Associations between community-level patterns of prenatal alcohol and tobacco exposure on brain structure in a non-clinical sample of 6-year-old children: a South African pilot study.

The current small study utilised prospective data collection of patterns of prenatal alcohol and tobacco exposure (PAE and PTE) to examine associations with structural brain outcomes in 6-year-olds and served as a pilot to determine the value of prospective data describing community-level patterns of PAE and PTE in a non-clinical sample of children. Participants from the Safe Passage Study in pregnancy were approached when their child was ∼6 years old and completed structural brain magnetic resonance imaging to examine with archived PAE and PTE data (n = 51 children-mother dyads). Linear regression was used to conduct whole-brain structural analyses, with false-discovery rate (FDR) correction, to examine: (a) main effects of PAE, PTE and their interaction; and (b) predictive potential of data that reflect patterns of PAE and PTE (e.g. quantity, frequency and timing (QFT)). Associations between PAE, PTE and their interaction with brain structural measures demonstrated unique profiles of cortical and subcortical alterations that were distinct between PAE only, PTE only and their interactive effects. Analyses examining associations between patterns of PAE and PTE (e.g. QFT) were able to significantly detect brain alterations (that survived FDR correction) in this small non-clinical sample of children. These findings support the hypothesis that considering QFT and co-exposures is important for identifying brain alterations following PAE and/or PTE in a small group of young children. Current results demonstrate that teratogenic outcomes on brain structure differ as a function PAE, PTE or their co-exposures, as well as the pattern (QFT) or exposure.

Behavioral and psychosocial factors related to mental distress among medical students.

Introduction: Physicians die by suicide at rates higher than the general population, with the increased risk beginning in medical school. To better understand why, this study examined the prevalence of mental distress (e.g., depressive symptoms and suicide risk) and behavioral and psychosocial risk factors for distress, as well as the associations between mental distress and risk factors among a sample of medical students in a pre-COVID-19-era. Methods: Students enrolled in a large California medical school in 2018-2019 (N = 134; 52% female) completed questionnaires assessing sociodemographic characteristics, depression and suicide family history, health behaviors, and psychosocial wellbeing. Assessment scores indexing mental distress (e.g., depressive symptoms, thoughts of suicide in the past 12 months, suicide risk, and history of suicidality) and risk factors (e.g., stress, subjective sleep quality, alcohol use, impostor feelings, and bill payment difficulty) were compared across biological sex using chi-squared tests, and associations between mental distress and risk factors were determined through logistic regression. Results: Elevated mental distress indicators were observed relative to the general public (e.g., 16% positive depression screen, 17% thought about suicide in previous 12 months, 10% positive suicide risk screen, and 34% history of suicidality), as well as elevated risk factors [e.g., 55% moderate or high stress, 95% at least moderate impostor feelings, 59% poor sleep quality, 50% screened positive for hazardous drinking (more likely in females), and 25% difficulty paying bills]. A positive depression screen was associated with higher stress, higher impostor feelings, poorer sleep quality, and difficulty paying bills. Suicidal ideation in the previous 12 months, suicide risk, and a history of suicidality were independently associated with higher levels of impostor feelings. Discussion: Higher scores on assessments of depressive symptoms and suicidal thoughts and behaviors were related to several individual-level and potentially modifiable risk factors (e.g., stress, impostor feelings, sleep quality, and bill payment difficulties). Future research is needed to inform customized screening and resources for the wellbeing of the medical community. However, it is likely that the modification of individual-level risk factors is limited by the larger medical culture and systems, suggesting that successful interventions mitigate suicide risk for medical providers need to address multiple socio-ecological levels.

Contextualizing the impact of prenatal alcohol and tobacco exposure on neurodevelopment in a South African birth cohort: an analysis from the socioecological perspective.

