Christine Cloak

Enlarged Striatum in Abstinent Methamphetamine Abusers: A Possible Compensatory Response

BACKGROUND Little is known about structural brain abnormalities associated with methamphetamine (METH) abuse; therefore, we aimed: 1) to evaluate possible morphometric changes, especially in the striatum of recently abstinent METH-dependent subjects; 2) to evaluate whether morphometric changes are related to cognitive performance; and 3) to determine whether there are sex-by-METH interactions on morphometry. METHODS Structural MRI was performed in 50 METH and 50 comparison subjects with the same age range and sex proportion; quantitative morphometric analyses were performed in the subcortical gray matter, cerebellum and corpus callosum. Neuropsychological tests were also performed in 44 METH and 28 comparison subjects. RESULTS METH users showed enlarged putamen (left: + 10.3%, p = .0007; right: + 9.6%, p = .001) and globus pallidus (left: + 9.3%, p = .002; right: + 6.6%, p = .01). Female METH subjects additionally showed larger mid-posterior corpus callosum (+ 9.7%, p = .05). Although METH users had normal cognitive function, those with smaller striatal structures had poorer cognitive performance and greater cumulative METH usage. CONCLUSIONS Since METH subjects with larger striatal structures had relatively normal cognitive performance and lesser cumulative METH usage, the enlarged putamen and globus pallidus might represent a compensatory response to maintain function. Possible mechanisms for the striatal enlargement include glial activation and inflammatory changes associated with METH-induced injury.

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.

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.

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.

Higher diffusion in striatum and lower fractional anisotropy in white matter of methamphetamine users

Methamphetamine (METH) users showed structural and chemical abnormalities on magnetic resonance (MRI) studies, particularly in the frontal and basal ganglia brain regions. Diffusion tensor imaging (DTI) may provide further insights regarding the microstructural changes in METH users. We investigated diffusion tensor measures in frontal white matter and basal ganglia of 30 adult METH users and 30 control subjects using a 3 T MR scanner. Compared with healthy control subjects, METH users showed lower fractional anisotropy (FA) in right frontal white matter, and higher apparent diffusion coefficient (ADC) in left caudate and bilateral putamen. Higher left putamen ADC was associated with earlier initiation of METH use, greater daily amounts, and a higher cumulative lifetime dose. Similarly, higher right putamen ADC was associated with greater daily amounts and a higher cumulative lifetime dose. The lower FA in the right frontal white matter suggests axonal injury in these METH users. The higher ADC in the basal ganglia suggests greater inflammation or less myelination in these brain regions of those with younger age of first METH use and greater METH usage.

Association between Psychiatric Symptoms and Craving in Methamphetamine Users

This study examined the differences in psychiatric symptoms between adult methamphetamine users (n = 46) and control subjects (n = 31), the relationship between psychiatric symptoms and the intensity of methamphetamine craving, and whether psychiatric symptoms were correlated to methamphetamine drug-usage variables (ie, length of abstinence, frequency, duration, and lifetime grams). We found that depressive symptoms on the Center for Epidemiology Studies-Depression (CES-D) and many other psychiatric symptoms on the Symptom Checklist-90 (SCL-90) significantly correlated with craving methamphetamine on the visual analog scale (VAS) for craving. Methamphetamine users had significantly more depressive symptoms (on CES-D) and psychotic symptoms (on SCL-90) compared to controls. There were no significant correlations between psychiatric symptoms and methamphetamine-usage variables. This study provides the first evidence to suggest that depressive symptoms (on CES-D) and psychiatric symptoms (on SCL-90) are strongly associated with the intensity of craving (on VAS) for the drug in methamphetamine users. However, the methamphetamine usage variables had no relationship with psychiatric symptoms. Therefore, methamphetamine users, regardless of their usage patterns, may benefit from treatment of their psychiatric symptoms in order to minimize craving and subsequent relapse to drug use.

