Neural Correlates of Novelty-Evoked Distress in 4-Month-Old Infants: A Synthetic Cohort Study.

BACKGROUND: Observational assessments of infant temperament have provided unparalleled insight into prediction of risk for social anxiety. However, it is challenging to administer and score these assessments alongside high-quality infant neuroimaging data. In the current study, we aimed to identify infant resting-state functional connectivity associated with both parent report and observed behavioral estimates of infant novelty-evoked distress. METHODS: Using data from the OIT (Origins of Infant Temperament) study, which includes deep phenotyping of infant temperament, we identified parent-report measures that were associated with observed novelty-evoked distress. These parent-report measures were then summarized into a composite score used for imaging analysis. Our infant magnetic resonance imaging sample was a synthetic cohort, harmonizing data from 2 functional magnetic resonance imaging studies of 4-month-old infants (OIT and BCP [Baby Connectome Project]; n = 101), both of which included measures of parent-reported temperament. Brain-behavior associations were evaluated using enrichment, a statistical approach that quantifies the clustering of brain-behavior associations within network pairs. RESULTS: Results demonstrated that parent-report composites of novelty-evoked distress were significantly associated with 3 network pairs: dorsal attention-salience/ventral attention, dorsal attention-default mode, and dorsal attention-control. These network pairs demonstrated negative associations with novelty-evoked distress, indicating that less connectivity between these network pairs was associated with greater novelty-evoked distress. Additional analyses demonstrated that dorsal attention-control network connectivity was associated with observed novelty-evoked distress in the OIT sample (n = 38). CONCLUSIONS: Overall, this work is broadly consistent with existing work and implicates dorsal attention network connectivity in novelty-evoked distress. This study provides novel data on the neural basis of infant novelty-evoked distress.

Multivariate Assessment of Inhibitory Control in Youth: Links With Psychopathology and Brain Function.

Inhibitory control is central to many theories of cognitive and brain development, and impairments in inhibitory control are posited to underlie developmental psychopathology. In this study, we tested the possibility of shared versus unique associations between inhibitory control and three common symptom dimensions in youth psychopathology: attention-deficit/hyperactivity disorder (ADHD), anxiety, and irritability. We quantified inhibitory control using four different experimental tasks to estimate a latent variable in 246 youth (8-18 years old) with varying symptom types and levels. Participants were recruited from the Washington, D.C., metro region. Results of structural equation modeling integrating a bifactor model of psychopathology revealed that inhibitory control predicted a shared or general psychopathology dimension, but not ADHD-specific, anxiety-specific, or irritability-specific dimensions. Inhibitory control also showed a significant, selective association with global efficiency in a frontoparietal control network delineated during resting-state functional magnetic resonance imaging. These results support performance-based inhibitory control linked to resting-state brain function as an important predictor of comorbidity in youth psychopathology.

Neonatal neural responses to novelty related to behavioral inhibition at 1 year.

Behavioral inhibition (BI), an early-life temperament characterized by vigilant responses to novelty, is a risk factor for anxiety disorders. In this study, we investigated whether differences in neonatal brain responses to infrequent auditory stimuli relate to children's BI at 1 year of age. Using functional magnetic resonance imaging (fMRI), we collected blood-oxygen-level-dependent (BOLD) data from N = 45 full-term, sleeping neonates during an adapted auditory oddball paradigm and measured BI from n = 27 of these children 1 year later using an observational assessment. Whole-brain analyses corrected for multiple comparisons identified 46 neonatal brain regions producing novelty-evoked BOLD responses associated with children's BI scores at 1 year of age. More than half of these regions (n = 24, 52%) were in prefrontal cortex, falling primarily within regions of the default mode or frontoparietal networks or in ventromedial/orbitofrontal regions without network assignments. Hierarchical clustering of the regions based on their patterns of association with BI resulted in two groups with distinct anatomical, network, and response-timing profiles. The first group, located primarily in subcortical and temporal regions, tended to produce larger early oddball responses among infants with lower subsequent BI. The second group, located primarily in prefrontal cortex, produced larger early oddball responses among infants with higher subsequent BI. These results provide preliminary insights into brain regions engaged by novelty in infants that may relate to later BI. The findings may inform understanding of anxiety disorders and guide future research. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Children's social wariness toward a different-race stranger relates to individual differences in temperament.

