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. Yet, it is challenging to administer and score these assessments alongside high-quality infant neuroimaging data. The current study aims to identify infant resting state functional connectivity (rsFC) associated with both parent-report and observed behavioral estimates of infant novelty-evoked distress. METHODS: Using data from the Origins of Infant Temperament (OIT) 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 MRI sample was a "synthetic cohort", harmonizing data from two fMRI studies of 4-month-old infants (OIT and Baby Connectome Project [BCP]; n=101) both of which included 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 three network pairs: Dorsal Attention-Salience/Ventral Attention, Dorsal Attention-Default, 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). CONCLUSION: 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.

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.

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.

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.

Action Experience Changes Attention to Kinematic Cues.

The current study used remote corneal reflection eye-tracking to examine the relationship between motor experience and action anticipation in 13-months-old infants. To measure online anticipation of actions infants watched videos where the actor's hand provided kinematic information (in its orientation) about the type of object that the actor was going to reach for. The actor's hand orientation either matched the orientation of a rod (congruent cue) or did not match the orientation of the rod (incongruent cue). To examine relations between motor experience and action anticipation, we used a 2 (reach first vs. observe first) × 2 (congruent kinematic cue vs. incongruent kinematic cue) between-subjects design. We show that 13-months-old infants in the observe first condition spontaneously generate rapid online visual predictions to congruent hand orientation cues and do not visually anticipate when presented incongruent cues. We further demonstrate that the speed that these infants generate predictions to congruent motor cues is correlated with their own ability to pre-shape their hands. Finally, we demonstrate that following reaching experience, infants generate rapid predictions to both congruent and incongruent hand shape cues-suggesting that short-term experience changes attention to kinematics.