Prenatal tobacco exposure on brain morphometry partially mediated poor cognitive performance in preadolescent children.

Objectives: To evaluate whether prenatal tobacco exposure (PTE) is related to poorer cognitive performance, abnormal brain morphometry, and whether poor cognitive performance is mediated by PTE-related structural brain differences. Methods: The Adolescent Brain Cognitive Development study dataset was used to compare structural MRI data and neurocognitive (NIH Toolbox®) scores in 9-to-10-year-old children with (n=620) and without PTE (n=10,989). We also evaluated whether PTE effects on brain morphometry mediated PTE effects on neurocognitive scores. Group effects were evaluated using Linear Mixed Models, covaried for socio-demographics and prenatal exposures to alcohol and/or marijuana, and corrected for multiple comparisons using the false-discovery rate (FDR). Results: Compared to unexposed children, those with PTE had poorer performance (all p-values <0.05) on executive function, working memory, episodic memory, reading decoding, crystallized intelligence, fluid intelligence and overall cognition. Exposed children also had thinner parahippocampal gyri, smaller surface areas in the posterior-cingulate and pericalcarine cortices; the lingual and inferior parietal gyri, and smaller thalamic volumes (all p-values <0.001). Furthermore, among children with PTE, girls had smaller surface areas in the superior-frontal (interaction-FDR-p=0.01), precuneus (interaction-FDR-p=0.03) and postcentral gyri (interaction-FDR-p=0.02), while boys had smaller putamen volumes (interaction-FDR-p=0.02). Smaller surface areas across regions of the frontal and parietal lobes, and lower thalamic volumes, partially mediated the associations between PTE and poorer neurocognitive scores (p-values <0.001). Conclusions: Our findings suggest PTE may lead to poorer cognitive performance and abnormal brain morphometry, with sex-specific effects in some brain regions, in pre-adolescent children. The poor cognition in children with PTE may result from the smaller areas and subcortical brain volumes.

Longitudinal alterations in brain morphometry mediated the effects of bullying victimization on cognitive development in preadolescents.

Bullying victimization is associated with a doubled risk of attempting suicide in adulthood. Two longitudinal brain morphometry studies identified the fusiform gyrus and putamen as vulnerable to bullying. No study identified how neural alterations may mediate the effect of bullying on cognition. We assessed participants with caregiver-reported bullying (N = 323) and matched non-bullied controls (N = 322) from the Adolescent Brain Cognitive Development Study dataset to identify changes in brain morphometry associated with ongoing bullying victimization over two years and determine whether such alterations mediated the effect of bullying on cognition. Bullied children (38.7% girls, 47.7% racial minorities, 9.88 ± 0.62 years at baseline) had poorer cognitive performance (P < 0.05), larger right hippocampus (P = 0.036), left entorhinal cortex, left superior parietal cortex, and right fusiform gyrus volumes (all P < 0.05), as well as larger surface areas in multiple other frontal, parietal, and occipital cortices. Thinner cortices were also found in the left hemisphere, particularly in the left temporal lobe, and right frontal region (all P < 0.05). Importantly, larger surface area in the fusiform cortices partially suppressed (12-16%), and thinner precentral cortices partially mitigated, (7%) the effect of bullying on cognition (P < 0.05). These findings highlight the negative impact of prolonged bullying victimization on brain morphometry and cognition.

Peer victimization (bullying) on mental health, behavioral problems, cognition, and academic performance in preadolescent children in the ABCD Study.

Objective: Peer victimization is a substantial early life stressor linked to psychiatric symptoms and poor academic performance. However, the sex-specific cognitive or behavioral outcomes of bullying have not been well-described in preadolescent children. Methods: Using the baseline dataset of the Adolescent Brain Cognitive Development (ABCD) Study 2.0.1 data repository (N = 11,875), we evaluated associations between parent-reported bullying victimization, suicidality (suicidal ideation, intent, and/or behavior), and non-suicidal self-injury (NSSI), as well as internalizing and externalizing behavioral problems, cognition, and academic performance. Results: Of the 11,015 9-10-year-old children included in the analyses (5,263 girls), 15.3% experienced bullying victimization, as reported by the primary caregiver. Of these, boys were more likely to be bullied than girls (odds ratio [OR], 1.2 [95% CI, 1.1-1.3]; p = 0.004). Children who were bullied were more likely to display NSSI or passive suicidality (OR, 2.4 [95% CI, 2.0-2.9]; p < 0.001) and active suicidality (OR, 3.4 [95% CI, 2.7-4.2]; p < 0.001). Bullied children also had lower cognitive scores, greater behavioral problems, and poorer grades (p < 0.001). Across all participants, boys had poorer grades and greater behavioral problems than girls; however, bullied boys had greater behavioral problems than girls in several areas (p < 0.001). Compared to their non-bullied peers, bullied children with greater non-suicidal self-injury or suicidality also had greater behavioral problems and poorer grades (p < 0.001). Conclusion: These findings highlight the sex-specific effects of bullying, and the negative associations of bullying victimization with cognitive performance, behavioral problems, and academic performance. Future longitudinal studies will identify the natural history and neural correlates of these deficits during adolescence.