When children first meet a stranger, there is great variation in how much they will approach and engage with the stranger. While individual differences in this type of behavior-called social wariness-are well-documented in temperament research, surprisingly little attention has been paid to the social groups (such as race) of the stranger and how these characteristics might influence children's social wariness. In contrast, research on children's social bias and interracial friendships rarely examines individual differences in temperament and how temperament might influence cross-group interactions. The current study bridges the gap across these different fields of research by examining whether the racial group of an unfamiliar peer or adult moderates the association between temperament and the social wariness that children display. Utilizing a longitudinal dataset that collected multiple measurements of children's temperament and behaviors (including parent-reported shyness and social wariness toward unfamiliar adults and peers) across early childhood, we found that 2- to 7-year-old children with high parent-reported shyness showed greater social wariness toward a different-race stranger compared to a same-race stranger, whereas children with low parent-reported shyness did not. These results point to the importance of considering racial group membership in temperament research and the potential role that temperament might play in children's cross-race interactions. RESEARCH HIGHLIGHTS: Previous research on temperament has not considered how the race of strangers could influence children's social wariness. We find evidence that 2- to 7-year-old children with high parent-reported shyness show greater social wariness toward a different-race stranger compared to a same-race stranger. These results point to the importance of considering racial group membership in temperament research. Our findings also suggest temperament may play a role in children's cross-race interactions.

Parenting and childhood irritability: Negative emotion socialization and parental control moderate the development of irritability.

Irritability, characterized by anger in response to frustration, is normative in childhood. While children typically show a decline in irritability from toddlerhood to school age, elevated irritability throughout childhood may predict later psychopathology. The current study (n = 78) examined associations between trajectories of irritability in early childhood (ages 2-7) and irritability in adolescence (age 12) and tested whether these associations are moderated by parenting behaviors. Results indicate that negative emotion socialization moderated trajectories of irritability - relative to children with low stable irritability, children who exhibited high stable irritability in early childhood and who had parents that exhibited greater negative emotion socialization behaviors had higher irritability in adolescence. Further, negative parental control behavior moderated trajectories of irritability - relative to children with low stable irritability, children who had high decreasing irritability in early childhood and who had parents who exhibited greater negative control behaviors had higher irritability in adolescence. In contrast, positive emotion socialization and control behaviors did not moderate the relations between early childhood irritability and later irritability in adolescence. These results suggest that both irritability in early childhood and negative parenting behaviors may jointly influence irritability in adolescence. The current study underscores the significance of negative parenting behaviors and could inform treatment.

Cross-sectional and Longitudinal Associations of Anxiety and Irritability With Adolescents' Neural Responses to Cognitive Conflict.

BACKGROUND: Psychiatric symptoms are commonly comorbid in childhood. The ability to disentangle unique and shared correlates of comorbid symptoms facilitates personalized medicine. Cognitive control is implicated broadly in psychopathology, including in pediatric disorders characterized by anxiety and irritability. To disentangle cognitive control correlates of anxiety versus irritability, the current study leveraged both cross-sectional and longitudinal data from early childhood into adolescence. METHODS: For this study, 89 participants were recruited from a large longitudinal research study on early-life temperament to investigate associations of developmental trajectories of anxiety and irritability symptoms (from ages 2 to 15) as well as associations of anxiety and irritability symptoms measured cross-sectionally at age 15 with neural substrates of conflict and error processing assessed at age 15 using the flanker task. RESULTS: Results of whole-brain multivariate linear models revealed that anxiety at age 15 was uniquely associated with decreased neural response to conflict across multiple regions implicated in attentional control and conflict adaptation. Conversely, irritability at age 15 was uniquely associated with increased neural response to conflict in regions implicated in response inhibition. Developmental trajectories of anxiety and irritability interacted in relation to neural responses to both error and conflict. CONCLUSIONS: Our findings suggest that neural correlates of conflict processing may relate uniquely to anxiety and irritability. Continued cross-symptom research on the neural correlates of cognitive control could stimulate advances in individualized treatment for anxiety and irritability during child and adolescent development.

