Assessing the dominance behavioral system in early childhood using observational methods.

BACKGROUND: The dominance behavioral system (DBS) is a biologically based system that underpins individual differences in motivation for dominance and power. However, little is known about the DBS in childhood. In order to make strong claims about the DBS's trait-like properties and predictive validity, a clearer understanding of its early development is required. PARTICIPANTS AND PROCEDURE: In a pilot study aimed at developing a behavioral coding system for dominance, a key facet of the DBS, we collected and coded observational data from 58 children, assessed at ages 3 and 5-6. These data were examined in conjunction with measures of child temperament via observational measures, and symptoms of psychopathology. RESULTS: Dominance was moderately stable in early childhood to a degree comparable to other early child temperament traits. Consistent with the study hypotheses, boys were more dominant than girls, and dominance was negatively associated with children's behavioral inhibition, effortful control, and internalizing symptoms. CONCLUSIONS: These results provide initial support for the validity and developmental sensitivity of an objective coding system for assessing facets of the DBS in early childhood. Ultimately, the use of this coding system will facilitate future studies of how early DBS predicts psychological adjustment later in life.

Total cortisol output during an acute stressor predicts youths' internalizing symptoms during the COVID-19 pandemic.

Individual differences in cortisol output may influence adolescents' adjustment to the COVID-19 pandemic; however, boys and girls may differ in terms of associations between cortisol output and internalizing symptoms in the context of COVID-19-related stress. We examined whether pre-pandemic cortisol output during an acute stressor, assessed approximately three years prior to the pandemic, predicted change in adolescents' internalizing symptoms early during the COVID-19 pandemic. Consistent with previous work on other life stressors, girls' cortisol output was positively associated with anxious and somatic symptoms early in the pandemic. Conversely, cortisol output and depressive symptoms were negatively associated for boys; boys with higher cortisol had depressive symptoms which significantly decreased over time. Findings suggest that hypothalamic-pituitary-adrenal axis stress functioning plays a role in shaping differences between adolescent boys' and girls' adjustment during the experience of a ubiquitous chronic stressor.

Associations between childhood irritability and neural reactivity to maternal feedback in adolescence.

Early irritability, a transdiagnostic vulnerability for psychopathology, is associated with alterations in neural reactivity to emotional stimuli and reward; however, associations between childhood irritability and neural markers of risk may be mitigated by the quality of caregiving youth receive. We examined longitudinal relationships between irritability in childhood and young adolescents' neural activity of regions typically associated with emotion regulation and reward processing during processing of maternal feedback and tested whether these associations were moderated by youth's perceptions of the parent-child relationship quality. Eighty-one adolescents (Mage = 11.1 years) listened to maternal critical and praising feedback while undergoing functional magnetic resonance imaging. Age 3 irritability, assessed observationally, was negatively associated with age 11 neural reactivity to maternal criticism in a cluster in the right dorsolateral prefrontal cortex (dlPFC), particularly for youths who reported more positive maternal parenting. Given the role of the dlPFC activation in the effortful processing of emotional stimuli, decreased activation may reflect disengagement from negatively valenced interpersonal feedback in the context of a positive caregiving environment, thereby mitigating psychopathology risk associated with irritability.

Early childhood impulsivity and parenting predict children's development of externalizing psychopathology.

Parenting and child impulsivity are consistent predictors of children's externalizing symptoms; however, the role of the range of parenting (i.e., variation in parenting across contexts), and its interactions with child impulsivity, are poorly understood. We examined whether characteristic parenting practices and parenting range predicted the course of externalizing symptoms in 409 children (Mage = 3.43 years at baseline, 208 girls) across ages 3, 5, 8, and 11. We assessed parent positive affectivity (PPA), hostility, and parenting structure at child age 3 using three behavioral tasks that varied in context, examining range by modeling a latent difference score for each parenting dimension. Greater PPA range, mean structure, and parenting structure range all predicted fewer symptoms at age 3 for children with higher impulsivity. Lower mean hostility predicted fewer symptoms at age 3 for children with lower impulsivity. Greater PPA, and smaller PPA range, predicted a decrease in symptoms for children higher in impulsivity. Lower hostility range predicted a decrease in symptoms for children with lower impulsivity but predicted maintaining symptoms for children with higher impulsivity. Results demonstrate the differential roles average parenting practices and parenting range play in the development of child externalizing psychopathology, especially in the context of child impulsivity.