Background: Alcohol and tobacco are known teratogens. Historically, more severe prenatal alcohol exposure (PAE) and prenatal tobacco exposure (PTE) have been examined as the principal predictor of neurodevelopmental alterations, with little incorporation of lower doses or ecological contextual factors that can also impact neurodevelopment, such as socioeconomic resources (SER) or adverse childhood experiences (ACEs). Here, a novel analytical approach informed by a socio-ecological perspective was used to examine the associations between SER, PAE and/or PTE, and ACEs, and their effects on neurodevelopment. Methods: N = 313 mother-child dyads were recruited from a prospective birth cohort with maternal report of PAE and PTE, and cross-sectional structural brain neuroimaging of child acquired via 3T scanner at ages 8-11 years. In utero SER was measured by maternal education, household income, and home utility availability. The child's ACEs were measured by self-report assisted by the researcher. PAE was grouped into early exposure (<12 weeks), continued exposure (>=12 weeks), and no exposure controls. PTE was grouped into exposed and non-exposed controls. Results: Greater access to SER during pregnancy was associated with fewer ACEs (maternal education: ß = -0.293,p = 0.01; phone access: ß = -0.968,p = 0.05). PTE partially mediated the association between SER and ACEs, where greater SER reduced the likelihood of PTE, which was positively associated with ACEs (ß = 1.110,p = 0.01). SER was associated with alterations in superior frontal (ß = -1336.036, q = 0.046), lateral orbitofrontal (ß = -513.865, q = 0.046), caudal anterior cingulate volumes (ß = -222.982, q = 0.046), with access to phone negatively associated with all three brain volumes. Access to water was positively associated with superior frontal volume (ß=1569.527, q = 0.013). PTE was associated with smaller volumes of lateral orbitofrontal (ß = -331.000, q = 0.033) and nucleus accumbens regions (ß = -34.800, q = 0.033). Conclusion: Research on neurodevelopment following community-levels of PAE and PTE should more regularly consider the ecological context to accelerate understanding of teratogenic outcomes. Further research is needed to replicate this novel conceptual approach with varying PAE and PTE patterns, to disentangle the interplay between dose, community-level and individual-level risk factors on neurodevelopment.

The implications of socioeconomic factors on salivary bioscience methodological variables in a large pediatric multi-site study.

Introduction: Salivary bioscience has found increased utilization within pediatric research, given the non-invasive nature of self-collecting saliva for measuring biological markers. With this growth in pediatric utility, more understanding is needed of how social-contextual factors, such as socioeconomic factors or status (SES), influence salivary bioscience in large multi-site studies. Socioeconomic factors have been shown to influence non-salivary analyte levels across childhood and adolescent development. However, less is understood about relationships between these socioeconomic factors and salivary collection methodological variables (e.g., time of saliva collection from waking, time of day of saliva collection, physical activity prior to saliva collection, and caffeine intake prior to saliva collection). Variability in salivary methodological variables between participants may impact the levels of analytes measured in a salivary sample, thus serving as a potential mechanism for non-random systematic biases in analytes. Methods: Our objective is to examine relationships between socioeconomic factors and salivary bioscience methodological variables within the Adolescent Brain Cognitive Development Study© cohort of children aged 9-10 years old (n = 10,567 participants with saliva samples). Results: We observed significant associations between household socioeconomic factors (poverty status, education) and salivary collection methodological variables (time since waking, time of day of sampling, physical activity, and caffeine intake). Moreover, lower levels of household poverty and education were significantly associated with more sources of potential bias in salivary collection methodological variables (e.g., longer times since waking, collections later in the day, higher odds of caffeine consumption, and lower odds of physical activity). Consistent associations were not observed with neighborhood socioeconomic factors and salivary methodological variables. Discussion: Previous literature demonstrates associations between collection methodological variables and measurements of salivary analyte levels, particularly with analytes that are more sensitive to circadian rhythms, pH levels, or rigorous physical activity. Our novel findings suggest that unintended distortions in measured salivary analyte values, potentially resulting from the non-random systematic biases in salivary methodology, need to be intentionally incorporated into analyses and interpretation of results. This is particularly salient for future studies interested in examining underlying mechanisms of childhood socioeconomic health inequities in future analyses.