Prenatal nicotine increases testosterone levels in the fetus and female offspring.

Epidemiological studies have shown that smoking during pregnancy markedly increases the risk for future tobacco use by adolescent female offspring. It has been hypothesized that the increased smoking risk in females is secondary to a nicotine-induced increase in fetal plasma testosterone levels that persist to adult life. To test this hypothesis, we randomized pregnant Sprague-Dawley rats to receive either saline or nicotine from Day 4 until the end of gestation. Blood samples for testosterone levels were obtained from 30- and 120-day-old offspring. In addition, blood samples for testosterone levels were obtained prior to and following a 2-day infusion of nicotine to chronically catheterized ovine fetuses. Maternal nicotine exposure resulted in increased plasma testosterone in 30-day-old female rat offspring, with no differences found in nicotine-exposed males. In addition, plasma testosterone levels increased in ovine fetuses in response to the nicotine infusion. We conclude that prenatal nicotine exposure increases plasma testosterone levels chronically in adolescent female rat offspring and acutely in both male and female ovine fetuses. Although our findings lack correlative behavioral information on the female offspring, these data are consistent with human epidemiological data suggesting that prenatal environmental influences may have marked effects on the subsequent smoking behaviors of offspring.

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.

Genetic influences on brain developmental trajectories on neuroimaging studies: from infancy to young adulthood

Human brain development has been studied intensively with neuroimaging. However, little is known about how genes influence developmental brain trajectories, even though a significant number of genes (about 10,000, or approximately one-third) in the human genome are expressed primarily in the brain and during brain development. Interestingly, in addition to showing differential expression among tissues, many genes are differentially expressed across the ages (e.g., antagonistic pleiotropy). Age-specific gene expression plays an important role in several critical events in brain development, including neuronal cell migration, synaptogenesis and neurotransmitter receptor specificity, as well as in aging and neurodegenerative disorders (e.g., Alzheimer disease or amyotrophic lateral sclerosis). In addition, the majority of psychiatric and mental disorders are polygenic, and many have onsets during childhood and adolescence. In this review, we summarize the major findings from neuroimaging studies that link genetics with brain development, from infancy to young adulthood. Specifically, we focus on the heritability of brain structures across the ages, age-related genetic influences on brain development and sex-specific developmental trajectories.

Age and sex effects levels of choline compounds in the anterior cingulate cortex of adolescent methamphetamine users

BACKGROUND Methamphetamine can be neurotoxic to the adult brain; however, many individuals first use methamphetamine during adolescence, and the drugs impact on this period of brain development is unknown. Therefore, we evaluated young methamphetamine users for possible abnormalities in brain metabolite concentrations. METHODS Anterior cingulate cortex (ACC), frontal white matter (FWM), basal ganglia, and thalamus were studied with localized proton magnetic resonance spectroscopy in 54 periadolescent (ages 13-23 years) methamphetamine users and 53 comparison subjects. The concentrations of major brain metabolites and their associations with age, sex and cognition were assessed. RESULTS FWM total-creatine correlated with age in methamphetamine-using males and comparison females, but not comparison males or methamphetamine-using females, leading to a drug by sex by age interaction (p=0.003) and ACC choline-containing compounds (CHO) correlated with age only in comparison males leading to a drug by sex by age interaction (p=0.03). Higher ACC CHO was associated with faster performance on the Stroop Interference task in the control males. Male methamphetamine users had slowest performance on the Stroop Interference task and did not show age-appropriate levels of ACC CHO. CONCLUSIONS The altered age-appropriate levels of ACC CHO and poorer executive function in male methamphetamine users suggest methamphetamine abuse may interfere with brain maturation. These periadolescents did not have the abnormal neuronal markers previously reported in adult methamphetamine users, suggesting that neuronal abnormalities may be the result of long-term use or interference in normal cortical maturation, emphasizing the need for early intervention for young methamphetamine users.