Mental Health Research Domain Research Articles

Managing clinical heterogeneity in psychopathology: Perspectives from brain research.

Clinical heterogeneity is a significant factor to contend with when seeking to organize, understand, and treat psychopathology. In recent years, the field has prioritized efforts to minimize nonmeaningful heterogeneity and leverage meaningful heterogeneity to improve assessment and diagnostics, inform mechanistic understanding, and facilitate the development of novel treatments. Indeed, exciting developments such as the National Institute for Mental Health Research Domain Criteria and the Hierarchical Taxonomy of Psychopathology have provided powerful frameworks for facing clinical complexity. While these developments have spurred many advancements, the movement has yet to effectively harness the tremendous potential provided by the brain. Initial work incorporating brain data has focused on validating clinical observations with a biomarker rather than leveraging the brain to provide unique insight into meaningful clinical heterogeneity. To provide future guidance and examples of innovation in the area, we solicited articles from teams seeking to utilize brain research to manage clinical heterogeneity. The search resulted in a diverse illustration of how best to leverage brain data to greater mechanistic understanding and clinical utility. In this introduction, we consider this work and discuss strategies through which brain data can best be used to provide unique insight into clinical heterogeneity. As the science of psychopathology continues to grapple with the promise and costs inherent in utilizing this powerful and complex array of methodologies, it will be important to leverage unique insights from brain science. This special issue provides a useful guide for new and upcoming work and a catalyst for moving the field forward. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Frustrative Nonreward: Behavior, Circuits, Neurochemistry, and Disorders.

The surprising omission or reduction of vital resources (food, fluid, social partners) can induce an aversive emotion known as frustrative nonreward (FNR), which can influence subsequent behavior and physiology. FNR is an integral mediator of irritability/aggression, motivation (substance use disorders, depression), anxiety/fear/threat, learning/conditioning, and social behavior. Despite substantial progress in the study of FNR during the twentieth century, research lagged in the later part of the century and into the early twenty-first century until the National Institute of Mental Health's Research Domain Criteria initiative included FNR and loss as components of the negative valence domain. This led to a renaissance of new research and paradigms relevant to basic and clinical science alike. The COVID-19 pandemic's extensive individual and social restrictions were correlated with increased drug and alcohol use, social conflict, irritability, and suicide, all potential consequences of FNR. This article highlights animal models related to these psychiatric disorders and symptoms and presents recent advances in identifying the brain regions and neurotransmitters implicated.

Genetic Diversity in Schizophrenia: Developmental Implications of Ultra-Rare, Protein-Truncating Mutations.

The genetic basis of schizophrenia (SZ) remains elusive despite its characterization as a highly heritable disorder. This incomplete understanding has led to stagnation in therapeutics and treatment, leaving many suffering with insufficient relief from symptoms. However, recent large-cohort genome- and exome-wide association studies have provided insights into the underlying genetic machinery. The scale of these studies allows for the identification of ultra-rare mutations that confer substantial disease risk, guiding clinicians and researchers toward general classes of genes that are central to SZ etiology. One such large-scale collaboration effort by the Schizophrenia Exome Sequencing Meta-Analysis consortium identified ten, high-risk, ultra-rare, protein-truncating variants, providing the clearest picture to date of the dysfunctional gene products that substantially increase risk for SZ. While genetic studies of SZ provide valuable information regarding "what" genes are linked with the disorder, it is an open question as to "when" during brain development these genetic mutations impose deleterious effects. To shed light on this unresolved aspect of SZ etiology, we queried the BrainSpan developmental mRNA expression database for these ten high-risk genes and discovered three general expression trajectories throughout pre- and postnatal brain development. The elusiveness of SZ etiology, we infer, is not only borne out of the genetic heterogeneity across clinical cases, but also in our incomplete understanding of how genetic mutations perturb neurodevelopment during multiple critical periods. We contextualize this notion within the National Institute of Mental Health's Research Domain Criteria framework and emphasize the utility of considering both genetic variables and developmental context in future studies.

Fear, defense, and emotion: A neuroethological understanding of the negative valence research domain criteria.

