Suicide is defined as the act of a person attempting to take their own life by causing death. Suicide is a complex phenomenon that is influenced by a multitude of factors, including psychosocial, cultural, and religious aspects, as well as genetic, biochemical, and environmental factors. From a biochemical perspective, it is crucial to consider the communication between the endocrine, immune, and nervous systems when studying the etiology of suicide. Several pathologies involve the bidirectional communication between the peripheral activity and the central nervous system by the action of molecules such as cytokines, hormones, and neurotransmitters. These humoral signals, when present in optimal quantities, are responsible for maintaining physiological homeostasis, including mood states. Stress elevates the cortisol and proinflammatory cytokines levels and alter neurotransmitters balance, thereby increasing the risk of developing a psychiatric disorder and subsequently the risk of suicidal behavior. This review provides an integrative perspective about the neurochemical, immunological, and endocrinological disturbances associated with suicidal behavior, with a particular focus on those alterations that may serve as potential risk markers and/or indicators of the state preceding such a tragic act.

Anxiety and related disorders are prevalent across the lifespan, often have their onset during youth, and are associated with notable levels of impairment and burden across multiple domains. Elucidating the associations between differential patterns of neurodevelopment and anxiety in youth is a promising approach for developing deeper insights regarding the neurobiological etiologies and maintenance factors associated with anxiety and related disorders. A growing body of literature has yielded evidence of associations between patterns of brain structure (i.e., volume, cortical thickness, and cortical surface area) and anxiety. Here, we present a review and synthesis of the existing body of literature surrounding neurostructural correlates of anxiety in youth spanning multiple anxiety presentations and three neurostructural modalities. We reveal substantially more research focusing on brain volume than cortical thickness or surface area and a greater number of studies examining anxiety broadly defined, obsessive-compulsive disorder, or posttraumatic stress disorder. There is also evidence of considerable variability in the brain regions implicated and the direction of associations across studies. Finally, we discuss the gaps and limitations in this body of work, which suggest avenues for future directions.

Mental health professionals have relied primarily on clinical evaluations to identify in vivo pathology. As a result, mental health is largely reactive rather than proactive. In an effort to proactively assess mood, we collected continuous neurophysiologic data for ambulatory individuals 8-10 h a day at 1 Hz for 3 weeks (N = 24). Data were obtained using a commercial neuroscience platform (Immersion Neuroscience) that quantifies the neural value of social-emotional experiences. These data were related to self-reported mood and energy to assess their predictive accuracy. Statistical analyses quantified neurophysiologic troughs by the length and depth of social-emotional events with low values and neurophysiologic peaks as the complement. Participants in the study had an average of 2.25 (SD = 3.70, Min = 0, Max = 25) neurophysiologic troughs per day and 3.28 (SD = 3.97, Min = 0, Max = 25) peaks. The number of troughs and peaks predicted daily mood with 90% accuracy using least squares regressions and machine learning models. The analysis also showed that women were more prone to low mood compared to men. Our approach demonstrates that a simple count variable derived from a commercially-available platform is a viable way to assess low mood and low energy in populations vulnerable to mood disorders. In addition, peak Immersion events, which are mood-enhancing, may be an effective measure of thriving in adults.

Elevated threat appraisal is a postulated neurodevelopmental mechanism of anxiety disorders. However, laboratory-assessed threat appraisals are task-specific and subject to measurement error. We utilized latent variable analysis to integrate youth's self-reported threat appraisals across different experimental tasks; we next examined associations with pediatric anxiety as well as behavioral and psychophysiological task indices. Ninety-two youth ages 8-17 years (M age=13.07, 65% female), including 51 with a primary anxiety disorder and 41 with no Axis I diagnosis, completed up to eight threat-exposure tasks. Anxiety symptoms were assessed using questionnaires and ecological momentary assessment. Appraisals both prior to and following threat exposures evidenced shared variance across tasks. Derived factor scores for threat appraisal were associated significantly with anxiety symptoms and variably with task indices; findings were comparable to task-specific measures and had several advantages. Results support an overarching construct of threat appraisal linked with pediatric anxiety, providing groundwork for more robust laboratory-based measurement.

Interpretation bias, or the threatening appraisal of ambiguous information, has been linked to anxiety disorder. Interpretation bias has been demonstrated for linguistic (e.g., evaluation of ambiguous sentences) and visual judgments (e.g., categorizing emotionally ambiguous facial expressions). It is unclear how these separate components of bias might be associated. We examined linguistic and visual interpretation biases in youth and emerging adults with (n = 44) and without (n = 40) anxiety disorder, and in youth-parent dyads (n = 40). Linguistic and visual biases were correlated with each other, and with anxiety. Compared to non-anxious participants, those with anxiety demonstrated stronger biases, and linguistic bias was especially predictive of anxiety symptoms and diagnosis. Age did not moderate these relationships. Parent linguistic bias was correlated with youth anxiety but not linguistic bias; parent and youth visual biases were correlated. Linguistic and visual interpretation biases are linked in clinically-anxious youth and emerging adults.

Despite broad recognition of the central role of avoidance in anxiety, a lack of specificity in its operationalization has hindered progress in understanding this clinically significant construct. The current study uses a multimodal approach to investigate how specific measures of avoidance relate to neural reactivity to threat in youth with anxiety disorders.

Children with anxiety disorders (ages 6-12 years; n = 65 for primary analyses) completed laboratory task- and clinician-based measures of avoidance, as well as a functional magnetic resonance imaging task probing neural reactivity to threat. Primary analyses examined the ventral anterior insula (vAI), amygdala, and ventromedial prefrontal cortex (vmPFC).

Significant but distinct patterns of association with task- versus clinician-based measures of avoidance emerged. Clinician-rated avoidance was negatively associated with right and left vAI reactivity to threat, whereas laboratory-based avoidance was positively associated with right vAI reactivity to threat. Moreover, left vAI-right amygdala and bilateral vmPFC-right amygdala functional connectivity were negatively associated with clinician-rated avoidance but not laboratory-based avoidance.

