A network approach to the investigation of childhood irritability: probing frustration using social stimuli.

BACKGROUND: Self-regulation in early childhood develops within a social context. Variations in such development can be attributed to inter-individual behavioral differences, which can be captured both as facets of temperament and across a normal:abnormal dimensional spectrum. With increasing emphasis on irritability as a robust early-life transdiagnostic indicator of broad psychopathological risk, linkage to neural mechanisms is imperative. Currently, there is inconsistency in the identification of neural circuits that underlie irritability in children, especially in social contexts. This study aimed to address this gap by utilizing a functional magnetic resonance imaging (fMRI) paradigm to investigate pediatric anger/frustration using social stimuli. METHODS: Seventy-three children (M = 6 years, SD = 0.565) were recruited from a larger longitudinal study on irritability development. Caregivers completed questionnaires assessing irritable temperament and clinical symptoms of irritability. Children participated in a frustration task during fMRI scanning that was designed to induce frustration through loss of a desired prize to an animated character. Data were analyzed using both general linear modeling (GLM) and independent components analysis (ICA) and examined from the temperament and clinical perspectives. RESULTS: ICA results uncovered an overarching network structure above and beyond what was revealed by traditional GLM analyses. Results showed that greater temperamental irritability was associated with significantly diminished spatial extent of activation and low-frequency power in a network comprised of the posterior superior temporal sulcus (pSTS) and the precuneus (p < .05, FDR-corrected). However, greater severity along the spectrum of clinical expression of irritability was associated with significantly increased extent and intensity of spatial activation as well as low- and high-frequency neural signal power in the right caudate (p < .05, FDR-corrected). CONCLUSIONS: Our findings point to specific neural circuitry underlying pediatric irritability in the context of frustration using social stimuli. Results suggest that a deliberate focus on the construction of network-based neurodevelopmental profiles and social interaction along the normal:abnormal irritability spectrum is warranted to further identify comprehensive transdiagnostic substrates of the irritability.

Using Smartphone Sensors for Ataxia Trials: Consensus Guidance by the Ataxia Global Initiative Working Group on Digital-Motor Biomarkers.

Smartphone sensors are used increasingly in the assessment of ataxias. To date, there is no specific consensus guidance regarding a priority set of smartphone sensor measurements, or standard assessment criteria that are appropriate for clinical trials. As part of the Ataxia Global Initiative Digital-Motor Biomarkers Working Group (AGI WG4), aimed at evaluating key ataxia clinical domains (gait/posture, upper limb, speech and oculomotor assessments), we provide consensus guidance for use of internal smartphone sensors to assess key domains. Guidance was developed by means of a literature review and a two stage Delphi study conducted by an Expert panel, which surveyed members of AGI WG4, representing clinical, research, industry and patient-led experts, and consensus meetings by the Expert panel to agree on standard criteria and map current literature to these criteria. Seven publications were identified that investigated ataxias using internal smartphone sensors. The Delphi 1 survey ascertained current practice, and systems in use or under development. Wide variations in smartphones sensor use for assessing ataxia were identified. The Delphi 2 survey identified seven measures that were strongly endorsed as priorities in assessing 3/4 domains, namely gait/posture, upper limb, and speech performance. The Expert panel recommended 15 standard criteria to be fulfilled in studies. Evaluation of current literature revealed that none of the studies met all criteria, with most being early-phase validation studies. Our guidance highlights the importance of consensus, identifies priority measures and standard criteria, and will encourage further research into the use of internal smartphone sensors to measure ataxia digital-motor biomarkers.

Setting boundaries: Development of neural and behavioral event cognition in early childhood.