We describe the close correspondence between predatory imminence continuum theory (PICT) and the National Institute of Mental Health's Research Domain Criteria (RDoC) for negative valence. RDoC's negative valence constructs relate aversively motivated behavioral reactions to various levels of threat. PICT divides defensive responses into distinct modes that vary along a continuum of the psychological closeness of predatory threat. While there is a close correspondence between PICT modes and negative valence threat constructs, based on PICT, we describe some potential elaborations of RDoC constructs. Both have consonant views of fear and anxiety and provide explicit distinctions between these emotional states, relating them to specific defensive behaviors and functions. We describe recent data that causally implicate human subjective emotional states with amygdala activity, which is also critical for defensive behavior. We conclude that attention to neuroethological views of defense can advance our understanding of the etiology and treatment of anxiety and stress disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Neural Substrates of Emotion Processing and Cognitive Control Over Emotion in Youth Anxiety: An RDoC-Informed Study Across the Clinical to Nonclinical Continuum of Severity

Clinically anxious youth are hypervigilant to emotional stimuli and display difficulty shifting attention from emotional to nonemotional stimuli, suggesting impairments in cognitive control over emotion. However, it is unknown whether the neural substrates of such biases vary across the clinical-to-nonclinical range of anxiety or by age. Youth aged 7 to 17 years with clinical anxiety (n= 119) or without an anxiety diagnosis (n= 41) matched emotional faces or matched shapes flanked by emotional face distractors during magnetic resonance imaging, probing emotion processing and cognitive control over emotion, respectively. Building from the National Institute of Mental Health Research Domain Criteria (RDoC) framework, clinically anxious youth were sampled across diagnostic categories, and non-clinically affected youth were sampled across minimal-to-subclinical severity. Across both conditions, anxiety severity was associated with hyperactivation in the right inferior parietal lobe, a substrate of hypervigilance. Brain-anxiety associations were also differentiated by attentional state; anxiety severity was associated with greater left ventrolateral prefrontal cortex activation during emotion processing (face matching) and greater activation in the left posterior superior temporal sulcus and temporoparietal junction (and slower responses) during cognitive control over emotion (shape matching). Age also moderated associations between anxiety and cognitive control over emotion, such that anxiety was associated with greater right thalamus and bilateral posterior cingulate cortex activation for children at younger and mean ages, but not for older youth. Aberrant function in brain regions implicated in stimulus-driven attention to emotional distractors may contribute to anxiety in youth. Results support the potential utility of attention modulation interventions for anxiety that are tailored to developmental stage. Dimensional Brain Behavior Predictors of CBT Outcomes in Pediatric Anxiety; https://clinicaltrials.gov; NCT02810171.

Dimensional Measures of Psychopathology in Children and Adolescents Using Large Language Models

BackgroundTo enable greater use of National Institute of Mental Health Research Domain Criteria (RDoC) in real-world settings, we applied large language models (LLMs) to estimate dimensional psychopathology from narrative clinical notes. MethodsWe conducted a cohort study using health records from individuals age ≤18 years evaluated in the psychiatric emergency department of a large academic medical center between November 2008 and March 2015. Outcomes were hospital admission and length of emergency department stay. RDoC domains were estimated using a Health Insurance Portability and Accountability Act–compliant LLM (gpt-4-1106-preview) and compared with a previously validated token-based approach. ResultsThe cohort included 3059 individuals (median age 16 years [interquartile range, 13–18]; 1580 [52%] female, 1479 [48%] male; 105 [3.4%] identified as Asian, 329 [11%] as Black, 288 [9.4%] as Hispanic, 474 [15%] as other race, and 1863 [61%] as White), of whom 1695 (55%) were admitted. Correlation between LLM-extracted RDoC scores and the token-based scores ranged from small to medium as assessed by Kendall’s tau (0.14–0.22). In logistic regression models adjusting for sociodemographic and clinical features, admission likelihood was associated with greater scores on all domains, with the exception of the sensorimotor domain, which was inversely associated (p < .001 for all adjusted associations). Tests for bias suggested modest but statistically significant differences in positive valence scores by race (p < .05 for Asian, Black, and Hispanic individuals). ConclusionsAn LLM extracted estimates of 6 RDoC domains in an explainable manner, which were associated with clinical outcomes. This approach can contribute to a new generation of prediction models or biological investigations based on dimensional psychopathology.

