Difficulties with emotion regulation are integral to borderline personality disorder (BPD) and its hypothesized developmental pathway. Here, we prospectively assess trajectories of emotion processing across childhood, how BPD symptoms impact these trajectories, and whether developmental changes are transdiagnostic or specific to BPD, as major depressive (MDD) and conduct disorders (CD) are also characterized by emotion regulation difficulties. This study included 187 children enriched for those with early symptoms of depression and disruptive behaviors from a longitudinal study. We created multilevel models of multiple components of emotional processing from mean ages 9.05 to 18.55 years, and assessed the effect of late adolescent BPD, MDD, and CD symptoms on these trajectories. Linear trajectories of coping with sadness and anger, and quadratic trajectories of dysregulated expressions of sadness and anger were transdiagnostic, but also exhibited independent relationships with BPD symptoms. Only inhibition of sadness was related to BPD symptoms. The quadratic trajectories of poor emotional awareness and emotional reluctance were also independently related to BPD. Findings support examining separable components of emotion processing across development as potential precursors to BPD, underscoring the importance of understanding these trajectories as not only a marker of potential risk but also potential targets for prevention and intervention.

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

Temper tantrums are sudden, overt negative emotional displays that are disproportionate to the eliciting event. Research supports that severe temper tantrums during the preschool period are associated with preschool psychopathology, but few studies have identified which characteristics of preschool tantrums are predictive of distal psychopathological outcomes in later childhood and adolescence. To examine this question, we used a prospective, longitudinal dataset enriched for early psychopathology. Participants (N = 299) included 3-to 6-year-old children (47.8% female) assessed for tantrums and early childhood psychopathology using diagnostic interviews and then continually assessed using diagnostic interviews over 10 subsequent time points throughout childhood and adolescence. We identified two unique groupings of tantrum behaviors: aggression towards others/objects (e.g., hitting others) and aggression towards self (e.g., hitting self). While both types of tantrum behaviors were associated with early childhood psychopathology severity, tantrum behaviors characterized by aggression towards self were more predictive of later psychopathology. Children displaying high levels of both types of tantrum behaviors had more severe externalizing problems during early childhood and more severe depression and oppositional defiant disorder across childhood and adolescence. Findings suggest that tantrum behaviors characterized by aggression towards self are particularly predictive of later psychopathology.

The National Institute of Mental Health's Research Domain Criteria (RDoC) framework has prompted a paradigm shift from categorical psychiatric disorders to considering multiple levels of vulnerability for probabilistic risk of disorder. However, the lack of neurodevelopmentally based tools for clinical decision making has limited the real-world impact of the RDoC. Integration with developmental psychopathology principles and statistical methods actualize the clinical implementation of RDoC to inform neurodevelopmental risk. In this conceptual paper, we introduce the probabilistic mental health risk calculator as an innovation for such translation and lay out a research agenda for generating an RDoC- and developmentally informed paradigm that could be applied to predict a range of developmental psychopathologies from early childhood to young adulthood. We discuss methods that weigh the incremental utility for prediction based on intensity and burden of assessment, the addition of developmental change patterns, considerations for assessing outcomes, and integrative data approaches. Throughout, we illustrate the risk calculator approach with different neurodevelopmental pathways and phenotypes. Finally, we discuss real-world implementation of these methods for improving early identification and prevention of developmental psychopathology. We propose that mental health risk calculators can build a needed bridge between the RDoC multiple units of analysis and developmental science.