A call to leverage a health equity lens to accelerate human neuroscience research.

Investigation of health inequities tend to be examined, in human neurosciences, as biological factors at the level of the individual. In actuality, health inequities arise, due largely in part, to deep-seated structural factors. Structural inequality refers to the systemic disadvantage of one social group compared to others with whom they coexist. The term encompasses policy, law, governance, and culture and relates to race, ethnicity, gender or gender identity, class, sexual orientation, and other domains. These structural inequalities include but are not limited to social segregation, the intergenerational effects of colonialism and the consequent distribution of power and privilege. Principles to address inequities influenced by structural factors are increasingly prevalent in a subfield of the neurosciences, i.e., cultural neurosciences. Cultural neuroscience articulates the bidirectional relationship between biology and environmental contextual factors surrounding research participants. However, the operationalization of these principles may not have the intended spillover effect on the majority of human neurosciences: this limitation is the overarching focus of the present piece. Here, we provide our perspective that these principles are missing and very much needed in all human neuroscience subdisciplines to accelerate our understanding of the human brain. Furthermore, we provide an outline of two key tenets of a health equity lens necessary for achieving research equity in human neurosciences: the social determinants of health (SDoH) framework and how to deal with confounders using counterfactual thinking. We argue that these tenets should be prioritized across future human neuroscience research more generally, and doing so is a pathway to further gain an understanding of contextual background intertwined with the human brain, thus improving the rigor and inclusivity of human neuroscience research.

Prenatal tobacco exposure associations with physical health and neurodevelopment in the ABCD cohort.

OBJECTIVE: To investigate the strength and reproducibility of the teratogenic impact of prenatal tobacco exposure (PTE) on child physical health and neurodevelopmental outcomes, in the context of intersecting sociodemographic and other prenatal correlates, and test if early postnatal health mediates PTE associations with childhood outcomes. METHOD: Among 9-10-year-olds (N = 8,803) in the Adolescent Brain Cognitive Development Study, linear mixed-effect models tested PTE associations with birth and childhood outcomes of physical health, cognitive performance, and brain structure, controlling for confounding sociodemographic and prenatal health correlates. Mediation analysis tested the extent to which health at birth explained the associations between PTE and childhood outcomes. RESULTS: PTE was reported by 12% of mothers (8% [n = 738] pre-knowledge of pregnancy only, and 4% [n = 361] pre- and post-knowledge of pregnancy). PTE was highest for children with a risk for passive smoke exposure. Overall, children with any PTE had shorter breastfeeding durations than those without PTE, and PTE following knowledge of pregnancy was associated with being small for gestational age having lower birth weight, and obesity and lower cortical volume and surface area in childhood. Among children from high-parent education households, any PTE was related to lower cognitive performance, which was partially mediated by duration of breastfeeding. CONCLUSIONS: PTE was linked to poorer health indicators at birth and neurodevelopmental outcomes at age 9-10 years in a large community cohort, independent of sociodemographic factors. Efficacious interventions for smoking-cessation during pregnancy are still needed and should incorporate support for breastfeeding to promote healthier development. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The impact of prenatal alcohol and/or tobacco exposure on brain structure in a large sample of children from a South African birth cohort.