COVID-19 pandemic amplified mortality rates among adolescents with bipolar disorder through family-related factors.

Recently, a growing number of adolescents have been afflicted with mental disorders, with annual morbidity rates on the rise. This trend has been exacerbated by the global coronavirus disease 2019 (COVID-19) pandemic, leading to a surge in suicide and self-harm rates among this demographic. To investigate the impact of the COVID-19 pandemic on adolescent bipolar disorder (BD), along with the underlying factors contributing to heightened rates of suicide and self-harm among adolescents. A comprehensive statistical analysis was conducted utilizing clinical interviews and self-reports obtained from patients or their guardians. Diagnostic criteria for BDs were based on the Diagnostic and statistical manual of mental disorders, international classification of diseases-11, and the National institute of mental health research domain criteria. Statistical analyses were performed using SPSS 26.0 software, with significance set at P < 0.05. A cohort of 171 adolescents diagnosed with BD between January 1, 2018, and December 31, 2022, was included in the analysis. The gender distribution was 2.8:1 (female to male), with ages ranging from 11 to 18 years old. Major factors contributing to adolescent BDs included familial influences, academic stress, genetic predisposition and exposure to school-related violence. Notably, a significant increase in suicide attempts and self-harm incidents was observed among adolescents with BD during the COVID-19 pandemic. Statistical analysis indicated that the pandemic exacerbated familial discord and heightened academic stress, thereby amplifying the prevalence of suicidal behavior and self-harm among adolescents. The COVID-19 pandemic has exacerbated familial tensions and intensified the incidence of suicide and self-harm among adolescents diagnosed with BD. This study underscores the urgent need for societal, familial and educational support systems to prioritize the well-being of adolescents and offers valuable insights and guidelines for the prevention, diagnosis and treatment of adolescent BDs.

Theta oscillatory dynamics serving cognitive control index psychosocial distress in youth

BackgroundPsychosocial distress among youth is a major public health issue characterized by disruptions in cognitive control processing. Using the National Institute of Mental Health's Research Domain Criteria (RDoC) framework, we quantified multidimensional neural oscillatory markers of psychosocial distress serving cognitive control in youth. MethodsThe sample consisted of 39 peri-adolescent participants who completed the NIH Toolbox Emotion Battery (NIHTB-EB) and the Eriksen flanker task during magnetoencephalography (MEG). A psychosocial distress index was computed with exploratory factor analysis using assessments from the NIHTB-EB. MEG data were analyzed in the time-frequency domain and peak voxels from oscillatory maps depicting the neural cognitive interference effect were extracted for voxel time series analyses to identify spontaneous and oscillatory aberrations in dynamics serving cognitive control as a function of psychosocial distress. Further, we quantified the relationship between psychosocial distress and dynamic functional connectivity between regions supporting cognitive control. ResultsThe continuous psychosocial distress index was strongly associated with validated measures of pediatric psychopathology. Theta-band neural cognitive interference was identified in the left dorsolateral prefrontal cortex (dlPFC) and middle cingulate cortex (MCC). Time series analyses of these regions indicated that greater psychosocial distress was associated with elevated spontaneous activity in both the dlPFC and MCC and blunted theta oscillations in the MCC. Finally, we found that stronger phase coherence between the dlPFC and MCC was associated with greater psychosocial distress. ConclusionsGreater psychosocial distress was marked by alterations in spontaneous and oscillatory theta activity serving cognitive control, along with hyperconnectivity between the dlPFC and MCC.

Effects of a single dose of amisulpride on functional brain changes during reward- and motivation-related processing using task-based fMRI in healthy subjects and patients with major depressive disorder — study protocol for a randomized clinical trial