These results should be considered in the context of the restricted range of our treatment-seeking sample, which limits the ability to draw conclusions about these associations across children with a broader range of symptomatology. In addition, the limited racial and ethnic diversity of our sample may limit the generalizability of findings.

These findings mark an important step towards bridging neural findings and behavioral patterns using a multimodal approach. Advancing understanding of behavioral avoidance in pediatric anxiety may guide future treatment optimization by identifying individual-specific targets for treatment.

Given the high prevalence of anxiety disorders and their associated impairment, elucidating neural mechanisms related to these disorders has been increasingly prioritized. The error-related negativity (ERN) has been identified as a neural marker that indexes risk for anxiety across development. The ERN seems to confer risk for developing anxiety, especially in the context of stressful life events. The present study sought to examine sleep-related difficulties as another stressful factor that might impact the ERN. In a sample of 221 girls, aged 8 to 15 years old, we first examined the relationship between longer-term (i.e., over the past month) and shorter-term (i.e., over the past week) sleep difficulties and the ERN. We then investigated whether specific sleep difficulties uniquely predict the ERN. In exploratory analyses, we assessed whether sleep difficulties moderate the relationship between the ERN and anxiety. Results indicated that youth who report longer-term lower sleep duration, longer-term worse sleep, and shorter-term lower sleep duration on school days over the past week have a larger (i.e., more negative) ERN. Additionally, only shorter-term sleep duration on school days over the past week uniquely predicted the ERN. Finally, an elevated ERN predicted greater clinical anxiety in the context of longer-term sleep difficulties. Future studies should clarify the direction of these associations via longitudinal designs.

Pediatric anxiety and depressive disorders are common, can be highly impairing, and can persist despite the best available treatments. Here, we review research into novel treatments for childhood anxiety and depressive disorders designed to target underlying cognitive, emotional, and neural circuit mechanisms. We highlight three novel treatments lying along a continuum relating to clinical impact of the disorder and the intensity of clinical management required. We review cognitive training, which involves the lowest risk and may be applicable for problems with mild to moderate impact; psychotherapy, which includes a higher level of clinical involvement and may be sufficient for problems with moderate impact; and brain stimulation, which has the highest potential risks and is therefore most appropriate for problems with high impact. For each treatment, we review the specific underlying cognitive, emotional, and brain circuit mechanisms that are being targeted, whether treatments modify those underlying mechanisms, and efficacy in reducing symptoms. We conclude by highlighting future directions, including the importance of work that leverages developmental windows of high brain plasticity to time interventions to the specific epochs in childhood that have the largest and most enduring life-long impact.

Behavioral inhibition (BI) is a temperamental style characterized by cautious and fearful behaviors in novel situations. The present multi-method, longitudinal study examined whether young children's observed and parent-reported BI in social versus non-social contexts predicts different long-term psychosocial outcomes. Participants (N = 279) were drawn from a longitudinal study of socioemotional development. BI in social contexts ("social BI") was measured via children's observed wariness toward unfamiliar adults and peers at 24 and 36 months and parents' reports of children's social fear/shyness at 24, 36, and 48 months. BI in non-social contexts ("non-social BI") was measured via children's observed fearful responses to masks and novel toys, and parents' reports of children's distress to non-social novelty at 9 months and non-social fear at 48 months. At 15 years, anxiety was assessed via adolescent- and parent-reports, and global internalizing and externalizing problems were assessed via parent-reports. Confirmatory factor analysis showed that a two-factor model fit the BI data significantly better than a single-factor model, providing evidence for the dissociation of BI in social versus non-social contexts. Social BI was uniquely associated with adolescent social anxiety, whereas non-social BI was specifically associated with adolescent separation anxiety. Neither social BI nor non-social BI predicted global internalizing and externalizing problems, providing evidence for the specific relations between BI and anxiety problems. Together, these results suggest that young children's inhibited responses in social versus non-social situations predict different subtypes of anxiety problems in adolescence, highlighting the multifaceted nature of BI and the divergent trajectories of different anxiety problems.

Loss-of-control (LOC) eating, a key feature of binge-eating disorder, may relate attentional bias (AB) to highly salient interpersonal stimuli. The current pilot study used magnetoencephalography (MEG) to explore neural features of AB to socially threatening cues in adolescent girls with and without LOC-eating.

Girls (12-17 years old) with overweight or obesity (BMI >85th percentile) completed an AB measure on an affective dot-probe AB task during MEG and evoked neural responses to angry or happy (vs. neutral) face cues were captured. A laboratory test meal paradigm measured energy intake and macronutrient consumption patterns.

Girls (N = 34; Mage = 15.5 ± 1.5 years; BMI-z = 1.7 ± 0.4) showed a blunted evoked response to the presentation of angry face compared with neutral face cues in the left dorsolateral prefrontal cortex, a neural region implicated in executive control and regulation processes, during attention deployment (p < 0.01). Compared with those without LOC-eating (N = 21), girls with LOC-eating (N = 13) demonstrated a stronger evoked response to angry faces in the visual cortex during attention deployment (p < 0.001). Visual and cognitive control ROIs had trends suggesting interaction with test meal intake patterns among girls with LOC-eating (ps = 0.01).

These findings suggest that girls with overweight or obesity may fail to adaptively engage neural regions implicated in higher-order executive processes. This difficulty may relate to disinhibited eating patterns that could lead to excess weight gain.

Anxiety is the most common manifestation of psychopathology in youth, negatively affecting academic, social, and adaptive functioning and increasing risk for mental health problems into adulthood. Anxiety disorders are diagnosed only after clinical symptoms emerge, potentially missing opportunities to intervene during critical early prodromal periods. In this study, we used a new empirical approach to extracting nonlinear features of the electroencephalogram (EEG), with the goal of discovering differences in brain electrodynamics that distinguish children with anxiety disorders from healthy children. Additionally, we examined whether this approach could distinguish children with externalizing disorders from healthy children and children with anxiety.

We used a novel supervised tensor factorization method to extract latent factors from repeated multifrequency nonlinear EEG measures in a longitudinal sample of children assessed in infancy and at ages 3, 5, and 7 years of age. We first examined the validity of this method by showing that calendar age is highly correlated with latent EEG complexity factors (r = 0.77). We then computed latent factors separately for distinguishing children with anxiety disorders from healthy controls using a 5-fold cross validation scheme and similarly for distinguishing children with externalizing disorders from healthy controls.

