Protein Kinase D1 Modulates Aldosterone-Induced ENaC Activity in a Renal Cortical Collecting Duct Cell Line

Aldosterone treatment of M1-CCD cells stimulated an increase in epithelial Na+ channel (ENaC) alpha-subunit expression that was mainly localized to the apical membrane. PKD1 suppressed cells constitutively expressed ENaC alpha at low abundance, with no increase after aldosterone treatment. Here ENaC alpha was mainly localized proximal to the basolateral surface of the epithelium both before and after aldosterone treatment. Apical membrane insertion of ENaC beta in response to aldosterone treatment was also sensitive to PKD1 suppression as was the aldosterone-induced rise in the amiloride-sensitive, trans-epithelial current (ITE). The interaction of the mineralocorticoid receptor (MR) with specific elements in the promoters of aldosterone responsive genes is stabilized by ligand interaction and phosphorylation. PKD1 suppression inhibited aldosterone-induced SGK-1 expression. The nuclear localization of MR was also blocked by PKD1 suppression and MEK antagonism implicating both these kinases in MR nuclear stabilization. PKD1 thus modulates aldosterone-induced ENaC activity through the modulation of sub-cellular trafficking and the stabilization of MR nuclear localization

Is there an association between prenatal testosterone and autistic traits in adolescents?

Prenatal testosterone (pT) is a crucial component in physiological masculinization in humans. In line with the Prenatal Sex Steroid Theory of autism, some studies have found a positive correlation between pT and autistic traits in childhood. However, effects in adolescence have not been explored. Hormonal and environmental changes occurring during puberty may alter the strength or the nature of prenatal effects on autistic traits. The current study examines if pT relates to autistic traits in a non-clinical sample of adolescents and young adults (N = 97, 170 observations; age 13-21 years old). It also explores pT interactions with pubertal stage and timing. PT concentrations were measured from amniotic fluid extracted in the 2nd trimester of gestation via amniocentesis conducted for clinical purposes. Autistic traits were measured by self- and parent-reports on the Autism Spectrum Quotient (AQ) which provides a total score and 5 sub-scores (social skills, communication, imagination, attention switching and attention to detail). Self-reported pubertal stage was regressed on age to provide a measure of relative timing. We found no statistical evidence for a direct association between pT and autistic traits in this adolescent sample (males, females or full sample). Exploratory analyses suggested that pT correlated positively with autistic traits in adolescents with earlier puberty-onset, but statistical robustness of this finding was limited. Further exploratory post-hoc tests suggested the pT-by-pubertal timing interaction was stronger in males relative to females, in self-reported compared to parent-reported AQ and specifically for social traits. These findings require replication in larger samples. Findings have implications for understanding the effects of pT on human behavior, specifically existence of effects in adolescence

Functional Outcomes Among Young People With Trajectories of Persistent Childhood Psychopathology