Individual-, peer-, and parent-level substance use-related factors among 9- and 10-year-olds from the ABCD Study: Prevalence rates and sociodemographic differences.

Background: Although a relatively large body of research has identified multiple factors associated with adolescent substance use, less is known about earlier substance-related factors during preadolescence, including curiosity to use substances. The present study examined individual-, peer-, and parent-level domains pertaining to substance use and how these domains vary by sociodemographic subgroups and substance type. Methods: Participants were 11,864 9- and 10-year-olds from the baseline sample of the Adolescent Brain Cognitive Development (ABCD) Study. Youth-reported measures were curiosity to use substances and perceived peer substance use. Parent-reported measures were availability of and rules about substances. Generalized logistic mixed models (GLMM) were used to compare these measures across alcohol, nicotine, and marijuana and across sociodemographic subgroupings (sex, race/ethnicity, household income, and family history of alcohol problems). GLMM was then used to examine predictors of curiosity to use by substance type. Results: The most striking descriptive differences were found between race/ethnicity and income categories (e.g., positive associations between greater income and greater availability of alcohol). In multivariable analyses, greater curiosity to use alcohol was associated with being male, higher household income, perceived peer alcohol use, and easy alcohol availability; greater curiosity to use nicotine was associated with being male, perceived peer cigarette use, easy availability of cigarettes, and no parental rules about cigarette use. Conclusions: This study identified substance use-related individual-, peer-, and parent-level factors among a diverse, national sample. Findings highlight the importance of considering sociodemographic and substance-specific variability and may help identify risk and protective factors preceding adolescent substance use.

Associations between potentially traumatic events and psychopathology among preadolescents in the Adolescent Brain and Cognitive Development Study®.

The current cross-sectional study aimed to extend the literature on childhood adversity by examining the unique associations between potentially traumatic events (PTEs) and a range of mental health concerns, including domain-specific versus comorbid concerns. Participants were 11,877 preadolescents (47.8% female, 15.0% Black, 20.3% Hispanic/Latinx, Mage  = 9.5 years) taking part in the Adolescent Brain and Cognitive Development (ABCD) Study® . The Kiddie Schedule for Affective Disorders and Schizophrenia was used to measure PTEs and caregiver- and child-reported mental health concerns. Adjusted odds ratios (aORs) were used for the outcomes of interest. Overall, PTEs were consistently associated with increased odds of experiencing comorbid posttraumatic stress disorder (PTSD), internalizing disorders, and externalizing disorders, significant AORs = 1.34-4.30, after accounting for children's experiences of other PTEs and polyvictimization. In contrast, PTEs were generally not associated with meeting the criteria for diagnoses within only one domain (i.e., internalizing-only or externalizing-only diagnoses). We also found PTEs to be differentially related to the various mental health outcomes. In particular, witnessing domestic violence was consistently associated with children's psychopathology. Other PTEs, such as witnessing community violence, were not associated with children's psychopathology in the final model. Associations between PTEs and mental health concerns did not differ as a function of sex. Overall, the results support the notion that PTEs are associated with comorbid concerns rather than individual disorders. These findings have important implications for the screening of PTEs, continued research on the conceptualization of traumatic stress, and the importance of accounting for comorbidities across mental health domains.

Substance use patterns in 9 to 13-year-olds: Longitudinal findings from the Adolescent Brain Cognitive Development (ABCD) study.