We found that latent factors derived from EEG recordings at age 7 years were required to distinguish children with an anxiety disorder from healthy controls; recordings from infancy, 3 years, or 5 years alone were insufficient. However, recordings from two (5, 7 years) or three (3, 5, 7 years) recordings gave much better results than 7 year recordings alone. Externalizing disorders could be detected using 3- and 5 years EEG data, also giving better results with two or three recordings than any single snapshot. Further, sex assigned at birth was an important covariate that improved accuracy for both disorder groups, and birthweight as a covariate modestly improved accuracy for externalizing disorders. Recordings from infant EEG did not contribute to the classification accuracy for either anxiety or externalizing disorders.

This study suggests that latent factors extracted from EEG recordings in childhood are promising candidate biomarkers for anxiety and for externalizing disorders if chosen at appropriate ages.

Rates of aggressive offending among Justice-Involved Young Women (JIYW) have increased over the past few decades. Yet, there is little discourse, research, or intervention to address it among young women.

This study hypothesized that a higher capacity for self-restraint measured on the Weinberger Adjustment Inventory (WAI) scale among 14-18-year-old JIYW would moderate the relationship between the exposure to violence and serious aggressive offending.

The pathways to desistance project, a multi-site, longitudinal study, included a sample of JIYW aged 14-18 years old (n = 184). The baseline data were analyzed using linear multiple regression.

After controlling for two variables, race and neighborhood conditions, the overall model was significant (F = 8.31 (df = 7,176), p = .001). The predictor variables (exposure to violence and self-restraint) explained 25% of the outcome variable (level of aggressive offending). The moderation result was significant such that higher self-restraint weakens the relationship between exposure to violence and aggressive offending (B = - 0.01, t (176) = -2.39, p = .018).

This study highlights the need to disrupt the trauma- to- prison pipeline by enhancing positive social skills in a trauma-responsive manner, which could mitigate the effect of exposure to violence among JIYW.

Asymmetry of EEG alpha power in the frontal lobe has been extensively studied over the past 30 years as a potential marker of emotion and motivational state. However, most studies rely on time consuming manipulations in which participants are placed in anxiety-provoking situations. Relatively fewer studies have examined alpha asymmetry in response to briefly presented emotionally evocative stimuli. If alpha asymmetry can be evoked in those situations, it would open up greater methodological possibilities for examining task-driven changes in neural activation. Seventy-seven children, aged 8-12 years old (36 of whom were high anxious), completed three different threat identification tasks (faces, images, and words) while EEG signal was recorded. Alpha power was segmented and compared across trials in which participants viewed threatening vs. neutral stimuli. Threatening images and faces, but not words, induced lower right vs. left alpha power (greater right asymmetry) that was not present when viewing neutral images or faces. Mixed results are reported for the effect of anxiety symptomatology on asymmetry. In a similar manner to studies of state- and trait-level withdrawal in adults, frontal neural asymmetry can be induced in school-aged children using presentation of brief emotional stimuli.

This review describes approaches to research on anxiety that attempt to link neural correlates to treatment response and novel therapies. The review emphasizes pediatric anxiety disorders since most anxiety disorders begin before adulthood.

Recent literature illustrates how current treatments for anxiety manifest diverse relations with a range of neural markers. While some studies demonstrate post-treatment normalization of markers in anxious individuals, others find persistence of group differences. For other markers, which show no pretreatment association with anxiety, the markers nevertheless distinguish treatment-responders from non-responders. Heightened error related negativity represents the risk marker discussed in the most depth; however, limitations in measures related to error responding necessitate multimodal and big-data approaches. Single risk markers show limits as correlates of treatment response. Large-scale, multimodal data analyzed with predictive models may illuminate additional risk markers related to anxiety disorder treatment outcomes. Such work may identify novel targets and eventually guide improvements in treatment response/outcomes.

Although the COVID-19 pandemic caused significant stress and anxiety among many, individuals' experiences varied. We examined if specific forms of anxiety predicted distinct trajectories of anxiety, perceived stress, and COVID-related worries during three early months of the pandemic. In a longitudinal study (N = 291), adolescents' (n = 194) social and generalized anxiety levels were assessed via parent- and self-reports and clinical diagnostic interviews. In young adulthood (n = 164), anxiety, stress, and COVID-related worries were assessed thrice during the pandemic. Pre-pandemic generalized anxiety predicted higher initial levels and maintenance of anxiety, stress, and COVID-related worries during the pandemic. In contrast, pre-pandemic social anxiety predicted lower initial levels of anxiety, stress, and COVID-related worries, but this initial effect on anxiety and stress was offset over time by social anxiety's positive effect on the slope. Our results highlight the importance of understanding how pre-pandemic factors influence individuals' experiences during the pandemic.

Childhood socioeconomic disadvantage is a form of adversity associated with alterations in critical frontolimbic circuits involved in the pathophysiology of psychiatric disorders. Most work has focused on individual-level socioeconomic position, yet individuals living in deprived communities typically encounter additional environmental stressors that have unique effects on the brain and health outcomes. Notably, chronic and unpredictable stressors experienced in the everyday lives of youth living in disadvantaged neighborhoods may impact neural responsivity to uncertain threat.

A community sample of children (N = 254) ages 8 to 15 years (mean = 12.15) completed a picture anticipation task during a functional magnetic resonance imaging scan, during which neutral and negatively valenced photos were presented in a temporally predictable or unpredictable manner. Area Deprivation Index (ADI) scores were derived from participants' home addresses as an index of relative neighborhood disadvantage. Voxelwise analyses examined interactions of ADI, valence, and predictability on neural response to picture presentation.

There was a significant ADI × valence interaction in the middle temporal gyrus, anterior cingulate cortex, hippocampus, and amygdala. Higher ADI was associated with less amygdala activation to negatively valenced images. ADI also interacted with predictability. Higher ADI was associated with greater activation of lingual and calcarine gyri for unpredictably presented stimuli. There was no three-way interaction of ADI, valence, and predictability.