The development of depressogenic self-schemas: Associations with children's regional grey matter volume in ventrolateral prefrontal cortex.

Cognitive theories of depression contend that biased cognitive information processing plays a causal role in the development of depression. Extensive research shows that deeper processing of negative and/or shallower processing of positive self-descriptors (i.e., negative and positive self-schemas) predicts current and future depression in adults and children. However, the neural correlates of the development of self-referent encoding are poorly understood. We examined children's self-referential processing using the self-referent encoding task (SRET) collected from 74 children at ages 6, 9, and 12; around age 10, these children also contributed structural magnetic resonance imaging data. From age 6 to age 12, both positive and negative self-referential processing showed mean-level growth, with positive self-schemas increasing relatively faster than negative ones. Further, voxel-based morphometry showed that slower growth in positive self-schemas was associated with lower regional gray matter volume (GMV) in ventrolateral prefrontal cortex (vlPFC). Our results suggest that smaller regional GMV within vlPFC, a critical region for regulatory control in affective processing and emotion development, may have implications for the development of depressogenic self-referential processing in mid-to-late childhood.

Associations Between Children's Telomere Length, Parental Intrusiveness, and the Development of Early Externalizing Behaviors.

Shorter telomeres mark cellular aging and are linked to chronic stress exposure as well as negative physical and psychological outcomes. However, it is unclear whether telomere length mediates associations between early stress exposure and later externalizing problems, or whether boys and girls differ in pathways to these concerns. We therefore examined associations between telomere length, early stress via negative caregiving, and children's externalizing symptom development over time in 409 three-year-old children and their parents. Telomere length mediated the association between early parental intrusiveness and later rule-breaking behavior; however, this association was moderated by children's biological sex such that parent intrusiveness was related only to boys' rule-breaking. Findings support the notion that children's telomere length may mark individual differences in responses to negative early caregiving, and highlight a potential mechanism contributing to the development of rule-breaking problems in boys.

A call for renewed attention to construct validity and measurement in psychopathology research.

Psychopathologists have failed to make significant progress toward understanding the causes of psychopathology. Despite the foundational importance of construct validity and measurement to our field, insufficient attention is paid to these concerns in the assessment of psychopathology vulnerabilities prior to their implementation in causal models. I review the current state of construct validity and measurement in psychopathology research, highlighting the lack of consensus regarding how we should define and measure vulnerability constructs. The limited capacity of open science practices to address these definitional and measurement challenges is discussed. Recommendations for progress are made, including the need for consensus agreement on (1) working definitions and (2) measures of vulnerability constructs. Other recommendations include (3) the need to incentivize 'pre-clinical' descriptive work focused on measurement development, (4) the formation of open-access databases designed to facilitate measurement evaluation and development, and (5) increased exploration of the use of novel technologies to facilitate the collection of high-quality measures of vulnerability.

Development and Preliminary Validation of the Pandemic Avoidance and Concern Scales (PACS).

The COVID-19 pandemic has led to radical disruptions to the routines of individuals and families, but there are few psychometrically assessed measures for indexing behavioural responses associated with a modern pandemic. Given the likelihood of future pandemics, valid tools for assessing pandemic-related behavioral responses relevant to mental health are needed. This need may be especially salient for studies involving families, as they may experience higher levels of stress and maladjustment related to school and business closures. We therefore created the Pandemic Avoidance and Concern Scales (PACS) to assess caregivers' and youths' adjustment to COVID-19 and future pandemics. Concern and Avoidance factors derived from exploratory factor analyses were associated with measures of internalizing symptoms, as well as other indices of pandemic-related disruption. Findings suggest that the PACS is a valid tool for assessing pandemic-related beliefs and behaviors in adults and adolescents. Preliminary findings related to differential adjustment between caregivers and youths are discussed.