Background: Though largely substance-naïve at enrollment, a proportion of the youth in the Adolescent Brain Cognitive Development (ABCD) Study are expected to initiate substance use (SU) as they transition into later adolescence. With annual data from youth 9-13 years-old, this study aims to describe their SU patterns over time. Here, prevalence rates of use are reported, along with predicted odds of use while analyzing common risk-factors associated with youth SU. Methods: The ABCD Study® enrolled 11,876 participants at Baseline (ages 9-10) and has followed them annually. Data through half of the third follow-up visit are available (ages 12-13; n = 6,251). SU descriptives for al psychoactive substances over time are outlined. General estimating equations (GEEs) assessed whether sociodemographic factors, internalizing and externalizing symptoms, and parental SU problems were associated with SU between Baseline and Y2 follow-up. Results: Across time, alcohol and nicotine remain the most used substances. Yearly rates of any SU increased (past year use: 13.9% in Y1; 14% Y2, 18.4% Y3). Cumulatively, by Y3, 39.7% of the cohort reported experimenting (e.g., sipping alcohol) with SU within their lifetime, while 7.4% reported a "full use" (a full alcohol drink, nicotine use, cannabis use, or any other SU) in their lifetime (past-year: 1.9% alcohol, 2.1% nicotine, 1.1% cannabis, 1.2% other substances). GEEs revealed ongoing longitudinal associations between sociodemographic factors, greater externalizing symptoms, and parental drug problems with increased odds of initiating SU. Conclusions: As ABCD participants transition into their teenage years, the cohort is initiating SU at increasing (though still low) rates.

Associations between frontal lobe structure, parent-reported obstructive sleep disordered breathing and childhood behavior in the ABCD dataset.

Parents frequently report behavioral problems among children who snore. Our understanding of the relationship between symptoms of obstructive sleep disordered breathing (oSDB) and childhood behavioral problems associated with brain structural alterations is limited. Here, we examine the associations between oSDB symptoms, behavioral measures such as inattention, and brain morphometry in the Adolescent Brain Cognitive Development (ABCD) study comprising 10,140 preadolescents. We observe that parent-reported symptoms of oSDB are associated with composite and domain-specific problem behaviors measured by parent responses to the Child Behavior Checklist. Alterations of brain structure demonstrating the strongest negative associations with oSDB symptoms are within the frontal lobe. The relationships between oSDB symptoms and behavioral measures are mediated by significantly smaller volumes of multiple frontal lobe regions. These results provide population-level evidence for an association between regional structural alterations in cortical gray matter and problem behaviors reported in children with oSDB.

Association Between Habitual Snoring and Cognitive Performance Among a Large Sample of Preadolescent Children.

Importance: Previous studies have identified an association between habitual snoring and lower cognitive performance in children. However, whether and to what extent this association is confounded by pertinent demographic, anthropometric, and socioeconomic characteristics is unknown. Objective: To assess the extent to which potential confounding factors modify the association between parent-reported habitual snoring and cognitive outcomes among a large and diverse sample of typically developing preadolescent children. Design, Setting, and Participants: This cross-sectional analysis used a baseline data set (version 2.0.1) from children enrolled in the ongoing Adolescent Brain Cognitive Development study between September 1, 2016, and October 15, 2018. Children aged 9 to 10 years without serious psychiatric or neurological comorbidities were recruited at 21 research sites in the US. Study recruitment was designed to approximate the racial and socioeconomic diversity of the US population. Data were analyzed from February 1 to March 31, 2020. Exposures: Parent-reported habitual snoring in children that occurs 3 or more nights per week. Main Outcomes and Measures: Associations between habitual snoring and cognitive performance were assessed using the Sleep Disturbance Scale for Children and the National Institutes of Health Toolbox Cognition Battery, which includes 7 domain-specific and 3 composite (total cognitive function, fluid cognition, and crystallized cognition) standard scores that are uncorrected for covariates. Cognitive performance was examined before and after adjustment for covariates, which included age, sex, body mass index percentile, annual household income before taxes, and highest educational level of caregiver. The extent of confounding was assessed by the effect size, represented by Cohen d, before and after inclusion of covariates using linear mixed-effects models. Results: A total of 11 873 children aged 9 to 10 years (6187 boys [52.1%]; 6174 White [52.0%]) with available data were included in the study. Of those, habitual snoring (≥3 nights per week) was reported in 810 children (6.8%), and nonhabitual snoring (1-2 nights per week) was reported in 4058 children (34.2%). In the unadjusted models, the total cognitive function composite score among children who habitually snored was significantly lower compared with children who never snored (Cohen d, 0.35; 95% CI, 0.28-0.42). Differences were also identified in the crystallized cognition (Cohen d, 0.34; 95% CI, 0.26-0.41) and fluid cognition (Cohen d, 0.28; 95% CI, 0.21-0.35) composite scores. The association between habitual snoring and cognitive performance was substantially attenuated after adjustment for covariates (Cohen d, 0.16 [95% CI, 0.09 to 0.24] for total cognitive function, 0.14 [95% CI, 0.07 to 0.21] for crystallized cognition, and 0.13 [95% CI, 0.06 to 0.21] for fluid cognition). Similar mitigation was also observed for all domain-specific scores. Conclusions: In this cross-sectional study, when adjusted for baseline demographic, anthropometric, and socioeconomic characteristics, the association between parent-reported habitual snoring and cognitive performance was substantially attenuated among children aged 9 to 10 years.