IMPORTANCE Understanding which children in the general population are at greatest risk of poor functional outcomes could improve early screening and intervention strategies. OBJECTIVE To investigate the odds of poor outcomes in emerging adulthood (ages 17 to 20 years) for children with different mental health trajectories at ages 9 to 13 years. DESIGN, SETTING, AND PARTICIPANTS Growing Up in Ireland is a longitudinal, nationally representative population-based cohort study. Data collection began in August 2007 and was repeated most recently in September 2018. All results were weighted to account for sampling bias and attrition and were adjusted for socioeconomic factors. Data analysis took place from October 2022 to April 2023. EXPOSURE Four latent classes captured variation in mental health in children aged 9 and 13 years, based on the parent-completed Strengths and Difficulties Questionnaire. Classes included no psychopathology, internalizing, externalizing, and high (comorbid) psychopathology. Those who remained in the same class from ages 9 to 13 years were included. MAIN OUTCOMES AND MEASURES Poor functional outcomes in emerging adulthood were measured at approximate ages 17 years (range, 16 to 18 years) and 20 years (range, 19 to 21 years). Outcomes included poor mental health, poor physical health, social isolation, heavy substance use, frequent health service use, poor subjective well-being, and adverse educational/economic outcomes. RESULTS Of 5141 included participants, 2618 (50.9%) were male. A total of 3726 (72.5%) were classed as having no childhood psychopathology, 1025 (19.9%) as having persistent externalizing psychopathology, 243 (4.7%) as having persistent internalizing psychopathology, and 147 (2.9%) as having persistent high psychopathology. Having any childhood psychopathology was associated with poorer functional outcomes in emerging adulthood. The internalizing group had elevated odds of most outcomes except for heavy substance use (range of odds ratios [ORs]: 1.38 [95% CI, 1.05-1.81] for frequent health service use to 3.08 [95% CI, 2.33-4.08] for poor mental health). The externalizing group had significantly elevated odds of all outcomes, albeit with relatively small effect sizes (range of ORs: 1.38 [95% CI, 1.19-1.60] for frequent health service use to 1.98 [95% CI, 1.67-2.35] for adverse educational/economic outcomes). The high psychopathology group had elevated odds of all outcomes (nonsignificantly for frequent health service use), though with wide confidence intervals (range of ORs: 1.53 [95% CI, 1.06-2.21] for poor physical health to 2.91 [95% CI, 2.05-4.12] for poor mental health). Female participants with any psychopathology had significantly higher odds of poor physical health and frequent health service use compared with male participants with any psychopathology

Prenatal Predictors of Child and Adolescent Mental Health

Background: The foetal period is characterised by rapid growth, epigenetic fine-tuning, and adaptation to the foetal-maternal environment. Prenatal factors such as low birth weight have been acknowledged as correlates of subsequent mental illness for many decades. However, much of the literature has focused on group differences (e.g., “Normal” Vs “Low” birth weight) in the risk for subsequent mental disorder, and it is unclear whether prenatal variables such as birth weight can be used for individual-level prediction. In this thesis, we modelled the dose-response association between birth weight and a range of mental health outcomes in large samples of children. We explored a range of prenatal variables— birth weight, gestational age at birth, prenatal testosterone levels, obstetric complications, and maternal substance-use during pregnancy— as risk factors for subsequent mental health problems, with particular focus on age and sex as potential moderators. Methods: Secondary analysis was performed on existing cohort studies: (1) the Adolescent Brain Cognitive Development (ABCD) study based in the United States of America, (2) the Growing Up in Ireland (GUI) study, for which two cohorts were recruited born around 1998 and 2008 respectively, and (3) the Cambridge Child Development Project, based in the United Kingdom. The ABCD and GUI are large nationally representative studies of US and Irish children, respectively. Our statistical methods mostly consisted of general and generalised linear models, including random effects and interactions were necessary to model clustering and interdependencies within the data. Results: Birth weight was most strongly linked with attention problems around age 9. This dose-response association was significant after controlling for gestational age at birth, suggesting that variation in foetal growth drove the association (Chapters 2-3). Foetal growth variation had long-lasting associations with mental health from ages 9 to 17. Associations with ADHD-type issues were stable and pervasive across this period, but associations between foetal growth and emotional problems only became apparent in the later adolescent years (Chapter 3). Across two independent cohorts, we showed that the association between foetal growth restriction and ADHD-type issues could be statistically decomposed into that explained by familial background factors (income, education, demographics; 26-30%) and potentially modifiable prenatal factors (pregnancy complications, maternal substance-use; 13-26%; Chapter 4). Eight percent of the variance in age 9 ADHD symptoms could be explained using pre/perinatal factors alone (R2 95% CI = 5.6-11.5%), many of which were modifiable (Chapter 5). Throughout, sex differences were identified regarding the strength of association between prenatal factors and child mental health. Chapter 6 found that prenatal testosterone was not correlated with autistic traits in adolescence, and therefore could not alone explain the sex difference in this construct. Conclusions: The association between birth weight and subsequent mental health issues in childhood is small but significant and highly replicable across cohorts. The strength and specificity of this association to certain aspects of mental health depend in part on age and sex of the child. Males may be a particularly vulnerable group when it comes to restricted foetal growth and certain obstetric complications. Our ability to predict mental health outcomes from prenatal data is modest, however interactions between prenatal factors and existing familial/social vulnerabilities may improve predictive capacity. Birth weight is a widely available and generalisable predictor of childhood mental health issues. Conversely, the specific prenatal factors underlying this association (e.g. maternal smoking, nutrition level, infection) may be context-specific, and therefore should be identified and targeted in a context-specific manner.</p