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.

Temperamental risk for anxiety: emerging work on the infant brain and later neurocognitive development.

Behavioral inhibition (BI), an infant temperament characterized by distress to novelty, is amongst the strongest early risk markers for future anxiety. In this review, we highlight three ways that recent research elucidates key details about the pathophysiology of anxiety in individuals with BI. First, atypical amygdala connectivity during infancy may be related to BI. Second, developmental shifts in cognitive control may portend risk for anxiety for children with BI. Lastly, distinct cognitive control processes moderate the BI-anxiety relation in different ways. Studying the intersection of these three streams of work may inform prevention or intervention work.

An ode to fetal, infant, and toddler neuroimaging: Chronicling early clinical to research applications with MRI, and an introduction to an academic society connecting the field.

Fetal, infant, and toddler neuroimaging is commonly thought of as a development of modern times (last two decades). Yet, this field mobilized shortly after the discovery and implementation of MRI technology. Here, we provide a review of the parallel advancements in the fields of fetal, infant, and toddler neuroimaging, noting the shifts from clinical to research use, and the ongoing challenges in this fast-growing field. We chronicle the pioneering science of fetal, infant, and toddler neuroimaging, highlighting the early studies that set the stage for modern advances in imaging during this developmental period, and the large-scale multi-site efforts which ultimately led to the explosion of interest in the field today. Lastly, we consider the growing pains of the community and the need for an academic society that bridges expertise in developmental neuroscience, clinical science, as well as computational and biomedical engineering, to ensure special consideration of the vulnerable mother-offspring dyad (especially during pregnancy), data quality, and image processing tools that are created, rather than adapted, for the young brain.

Dear reviewers: Responses to common reviewer critiques about infant neuroimaging studies.

The field of adult neuroimaging relies on well-established principles in research design, imaging sequences, processing pipelines, as well as safety and data collection protocols. The field of infant magnetic resonance imaging, by comparison, is a young field with tremendous scientific potential but continuously evolving standards. The present article aims to initiate a constructive dialog between researchers who grapple with the challenges and inherent limitations of a nascent field and reviewers who evaluate their work. We address 20 questions that researchers commonly receive from research ethics boards, grant, and manuscript reviewers related to infant neuroimaging data collection, safety protocols, study planning, imaging sequences, decisions related to software and hardware, and data processing and sharing, while acknowledging both the accomplishments of the field and areas of much needed future advancements. This article reflects the cumulative knowledge of experts in the FIT'NG community and can act as a resource for both researchers and reviewers alike seeking a deeper understanding of the standards and tradeoffs involved in infant neuroimaging.

Developmental Changes in the Association Between Cognitive Control and Anxiety.

Anxiety has been associated with reliance on reactive (stimulus-driven/reflexive) control strategies in response to conflict. However, this conclusion rests primarily on indirect evidence. Few studies utilize tasks that dissociate the use of reactive ('just in time') vs. proactive (anticipatory/preparatory) cognitive control strategies in response to conflict, and none examine children diagnosed with anxiety. The current study utilizes the AX-CPT, which dissociates these two types of cognitive control, to examine cognitive control in youth (ages 8-18) with and without an anxiety diagnosis (n = 56). Results illustrate that planful behavior, consistent with using a proactive strategy, varies by both age and anxiety symptoms. Young children (ages 8-12 years) with high anxiety exhibit significantly less planful behavior than similarly-aged children with low anxiety. These findings highlight the importance of considering how maturation influences relations between anxiety and performance on cognitive-control tasks and have implications for understanding the pathophysiology of anxiety in children.

Amygdala Functional Connectivity and Negative Reactive Temperament at Age 4 Months.