Children's neural reactivity to maternal praise and criticism: Associations with early depressive symptoms and maternal depression.

Caregiving experiences are implicated in children's depression risk; however, children's neural reactivity to positive and negative feedback from mothers, a potential mediator of depression risk, is poorly understood. In a sample of 81 children (Mage = 11.12 years, SDage = 0.63), some of whom were recruited based on a maternal history of depression (n = 29), we used fMRI to characterize children's neural responses to maternal praise and criticism. Maternal history of depression was unrelated to children's brain activity during both the praise and criticism conditions; however, ROI analyses showed that children's self-reported depressive symptoms were negatively associated with functional activity in the left anterior insula and right putamen while hearing maternal criticism. Whole-brain analyses showed that children's depressive symptoms were positively associated with left inferior frontal gyrus activity while listening to maternal praise. These findings complement past work implicating these brain regions in the processing of emotionally salient stimuli, reward processing, and internal speech. Given associations between early depressive symptoms and later disorder, findings suggest that maladaptive neural processing of maternal feedback may contribute to children's early emerging risk for depression.

Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-analysis.

Temperament involves stable behavioral and emotional tendencies that differ between individuals, which can be first observed in infancy or early childhood and relate to behavior in many contexts and over many years.1 One of the most rigorously characterized temperament classifications relates to the tendency of individuals to avoid the unfamiliar and to withdraw from unfamiliar people, objects, and unexpected events. This temperament is referred to as behavioral inhibition or inhibited temperament (IT).2 IT is a moderately heritable trait1 that can be measured in multiple species.3 In humans, levels of IT can be quantified from the first year of life through direct behavioral observations or reports by caregivers or teachers. Similar approaches as well as self-report questionnaires on current and/or retrospective levels of IT1 can be used later in life.

Influence of Tyrosine Kinase Inhibition on Organic Anion Transporting Polypeptide 1B3-Mediated Uptake.

The organic anion transporting polypeptide family member (OATP) 1B3 is a hepatic uptake transporter that has a broad substrate recognition and plays a significant role in regulating elimination of endogenous biomolecules or xenobiotics. OATP1B3 works in tandem with OATP1B1, with which it shares approximately 80% sequence homology and a high degree of substrate overlap. Despite some substrates being recognized solely by OATP1B3, its ability to compensate for loss of OATP1B1-mediated elimination and recognition by regulatory agencies, little is known about OATP1B3 regulatory factors and how they are involved with drug-drug interaction. It was recently discovered that OATP1B1 function is mediated by the activity of a particular tyrosine kinase that is sensitive to a variety of tyrosine kinase inhibitors (TKIs). This study reports that OATP1B3 is similarly regulated, as at least 50% of its activity is reduced by 20 US Food and Drug Administration -approved TKIs. Nilotinib was assessed as the most potent OATP1B3 inhibitor among the investigated TKIs, which can occur at clinically relevant concentrations and acted predominantly through noncompetitive inhibition without impacting membrane expression. Finally, OATP1B3 function was determined to be sensitive to the knockdown of the Lck/Yes novel tyrosine kinase that is sensitive to nilotinib and has been previously implicated in mediating OATP1B1 activity. Collectively, our findings identify tyrosine kinase activity as a major regulator of OATP1B3 function which is sensitive to kinase inhibition. Given that OATP1B1 is similarly regulated, simultaneous disruption of these transporters can have drastic effects on systemic drug concentrations, which would promote adverse events. SIGNIFICANCE STATEMENT: The organic anion transporting polypeptide family member (OATP) 1B3 is a facilitator of hepatic drug elimination, although much is unknown of how OATP1B3 activity is mediated, or how such regulators contribute to drug-drug interactions. This study reports that OATP1B3 activity is dependent on the Lck/Yes novel tyrosine kinase, which is sensitive to numerous tyrosine kinase inhibitors. These findings provide insight into the occurrence of many clinical drug-drug interactions, and a rationale for future study of tyrosine kinases regulating drug disposition.