BackgroundAnhedonia and other deficits in reward- and motivation-related processing in psychiatric patients, including patients with major depressive disorder (MDD), represent a high unmet medical need. Neurobiologically, these deficits in MDD patients are mainly associated with low dopamine function in a frontostriatal network. In this study, alterations in brain activation changes during reward processing and at rest in MDD patients compared with healthy subjects are explored and the effects of a single low dose of the dopamine D2 receptor antagonist amisulpride are investigated.MethodsThis is a randomized, controlled, double-blind, single-dose, single-center parallel-group clinical trial to assess the effects of a single dose of amisulpride (100 mg) on blood-oxygenation-level-dependent (BOLD) responses during reward- and motivation-related processing in healthy subjects (n = 60) and MDD patients (n = 60). Using functional magnetic resonance imaging (fMRI), BOLD responses are assessed during the monetary incentive delay (MID) task (primary outcome). Exploratory outcomes include BOLD responses and behavioral measures during the MID task, instrumental learning task, effort-based decision-making task, social incentive delay task, and probabilistic reward task as well as changes in resting state functional connectivity and cerebral blood flow.DiscussionThis study broadly covers all aspects of reward- and motivation-related processing as categorized by the National Institute of Mental Health Research Domain Criteria and is thereby an important step towards precision psychiatry. Results regarding the immediate effects of a dopaminergic drug on deficits in reward- and motivation-related processing not only have the potential to significantly broaden our understanding of underlying neurobiological processes but might eventually also pave the way for new treatment options.Trial registrationClinicalTrials.gov NCT05347199. April 12, 2022.

Studying fine-grained elements of psychopathology to advance mental health science.

Given the now well-recognized limitations of traditional classification systems for research, this editorial proposes to advance mental health science by focusing research efforts on studying fine-grained elements of mental health and illness such as symptoms, mechanisms, and processes. Our own perspectives are informed by three approaches in particular that have gained traction over the last decade: the Hierarchical Taxonomy of Psychopathology, the network or systems approach, and the National Institute of Mental Health Research Domain Criteria. Drawing on these and other perspectives as well as the diverse views of the author teams that contributed to this Special Section, we summarize the state of the field and propose an ambitious plan for the way ahead. Specifically, we propose that embracing pluralistic, multimethod, and multisystem approaches offers a way forward. This will require strategies to reduce research waste and much stronger channels for communication to identify confluence, discoveries, and dead ends within and between disciplines. We are optimistic this will lead to a better understanding of the mechanisms underpinning psychopathology and ultimately to more effective interventions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Applying Research Domain Criteria to the study of emotion dysregulation in infancy and early childhood

AbstractEmotion regulation is a principal task of early development. The failure to develop effective emotion regulation skills is associated with behavioural, academic, psychological and socioemotional difficulties. Although researchers have studied emotion regulation for decades, work on emotion dysregulation—defined as the inability to maintain emotional control, engage with the environment or recover from distress in a developmentally appropriate manner—is rare and there are discrepancies in its conceptualisation among very young samples. While some scientists refer to emotion dysregulation as if it were a discrete concept, it may be more accurately depicted as a multidimensional system of developmental processes. The National Institute of Mental Health's Research Domain Criteria (RDoC) is a framework that allows researchers to track dysfunction across multiple areas of analysis and may be an ideal system for exploring the multidimensional nature of infant emotion dysregulation. In this paper, we draw on empirical studies to describe how the RDoC framework can be used to support studies of emotion dysregulation in infancy. This proposed model can also serve as a roadmap for future researchers to follow to generate the evidence base for a multidimensional conceptualisation of infant emotion dysregulation and its underlying mechanisms.

Dimensional clinical phenotyping using post-mortem brain donor medical records: post-mortem RDoC profiling is associated with Alzheimer's disease neuropathology.

Transdiagnostic dimensional phenotypes are essential to investigate the relationship between continuous symptom dimensions and pathological changes. This is a fundamental challenge to post-mortem work, as assessments of phenotypic concepts need to rely on existing records. We adapted well-validated methodologies to compute National Institute of Mental Health Research Domain Criteria (RDoC) scores using natural language processing (NLP) from electronic health records (EHRs) obtained from post-mortem brain donors and tested whether cognitive domain scores were associated with Alzheimer's disease neuropathological measures. Our results confirm an association of EHR-derived cognitive scores with neuropathological findings. Notably, higher neuropathological load, particularly neuritic plaques, was associated with higher cognitive burden scores in the frontal (ß=0.38, P=0.0004), parietal (ß=0.35, P=0.0008), temporal (ß=0.37, P=0.0004) and occipital (ß=0.37, P=0.0003) lobes. This proof-of-concept study supports the validity of NLP-based methodologies to obtain quantitative measures of RDoC clinical domains from post-mortem EHR. The associations may accelerate post-mortem brain research beyond classical case-control designs.