Reciprocal Influences of HIV and Cannabinoids on the Brain and Cognitive Function.

Globally, cannabis is the most commonly used illicit drug, with disproportionately high use among persons with HIV. Despite advances in HIV care, nearly half of persons living with HIV continue to experience neurocognitive deficits or impairments that may have negative impacts on their daily function. Chronic cannabis use may play a role in the development or exacerbation of these impairments. Here we present a review summarizing existing research detailing the effect of cannabis use associated with the neuropathogenesis of HIV. We examine evidence for possible additive or synergistic effects of HIV infection and cannabis use on neuroHIV in both the preclinical and adult human literatures, including in vitro studies, animal models, clinical neuroimaging research, and studies examining the cognitive effects of cannabis. We discuss the limitations of existing research, including methodological challenges involved with clinical research with human subjects. We identify gaps in the field and propose critical research questions to advance our understanding of how cannabis use affects neuroHIV. Graphical Abstract.

Correspondence Between Perceived Pubertal Development and Hormone Levels in 9-10 Year-Olds From the Adolescent Brain Cognitive Development Study.

Aim: To examine individual variability between perceived physical features and hormones of pubertal maturation in 9-10-year-old children as a function of sociodemographic characteristics. Methods: Cross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study-a multi-site sample of 9-10 year-olds (n = 11,875)-and included perceived physical features via the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels. Results: PDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child's weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample. Conclusions: Sociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9-10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes.

Psychiatric Symptoms, Salivary Cortisol and Cytokine Levels in Young Marijuana Users.

Psychological maturation continues into young adulthood when substance abuse and several psychiatric disorders often emerge. Marijuana is the most common illicit drug abused by youths, typically preceding other illicit substances. We aimed to evaluate the complex and poorly studied relationships between marijuana use, psychiatric symptoms, and cortisol levels in young marijuana users. Psychiatric symptoms and salivary cortisol were measured in 122 youths (13-23 years old) with and without marijuana use. Psychiatric symptoms were evaluated using the Symptom-Checklist-90-R and Brief Psychiatric Rating Scale. Mid-day salivary cortisol levels were measured. Additionally, salivary cytokine levels were measured in a subset of participants. Although the cortisol levels and salivary cytokine levels were similar, the young marijuana users had more self-reported and clinician rated psychiatric symptoms than controls, especially anxiety-associated symptoms. Moreover, marijuana users with earlier age of first use had more symptoms, while those with longer abstinence had fewer symptoms. Greater cumulative lifetime marijuana use was also associated with greater psychiatric symptoms. The discordant anxiety (feeling stressed or anxious despite normal cortisol) in the marijuana users, as well as symptom exacerbations with early and continued marijuana use in young marijuana users suggest that marijuana use may contribute to an aberrant relationship between stress response and psychiatric symptoms. The greater symptomatology, especially in those with earlier initiation and greater marijuana usage, emphasize the need to intervene for substance use and perceived anxiety in this population.

Lower glial metabolite levels in brains of young children with prenatal nicotine exposure.