BACKGROUND: Neuroimaging studies have emphasized the impact of prenatal alcohol exposure (PAE) on brain development, traditionally in heavily exposed participants. However, less is known about how naturally occurring community patterns of PAE (including light to moderate exposure) affect brain development, particularly in consideration of commonly occurring concurrent impacts of prenatal tobacco exposure (PTE). METHODS: Three hundred thirty-two children (ages 8 to 12) living in South Africa's Cape Flats townships underwent structural magnetic resonance imaging. During pregnancy, their mothers reported alcohol and tobacco use, which was used to evaluate PAE and PTE effects on their children's brain structure. Analyses involved the main effects of PAE and PTE (and their interaction) and the effects of PAE and PTE quantity on cortical thickness, surface area, and volume. RESULTS: After false-discovery rate (FDR) correction, PAE was associated with thinner left parahippocampal cortices, while PTE was associated with smaller cortical surface area in the bilateral pericalcarine, left lateral orbitofrontal, right posterior cingulate, right rostral anterior cingulate, left caudal middle frontal, and right caudal anterior cingulate gyri. There were no PAE × PTE interactions nor any associations of PAE and PTE exposure on volumetrics that survived FDR correction. CONCLUSION: PAE was associated with reduction in the structure of the medial temporal lobe, a brain region critical for learning and memory. PTE had stronger and broader associations, including with regions associated with executive function, reward processing, and emotional regulation, potentially reflecting continued postnatal exposure to tobacco (i.e., second-hand smoke exposure). These differential effects are discussed with respect to reduced PAE quantity in our exposed group versus prior studies within this geographical location, the deep poverty in which participants live, and the consequences of apartheid and racially and economically driven payment practices that contributed to heavy drinking in the region. Longer-term follow-up is needed to determine potential environmental and other moderators of the brain findings here and assess the extent to which they endure over time.

A Researcher's Guide to the Measurement and Modeling of Puberty in the ABCD Study® at Baseline.

The Adolescent Brain Cognitive Development℠ (ABCD) Study is an ongoing, diverse, longitudinal, and multi-site study of 11,880 adolescents in the United States. The ABCD Study provides open access to data about pubertal development at a large scale, and this article is a researcher's guide that both describes its pubertal variables and outlines recommendations for use. These considerations are contextualized with reference to cross-sectional empirical analyses of pubertal measures within the baseline ABCD dataset by Herting, Uban, and colleagues (2021). We discuss strategies to capitalize on strengths, mitigate weaknesses, and appropriately interpret study limitations for researchers using pubertal variables within the ABCD dataset, with the aim of building toward a robust science of adolescent development.

Positive Economic, Psychosocial, and Physiological Ecologies Predict Brain Structure and Cognitive Performance in 9-10-Year-Old Children.

While low socioeconomic status (SES) introduces risk for developmental outcomes among children, there are an array of proximal processes that determine the ecologies and thus the lived experiences of children. This study examined interrelations between 22 proximal measures in the economic, psychosocial, physiological, and perinatal ecologies of children, in association with brain structure and cognitive performance in a diverse sample of 8,158 9-10-year-old children from the Adolescent Brain Cognitive Development (ABCD) study. SES was measured by the income-to-needs ratio (INR), a measure used by federal poverty guidelines. Within the ABCD study, in what is one of the largest and most diverse cohorts of children studied in the United States, we replicate associations of low SES with lower total cortical surface area and worse cognitive performance. Associations between low SES (<200% INR) and measures of development showed the steepest increases with INR, with apparent increases still visible beyond the level of economic disadvantage in the range of 200-400% INR. Notably, we found three latent factors encompassing positive ecologies for children across the areas of economic, psychosocial, physiological, and perinatal well-being in association with better cognitive performance and the higher total cortical surface area beyond the effects of SES. Specifically, latent factors encompassing youth perceived social support and perinatal well-being were positive predictors of developmental measures for all children, regardless of SES. Further, we found a general latent factor that explained relationships between 20 of the proximal measures and encompassed a joint ecology of higher social and economic resources relative to low adversity across psychosocial, physiological, and perinatal domains. The association between the resource-to-adversity latent factor and cognitive performance was moderated by SES, such that for children in higher SES households, cognitive performance progressively increased with these latent factor scores, while for lower SES, cognitive performance increased only among children with the highest latent factor scores. Our findings suggest that both positive ecologies of increased access to resources and lower adversity are mutually critical for promoting better cognitive development in children from low SES households. Our findings inform future studies aiming to examine positive factors that influence healthier development in children.

The Relationship Between Socioeconomic Status and Brain Volume in Children and Adolescents With Prenatal Alcohol Exposure.