Neighborhood disadvantage may impact how the brain perceives and responds to potential threats. Future longitudinal work is critical for delineating how such effects may persist across the life span and how health outcomes may be modifiable with community-based interventions and policies.

This study examined associations between anxiety symptomatology and cognitive and physiological threat responses during threat learning in a large sample of children and adolescents. Anxiety symptomatology severity along different dimensions (generalized anxiety, separation anxiety, social anxiety, and panic symptoms) was measured using parental and self-reports. Participants completed differential threat acquisition and extinction using an age-appropriate threat conditioning task. They then returned to the lab after 7-10 days to complete an extinction recall task that also assessed threat generalization. Results indicated that more severe overall anxiety was associated with greater cognitive and physiological threat responses during acquisition, extinction, and extinction recall. During acquisition and extinction, all anxiety dimensions manifested greater cognitive threat responses, while panic, separation anxiety, and social anxiety symptoms, but not generalized anxiety, were related to heightened physiological threat responses. In contrast, when we assessed generalization of cognitive threat responses, we found only generalized anxiety symptoms were associated with greater threat response generalization. The study provides preliminary evidence of specificity in threat responses during threat learning across youth with different anxiety symptoms.

Social anxiety is amongst the most prevalent adolescent mental health problems; however, it is often unrecognized due to its comorbidity with other anxiety problems such as generalized anxiety. Thus, understanding the unique developmental pathways to social anxiety is critical for improving its prevention. We examined the pathway from maternal shyness, when children were 4 years old, to adolescents' social anxiety at age 15 through social wariness at age 7. We hypothesized that childhood social wariness would mediate the association between maternal shyness and social anxiety in adolescence.

Participants (N = 291; 54% female) were followed from early childhood to adolescence. Mothers reported on their own shyness when children were 4 years old. Social wariness toward unfamiliar peers was observed in the laboratory at ages 4 and 7. Adolescent social anxiety and generalized anxiety were assessed via self-report, parent-report, and clinical diagnoses at age 15.

Maternal shyness was positively associated with adolescent social anxiety but not generalized anxiety at age 15. Higher levels of maternal shyness at age 4 predicted greater social wariness at age 7, which in turn predicted greater social anxiety but not generalized anxiety at age 15. Social wariness at age 7 partially mediated the association between maternal shyness and adolescent social anxiety.

This study identifies a unique developmental pathway from maternal shyness to adolescent social anxiety. Findings suggest that childhood social wariness connects maternal shyness to adolescent social anxiety.

In the last decade, an abundance of research has utilized the NIMH Research Domain Criteria (RDoC) framework to examine mechanisms underlying anxiety and depression in youth. However, relatively little work has examined how these mechanistic intrapersonal processes intersect with context during childhood and adolescence. The current paper covers reviews and meta-analyses that have linked RDoC-relevant constructs to ecological systems in internalizing problems in youth. Specifically, cognitive, biological, and affective factors within the RDoC framework were examined. Based on these reviews and some of the original empirical research they cover, we highlight the integral role of ecological factors to the RDoC framework in predicting onset and maintenance of internalizing problems in youth. Specific recommendations are provided for researchers using the RDoC framework to inform future research integrating ecological systems and development. We advocate for future research and research funding to focus on better integration of the environment and development into the RDoC framework.

An increased neural response to making errors has emerged as a biomarker of anxiety. Error negativity (Ne) or errorrelated negativity (ERN) is an event-related potential generated when people commit errors; the Ne/ERN is greater among people with anxiety and predicts increases in anxiety. However, no previous study has examined whether the Ne/ERN can be used as a prognostic indicator among people with current anxiety. The present study addressed this gap by examining whether the Ne/ERN prospectively predicts increases in anxiety symptoms in clinically anxious children and adolescents.

The sample included 34 female participants between the ages of 8 and 14 years who met the criteria for a clinical anxiety disorder based on clinical interview. The Ne/ERN was measured using a flanker task.

Increased Ne/ERN at baseline predicted increases in total anxiety symptoms 2 years later, even when accounting for baseline symptoms. The Ne/ERN predicted increases in the symptom domains of generalized anxiety, social anxiety and harm avoidance/perfectionism, but not panic, separation anxiety, school avoidance or physical symptoms.

The sample size was small, which may have inflated the false discovery rate. To mitigate this possibility, we used multiple self-report measures, and the results for the 2 measures (as well as their symptom domains) converged.

These data suggest that the Ne/ERN can delineate specific risk trajectories, even among those who already meet the criteria for a clinical anxiety disorder. Considering the need for prognostic markers among people with clinical anxiety, the current findings are an important and novel extension of previous work.

It has been proposed that individuals with generalized anxiety disorder (GAD) show dysfunctional computations related to approach-avoidance decision-making. However, few studies have examined the neural basis of this impairment, particularly in adolescents with GAD. The goal of the current study was to address this gap in the literature.

The study involved 51 adolescents with GAD and 51 typically developing (TD) comparison individuals matched on age (16.10 and 15.75 respective means), gender (30 F/21 M and 24 F/27 M), and IQ (103.20 and 103.18 respective means). Participants underwent functional magnetic resonance imaging during a passive avoidance task.

We found a significant Group-by-Reinforcement interaction within reward-related brain regions including the caudate, putamen, mid cingulate/paracentral lobule, and superior and middle frontal gyrus. TD adolescents showed a greater differential response to reward versus punishment feedback within these regions relative to adolescents with GAD. In particular, this reflected reduced responses to rewards in the adolescents with GAD. There were no group differences in neural responses when making approach/avoidance responses.

The results of this study suggest reduced differential responsiveness to reinforcement as a component of the pathophysiology seen in adolescents with GAD. This dysfunction likely underpins decision-making impairments that may exacerbate the participants' worry.

Excessive response to unexpected or "deviant" stimuli during infancy and early childhood represents an early risk marker for anxiety disorders. However, research has yet to delineate the specific brain regions underlying the neonatal response to deviant stimuli near birth and the relation to risk for anxiety disorders. The authors used task-based functional MRI (fMRI) to delineate the neonatal response to deviant stimuli and its relationship to maternal trait anxiety.