The ongoing stream of sensory experience is so complex and ever-changing that we tend to parse this experience at "event boundaries," which structures and strengthens memory. Memory processes undergo profound change across early childhood. Whether young children also divide their ongoing processing along event boundaries, and if those boundaries relate to memory, could provide important insight into the development of memory systems. In Study 1, 4-7-year-old children and adults segmented a cartoon, and we tested their memory. Children's event boundaries were more variable than adults' and differed in location and consistency of agreement. Older children's event segmentation was more adult-like than younger children's, and children who segmented events more like adults had better memory for those events. In Study 2, we asked whether these developmental differences in event segmentation had their roots in distinct neural representations. A separate group of 4-8-year-old children watched the same cartoon while undergoing an fMRI scan. In the right hippocampus, greater pattern dissimilarity across event boundaries compared to within events was evident for both child and adult behavioral boundaries, suggesting children and adults share similar event cognition. However, the boundaries identified by a data-driven Hidden Markov Model found that a different brain region-the left and right angular gyrus-aligned only with event boundaries defined by children. Overall, these data suggest that children's event cognition is reasonably well-developed by age 4 but continues to become more adult-like across early childhood. RESEARCH HIGHLIGHTS: Adults naturally break their experience into events, which structures and strengthens memory, but less is known about children's event perception and memory. Study 1 had adults and children segment and remember events from an animated show, and Study 2 compared those segmentations to other children's fMRI data. Children show better recognition and temporal order memory and more adult-like event segmentation with age, and children who segment more like adults have better memory. Children's and adults' behavioral boundaries mapped onto pattern similarity differences in hippocampus, and children's behavioral boundaries matched a data-driven model's boundaries in angular gyrus.

Prefrontal activation in preschool children is associated with maternal adversity and child temperament: A preliminary fNIRS study of inhibitory control.

Exposure to adversity is a well-documented risk factor for cognitive, behavioral, and mental health problems. In fact, the consequences of adversity may be intergenerational. A growing body of research suggests that maternal exposures to adversity, including those prior to childbirth, are associated with offspring biobehavioral development. In a sample of 36 mothers and their preschool-age children (mean child age = 4.21 ± 0.92 years), we used functional near-infrared spectroscopy to replicate and extend this work to include brain activation during inhibitory control in young children. We found that measures of maternal exposure to adversity, including cumulative, childhood, and preconception exposures, were significantly and positively associated with activation in the right frontopolar prefrontal cortex (PFC) and in the left temporal and parietal clusters during inhibitory control. In addition, and consistent with previous findings, children's increased negative affect and decreased effortful control were associated with increased right PFC activation during inhibitory control. These findings provide preliminary evidence that maternal and dispositional risk factors are linked to alterations in PFC functioning during the preschool years. Children of mothers with a history of exposure to adversity, as well as children who are less temperamentally regulated, may require increased neural resources to meet the cognitive demands of inhibitory control.

Getting in synch: Unpacking the role of parent-child synchrony in the development of internalizing and externalizing behaviors.

While substantial research supports the role of parent-child interactions on the emergence of psychiatric symptoms, few studies have explored biological mechanisms for this association. The current study explored behavioral and neural parent-child synchronization during frustration and play as predictors of internalizing and externalizing behaviors across a span of 1.5 years. Parent-child dyads first came to the laboratory when the child was 4-5 years old and completed the Disruptive Behavior Diagnostic Observation Schedule: Biological Synchrony (DB-DOS: BioSync) task while functional near-infrared spectroscopy (fNIRS) data were recorded. Parents reported on their child's internalizing and externalizing behaviors using the Child Behavior Checklist (CBCL) four times over 1.5 years. Latent growth curve (LGC) modeling was conducted to assess neural and behavioral synchrony as predictors of internalizing and externalizing trajectories. Consistent with previous investigations in this age range, on average, internalizing and externalizing behaviors decreased over the four time points. Parent-child neural synchrony during a period of play predicted rate of change in internalizing but not externalizing behaviors such that higher parent-child neural synchrony was associated with a more rapid decrease in internalizing behaviors. Our results suggest that a parent-child dyad's ability to coordinate neural activation during positive interactions might serve as a protective mechanism in the context of internalizing behaviors.