The positive relationship between socioeconomic status (SES) and cognitive performance is mediated, in part, by differences in brain structure in typically developing youth. Associations between brain regions that relate to SES overlap with brain regions known to be sensitive to prenatal alcohol exposure (PAE). Animal models demonstrate that PAE attenuates neural and cognitive benefits of early life enrichment. However, whether or not environmental factors related to SES are associated with brain development in youth affected by PAE remains unknown in humans. METHODS: T1-weighted magnetic resonance imaging (MRI) scans were obtained in participants with PAE and compared to age- and sex- matched Controls (n = 197, 48% with PAE, 44% girls, 6.5-17.7 years old). General linear modeling was utilized to examine associations between SES and subcortical brain volumes for youth with PAE compared to Controls. RESULTS: Group by SES interactions were observed within the hippocampus (HPC), nucleus accumbens (NAc) and ventral diencephalon (vDC) (corrected p values <0.05), where positive associations (e.g., higher SES related to larger subcortical volumes) were observed within Controls, but not youth with PAE. Post hoc analyses examined associations between SES and brain volumes within each group independently, and revealed widespread positive associations among Controls (Amyg, HPC, NAc, Pallidum, Putamen, vDC), but not youth with PAE. Across both groups, larger subcortical volumes were related to higher cognitive performance. CONCLUSION: Typically developing youth exhibit increased subcortical volumes with increased SES, and surprisingly, this relationship is absent in adolescents with PAE. Findings suggest that subcortical brain volumes are neurocognitively relevant in both groups. The present results expand our understanding of the impact of PAE on the developing human brain within varying environmental contexts, and may inform novel environmental interventions that aim to improve, in part, on-going disruptions in brain development among youth with PAE. Our study highlights novel complexities in the pursuit to understand SES-brain associations, as we provide evidence that SES matters for brain outcomes among typically developing youth, and possibly not as much on an already altered brain as a result of PAE.

Brain morphometric differences in youth with and without perinatally-acquired HIV: A cross-sectional study.

Youth with perinatally-acquired HIV (PHIV) experience specific and global cognitive deficits at increased rates compared to typically-developing HIV-uninfected youth. In youth with PHIV, HIV infects the brain early in development. Neuroimaging studies have demonstrated altered grey matter morphometry in youth with PHIV compared to typically-developing youth. This study examined cortical thickness, surface area, and gyrification of grey matter in youth (age 11-20 years old) with PHIV (n = 40) from the Pediatric HIV/AIDS Cohort Study (PHACS) compared to typically-developing presumed HIV uninfected and unexposed youth (n = 80) from the Pediatric Imaging, Neurocognition and Genetics Study (PING) using structural magnetic resonance imaging. This study also examined the relationship between grey matter morphometry and age. Youth with PHIV had reduced cortical thickness, surface area, and gyrification compared to typically-developing youth. In addition, an inverse relationship between age and grey matter volume was found in typically-developing youth, but was not observed in youth with PHIV. Longitudinal studies are necessary to understand the neurodevelopmental trajectory of youth with PHIV.

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.

Structural white matter alterations in male adults with high functioning autism spectrum disorder and concurrent depressive symptoms; a diffusion tensor imaging study.

BACKGROUND: Autism spectrum disorder (ASD), a prevalent developmental condition, is associated with comorbid mood disorders, most importantly depression. Here, we explored the underlying association between brain white matter microstructural integrity, assessed by diffusion tensor imaging (DTI), and depressive symptoms, in male adults with high-functioning ASD. METHOD: To assess our main purpose, Autism Brain Imaging Data Exchange II dataset was used to acquire brain diffusion imaging from 26 adult male patients with ASD ranging from 18 to 62 years of age, and 26 age and gender-matched typically developed control subjects. Participants were evaluated for depressive symptoms manifestation by the Beck Depression Index (BDI). DWI images were preprocessed and analyzed for DTI scalers in the "ExploreDTI" toolbox. Adjusted linear regression models were used. Association between normalized BDI score and its interaction with diagnosis, as predictors, and measures of fractional anisotropy (FA) and mean diffusivity (MD) of regions of interest according to Mori atlas was assessed. RESULT: Significant lower microstructural integrity of white matter was found in association with higher BDI scores in ASD group, mainly in regions of anterior limb of internal capsule (ALIC) and corona radiata. Also, a statistically significant positive interaction between BDI and ASD was seen in FA of left ALIC. DISCUSSION: Considering similar regional brain white matter involvement with the imaging studies of depression in the typically developed population, we propose that these alterations of white matter tracts in depressive symptoms of adult ASD subjects might be, at least, similar to depression in typically developed population.

