while MA-treated cats had elevated gamma-aminobutyric acid (GABA). The decreased glutamate in FIV cats normalized with MA exposure. FIV and MA both affect brain metabolites individually and combined. 1HMRS is useful for evaluating the effects of FIV and drug abuse in the brain.

Effect of cigarette smoking on coumarin metabolism in humans.

Extant data, mostly from studies in vitro, suggest that coumarin and nicotine are both metabolized by CYP2A6, a cytochrome P450 isozyme. In order to investigate this issue further, the activity of this enzyme in vivo was measured in 37 non-smokers and 37 smokers using coumarin (2.0 mg, PO) as the metabolic probe. The percentage of coumarin metabolized to 7-hydroxycoumarin in 8 h was measured in urine by high-pressure liquid chromatography. There was more than 10-fold variability in coumarin metabolism in both groups. Coumarin metabolism was significantly reduced in smokers (46.6 +/- 4.4%) as compared to non-smokers (66.4 +/- 3.5%; p < or = .001). The results support previous in vitro findings that both coumarin and nicotine are metabolized, at least in part, by a common pathway, which most likely is CYP2A6.

Brain N-acetyl aspartate concentrations measured by H MRS are reduced in adult male rats subjected to perinatal stress: preliminary observations and hypothetical implications for neurodevelopmental disorders.

The present study was undertaken to determine if the concentration of brain N-acetyl-aspartate (NAA), a putative neuronal marker, is reduced in adult rats subjected to stress during the perinatal period. As the prenatal stressor, pregnant rats were subjected to restraint stress for one hour twice daily from days 14-21 of gestation; stressed offspring were reared by normal dams and studied as adults. As the postnatal stressor, normal pups were reared by prenatally 'stressed' dams and studied as adults. As compared to non-stressed controls (n=6), NAA concentrations were significantly reduced 21 and 25% in left frontal cortex from the prenatal (n=4) and postnatal (n=6) stress groups. respectively. The data suggest that in perinatally stressed adult offspring permanent neuronal damage or loss has occurred. While no direct causal associations between perinatal stress and the developmental of particular disorders can be inferred from these limited data, the effects of perinatal stress on subsequent brain neuropathology are reviewed. particularly in relation to NAA. For hypothesis-generating purposes, the possible relevance of stress and NAA to the neurodevelopmental hypothesis of schizophrenia is discussed in greater detail.