The authors used fMRI to measure brain activity evoked by deviant auditory stimuli in 45 sleeping neonates (mean age, 27.8 days; 60% female; 64% African American). In 41 of the infants, neural response to deviant stimuli was examined in relation to maternal trait anxiety on the State-Trait Anxiety Inventory, a familial risk factor for offspring anxiety.

Neonates manifested a robust and widespread neural response to deviant stimuli that resembles patterns found previously in adults. Higher maternal trait anxiety was related to higher responses within multiple brain regions, including the left and right anterior insula, the ventrolateral prefrontal cortex, and multiple areas within the anterior cingulate cortex. These areas overlap with brain regions previously linked to anxiety disorders and other psychiatric illnesses in adults.

The neural architecture sensitive to deviant stimuli robustly functions in newborns. Excessive responsiveness of some circuitry components at birth may signal risk for anxiety and other psychiatric disorders.

Identification of behavioral mechanisms underlying psychopathology is essential for the development of novel targeted therapeutics. However, this work relies on rigorous, time-intensive, clinic-based laboratory research, making it difficult to translate research paradigms into tools that can be used by clinicians in the community. The broad adoption of smartphone technology provides a promising opportunity to bridge the gap between the mechanisms identified in the laboratory and the clinical interventions targeting them in the community. The goal of the current study is to develop a developmentally appropriate, engaging, novel mobile application called CALM-IT that probes a narrow biologically informed process, inhibitory control. We aim to leverage the rigorous and robust methods traditionally used in laboratory settings to validate this novel mechanism-driven but easily disseminatable tool that can be used by clinicians to probe inhibitory control in the community. The development of CALM-IT has significant implications for the ability to screen for inhibitory control deficits in the community by both clinicians and researchers. By facilitating assessment of inhibitory control outside of the laboratory setting, researchers could have access to larger and more diverse samples. Additionally, in the clinical setting, CALM-IT represents a novel clinical screening measure that could be used to determine personalized courses of treatment based on the presence of inhibitory control deficits.

Anxiety disorders are the most common form of mental illness and are more likely to emerge during childhood compared with most other psychiatric disorders. While research on children is the gold standard for understanding the behavioral expression of anxiety and its neural circuitry, the ethical and technical limitations in exploring neural underpinnings limit our understanding of the child's developing brain. Instead, we must rely on animal models to build strong methodological bridges for bidirectional translation to child development research. Using the caregiver-infant context, we review the rodent literature on early-life fear development to characterize developmental transitions in amygdala function underlying age-specific behavioral transitions. We then describe how this system can be perturbed by early-life adversity, including reduced efficacy of the caregiver as a safe haven. We suggest that greater integration of clinically informed animal research enhances bidirectional translation to permit new approaches to therapeutics for children with early onset anxiety disorders.

Avoidant behavior is a defining feature of pediatric anxiety disorders. Although prior research has examined it from the perspective of early information processing events, there has been relatively less consideration of the processes by which anxious youth make avoidant decisions and how these choices are reinforced over time. Studies of risk taking are valuable in this regard because they consider how individuals identify the pros and cons of their choices, how they weigh potential gains and losses and estimate their respective probabilities, and how they tolerate the uncertainty intrinsic to any decision. In this review, we place risk taking within existing models of information processing in pediatric anxiety disorders and highlight the particular value of this construct for informing models of developmental psychopathology and individual differences in outcome over time. We review existing behavioral and neurobiological studies of risk taking in anxious youth and conclude by identifying directions for future research.

Children who live on the margins of society are disadvantaged in achieving their developmental potential because of the lack of a necessary stable environment and nurturing care. Many early prevention programs aim at mitigating such effects, but often the evaluation of their long-term effect is missing. The aim of the study presented here was to evaluate such long-term effects in two prevention programs for children-at-risk growing up in deprived social environments focusing on child attachment representation as the primary outcome as well as on self-reflective capacities of teachers taking care of these children. The latter was a key component for promoting resilient behavior in children. Five hundred and twenty-six children aged 36 to 60 months at risk due to immigration status, low family socio-economic status and child behavior were examined in a cluster-randomized study comparing two preventions, the psychodynamic, attachment-based holistic approach EARLY STEPS (ES) with the classroom based FAUSTLOS (FA) for their efficacy. Primary outcome was the child attachment representation measured by the Manchester Child Attachment Story Task (MCAST). Secondary outcomes were derived from (a) the Caregiver-Teacher Report Form (C-TRF: problem behaviors, including anxiety/depressive symptoms, emotional-reactive and somatic problems, social withdrawal, aggressive behavior, and attention deficit), from (b) the Strength and Difficulties Questionnaire (SDQ, parent version: resilience and wellbeing) and (c) Self-Reflective Scales for teachers (SRS: self-reflective capacities of teachers). Compared to baseline, attachment and behavioral problems improved in both programs. ES led to more secure and more organized attachment representations (medium effect sizes). Aggressive behavior and externalizing problems were reduced in the FA group compared with ES, particularly in boys (medium effect sizes). Self-reflective capacities of the teachers increased only in the ES group. High correlation between children's attachment type with the number of social risk factors and the increase of problematic social behavior strongly indicate that an increase in teachers' self-reflective capacities helps to change children's attachment patterns which thus strengthens the resilience of these children-at-risk [An ethical vote from LPPKJP 2009-02-25 was obtained and the trial registered; Clinical trial registration information: The trial was registered 14.02.2012 (DRKS00003500; https://www.drks.de)].