Biospecimens and the ABCD study: Rationale, methods of collection, measurement and early data.

Biospecimen collection in the Adolescent Brain Cognitive Development (ABCD) study - of hair samples, shed deciduous (baby) teeth, and body fluids - will serve dual functions of screening for study eligibility, and providing measures of biological processes thought to predict or correlate with key study outcomes on brain and cognitive development. Biosamples are being collected annually to screen for recency of drug use prior to the neuroimaging or cognitive testing visit, and to store for the following future studies: (1) on the effects of exposure to illicit and recreational drugs (including alcohol and nicotine); (2) of pubertal hormones on brain and cognitive developmental trajectories; (3) on the contribution of genomics and epigenomics to child and adolescent development and behavioral outcomes; and (4) with pre- and post-natal exposure to environmental neurotoxicants and drugs of abuse measured from novel tooth analyses. The present manuscript describes the rationales for inclusion and selection of the specific biospecimens, methodological considerations for each measure, future plans for assessment of biospecimens during follow-up visits, and preliminary ABCD data to illustrate methodological considerations.

Longitudinal changes in pubertal maturation and white matter microstructure.

Emerging evidence in the field of adolescent neurodevelopment suggests that pubertal processes may contribute to known trajectories of brain maturation, and may contribute, in part, to sex differences in related cognitive, behavioral and mental health outcomes. The current longitudinal study examined how changes in physical pubertal maturation (measured by the Peterson Developmental Scale) predict changes in white matter microstructure in 18 boys and 15 girls over an approximate 2-year follow-up period, while accounting for age. Using Tract-Based Spatial Statistics and multi-level modeling, the results showed that physical pubertal changes predict patterns of changes in fractional anisotropy (FA) in white matter regions in the thalamus, precentral gyrus, superior corona radiata, corpus callosum (genu), superior corona radiata, and superior frontal gyrus. Sex specific changes were also seen, as changes in gonadal and adrenal development related to increases in FA in the superior frontal gyrus and precentral gyrus in boys, but gonadal development related to decreases in FA in the anterior corona radiata in girls. These findings are the first to show how changes over time in pubertal development influence white matter development. In addition, they support a larger body of emerging research suggesting that pubertal processes contribute to distinct changes in boys and girls across brain development.

Lower total and regional grey matter brain volumes in youth with perinatally-acquired HIV infection: Associations with HIV disease severity, substance use, and cognition.

Despite improved survival due to combination antiretroviral therapy (cART), youth with perinatally-acquired HIV (PHIV) show cognitive deficits and developmental delay at increased rates. HIV affects the brain during critical periods of development, and the brain may be a persistent reservoir for HIV due to suboptimal blood brain barrier penetration of cART. We conducted structural magnetic resonance imaging (sMRI) and cognitive testing in 40 PHIV youth (mean age=16.7years) recruited from the NIH Pediatric HIV/AIDS Cohort Study (PHACS) who are part of the first generation of PHIV youth surviving into adulthood. Historical and current HIV disease severity and substance use measures were also collected. Total and regional cortical grey matter brain volumes were compared to a group of 334 typically-developing, HIV-unexposed and uninfected youth (frequency-matched for age and sex) from the Pediatric Imaging, Neurocognition, and Genetics (PING) study (mean age=16.1years). PHIV youth had smaller (2.8-5.1%) total and regional grey matter volumes than HIV-unexposed and uninfected youth, with smallest volumes seen among PHIV youth with higher past peak viral load (VL) and recent unsuppressed VL. In PHIV youth, worse cognitive performance correlated with smaller volumes. This pattern of smaller grey matter volumes suggests that PHIV infection may influence brain development and underlie cognitive dysfunction seen in this population. Among PHIV youth, smaller volumes were also linked to substance use (alcohol use: 9.0-13.4%; marijuana use: 10.1-16.0%). In this study, collection of substance use information was limited to the PHIV cohort; future studies should also collect substance use information in controls to further address interactions between HIV and substance use on brain volume.