Perimenopausal Effects of Estradiol on Anhedonia and Psychosis Study (PEEPs): study protocol for a neural and molecular mechanistic clinical trial

BackgroundThe perimenopausal transition is accompanied by psychiatric symptoms in over 10% of women. Symptoms commonly include depressed mood and anhedonia and less commonly include psychosis. Psychiatric symptoms have been linked to the depletion and/or variability of circulating estradiol, and estradiol treatment reduces perimenopausal anhedonia and psychosis in some women. Estrogen fluctuations may disrupt function in the mesolimbic reward system in some women, leading to psychiatric symptoms like anhedonia or psychosis. The Perimenopausal Effects of Estradiol on Anhedonia and Psychosis Study (PEEPs) is a mechanistic clinical trial that aims to (1) identify relationships between perimenopausal-onset anhedonia and psychosis and neuromolecular markers of mesolimbic reward responses and (2) determine the extent to which estradiol treatment-induced changes in mesolimbic reward responses are associated with alleviation of perimenopausal onset anhedonia or psychosis.MethodsThis study will recruit 100 unmedicated women ages 44–55 in the late-stage perimenopausal transition, sampling across the range of mild-to-high anhedonia and absent-to-moderate psychosis symptoms. Patients will be randomized to receive either estradiol or placebo treatment for 3 weeks. Clinical outcome measures will include symptoms of anhedonia (measured with Snaith–Hamilton Pleasure Scale; SHAPS) and psychosis (measured with Brief Psychiatric Rating Scale; BPRS psychosis subscale) as well as neural markers of mesolimbic reward system functioning, including reward-related fMRI activation and PET-derived measure of striatal dopamine binding. Pre-treatment associations between (1) SHAPS/BPRS scores and (2) reward-related striatal dopamine binding/BOLD activation will be examined. Furthermore, longitudinal mixed models will be used to estimate (1) symptom and neuromolecular trajectories as a function of estradiol vs. placebo treatment and (2) how changes in reward-related striatal dopamine binding and BOLD activation predict variability in symptom trajectories in response to estradiol treatment.DiscussionThis clinical trial will be the first to characterize neural and molecular mechanisms by which estradiol treatment ameliorates anhedonia and psychosis symptoms during the perimenopausal transition, thus laying the groundwork for future biomarker research to predict susceptibility and prognosis and develop targeted treatments for perimenopausal psychiatric symptoms. Furthermore, in alignment with the National Institute for Mental Health Research Domain Criteria initiative, this trial will improve our understanding of a range of disorders characterized by anhedonia, psychosis, and reward system dysfunction.Trial registrationClinicalTrials.gov NCT05282277

Restoring the missing person to personalized medicine and precision psychiatry.

Precision psychiatry has emerged as part of the shift to personalized medicine and builds on frameworks such as the U.S. National Institute of Mental Health Research Domain Criteria (RDoC), multilevel biological "omics" data and, most recently, computational psychiatry. The shift is prompted by the realization that a one-size-fits all approach is inadequate to guide clinical care because people differ in ways that are not captured by broad diagnostic categories. One of the first steps in developing this personalized approach to treatment was the use of genetic markers to guide pharmacotherapeutics based on predictions of pharmacological response or non-response, and the potential risk of adverse drug reactions. Advances in technology have made a greater degree of specificity or precision potentially more attainable. To date, however, the search for precision has largely focused on biological parameters. Psychiatric disorders involve multi-level dynamics that require measures of phenomenological, psychological, behavioral, social structural, and cultural dimensions. This points to the need to develop more fine-grained analyses of experience, self-construal, illness narratives, interpersonal interactional dynamics, and social contexts and determinants of health. In this paper, we review the limitations of precision psychiatry arguing that it cannot reach its goal if it does not include core elements of the processes that give rise to psychopathological states, which include the agency and experience of the person. Drawing from contemporary systems biology, social epidemiology, developmental psychology, and cognitive science, we propose a cultural-ecosocial approach to integrating precision psychiatry with person-centered care.