Basic research of fear and anxiety in rodents has historically utilized a limited set of behavioral paradigms, for example, Pavlovian (classical) fear conditioning, the elevated plus-maze, or inhibitory (passive) avoidance. These traditional paradigms measure a limited selection of variables over a short duration, providing only a "snapshot" of fear and anxiety-related behavior. Overreliance on these paradigms and such behavioral snapshots ultimately lead to a narrow understanding of these complex motivational states. Here, we elaborate on the closed economy; a seldom-used paradigm that has been modified to comprehensively study fear and anxiety-related behavior and neurocircuitry in rodents. In this modified "Risky Closed Economy (RCE)" paradigm, animals live nearly uninterrupted in behavioral chambers where the need to acquire food and water and avoid threat is integrated into the task. Briefly, animals are free to acquire all of their food and water in a designated foraging zone. An unsignaled, unpredictable threat (footshock) is introduced into the foraging zone after a baseline activity and consumption period to model the risk of predation, which is then removed for a final extinction assessment. This longitudinal design, wherein data from a multitude of variables are collected automatically and continuously for 23 h/day over several weeks to months, affords a more holistic understanding of the effects of fear and anxiety on day-to-day behavior. Also, we discuss its general benefits relevant to other topics in neuroscience research, its limitations, and present data demonstrating for the first time The Risky Closed Economy's viability in mice.

The amygdala, a subcortical structure known for social and emotional processing, consists of multiple subnuclei with unique functions and connectivity patterns. Tracer studies in adult macaques have shown that the basolateral subnuclei differentially connect to parts of visual cortex, with stronger connections to anterior regions and weaker connections to posterior regions; infant macaques show robust connectivity even with posterior visual regions. Do these developmental differences also exist in the human amygdala, and are there specific functional regions that undergo the most pronounced developmental changes in their connections with the amygdala? To address these questions, we explored the functional connectivity (from resting-state fMRI data) of the basolateral amygdala to occipitotemporal cortex in human neonates scanned within one week of life and compared the connectivity patterns to those observed in young adults. Specifically, we calculated amygdala connectivity to anterior-posterior gradients of the anatomically-defined occipitotemporal cortex, and also to putative occipitotemporal functional parcels, including primary and high-level visual and auditory cortices (V1, A1, face, scene, object, body, high-level auditory regions). Results showed a decreasing gradient of functional connectivity to the occipitotemporal cortex in adults-similar to the gradient seen in macaque tracer studies-but no such gradient was observed in neonates. Further, adults had stronger connections to high-level functional regions associated with face, body, and object processing, and weaker connections to primary sensory regions (i.e., A1, V1), whereas neonates showed the same amount of connectivity to primary and high-level sensory regions. Overall, these results show that functional connectivity between the amygdala and occipitotemporal cortex is not yet differentiated in neonates, suggesting a role of maturation and experience in shaping these connections later in life.

Anxiety disorders often begin early in life and there is substantial interest in identifying neural markers that characterize developmental trajectories that result in anxiety. The error-related negativity (ERN) is elicited when people make errors on lab-based reaction-time tasks, is increased in anxious children, and can predict the onset of anxiety across development. In light of this, there is an increasing interest in identifying environmental factors that may shape the ERN in children. Previous work suggests that controlling parenting styles may relate to the ERN in offspring. However, no study had yet examined the specific mechanism whereby parenting style may impact the ERN in children. We propose that it may be children's repeated exposure to making mistakes in the context of their parents' reactions (i.e., verbal or non-verbal reactions, displays of parental control, etc.) that may lead to an increased ERN. We test this novel hypothesis by measuring the ERN in 94 children between the ages of 5-7 years old, while their parent observes them and then while an experimenter observes them complete a Go-No/Go task. Results suggest that the presence of parents characterized by high control potentiates the ERN in their children. Moreover, the relationship between controlling parenting styles and child anxiety disorder status was mediated by the parent presence potentiation of the ERN. These findings are important and novel insofar as they highlight the impact of an environmental factor (i.e., parenting) in shaping a neural marker of risk for anxiety in children (i.e., the ERN).

Anxiety is the most common form of psychopathology, and it is often characterized by chronic impairment across the lifespan. Researchers have identified core neural markers that confer risk for anxious outcomes. An increased error-related negativity (ERN) in anxious individuals has been shown to prospectively predict onset of anxiety disorders across development. Hence, it is critical to examine environmental factors that may shape the ERN. In the current study, we use a large sample of 170 female adolescents aged 10-17 to investigate whether the ERN mediates the relationship between parenting style and anxiety diagnostic status. This study replicates previous findings, and it extends previous work by suggesting that this relationship is more robust in young children as compared to adolescents. Interventions targeting the ERN via parenting may be most effective during childhood.

Early exposure to stressful life events is associated with greater risk of chronic diseases and mental health problems, including anxiety. However, there is significant variation in how individuals respond to environmental adversity, perhaps due to individual differences in processing and regulating emotional information. Differences in cognitive control - processes necessary for implementing goal directed behavior - have been linked to both stress exposure and anxiety, but the directionality of these links is unclear. The present study investigated the longitudinal pathway of environmental stress exposure during early adolescence on later adolescent anxiety, and the possible mediating mechanism of cognitive control. Participants were 674 Mexican-origin adolescents (meanage = 10.8 years, 50% male) enrolled in the California Families Project, an ongoing longitudinal study of Mexican-origin families. In the current analysis, we examined self-reports of environmental stressors at age 14 (Time 1), cognitive control at age 16 (Time 2), and anxiety at age 18 (Time 3). Structural equation modeling revealed that environmental stressors (Time 1) had both direct and indirect effects on later anxiety (Time 3) through their effects on cognitive control (Time 2), even when accounting for prior levels of anxiety (Time 2). Cognitive control accounted for 18% of the association between environmental stressors and adolescent anxiety: an increase in stressors decreased cognitive control (β = -0.20, p < 0.001), however, cognitive control buffers against anxiety (β = -0.10, p = 0.004). These findings deepen our understanding of the mechanisms underlying the development of anxiety and highlight the importance of cognitive control as a potential protective factor.