Trajectory of emotion dysregulation in positive and negative affect across childhood predicts adolescent emotion dysregulation and overall functioning.

Emotion dysregulation is cross-diagnostic and impairing. Most research has focused on dysregulated expressions of negative affect, often measured as irritability, which is associated with multiple forms of psychopathology and predicts negative outcomes. However, the Research Domain Criteria (RDoC) include both negative and positive valence systems. Emerging evidence suggests that dysregulated expressions of positive affect, or excitability, in early childhood predict later psychopathology and impairment above and beyond irritability. Typically, irritability declines from early through middle childhood; however, the developmental trajectory of excitability is unknown. The impact of excitability across childhood on later emotion dysregulation is also yet unknown. In a well-characterized, longitudinal sample of 129 children studied from ages 3 to 5.11 years through 14 to 19 years, enriched for early depression and disruptive symptoms, we assessed the trajectory of irritability and excitability using multilevel modeling and how components of these trajectories impact later emotion dysregulation. While irritability declines across childhood, excitability remains remarkably stable both within and across the group. Overall levels of excitability (excitability intercept) predict later emotion dysregulation as measured by parent and self-report and predict decreased functional magnetic resonance imaging activity in cognitive emotion regulation regions during an emotion regulation task. Irritability was not related to any dysregulation outcome above and beyond excitability.

Links between socioeconomic disadvantage, neural function, and working memory in early childhood.

Children reared in socioeconomically disadvantaged environments are at risk for academic, cognitive, and behavioral problems. Mounting evidence suggests that childhood adversities, encountered at disproportionate rates in contexts of socioeconomic risk, shape the developing brain in ways that explain disparities. Circuitries that subserve neurocognitive functions related to memory, attention, and cognitive control are especially affected. However, most work showing altered neural function has focused on middle childhood and adolescence. Understanding alterations in brain development during foundational points in early childhood is a key next step. To address this gap, we examined functional near-infrared-spectroscopy-based neural activation during a working memory (WM) task in young children aged 4-7 years (N = 30) who varied in socioeconomic risk exposure. Children who experienced greater disadvantage (lower income to needs ratio and lower Hollingshead index) exhibited lower activation in the lateral prefrontal cortex than children who experienced less to no disadvantage. Variability in prefrontal cortex activation, but not behavioral performance on the WM task, was associated with worse executive functioning in children as reported by parents. These findings add to existing evidence that exposure to early adversity, such as socioeconomic risk, may lead to foundational changes in the developing brain, which increases risk for disparities in functioning across multiple cognitive and social domains.

Does the child brain rest?: An examination and interpretation of resting cognition in developmental cognitive neuroscience.

In cognitive neuroscience, measurements of "resting baseline" are often considered stable across age and used as a reference point against which to judge cognitive state. The task-based approach-comparing resting baseline to task conditions-implies that resting baseline is an equalizer across participants and-in the case of studies of developmental changes in cognition-across age groups. In contrast, network neuroscience explicitly examines the development of "resting state" networks across age, at odds with the idea of a consistent resting baseline. Little attention has been paid to how cognition during rest may shift across development, particularly in children under the age of eight. Childhood is marked by striking maturation of neural systems, including a protracted developmental period for cognitive control systems. To grow and shape these cognitive systems, children have a developmental imperative to engage their neural circuitry at every possible opportunity. Thus, periods of "rest" without specific instructions may require additional control for children as they fight against developmental expectation to move, speak, or otherwise engage. We therefore theorize that the child brain does not rest in a manner consistent with the adult brain as longer rest periods may represent increased cognitive control. To shape this theory, we first review the extant literature on neurodevelopment across early childhood within the context of cognitive development. Next, we present nascent evidence for a destabilized baseline for comparisons across age. Finally, we present recommendations for designing, analyzing, and interpreting tasks conducted with young children as well as for resting state. Future work must aim to tease apart the cognitive context under which we examine functional brain development in young children and take considerations into account unique to each age.