Regulation of Drug Transport Proteins-From Mechanisms to Clinical Impact: A White Paper on Behalf of the International Transporter Consortium.

Membrane transport proteins are involved in the absorption, disposition, efficacy, and/or toxicity of many drugs. Numerous mechanisms (e.g., nuclear receptors, epigenetic gene regulation, microRNAs, alternative splicing, post-translational modifications, and trafficking) regulate transport protein levels, localization, and function. Various factors associated with disease, medications, and dietary constituents, for example, may alter the regulation and activity of transport proteins in the intestine, liver, kidneys, brain, lungs, placenta, and other important sites, such as tumor tissue. This white paper reviews key mechanisms and regulatory factors that alter the function of clinically relevant transport proteins involved in drug disposition. Current considerations with in vitro and in vivo models that are used to investigate transporter regulation are discussed, including strengths, limitations, and the inherent challenges in predicting the impact of changes due to regulation of one transporter on compensatory pathways and overall drug disposition. In addition, translation and scaling of in vitro observations to in vivo outcomes are considered. The importance of incorporating altered transporter regulation in modeling and simulation approaches to predict the clinical impact on drug disposition is also discussed. Regulation of transporters is highly complex and, therefore, identification of knowledge gaps will aid in directing future research to expand our understanding of clinically relevant molecular mechanisms of transporter regulation. This information is critical to the development of tools and approaches to improve therapeutic outcomes by predicting more accurately the impact of regulation-mediated changes in transporter function on drug disposition and response.

Observational measures of early irritability predict children's psychopathology risk.

Irritability is a transdiagnostic feature of diverse forms of psychopathology and a rapidly growing literature implicates the construct in child maladaptation. However, most irritability measures currently used are drawn from parent-report questionnaires not designed to measure irritability per se; furthermore, parent report methods have several important limitations. We therefore examined the utility of observational ratings of children's irritability in predicting later psychopathology symptoms. Four-hundred and nine 3-year-old children (208 girls) completed observational tasks tapping temperamental emotionality and parents completed questionnaires assessing child irritability and anger. Parent-reported child psychopathology symptoms were assessed concurrently to the irritability assessment and when children were 5 and 8 years old. Children's irritability observed during tasks that did not typically elicit anger predicted their later depressive and hyperactivity symptoms, above and beyond parent-reported irritability and context-appropriate observed anger. Our findings support the use of observational indices of irritability and have implications for the development of observational paradigms designed to assess this construct in childhood.

Resting-state functional connectivity and reading subskills in children.

Individual differences in reading ability have been linked to characteristics of functional connectivity in the brain in both children and adults. However, many previous studies have used single or composite measures of reading, leading to difficulty characterizing the role of functional connectivity in discrete subskills of reading. The present study addresses this issue using resting-state fMRI to examine how resting-state functional connectivity (RSFC) related to individual differences in children's reading subskills, including decoding, sight word reading, reading comprehension, and rapid automatized naming (RAN). Findings showed both positive and negative RSFC-behaviour relationships that diverged across different reading subskills. Positive relationships included increasing RSFC among left dorsal and anterior regions with increasing decoding proficiency, and increasing RSFC between the left thalamus and right fusiform gyrus with increasing sight word reading, RAN, and reading comprehension abilities. In contrast, negative relationships suggested greater functional segregation of attentional and reading networks with improved performance on RAN, decoding, and reading comprehension tasks. Importantly, the results suggest that although reading subskills rely to some extent on shared functional networks, there are also distinct functional connections supporting different components of reading ability in children.

Regulation of OATP1B1 Function by Tyrosine Kinase-mediated Phosphorylation.