Anxiety disorders tend to onset early in development and often result in chronic impairment across the lifespan. Thus, there is substantial interest in identifying early neural markers of anxiety and leveraging these markers to better understand processes leading to anxiety. The late positive potential (i.e., LPP) indexes sustained attention to motivationally relevant stimuli; and the LPP to negative images is increased in individuals with anxiety. In the current study, we examined how parental presence impacts the LPP to threatening images in children (52.6% male) between 5 and 7 years-old (N = 78). Moreover, we explored interactions with parental sensitivity to child anxiety symptoms. Results suggest that when children are in the presence of their parent (compared to the presence of an experimenter), they displayed a larger LPP to threatening images. LPP activity was modulated by parental response to their child's anxiety symptoms, such that children with parents who were overly reactive to their children's anxiety symptoms had the greatest LPP response when viewing threatening stimuli in their parent's presence. Additionally, exploratory analyses indicated that children with clinical and subclinical anxiety were characterized by an increased LPP to negative images, but only when the LPP was measured with parents in the room. Findings are novel and extend previous work by suggesting that parents who react strongly when observing their children's anxiety symptoms in turn increase their child's engagement with threatening stimuli, thereby placing them at greater risk for anxiety.

Anxiety disorders are often preceded by interpersonal stress; however, most individuals who experience stress do not develop anxiety, making it difficult to predict who is most susceptible to stress. One proposed trans-diagnostic neural risk marker for anxiety is the error-related negativity (ERN), a negative deflection in the event-related potential waveform occurring within 100 ms of error commission. The present study sought to investigate whether interpersonal stress experienced over the course of a year interacts with ERN magnitude to prospectively predict anxiety symptoms. A sample of 57 emerging adults performed an arrow flanker task to elicit the ERN at the start of the academic school year (time one). Toward the end of the academic year (time two), participants reported on past-year interpersonal stress and anxiety symptoms. Stress interacted with ERN magnitude to predict anxiety symptoms, whereby, for individuals with an enhanced ERN at time one, greater interpersonal stress over the course of a year was significantly associated with increased anxiety symptoms at time two, even controlling for anxiety symptoms at time one. These findings suggest that enhanced performance monitoring may render individuals more susceptible to the adverse effects of interpersonal stress, thereby increasing risk for heightened anxiety.

Traditional attempts to characterize the brain pathophysiology associated with mental illnesses have relied on relating symptoms to a static snapshot of abnormal brain structure or function. Over the last few decades, however, it has become increasingly clear that many or most psychiatric disorders are the consequence of atypical brain development.¹ As such, the pathophysiology of mental illnesses may be better understood by characterizing the dynamic changes in brain structure or function that unfold over time and ultimately result in psychiatric symptoms. One important concept that has emerged out of studies that have examined longitudinal trajectories resulting in mental illnesses is the concept of equifinality-that multiple different trajectories can result in the same symptoms in adolescence or adulthood.² If proved to be true, equifinality is a fundamentally important principle because it suggests that even if two patients have the same symptoms, the cascade of brain changes that ultimately resulted in these symptoms differed. Potentially diverse monitoring and treatment strategies would be required to detect and treat patients with the same set of symptoms. There would be no "one-size fits all" approach to screening and treating patients, and clinicians would ultimately have to learn to identify and alter multiple different risk trajectories.

Socioeconomic disadvantage is associated with higher rates of psychopathology as well as hippocampus, amygdala and prefrontal cortex structure. However, little is known about how variations in brain morphometry are associated with socio-emotional risks for mood disorders in children growing up in families experiencing low income. In the current study, using structural magnetic resonance imaging, we examined the relationship between socioeconomic disadvantage and gray matter volume in the hippocampus, amygdala, and ventrolateral prefrontal cortex in a sample of children (n = 34) in middle childhood. Using an affective dot probe paradigm, we examined the association between gray matter volume in these regions and attentional bias to threat, a risk marker for mood disorders including anxiety disorders. We found that lower income-to-needs ratio was associated with lower bilateral hippocampal and right amygdala volume, but not prefrontal cortex volumes. Moreover, lower attentional bias to threat was associated with greater left hippocampal volume. We provide evidence of a relationship between income-related variations in brain structure and attentional bias to threat, a risk for mood disorders. Therefore, these findings support an environment-morphometry-behavior relationship that contributes to the understanding of income-related mental health disparities in childhood.

Structural variations of neural regions implicated in fear responses have been well documented in the pathophysiology of anxiety and may play an important role in treatment response. We examined whether gray matter volume of three neural regions supporting fear and avoidance responses [bilateral amygdala, nucleus accumbens (NAcc), and ventromedial prefrontal cortex (PFC)] predicted cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitor (SSRI) treatment outcome in two independent samples of patients with anxiety disorders. Study 1 consisted of 81 adults with anxiety disorders and Study 2 included 55 children and adolescents with anxiety disorders. In both studies, patients completed baseline structural MRI scans and received either CBT or SSRI treatment. Clinician-rated interviews of anxiety symptoms were assessed at baseline and posttreatment. Among the adult sample, greater pre-treatment bilateral NAcc volume was associated with a greater reduction in clinician-rated anxiety symptoms pre-to-post CBT and SSRI treatment. Greater left NAcc volume also predicted greater decreases in clinician-rated anxiety symptoms pre-to-post CBT and SSRI treatment among youth with current anxiety. Across studies, results were similar across treatments, and findings were maintained when adjusting for patient's age, sex, and total intracranial brain volume. We found no evidence for baseline amygdala or ventromedial PFC volume serving as treatment predictors across the two samples. Together, these findings provide promising support for the role of NAcc volume as an objective marker of anxiety treatment improvement that spans across development. Future studies should clarify the specific mechanisms through which NAcc volume exerts its therapeutic effects.

Adolescence marks a key developmental window during which emotion dysregulation increases, along with risk for the onset of anxiety and other affect-related pathologies. Although emotion dysregulation and related pathologies normatively decline during the transition into adulthood, this does not occur for a sizable minority of individuals. Finally, sex differences in anxiety emerge during adolescence, with females developing a 2-fold increase in risk relative to males. Unfortunately, a neurobiological model of the mechanisms that cause these changes during adolescence has yet to be proposed. In the present work, we first provide brief reviews of relevant literature. Next, we outline a dual-mechanism model focused on (i) the influence of pubertal testosterone on key emotion-regulation circuitry (i.e., orbitofrontal cortex-amygdala coupling) and (ii) myelination of the fiber bundles connecting such circuitry (i.e., uncinate fasciculus). The proposed model offers a set of specific, testable hypotheses that will hopefully spur much needed cross-disciplinary research.