Clinical, cortical thickness and neural activity predictors of future affective lability in youth at risk for bipolar disorder: initial discovery and independent sample replication.

We aimed to identify markers of future affective lability in youth at bipolar disorder risk from the Pittsburgh Bipolar Offspring Study (BIOS) (n = 41, age = 14, SD = 2.30), and validate these predictors in an independent sample from the Longitudinal Assessment of Manic Symptoms study (LAMS) (n = 55, age = 13.7, SD = 1.9). We included factors of mixed/mania, irritability, and anxiety/depression (29 months post MRI scan) in regularized regression models. Clinical and demographic variables, along with neural activity during reward and emotion processing and gray matter structure in all cortical regions at baseline, were used to predict future affective lability factor scores, using regularized regression. Future affective lability factor scores were predicted in both samples by unique combinations of baseline neural structure, function, and clinical characteristics. Lower bilateral parietal cortical thickness, greater left ventrolateral prefrontal cortex thickness, lower right transverse temporal cortex thickness, greater self-reported depression, mania severity, and age at scan predicted greater future mixed/mania factor score. Lower bilateral parietal cortical thickness, greater right entorhinal cortical thickness, greater right fusiform gyral activity during emotional face processing, diagnosis of major depressive disorder, and greater self-reported depression severity predicted greater irritability factor score. Greater self-reported depression severity predicted greater anxiety/depression factor score. Elucidating unique clinical and neural predictors of future-specific affective lability factors is a step toward identifying objective markers of bipolar disorder risk, to provide neural targets to better guide and monitor early interventions in bipolar disorder at-risk youth.

Parent-child neural synchrony: a novel approach to elucidating dyadic correlates of preschool irritability.

BACKGROUND: Research to date has largely conceptualized irritability in terms of intraindividual differences. However, the role of interpersonal dyadic processes has received little consideration. Nevertheless, difficulties in how parent-child dyads synchronize during interactions may be an important correlate of irritably in early childhood. Innovations in developmentally sensitive neuroimaging methods now enable the use of measures of neural synchrony to quantify synchronous responses in parent-child dyads and can help clarify the neural underpinnings of these difficulties. We introduce the Disruptive Behavior Diagnostic Observation Schedule: Biological Synchrony (DB-DOS:BioSync) as a paradigm for exploring parent-child neural synchrony as a potential biological mechanism for interpersonal difficulties in preschool psychopathology. METHODS: Using functional near-infrared spectroscopy (fNIRS) 4- to 5-year-olds (N = 116) and their mothers completed the DB-DOS:BioSync while assessing neural synchrony during mild frustration and recovery. Child irritability was measured using a latent irritability factor that was calculated from four developmentally sensitive indicators. RESULTS: Both the mild frustration and the recovery contexts resulted in neural synchrony. However, less neural synchrony during the recovery context only was associated with more child irritability. CONCLUSIONS: Our results suggest that recovering after a frustrating period might be particularly challenging for children high in irritability and offer support for the use of the DB-DOS:BioSync task to elucidate interpersonal neural mechanisms of developmental psychopathology.

Faces in the wild: A naturalistic study of children's facial expressions in response to an Internet prank.

There is surprisingly little empirical evidence supporting theoretical and anecdotal claims regarding the spontaneous production of prototypic facial expressions used in numerous emotion recognition studies. Proponents of innate prototypic expressions believe that this lack of evidence may be due to ethical restrictions against presenting powerful elicitors in the lab. The current popularity of internet platforms designed for public sharing of videos allows investigators to shed light on this debate by examining naturally-occurring facial expressions outside the laboratory. An Internet prank ("Scary Maze") has provided a unique opportunity to observe children reacting to a consistent fear- and surprise-inducing stimulus: The unexpected presentation of a "scary face" during an online maze game. The purpose of this study was to examine children's facial expressions in this naturalistic setting. Emotion ratings of non-facial behaviour (provided by untrained undergraduates) and anatomically-based facial codes were obtained from 60 videos of children (ages 4-7) found on YouTube. Emotion ratings were highest for fear and surprise. Correspondingly, children displayed more facial expressions of fear and surprise than for other emotions (e.g. anger, joy). These findings provide partial support for the ecological validity of fear and surprise expressions. Still prototypic expressions were produced by fewer than half the children.