Differences in unity: The go/no-go and stop signal tasks rely on different mechanisms

Response inhibition refers to the suppression of prepared or initiated actions. Typically, the go/no-go task (GNGT) or the stop signal task (SST) are used interchangeably to capture individual differences in response inhibition. On the one hand, factor analytic and conjunction neuroimaging studies support the association of both tasks with a single inhibition construct. On the other hand, studies that directly compare the two tasks indicate distinct mechanisms, corresponding to action restraint and cancellation in the GNGT and SST, respectively. We addressed these contradictory findings with the aim to identify the core differences in the temporal dynamics of the functional networks that are recruited in both tasks. We extracted the time-courses of sensory, motor, attentional, and cognitive control networks by group independent component (G-ICA) analysis of electroencephalography (EEG) data from both tasks. Additionally, electromyography (EMG) from the responding effector muscles was recorded to detect the timing of response inhibition. The results indicated that inhibitory performance in the GNGT may be comparable to response selection mechanisms, reaching peripheral muscles at around 316 ​ms. In contrast, inhibitory performance in the SST is achieved via biasing of the sensorimotor system in preparation for stopping, followed by fast sensory, motor and frontal integration during outright stopping. Inhibition can be detected at the peripheral level at 140 ​ms after stop stimulus presentation. The GNGT and the SST therefore seem to recruit widely different neural dynamics, implying that the interchangeable use of superficially similar inhibition tasks in both basic and clinical research is unwarranted

Birth weight and childhood psychopathology in the ABCD cohort: association is strongest for attention problems and is moderated by sex

Many studies have shown low birth weight is associated with psychopathology later in life, particularly attention-deficit/hyperactivity disorder (ADHD). The association is well-replicated, independent from a variety of potential familial confounds, and follows a dose–response curve (decreasing birth weight linked with increasing odds of disorder). However, the specificity of the association to attention problems is called into question by the extent of comorbidity in ADHD, and recent findings that the association is stronger for autism than ADHD. We test the relative dose–response strength of birth weight on multiple aspects of behavior to explore specificity of the effect to attention problems. We also test recent suggestions that the association between birth weight and attention problems is driven by males. Our sample consisted of 9,076 children aged 9–10 from the United States (Adolescent Brain Cognitive Development study). Outcomes included 9 problem-scales and the total problems scale from the Child Behavior Checklist (CBCL). Attention problems were the most strongly associated with birth weight after controlling for gestational age, potential familial confounds, and multiple testing, supporting the outcome-specificity of this association. Contrary to recent registry-based findings, an association between birth weight and an autism scale was not observed. Sex moderated the effect of birth weight on total problems, attention problems and aggressive behavior such that these inverse associations were strongly driven by males. Our findings have strong implications for sex-specific prediction and etiological models of childhood psychopathology.</p

Explaining the association between fetal growth and childhood ADHD symptoms: cross-cohort replication.