Default Mode Connectivity in Youth With Perinatally Acquired HIV.

Youth with perinatally acquired human immunodeficiency virus (PHIV+) survive longer with combination antiretroviral therapy, but remain at risk for poor cognitive outcomes. We evaluated whether markers of HIV disease severity relate to default mode resting-state functional connectivity in PHIV+ youth. We conducted resting-state functional neuroimaging and cognitive testing in a subset of 40 PHIV+ youth recruited from a single study site of the Adolescent Master Protocol study conducted by the Pediatric HIV/AIDS Cohort Study (PHACS) network. Current and past HIV disease severity measures (nadir CD4 lymphocyte percentages and peak HIV RNA plasma levels) were obtained from medical charts. We evaluated associations of both HIV disease severity measures and cognitive functioning with between- and within- default mode network (DMN) connectivity using Analysis of Functional NeuroImaging multiple regression analyses, controlling for multiple comparisons. Of the 40 youth, 31 (mean age = 16.5 years) with minimal motion during scans were included. We observed global alterations in DMN within- and between-network connectivity, with significant associations between disease severity and DMN BOLD correlations. Furthermore, patterns of connectivity with the posterior cingulate cortex (PCC) and medial prefrontal cortex (mPFC) that varied as a function of peak HIV RNA were found to predict processing speed ability. Alterations in within- and between-network DMN connectivity in PHIV+ youth may reflect global reorganization of the DMN; this could lead to compensatory alterations in both the within- and between-connectivity of large-scale networks, which may ultimately relate to known cognitive processing difficulties in PHIV+ youth.

White matter microstructure among youth with perinatally acquired HIV is associated with disease severity.

OBJECTIVES: We investigated whether HIV disease severity was associated with alterations in structural brain connectivity, and whether those alterations in turn were associated with cognitive deficits in youth with perinatally acquired HIV (PHIV). DESIGN: PHIV youth (n = 40) from the Pediatric HIV/AIDS Cohort Study (PHACS) (mean age: 16 ±â€Š2 years) were included to evaluate how current and past disease severity measures (recent/nadir CD4%; peak viral load) relate to white matter microstructure within PHIV youth. PHIV youth were compared with 314 controls from the Pediatric Imaging, Neurocognition and Genetics (PING) study. METHODS: Diffusion tensor imaging and tractography were utilized to assess white matter microstructure. Mediation analyses were conducted to examine whether microstructure alterations contributed to relationships between higher disease severity and specific cognitive domains in PHIV youth. RESULTS: Whole brain fractional anisotropy was reduced, but radial and mean diffusivity were increased in PHIV compared with control youth. Within PHIV youth, more severe past HIV disease was associated with reduced fractional anisotropy of the right inferior fronto-occipital (IFO) and left uncinate tracts; elevated mean diffusivity of the F minor; and increased streamlines comprising the left inferior longitudinal fasciculus (ILF). Associations of higher peak viral load with lower working memory performance were partly mediated by reductions in right IFO fractional anisotropy levels. CONCLUSION: Our findings suggest that PHIV youth have a higher risk of alterations in white matter microstructure than typically developing youth, and certain alterations are related to past disease severity. Further, white matter alterations potentially mediate associations between HIV disease and working memory.

Amphetamine sensitization and cross-sensitization with acute restraint stress: impact of prenatal alcohol exposure in male and female rats.