Neural architecture supporting active emotion processing in children: A multivariate approach.

BACKGROUND: Adaptive emotion processing is critical for nearly all aspects of social and emotional functioning. There are distinct developmental trajectories associated with improved emotion processing, with a protracted developmental course for negative or complex emotions. The specific changes in neural circuitry that underlie this development, however are still scarcely understood. We employed a multivariate approach in order to elucidate distinctions in complex, naturalistic emotion processing between childhood and adulthood. METHOD: Twenty-one adults (M±SD age = 26.57 ±â€¯5.08 years) and thirty children (age = 7.75 ±â€¯1.80 years) completed a free-viewing movie task during BOLD fMRI scanning. This task was designed to assess naturalistic processing of movie clips portraying positive, negative, and neutral emotions. Multivariate support vector machines (SVM) were trained to classify age groups based on neural activation during the task. RESULTS: SVMs were able to successfully classify condition (positive, negative, and neutral) across all participants with high accuracy (61.44%). SVMs could successfully distinguish adults and children within each condition (ps < 0.05). Regions that informed the age group SVMs were associated with sensory and socio-emotional processing (inferior parietal lobule), emotion regulation (inferior frontal gyrus), and sensory regions of the temporal and occipital lobes. CONCLUSIONS: These results point to distributed differences in activation between childhood and adulthood unique to each emotional condition. In the negative condition specifically, there is evidence for a shift in engagement from regions of sensory and socio-emotional integration to emotion regulation regions between children and adults. These results provide insight into circuitry contributing to maturation of emotional processing across development.

Irritability uniquely predicts prefrontal cortex activation during preschool inhibitory control among all temperament domains: A LASSO approach.

Temperament, defined as individual variation in the reactivity and regulation of emotional, motor, and attentional processes, has been shown to influence emotional and cognitive development during the preschool period (ages 4-5). While relationships between temperament and neural activity have been investigated previously, these have typically investigated individual temperament dimensions selected ad hoc. Since significant correlations exist between various temperament dimensions, it remains unclear whether these findings would replicate while analyzing all temperament dimensions simultaneously. Using functional near infrared spectroscopy (fNIRS), 4-5-year-old children (N = 118) were administered a Go/No-Go task to assess prefrontal cortex activation during inhibitory control. The relationship between PFC activation and all 15 temperament domains defined by the Children's Behavior Questionnaire (CBQ) was assessed using automatic feature selection via LASSO regression. Results indicate that only the Anger/Frustration dimension was predictive of activation during the inhibitory control task. These findings support previous work showing relationships between irritability and prefrontal activation during executive function and extend those findings by demonstrating the specificity of the activation-irritability relationship among temperament dimensions.

Fathers with Childhood ADHD, Parenting, and Their Young Children's Behavior: Offspring of the Pittsburgh ADHD Longitudinal Study (PALS).

Despite high heritability, no research has followed children with ADHD to parenthood to study their offspring and parenting behaviors. Given greater prevalence of ADHD in males and lack of research involving fathers, this study evaluated offspring of fathers with and without ADHD histories for ADHD and disruptive behavior and compared fathers' parenting behaviors. Male fathers (N = 29) from the Pittsburgh ADHD Longitudinal Study (PALS) participated with their preschool-aged offspring. Fathers completed self-reported measures, and father-child dyads completed an interaction task. ADHD offspring had elevated ADHD symptoms and behavior dysregulation. All fathers displayed positive parenting. ADHD fathers reported lower supportive responses to their child's negative emotions than comparison fathers, yet rated their parenting as more efficacious. ADHD offspring were distinguishable as early as age 3; thus, earlier diagnosis and intervention may be feasible for this at-risk population. Future research should investigate the acceptability and efficacy of parent training for fathers with ADHD.