OBJECTIVE: Infant amygdala connectivity correlates with maternal reports of infant temperament characterized by novelty-evoked distress and avoidance. However, no studies have examined how human infant amygdala connectivity relates to direct observations of novelty-evoked distress. This study examined the link between amygdala connectivity and infant novelty-evoked distress using direct observation of temperament. METHOD: Novelty-evoked distress was assessed at 4 months of age (N = 90) using a standardized reactivity assessment and parent report. Within 3 weeks of assessment, resting-state functional magnetic resonance imaging was collected in a subset of infants (n = 34). Using a whole-brain voxelwise approach, amygdala connectivity associated with positive and negative affect during the reactivity assessment was examined. Regions where the association of amygdala connectivity with negative affect was higher than with positive affect were then examined. Associations between amygdala connectivity and parent report of temperament were also examined. RESULTS: Greater amygdala-cingulate and amygdala-superior frontal gyrus connectivity was associated with lower positive affect during the reactivity assessment. Further, the association between amygdala-cingulate connectivity was greater for negative affect compared with positive affect. There were no significant associations between latency to approach novelty (as measured by parent report) and amygdala connectivity. Validation analyses conducted using a large independent longitudinal sample (N = 323) demonstrated that negative reactivity was associated with increased child-reported anxiety symptoms in adolescence. CONCLUSION: These results provide novel insight into the developmental pathophysiology of novelty-evoked distress. This is consistent with research linking an altered cognitive control mechanism to temperamental risk for anxiety.

Infant behavioral reactivity predicts change in amygdala volume 12 years later.

The current study examined the link between temperamental reactivity in infancy and amygdala development in middle childhood. A sample (n = 291) of four-month-old infants was assessed for infant temperament, and two groups were identified: those exhibiting negative reactivity (n = 116) and those exhibiting positive reactivity (n = 106). At 10 and 12 years of age structural imaging was completed on a subset of these participants (n = 75). Results indicate that, between 10 and 12 years of age, left amygdala volume increased more slowly in those with negative compared to positive reactive temperament. These results provide novel evidence linking early temperament to distinct patterns of brain development over middle childhood.

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

Levels of early-childhood behavioral inhibition predict distinct neurodevelopmental pathways to pediatric anxiety.

BACKGROUND: Anxiety symptoms gradually emerge during childhood and adolescence. Individual differences in behavioral inhibition (BI), an early-childhood temperament, may shape developmental paths through which these symptoms arise. Cross-sectional research suggests that level of early-childhood BI moderates associations between later anxiety symptoms and threat-related amygdala-prefrontal cortex (PFC) circuitry function. However, no study has characterized these associations longitudinally. Here, we tested whether level of early-childhood BI predicts distinct evolving associations between amygdala-PFC function and anxiety symptoms across development. METHODS: Eighty-seven children previously assessed for BI level in early childhood provided data at ages 10 and/or 13 years, consisting of assessments of anxiety and an fMRI-based dot-probe task (including threat, happy, and neutral stimuli). Using linear-mixed-effects models, we investigated longitudinal changes in associations between anxiety symptoms and threat-related amygdala-PFC connectivity, as a function of early-childhood BI. RESULTS: In children with a history of high early-childhood BI, anxiety symptoms became, with age, more negatively associated with right amygdala-left dorsolateral-PFC connectivity when attention was to be maintained on threat. In contrast, with age, low-BI children showed an increasingly positive anxiety-connectivity association during the same task condition. Behaviorally, at age 10, anxiety symptoms did not relate to fluctuations in attention bias (attention bias variability, ABV) in either group; by age 13, low-BI children showed a negative anxiety-ABV association, whereas high-BI children showed a positive anxiety-ABV association. CONCLUSIONS: Early-childhood BI levels predict distinct neurodevelopmental pathways to pediatric anxiety symptoms. These pathways involve distinct relations among brain function, behavior, and anxiety symptoms, which may inform diagnosis and treatment.

Neural correlates of infant action processing relate to theory of mind in early childhood.