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

Callous–unemotional (CU) behaviors (i.e., low concern and active disregard for others) uniquely predict severe conduct problems and substance use when present by late childhood. Less is known about the predictive utility of CU behaviors displayed in early childhood, when morality is developing and interventions may be more effective. Children aged 4–7 years (N = 246; 47.6% girls) completed an observational task wherein they were encouraged to tear an experimenter's valued photograph, and blind raters coded children's displayed CU behaviors. During the next 14 years, children's conduct problems (i.e., oppositional defiant and conduct symptoms) and age of onset of substance use were assessed. Compared to children displaying fewer CU behaviors, children displaying greater CU behaviors were 7.61 times more likely to meet criteria for a conduct disorder (n = 52) into early adulthood (95% CI, 2.96–19.59; p = <.0001), and their conduct problems were significantly more severe. Greater CU behaviors were associated with earlier onset of substance use (B = −.69, SE = .32, t = −2.14, p = .036). An ecologically valid observed indicator of early CU behavior was associated with substantially heightened risk for conduct problems and earlier onset substance use into adulthood. Early CU behavior is a powerful risk marker identifiable using a simple behavioral task which could be used to target children for early intervention.

Prior research has shown that sipping of alcohol begins to emerge during childhood and is potentially etiologically significant for later substance use problems. Using a large, community sample of 9- and 10-year-olds (N = 11,872; 53% female), we examined individual differences in precocious alcohol use in the form of alcohol sipping. We focused explicitly on features that are robust and well-demonstrated correlates of, and antecedents to, alcohol excess and related problems later in the lifespan, including youth- and parent-reported externalizing traits (i.e., impulsivity, behavioral inhibition and activation) and psychopathology. Seventeen percent of the sample reported sipping alcohol outside of a religiously sanctioned activity by age 9 or 10. Several aspects of psychopathology and personality emerged as small but reliable correlates of sipping. Nonreligious sipping was related to youth-reported impulsigenic traits, aspects of behavioral activation, prodromal psychotic-like symptoms, and mood disorder diagnoses, as well as parent-reported externalizing disorder diagnoses. Religious sipping was unexpectedly associated with certain aspects of impulsivity. Together, our findings point to the potential importance of impulsivity and other transdiagnostic indicators of psychopathology (e.g., emotion dysregulation, novelty seeking) in the earliest forms of drinking behavior.

Emotion dysregulation is a risk factor for the development of a variety of psychopathologic outcomes. In children, irritability, or dysregulated negative affect, has been the primary focus, as it predicts later negative outcomes even in very young children. However, dysregulation of positive emotion is increasingly recognized as a contributor to psychopathology. Here we used an exploratory factor analysis and defined four factors of emotion dysregulation: irritability, excitability, sadness, and anhedonia, in the preschool-age psychiatric assessment collected in a sample of 302 children ages 3–5 years enriched for early onset depression. The irritability and excitability factor scores defined in preschoolers predicted later diagnosis of mood and externalizing disorders when controlling for other factor scores, social adversity, maternal history of mood disorders, and externalizing diagnoses at baseline. The preschool excitability factor score predicted emotion lability in late childhood and early adolescence when controlling for other factor scores, social adversity, and maternal history. Both excitability and irritability factor scores in preschoolers predicted global functioning into the teen years and early adolescence, respectively. These findings underscore the importance of positive, as well as negative, affect dysregulation as early as the preschool years in predicting later psychopathology, which deserves both further study and clinical consideration.