Using facial muscular movements to understand young children's emotion regulation and concurrent neural activation.

Individual differences in young children's frustration responses set the stage for myriad developmental outcomes and represent an area of intense empirical interest. Emotion regulation is hypothesized to comprise the interplay of complex behaviors, such as facial expressions, and activation of concurrent underlying neural systems. At present, however, the literature has mostly examined children's observed emotion regulation behaviors and assumed underlying brain activation through separate investigations, resulting in theoretical gaps in our understanding of how children regulate emotion in vivo. Our goal was to elucidate links between young children's emotion regulation-related neural activation, facial muscular movements, and parent-rated temperamental emotion regulation. Sixty-five children (age 3-7) completed a frustration-inducing computer task while lateral prefrontal cortex (LPFC) activation and concurrent facial expressions were recorded. Negative facial expressions with eye constriction were inversely associated with both parent-rated temperamental emotion regulation and concurrent LPFC activation. Moreover, we found evidence that positive expressions with eye constriction during frustration may be associated with stronger LPFC activation. Results suggest a correspondence between facial expressions and LPFC activation that may explicate how children regulate emotion in real time.

Neurodevelopmental maturation as a function of irritable temperament: Insights From a Naturalistic Emotional Video Viewing Paradigm.

Few studies have investigated the neural systems involved in decreasing behavioral reactivity to emotional stimuli as children age. It has been suggested that this process may interact with temperament-linked variations in neurodevelopment to better explain individual differences in the maturation of emotion regulation. In this investigation, children ages 4 to 12 (n = 30, mean age = 7.62 years, SD = 1.71 years) and adults (n = 21, mean age = 26.67 years) watched clips from popular children's films containing positive, negative, or neutral emotional content during functional magnetic resonance imaging. Compared to adults, children demonstrated greater activation in subcortical and visual regions (hippocampus, thalamus, visual cortex, fusiform) during negative clips and greater activation of subcortical and prefrontal regions during positive clips (hippocampus, thalamus, caudate, ACC, OFC, superior frontal cortex). In children only, we found an age by temperament interaction in frontal and subcortical regions indicating that activation increased as a function of age in the most irritable children, but decreased as a function of age in the least irritable children. Findings were not present in the temperament domain of fear. Findings replicate and extend the existing irritability literature, indicating that healthy children highest in irritability may develop comparatively greater activation of the lateral prefrontal cortex in order to support adaptive regulation during emotional challenges. These results are discussed within the context of the emerging literature on the utility of complex, multidimensional, and naturalistic stimuli, which present a complementary alternative to understanding ecologically valid and sustained neural responses to emotionally evocative stimuli. Hum Brain Mapp 38:5307-5321, 2017. © 2017 Wiley Periodicals, Inc.

Functional Near-Infrared Spectroscopy Evidence for Development of Prefrontal Engagement in Working Memory in Early Through Middle Childhood.

The neural underpinnings of working memory are hypothesized to develop incrementally across preschool and early school age, coinciding with the rapid maturation of executive function occurring during this period. This study investigates the development of prefrontal cortex function between the ages of 3 and 7. Children (n = 68) participated in a novel spatial working memory task while their middle and lateral prefrontal cortex (LPFC) was monitored using functional near infrared spectroscopy (fNIRS). We found increased activation of the LPFC when comparing working memory to rest. Greater LPFC increase was noted for longer compared with shorter delay periods. Increase in LPFC activation, accuracy, and response speed were positively correlated with child age, suggesting that developmental changes in prefrontal function might underlie effective development of executive function in this age range.

fNIRS evidence of prefrontal regulation of frustration in early childhood.