The error-related negativity (ERN) is a neurophysiologic response to errors that associates with anxiety. Despite the potential relevance of the ERN for understanding mechanisms of early anxiety problems in the developing brain, the relation between ERN and anxious symptoms in young children remains poorly understood. Emerging evidence suggests that ERN-anxiety associations could vary by developmental stage, but this work requires replication and consideration of gender effects, given earlier maturation of the ERN and higher rates of anxiety problems in girls relative to boys. To address this gap, the ERN was collected in 49 preschool- to school-aged children (ages 4-9; 26 girls) sampled across a wide range of anxiety severity. Regression analyses revealed that ERN - anxiety associations depended on age and gender. Specifically, larger (more negative) ERN associated with more anxiety in older girls, whereas smaller ERN associated with more anxiety symptoms in younger girls. No ERN-anxiety association was found in boys. These findings suggest that age and gender moderate the direction of the relation between ERN and anxiety in early childhood and could have important implications for the development of ERN-based risk identification and targeted treatment strategies tailored to individual children.

Irritability and anxiety are two common clinical phenotypes that involve high-arousal negative affect states (anger and fear), and that frequently co-occur. Elucidating how these two forms of emotion dysregulation relate to perturbed neurodevelopment may benefit from alternate phenotyping strategies. One such strategy applies a bifactor latent variable approach that can parse shared versus unique mechanisms of these two phenotypes. Here, we aim to replicate and extend this approach and examine associations with neural structure in a large transdiagnostic sample of youth (N = 331; M = 13.57, SD = 2.69 years old; 45.92% male). FreeSurfer was used to extract cortical thickness, cortical surface area, and subcortical volume. The current findings replicated the bifactor model and demonstrate measurement invariance as a function of youth age and sex. There were no associations of youth's factor scores with cortical thickness, surface area, or subcortical volume. However, we found strong convergent and divergent validity between parent-reported irritability and anxiety factors with clinician-rated symptoms and impairment. A general negative affectivity factor was robustly associated with overall functional impairment across symptom domains. Together, these results support the utility of the bifactor model as an alternative phenotyping strategy for irritability and anxiety, which may aid in the development of targeted treatments.

Poor attentional control, defined as difficulty focusing attention on a task or shifting attention flexibly between tasks, is a transdiagnostic construct theorized to confer risk for, and maintain, depression and anxiety. Research to date in non-clinical samples has suggested a dissociable relationship between the two factors of self-reported attentional control and psychopathology, with depression being associated with difficulties shifting and anxiety being associated with focusing. However, to our knowledge no study has tested this differential set of relationships in a clinical sample.

Adults (N = 493) presenting for psychiatric treatment completed measures of depressive and anxiety symptom severity and self-reported attentional control. Hierarchical linear regression and Zou's (2007) confidence interval method were used to examine the relationship between clinical symptoms and attentional control.

Both shifting and focusing were significantly correlated with anxiety and depressive symptoms in this sample. However, focusing was more strongly associated with clinical symptomatology than shifting, which showed a weak correlation.

All constructs were measured cross-sectionally by self-report questionnaires.

In contrast to studies conducted in non-clinical samples, attentional focusing appears to be more relevant than attentional shifting in a clinical sample for both depression and anxiety symptoms. These findings lend support to efforts to develop neurocognitive interventions that improve focusing. Replication of these findings, particularly in longitudinal studies, is warranted.

Cross-sectional evidence suggests that attention bias to threat is linked to anxiety disorders and anxiety vulnerability in both children and adults. However, there is a lack of developmental evidence regarding the causal mechanisms through which attention bias to threat might convey risks for socioemotional problems, such as anxiety. Gaining insights into this question demands longitudinal research to track the complex interplay between threat-related attention and socioemotional functioning. Developing and implementing reliable and valid assessments tools is essential to this line of work. This review presents theoretical accounts and empirical evidence from behavioral, eye-tracking, and neural assessments of attention to discuss our current understanding of the development of normative threat-related attention in infancy, as well as maladaptive threat-related attention patterns that may be associated with the development of anxiety. This review highlights the importance of measuring threat-related attention using multiple attention paradigms at multiple levels of analysis. In order to understand if and how threat-related attention bias in real-life, social interactive contexts can predict socioemotional development outcomes, this review proposes that future research cannot solely rely on screen-based paradigms but needs to extend the assessment of threat-related attention to naturalistic settings. Mobile eye-tracking technology provides an effective tool for capturing threat-related attention processes in vivo as children navigate fear-eliciting environments and may help us uncover more proximal bio-psycho-behavioral markers of anxiety.

A cognitive neuroscience perspective seeks to understand behavior, in this case disruptive behavior disorders (DBD), in terms of dysfunction in cognitive processes underpinned by neural processes. While this type of approach has clear implications for clinical mental health practice, it also has implications for school-based assessment and intervention with children and adolescents who have disruptive behavior and aggression. This review articulates a cognitive neuroscience account of DBD by discussing the neurocognitive dysfunction related to emotional empathy, threat sensitivity, reinforcement-based decision-making, and response inhibition. The potential implications for current and future classroom-based assessments and interventions for students with these deficits are discussed.

Behavioral inhibition (BI) is an early temperamental profile characterized by negative reactivity to novelty, withdrawal from social situations, and increased risk for social anxiety. Previous research associated BI assessed in early childhood to striatal hypersensitivity in mid-to-late adolescence. The present study examined this association among 10 year-olds, characterized with BI at ages 24 and 36 months on measures of temperamental reactivity. Participants (n = 40) were studied at age 10 using a reward processing task during functional magnetic resonance imaging (fMRI). Child- and maternal-report of social anxiety symptoms was collected at ages 10 and 13. Findings indicate greater caudate activation and stronger striatal connectivity in high, compared to low, behaviorally inhibited children. Caudate activation related to social anxiety symptoms at both ages. These findings suggest that enhanced striatal responsivity reliably manifests among high behaviorally inhibited children as early as age 10. This may reflect hyper-sensitivity to reward or excessive motivation to avoid errors.