The association between restricted fetal growth and symptoms of attention deficit/hyperactivity disorder (ADHD) in childhood is well-replicated and robust. However, fetal growth is determined by many prenatal factors and associations with mental health may be confounded by familial and social context. In this study, we sought to quantify the relative contributions of prenatal factors and familial confounds to the association between fetal growth and ADHD symptoms. Two independent cohorts were analyzed, the Adolescent Brain Cognitive Development study (ABCD; United States) and the Growing Up in Ireland (GUI) study. ADHD symptoms were measured by the Child Behavior Checklist (ABCD) and the Strengths & Difficulties questionnaire (GUI) at age 9-10. Using sequential regression models, we assessed the change-in-association between fetal growth and ADHD symptoms after controlling for sex, familial factors (socioeconomic/demographic factors & family psychiatric history) and prenatal factors (pregnancy complications & maternal substance-use during pregnancy). Converging findings from cohorts suggested that over a quarter of the association between fetal growth and ADHD symptoms is attributable to familial confounds. The degree to which the association was explained by prenatal factors differed by cohort-pregnancy complications explained a larger proportion of the effect in ABCD (7.9%) than GUI (2.7%), and maternal substance-use explained a larger proportion of the effect in GUI (22.7%) compared to ABCD (4.8%). Different explanations of the fetal growth-ADHD association across cohorts suggests cohort-specific, and potentially nationally-specific, risk factors for fetal growth and related neurodevelopmental outcomes. The evidence suggests early prevention of ADHD in Ireland should focus on minimizing maternal smoking during pregnancy. In the US, prevention and treatment of pregnancy complications are highlighted as viable targets for intervention

Predicting childhood ADHD-linked symptoms from prenatal and perinatal data in the ABCD cohort

This study investigates the capacity of pre/perinatal factors to predict attention-deficit/hyperactivity disorder (ADHD) symptoms in childhood. It also explores whether predictive accuracy of a pre/perinatal model varies for different groups in the population. We used the ABCD (Adolescent Brain Cognitive Development) cohort from the United States (N = 9975). Pre/perinatal information and the Child Behavior Checklist were reported by the parent when the child was aged 9-10. Forty variables which are generally known by birth were input as potential predictors including maternal substance-use, obstetric complications and child demographics. Elastic net regression with 5-fold validation was performed, and subsequently stratified by sex, race/ethnicity, household income and parental psychopathology. Seventeen pre/perinatal variables were identified as robust predictors of ADHD symptoms in this cohort. The model explained just 8.13% of the variance in ADHD symptoms on average (95% CI = 5.6%-11.5%). Predictive accuracy of the model varied significantly by subgroup, particularly across income groups, and several pre/perinatal factors appeared to be sex-specific. Results suggest we may be able to predict childhood ADHD symptoms with modest accuracy from birth. This study needs to be replicated using prospectively measured pre/perinatal data. </p

Longitudinal Gray Matter Development Associated With Psychotic Experiences in Young People

Background: Gray matter abnormalities are observed across the psychosis spectrum. The trajectory of these abnormalities in healthy adolescents reporting subthreshold psychotic experiences (PEs) may provide insight into the neural mechanisms underlying psychotic symptoms. The risk of psychosis and additional psychopathology is even higher among these individuals who also report childhood adversity/DSM-5 diagnoses. Thus, the aims of this longitudinal study were to investigate PE-related volumetric changes in young people, noting any effects of childhood adversity/DSM-5 diagnosis. Methods: A total of 211 young people 11 to 13 years of age participated in the initial Adolescent Brain Development study. PE classification was determined by expert consensus at each time point. Participants underwent neuroimaging at 3 time points over 6 years. A total of 76 participants with at least one scan were included in the final sample; 34 who met criteria for PEs at least once across all the time points (PE group) and 42 control subjects. Data from 20 bilateral regions of interest were extracted for linear mixed-effects analyses. Results: Right hippocampal volume increased over time in the control group, with no increase in the PE group (p = .00352). DSM-5 diagnosis and childhood adversity were not significantly associated with right hippocampal volume. There was no significant effect of group or interaction in any other region. Conclusions: These findings further implicate right hippocampal volumetric abnormalities in the pathophysiology underlying PEs. Furthermore, as suggested by previous studies in those at clinical high risk for psychosis and those with first-episode psychosis, it is possible that these deficits may be a marker for later clinical outcomes