PURPOSE: OATP1B1 (SLCO1B1) is the most abundant and pharmacologically relevant uptake transporter in the liver and a key mediator of xenobiotic clearance. However, the regulatory mechanisms that determine OATP1B1 activity remain uncertain, and as a result, unexpected drug-drug interactions involving OATP1B1 substrates continue to be reported, including several involving tyrosine kinase inhibitors (TKI). EXPERIMENTAL DESIGN: OATP1B1-mediated activity in overexpressing HEK293 cells and hepatocytes was assessed in the presence of FDA-approved TKIs, while rosuvastatin pharmacokinetics in the presence of an OATP1B1 inhibiting TKI were measured in vivo. Tyrosine phosphorylation of OATP1B1 was determined by LC/MS-MS-based proteomics and transport function was measured following exposure to siRNAs targeting 779 different kinases. RESULTS: Twenty-nine of 46 FDA-approved TKIs studied significantly inhibit OATP1B1 function. Inhibition of OATP1B1 by TKIs, such as nilotinib, is predominantly noncompetitive, can increase systemic concentrations of rosuvastatin in vivo, and is associated with reduced phosphorylation of OATP1B1 at tyrosine residue 645. Using genetic screens and functional validation studies, the Src kinase LYN was identified as a potential regulator of OATP1B1 activity that is highly sensitive to inhibition by various TKIs at clinically relevant concentrations. CONCLUSIONS: A novel kinase-dependent posttranslational mechanism of OATP1B1 activation was identified and interference with this process by TKIs can influence the elimination of a broad range of xenobiotic substrates.

Sex Differences in Age of Diagnosis and First Concern among Children with Autism Spectrum Disorder.

OBJECTIVE: Early identification of autism spectrum disorder (ASD) is an essential healthcare priority. Girls may be at risk for late diagnosis, although research is equivocal regarding how sex and other factors relate to ASD identification. The goals of the current investigation were to (1) identify how child sex, cognitive abilities, and demographic factors relate to age of first concern (AOC) and age of diagnosis (AOD), (2) evaluate trends in AOC/AOD over time, and (3) consider whether main effects of sex on AOC/AOD are moderated by cognitive abilities or time. METHOD: Children (N = 365; 20% female; 85.6% identified as White) with ASD participated through the Province of Ontario Neurodevelopmental Disorders (POND) Network. Study records included AOD, date/timing of diagnosis (between 1996 and 2017), age of first parent concern, demographics, and standardized cognitive testing results (24.7% of children had IQ scores below standard scores of 70). RESULTS: Average AOC occurred before 2 years of age whereas average AOD occurred after 5 years of age. Girls did not differ on AOC but had a later AOD than boys. Higher verbal IQ was associated with later AOD more strongly in girls than boys. Regarding time-related changes, average AOC and AOD increased across the study period, more strongly for girls. CONCLUSIONS: Results support that sex is a key factor underlying delays in ASD identification and highlight the urgent need to improve diagnostic practices among girls. Limitations and implications for improving the diagnostic process are discussed.Abbreviations: ASD=autism spectrum disorder; IQ=intelligence quotient; AOC=parental report of age of first concern; AOD=age of diagnosis.

Orbitofrontal cortex grey matter volume is related to children's depressive symptoms.

Adults with a history of depression show distinct patterns of grey matter volume (GMV) in frontal cortical (e.g., prefrontal cortex, orbitofrontal cortex) and limbic (e.g., anterior cingulate, amygdala, hippocampus, dorsal striatum) structures, regions relevant to the processing and regulation of reward, which is impaired in the context of depression. However, it is unclear whether these GMV associations with depression precede depressive disorder onset or whether GMV is related to early emerging symptoms or familial depression. To address these questions, we used voxel-based morphometry (VBM) to examine GMV in 85 community-dwelling children (M = 11.12 years, SD = 0.63 years) screened for current and lifetime depression. Associations between children's depressive symptoms (self- and mother-report of children's symptoms), children's maternal depression history, and GMV were examined. Although maternal depression history was unrelated to children's GMV, child GMV in the orbitofrontal cortex (OFC) was negatively related to children's self-reported depressive symptoms, using both a priori ROI and whole-brain analyses. Moderated regression analyses indicated that girls' GMV was negatively related to girls' depressive symptoms (as indexed by both self- and mother-report of girls' symptoms), whereas boys' symptoms were positively related to GMV. Our findings suggest that brain morphology in the OFC, a region with functional roles in processes relevant to depressive symptoms (i.e., reward-based learning and reward processing), is associated with early depressive symptoms prior to the development of clinically significant depression.