RATIONALE: Individuals with fetal alcohol spectrum disorder (FASD) are at increased risk for substance use disorders (SUD). In typically developing individuals, susceptibility to SUD is associated with alterations in dopamine and hypothalamic-pituitary-adrenal (HPA) systems, and their interactions. Prenatal alcohol exposure (PAE) alters dopamine and HPA systems, yet effects of PAE on dopamine-HPA interactions are unknown. Amphetamine-stress cross-sensitization paradigms were utilized to investigate sensitivity of dopamine and stress (HPA) systems, and their interactions following PAE. METHODS: Adult Sprague-Dawley offspring from PAE, pair-fed, and ad libitum-fed control groups were assigned to amphetamine-(1-2 mg/kg) or saline-treated conditions, with injections every other day for 15 days. Fourteen days later, all animals received an amphetamine challenge (1 mg/kg) and 5 days later, hormones were measured under basal or acute stress conditions. Amphetamine sensitization (augmented locomotion, days 1-29) and cross-sensitization with acute restraint stress (increased stress hormones, day 34) were assessed. RESULTS: PAE rats exhibited a lower threshold for amphetamine sensitization compared to controls, suggesting enhanced sensitivity of dopaminergic systems to stimulant-induced changes. Cross-sensitization between amphetamine (dopamine) and stress (HPA hormone) systems was evident in PAE, but not in control rats. PAE males exhibited increased dopamine receptor expression (medial prefrontal cortex (mPFC)) compared to controls. CONCLUSIONS: PAE alters induction and expression of sensitization/cross-sensitization, as reflected in locomotor, neural, and endocrine changes, in a manner consistent with increased sensitivity of dopamine and stress systems. These results provide insight into possible mechanisms that could underlie increased prevalence of SUD, as well as the impact of widely prescribed stimulant medications among adolescents with FASD.

Basal regulation of HPA and dopamine systems is altered differentially in males and females by prenatal alcohol exposure and chronic variable stress.

Effects of prenatal alcohol exposure (PAE) on central nervous system function include an increased prevalence of mental health problems, including substance use disorders (SUD). The hypothalamic-pituitary-adrenal (HPA) and dopamine (DA) systems have overlapping neurocircuitries and are both implicated in SUD. PAE alters both HPA and dopaminergic activity and regulation, resulting in increased HPA tone and an overall reduction in tonic DA activity. However, effects of PAE on the interaction between HPA and DA systems have not been investigated. The present study examined PAE effects on basal regulation of central stress and DA systems in key brain regions where these systems intersect. Adult Sprague-Dawley male and female offspring from prenatal alcohol-exposed (PAE), pairfed (PF), and ad libitum-fed control (C) groups were subjected to chronic variable stress (CVS) or remained as a no stress (non-CVS) control group. Corticotropin releasing hormone (CRH) mRNA, as well as glucocorticoid and DA receptor (DA-R) expression were measured under basal conditions 24h following the end of CVS. We show, for the first time, that regulation of basal HPA and DA systems, and likely, HPA-DA interactions, are altered differentially in males and females by PAE and CVS. PAE augmented the typical attenuation in weight gain during CVS in males and caused increased weight loss in females. Increased basal corticosterone levels in control, but not PAE, females suggest that PAE alters the profile of basal hormone secretion throughout CVS. CVS downregulated basal CRH mRNA in the prefrontal cortex and throughout the bed nucleus of the stria terminalis (BNST) in PAE females but only in the posterior BNST of control females. PAE males and females exposed to CVS exhibited more widespread upregulation of basal mineralocorticoid receptor mRNA throughout the hippocampus, and an attenuated decrease in DA-R expression throughout the nucleus accumbens and striatum compared to CVS-exposed control males and females. Overall, these findings enhance our understanding of PAE effects on the cross-talk between HPA and DA systems, and provide insight into possible mechanisms underlying mental health problems that are related to stress and DA signaling, including SUD, which have a high prevalence among individuals with FASD.