OBJECTIVES/SPECIFIC AIMS: The objective of the study is to examine the ability of iTBS to improve depression and executive impairment in depressed older adults. If effective, this treatment will have the potential to improve the quality of life in LLD. METHODS/STUDY POPULATION: From 12- 2016 to date older adults (60 – 85 y/o) in a major depressive episode, with evidence of executive dysfunction (on the NIH Tool Box battery) were enrolled. iTBS protocol: This brief paradigm (3 min 9 seconds duration) was administered on weekdays for four weeks (20 sessions total). Stimulation intensity was set up to 120% of the observed motor threshold. Depression primary outcome: Change in the Montgomery Asberg Depression Rating Scale (MADRS) from baseline to the end of iTBS course. Executive function primary outcome: Change in executive measures from the electronic NIH Tool Box cognitive domain battery8. Executive secondary outcome: Change in scores from baseline to the end of iTBS on the Frontal Systems Behavior Scale (FrSBe), this self reported instrument measures dys-executive behavior. Statistical Analysis: paired t-test examined changes in depression and executive variables from baseline to post iTBS. Pearson correlation examined the association between degree of mood improvement and degree of improvement in executive function. SPSS v 24 was used for all analyses. RESULTS/ANTICIPATED RESULTS: We examined 11 subjects. Primary outcomes: Patients showed a significant decrease in scores on the Montgomery Asberg Depression Rating Scale (MADRS) from baseline Mean (M) = 27.73, Standard Deviation (SD) 8.2 to the end of 4 weeks of iTBS: M = 15.91, SD = 10.05, t = 7.4, p < .001. The Flanker Inhibitory Control and attention test significantly improved from baseline M = 91.0, SD = 7 to the end of iTBS M = 98.7, SD = 12.8, t = −2.9, p = .014 (higher scores at week 4 denote improvement). The List Sorting Working Memory test and the Dimensional Change Card sort a measure of cognitive flexibility improved but did not reach statistical significance. The self reported executive measure improved from baseline M = 48.6, SD = 9.4 to post iTBS M = 39.4, SD = 8.5, t = 3.8, p = .003 (lower scores at week 4 denote improvement). We also examined whether the degree of improvement in depression related to the degree of improvement in executive function. We found positive correlations between change in mood scores with iTBS with change in executive scores with iTBS, with a strong relationship with working memory r = 0.34. Tolerability and Side effects: Common side effects were twitching in facial muscles during the stimulation (n =11), headaches (n =10) and pain or discomfort at the stimulation site and face (n =4). One participant withdrew due to intolerance to the stimulation. DISCUSSION/SIGNIFICANCE OF IMPACT: The iTBS paradigm was effective in improving mood and executive function in older adults. Both the psychometric measure and the self reported executive function measure (indicative of dysexecutive behavior) reflected improvements post iTBS. Improvement in executive function was correlated with depression improvement. We targeted the Dorso Lateral Prefrontal cortex, which exhibits decreased connectivity with the dorsal anterior cingulate in depressed elderly and is a key in orchestration of executive function. Our findings are consistent with the conceptualization of depression as a circuit level disorder affecting interconnected networks involving mood and cognition. Although we demonstrated potential therapeutic effects, the mechanism of action of iTBS remains unknown. We are presently conducting a randomized controlled trial to examine the effects of iTBS on brain connectivity using functional MRI. Results of this study underway will hopefully demonstrate engagement of the TMS target and contribute to a neurocircuitry based approach treatment of geriatric depression.

Mental health research funding priorities in high-income countries must balance longer-term investment in identifying neurobiological mechanisms of disease with shorter-term funding of novel prevention and treatment strategies to alleviate the current burden of mental illness. Prioritising one area of science over others risks reduced returns on the entire scientific portfolio.

Structural and functional alterations in a variety of brain regions have been associated with depression and risk for depression across the life span. A majority of these regions are associated with emotion reactivity and/or regulation. However, it is generally unclear what mechanistic role these alterations play in the etiology of depression. A first step toward understanding this is to characterize the relationships between variation in brain structure/function and individual differences in depression severity and related processes, particularly emotion regulation. To this end, the current study examines how brain structure and function predict concurrent and longitudinal measures of depression symptomology and emotion regulation skills in psychiatrically healthy school-age children (N = 60). Specifically, we found that smaller hippocampus volumes and greater responses to sad faces in emotion reactivity regions predict increased depressive symptoms at the time of scan, whereas larger amygdala volumes, smaller insula volumes, and greater responses in emotion reactivity regions predict decreased emotion regulation skills. In addition, larger insula volumes predict improvements in emotion regulation skills even after accounting for emotion regulation at the time of scan. Understanding brain–behavior relationships in psychiatrically healthy samples, especially early in development, will help inform normative developmental trajectories and neural alterations in depression and other affective pathology.