Depressogenic self-schemas are associated with smaller regional grey matter volume in never-depressed preadolescents.

Self-referential processing (i.e., self-schemas that guide processing of self-descriptive information) emerges early in youth, with deeper encoding of negative self-descriptors and/or shallower encoding of positive self-descriptors causally linked to depression. However, the relationship between depressogenic self-schemas and brain structure is unclear. We investigated associations between self-schemas and regional grey matter volume (GMV) in 84 never-depressed preadolescents oversampled for depression risk based on maternal depression history. Self-schemas were assessed using a Self-Referent Encoding Task (SRET) and regional GMV was indexed via voxel-based morphometry analysis of structural magnetic resonance imaging data. Youths' positive self-schemas were associated with greater regional GMV within the ventrolateral prefrontal cortex (vlPFC) and posterior cingulate cortex (PCC), while negative self-schemas were associated with smaller regional GMV within vlPFC and PCC, areas important to emotion regulation and self-referential processing. These associations remained significant after controlling for youths' concurrent depressive symptoms. Exploratory mediation analysis suggested that adolescents' depressogenic self-schemas may mediate associations between GMV and depressive symptoms. Our findings suggest that the observed GMV variations within vlPFC and PCC may serve as neurobiological markers of depressogenic self-schemas during preadolescence.

Evaluating maternal psychopathology biases in reports of child temperament: An investigation of measurement invariance.

Parent reports of child temperament, especially those of mothers', are frequently used in research and clinical practice, but there are concerns that maternal characteristics, including a history of psychopathology, might bias reports on these measures. However, whether maternal reports of youth temperament show structural differences based on mothers' psychiatric history is unclear. We therefore conducted tests of measurement invariance to examine whether maternal psychopathology was associated with structural aspects of child temperament as a means of evaluating potential biases related to mothers' mental disorder history. From 2 community-based studies of child temperament, 935 mothers completed the Child Behavior Questionnaire (CBQ) and semistructured diagnostic interviews that assessed their own lifetime history of depressive symptoms, anxiety, and substance use disorders. Mothers also completed a measure of depressive symptoms concurrent to their completion of the CBQ. We found little evidence that mothers' current depressive symptoms or history of depressive symptoms, anxiety, or substance use disorders were associated with the structure of their reports of child temperament. Thus, there is little empirical support for systematic biases in reports of youth temperament as indexed by psychometric modeling. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Neural Activity During Self-referential Processing in Children at Risk for Depression.

BACKGROUND: According to cognitive theories of depression, more negative and less positive self-schemas are thought to play a causal role in the disorder. Existing evidence speaks to the neural substrates of self-referential processes in both healthy and depressed individuals, but little is known about how the brain relates to self-referential processing in the context of depression risk in children. We therefore studied the neural substrates of self-referential processing in never-depressed preadolescent children at high and low risk for depression based on maternal depression history. METHODS: A total of 87 never-depressed 10-12-year-old children (29 with maternal depression) completed a self-referential encoding task during a functional magnetic resonance imaging session, in which they were presented a series of positive and negative trait adjectives and endorsed whether each word was self-descriptive. Small volume correction analyses were conducted within 7 regions of interest that are important for self-referential and emotion-related processes. RESULTS: Analyses of small volume correction indicated that high-risk children showed greater activation in the ventrolateral prefrontal cortex and ventromedial prefrontal cortex during the positive-word self-referential encoding task condition than low-risk children. Ventrolateral prefrontal cortex activation mediated the association between maternal depression and child depressive symptoms only when children had lower positive self-schemas, indicating that more positive self-schemas may protect at-risk children from developing depressive symptoms. CONCLUSIONS: Cortical midline and prefrontal regions are important to self-, emotion-, and regulation-related processes. Heightened activation within these regions in never-depressed high-risk children indicates that these neurobiological substrates may mediate early vulnerability to depression in the context of cognitive processes relevant to self-concepts.