Many pregnant women smoke cigarettes during pregnancy, but the effect of nicotine on the developing human brain is not well understood, especially in young children. This study aims to determine the effects of prenatal nicotine exposure (PNE) on brain metabolite levels in young (3-4 years old) children, using proton magnetic resonance spectroscopy ((1)H MRS). Twenty-six children with PNE and 24 nicotine-unexposed children (controls) were evaluated with a structured examination, a battery of neuropsychological tests, and MRI/(1)H MRS (without sedation). Concentrations of N-acetyl compounds (NA), total creatine (tCR), choline-containing compounds (CHO), myo-inositol (MI), and glutamate+glutamine (GLX) were measured in four brain regions. Children with PNE had similar performance to controls on neuropsychological testing. However, compared to controls, the PNE group had lower MI (repeated measures ANOVA-p = 0.03) and tCr levels (repeated measures ANOVA-p = 0.003), especially in the basal ganglia of the girls (-19.3%, p = 0.01). In contrast, GLX was elevated in the anterior cingulate cortex of the PNE children (+9.4%, p = 0.03), and those with the highest GLX levels had the poorest performance on vocabulary (r = -0.67; p < 0.001) and visual motor integration (r = -0.53; p = 0.01). The amount of prenatal nicotine exposure did not correlate with metabolite concentrations. These findings suggest that PNE may lead to subclinical abnormalities in glial development, especially in the basal ganglia, and regionally specific changes in other neurometabolites. These alterations were not influenced by the amount of nicotine exposure prenatally. However, the effects of PNE on energy metabolism may be sex specific, with greater alterations in girls.

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 drug's 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.

Neurometabolite abnormalities in simian immunodeficiency virus-infected macaques with chronic morphine administration.

Opiate abuse increases the risk for human immunodeficiency virus (HIV) infection, while both opiates and HIV may impact the immune and nervous systems. To model potential interactions between opiate drugs and HIV on the brain, neurometabolite levels were evaluated in simian immunodeficiency virus (SIV)-infected macaques with or without chronic morphine administration. Over the course of the study, 58% of these SIV-infected animals progressed to acquired immune deficiency syndrome (AIDS). Brain extracts from four brain regions were evaluated with proton magnetic resonance spectroscopy. Animals with AIDS had lower N-acetyl-aspartate in all four brain regions (p ≤ 0.05) as well as lower frontal gray matter total creatine (p= 0.03), lower frontal white matter (p= 0.003) and caudate (p = 0.002) glutamate, and higher frontal white matter myo-inositol (p= 0.05) than the healthier non-AIDS macaques. Morphine-dependent animals had higher levels of myo-inositol in the putamen (p = 0.003), especially those with AIDS. In the animals with AIDS, those with morphine dependence had higher total creatine in the frontal white matter (p= 0.04) than those treated with saline, which in turn had lower creatine than saline-injected animals without AIDS (p = 0.04), leading to an interaction between the effects of morphine and AIDS on total creatine in this brain region (ANOVA p = 0.02). The majority of these brain metabolites correlated with viral counts indicating more severe metabolite abnormalities in animals with higher viral loads or set points. Collectively, these findings suggest that chronic morphine may protect against the neurotoxic effect of AIDS and reinforce the importance of maintaining a low viral load in AIDS.

The effects of repeated endotoxin exposure on rat brain metabolites as measured by ex vivo 1HMRS.

Abnormalities in brain chemistry induced by acute or chronic treatment with LPS were studied in the rat model. Ex vivo brain metabolites were measured using proton magnetic resonance spectroscopy, whereas serum corticosterone levels were determined using radioimmunoassay. We observed increased lactate levels in all measured brain regions and decreased choline in the hypothalamus after chronic LPS treatment. Acute LPS treatment led to an elevation of corticosterone, whereas chronic LPS treatment led to attenuation of the HPA response. These findings suggest that chronic inflammation induced by LPS could lead to cell loss/dysfunction, and hence, desensitization of the HPA axis, particularly in the hypothalamus.

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.

Magnetic resonance spectroscopy studies of GABA in neuropsychiatric disorders.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system and is integral to managing brain excitability. GABA concentrations vary according to age, gender, and brain region. Magnetic resonance spectroscopy (MRS), with editing or with localized 2-dimensional chemical shift methods, can measure GABA levels in vivo, ex vivo, or in vitro, particularly at ultra-high magnetic field strengths. Proton ((1)H) MRS studies have found reduced or abnormal GABA concentrations in several neuropsychiatric disorders, including epilepsy, anxiety disorders, major depression, and drug addiction. Disorders with low GABA levels may be treated by augmentation of GABAergic function, such as by medications that block the degradation or reuptake of GABA. Examples of such a rational therapeutic approach include anticonvulsants that elevate brain GABA levels and are effective for the treatment of epilepsy and anxiety disorder.