The experience of frustration is common in early childhood, yet some children seem to possess a lower tolerance for frustration than others. Characterizing the biological mechanisms underlying a wide range of frustration tolerance observed in early childhood may inform maladaptive behavior and psychopathology that is associated with this construct. The goal of this study was to measure prefrontal correlates of frustration in 3-5-year-old children, who are not readily adaptable for typical neuroimaging approaches, using functional near infrared spectroscopy (fNIRS). fNIRS of frontal regions were measured as frustration was induced in children through a computer game where a desired and expected prize was "stolen" by an animated dog. A fNIRS general linear model (GLM) was used to quantify the correlation of brain regions with the task and identify areas that were statistically different between the winning and frustrating test conditions. A second-level voxel-based ANOVA analysis was then used to correlate the amplitude of each individual's brain activation with measure of parent-reported frustration. Experimental results indicated increased activity in the middle prefrontal cortex during winning of a desired prize, while lateral prefrontal cortex activity increased during frustration. Further, activity increase in lateral prefrontal cortex during frustration correlated positively with parent-reported frustration tolerance. These findings point to the role of the lateral prefrontal cortex as a potential region supporting the regulation of emotion during frustration.

Irritability in Youths: A Critical Integrative Review.

Irritability, defined as proneness to anger that may impair an individual's functioning, is common in youths. There has been a recent upsurge in relevant research. The authors combine systematic and narrative review approaches to integrate the latest clinical and translational findings and provide suggestions for addressing research gaps. Clinicians and researchers should assess irritability routinely, and specific assessment tools are now available. Informant effects are prominent, are stable, and vary by age and gender. The prevalence of irritability is particularly high among individuals with attention deficit hyperactivity disorder, autism spectrum disorder, and mood and anxiety disorders. Irritability is associated with impairment and suicidality risk independent of co-occurring diagnoses. Developmental trajectories of irritability (which may begin early in life) have been identified and are differentially associated with clinical outcomes. Youth irritability is associated with increased risk of anxiety, depression, behavioral problems, and suicidality later in life. Irritability is moderately heritable, and genetic associations differ based on age and comorbid illnesses. Parent management training is effective for treating psychological problems related to irritability, but its efficacy in treating irritability should be tested rigorously, as should novel mechanism-informed interventions (e.g., those targeting exposure to frustration). Associations between irritability and suicidality and the impact of cultural context are important, underresearched topics. Analyses of large, diverse longitudinal samples that extend into adulthood are needed. Data from both animal and human research indicate that aberrant responses to frustration and threat are central to the pathophysiology of irritability, revealing important translational opportunities.

Irritability Moderates the Association between Cognitive Flexibility Task Performance and Related Prefrontal Cortex Activation in Young Children.

The association between cognitive flexibility and related neural functioning has been inconsistent. This is particularly true in young children, where previous studies have found heterogenous results linking behavior and neural function, raising the possibility of unexplored moderators. The current study explored the moderating role of dimensional irritability in the association between cognitive flexibility task performance and prefrontal activation in young children. A total of 106 3- to 7-year-old children were recruited to complete a custom-designed, child-adapted, cognitive flexibility task, and 98 of them were included in the data analysis. The children's dorsolateral prefrontal cortex activation was monitored using functional near-infrared spectroscopy, and their levels of irritability were reported by parents using the MAP-DB Temper Loss subscale. Results indicated that the mean reaction time of the cognitive flexibility task was negatively correlated with concurrent prefrontal activation. No evidence was found for the association between task accuracy and prefrontal activation. Moreover, irritability moderated the association between the mean reaction time and prefrontal activation. Children high in irritability exhibited a stronger negative association between the mean reaction time and related prefrontal activation than children low in irritability. The moderating model suggested a novel affective-cognitive interaction to investigate the associations between cognitive task performance and their neural underpinnings.