The mechanisms that support infant action processing are thought to be involved in the development of later social cognition. While a growing body of research demonstrates longitudinal links between action processing and explicit theory of mind (TOM), it remains unclear why this link emerges in some measures of action encoding and not others. In this paper, we recruit neural measures as a unique lens into which aspects of human infant action processing (i.e., action encoding and action execution; age 7 months) are related to preschool TOM (age 3 years; n = 31). We test whether individual differences in recruiting the sensorimotor system or attention processes during action encoding predict individual differences in TOM. Results indicate that reduced occipital alpha during action encoding predicts TOM at age 3. This finding converges with behavioral work and suggests that attentional processes involved in action encoding may support TOM. We also test whether neural processing during action execution draws on the proto-substrates of effortful control (EC). Results indicate that frontal alpha oscillatory activity during action execution predicted EC at age 3-providing strong novel evidence that infant brain activity is longitudinally linked to EC. Further, we demonstrate that EC mediates the link between the frontal alpha response and TOM. This indirect effect is specific in terms of direction, neural response, and behavior. Together, these findings converge with behavioral research and demonstrate that domain general processes show strong links to early infant action processing and TOM.

Developmental pathways to social anxiety and irritability: The role of the ERN.

Early behaviors that differentiate later biomarkers for psychopathology can guide preventive efforts while also facilitating pathophysiological research. We tested whether error-related negativity (ERN) moderates the link between early behavior and later psychopathology in two early childhood phenotypes: behavioral inhibition and irritability. From ages 2 to 7 years, children (n = 291) were assessed longitudinally for behavioral inhibition (BI) and irritability. Behavioral inhibition was assessed via maternal report and behavioral responses to novelty. Childhood irritability was assessed using the Child Behavior Checklist. At age 12, an electroencephalogram (EEG) was recorded while children performed a flanker task to measure ERN, a neural indicator of error monitoring. Clinical assessments of anxiety and irritability were conducted using questionnaires (i.e., Screen for Child Anxiety Related Disorders and Affective Reactivity Index) and clinical interviews. Error monitoring interacted with early BI and early irritability to predict later psychopathology. Among children with high BI, an enhanced ERN predicted greater social anxiety at age 12. In contrast, children with high childhood irritability and blunted ERN predicted greater irritability at age 12. This converges with previous work and provides novel insight into the specificity of pathways associated with psychopathology.

Actions speak louder than gestures when you are 2 years old.

Interpreting iconic gestures can be challenging for children. Here, we explore the features and functions of iconic gestures that make them more challenging for young children to interpret than instrumental actions. In Study 1, we show that 2.5-year-olds are able to glean size information from handshape in a simple gesture, although their performance is significantly worse than 4-year-olds'. Studies 2 to 4 explore the boundary conditions of 2.5-year-olds' gesture understanding. In Study 2, 2.5-year-old children have an easier time interpreting size information in hands that reach than in hands that gesture. In Study 3, we tease apart the perceptual features and functional objectives of reaches and gestures. We created a context in which an action has the perceptual features of a reach (extending the hand toward an object) but serves the function of a gesture (the object is behind a barrier and not obtainable; the hand thus functions to represent, rather than reach for, the object). In this context, children struggle to interpret size information in the hand, suggesting that gesture's representational function (rather than its perceptual features) is what makes it hard for young children to interpret. A distance control (Study 4) in which a person holds a box in gesture space (close to the body) demonstrates that children's difficulty interpreting static gesture cannot be attributed to the physical distance between a gesture and its referent. Together, these studies provide evidence that children's struggle to interpret iconic gesture may stem from its status as representational action. (PsycINFO Database Record

Motor System Activation Predicts Goal Imitation in 7-Month-Old Infants.

The current study harnessed the variability in infants' neural and behavioral responses as a novel method for evaluating the potential relations between motor system activation and social behavior. We used electroencephalography (EEG) to record neural activity as 7-month-old infants observed and responded to the actions of an experimenter. To determine whether motor system activation predicted subsequent imitation behavior, we assessed event-related desynchronization (ERD) at central sites during action observation as a function of subsequent behavior. Greater mu desynchronization over central sites was observed when infants subsequently reproduced the experimenter's goal than when they did not reproduce the goal and instead selected the nongoal object. We also found that mu desynchronization during action execution predicted the infants' later propensity to reproduce the experimenter's goal-directed behavior. These results provide the first evidence that motor system activation predicts the imitation of other individuals' goals during infancy.