Factor Analysis of the Beck Depression Inventory-II and Long-Term Hematopoietic Stem Cell Transplantation Survival Using the Research Domain Criteria Framework

The presence of depressive symptoms prior to hematopoietic stem cell transplantation (HSCT) is a common experience, with long-term impacts on survival. Using the National Institute of Mental Health Research Domain Criteria (RDoC) framework, this study sought to characterize depressive symptoms in patients prior to HSCT through exploratory factor analysis and to determine whether depressive factors were significant predictors of long-term survival. Individuals were included in the study if they were preparing to undergo HSCT and endorsed depressive symptoms measured by the Beck Depression Inventory-II (BDI-II). Patients were scheduled to undergo transplantation between 2005 and 2010. Survival analyses were conducted in 2022 to assess long-term outcomes. The primary outcomes were exploring the factor structure of the BDI-II and conducing univariate and multivariate Cox regression analyses of depression symptoms and known demographic and disease characteristics that impact survival. Of the 695 participants included in the study, most were male, middle aged (mean age, 55.08 ± 11.75 years), white, and married. Exploratory factor analysis revealed a 4-factor structure consisting of "negative valence systems: internalizing" (eg, worthlessness, guilt), "arousal and threat" (eg, agitation, irritability), "arousal and regulatory systems" (eg, loss of energy, fatigue), and "negative valence systems: externalizing" (eg, loss of pleasure, loss of interest). Univariate survival analyses identified age, sex, disease type, acute graft-versus-host disease (GVHD), and negative valence systems: externalizing as significant predictors of survival. Transplant type, chronic GVHD, performance status, and the other 3 depression factor structures were not significant in univariate models. In the multivariate model, older age (hazard ratio [HR], 1.031; 95% confidence interval [CI], 1.021 to 1.041; P < .001) and presence of negative valence systems: externalizing symptoms (HR, 1.132; 95% CI, 1.030 to 1.244; P = .010) were significant predictors of shorter survival. Additionally, individuals diagnosed with acute leukemia were significantly more likely to have shorter survival compared to those with other disease types, including amyloidosis (HR, .362; 95% CI, .229 to .575; P < .001) and non-Hodgkin lymphoma (HR, .526; 95% CI, .349 to .793; P = .002). Exploratory factor analysis of depressive symptoms mapped well onto the RDoC constructs. Loss of pleasure and loss of interest, two key components of depression, were predictive of shorter survival. Exploration of key components of depression rather than the total depression score may provide important prognostic information for long-term survivorship and may help inform future and more individualized care.

Translational models of addiction phenotypes to advance addiction pharmacotherapy.

Alcohol and substance use disorders are heterogeneous conditions with limited effective treatment options. While there have been prior attempts to classify addiction subtypes, they have not been translated into clinical practice. In an effort to better understand heterogeneity in psychiatric disorders, the National Institute for Mental Health Research Domain Criteria (RDoC) has challenged scientists to think beyond diagnostic symptoms and to consider the underlying features of psychopathology from a neuroscience-based framework. The field of addiction has grappled with this approach by considering several key constructs with the potential to capture RDoC domains. This critical review will focus on the efforts to apply translational models of addiction phenomenology in human clinical samples, including their relative strengths and weaknesses. Opportunities for forward and reverse translation are also discussed. Deep behavioral phenotyping using neuroscience-informed batteries shows promise for a better understanding of the clinical neuroscience of addiction and advancing precision medicine for alcohol and substance use disorders.

Development and environment in the National Institute of Mental Health (NIMH) Research Domain Criteria.

The integration of developmental processes is essential for a full understanding of psychopathology. The National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) provide a scaffold on which to organize the components and processes of psychopathology and to detail behavioral and biological disruptions in developmental processes gone awry. This special section on Integrating Developmental Psychopathology With the RDoC Framework provides the opportunity to comment on five extraordinary developmental psychopathology articles that report results and theory integral to RDoC. An introductory overview provides context for RDoC's approach to developmental issues. This is followed by brief summaries of each article and points regarding its particularly salient aspects, and concludes with broader comments about the import of the articles as a set. Collectively, the work by these eminent translational scholars illustrates how to conduct significant research on developmental psychopathology using RDoC, and simultaneously raises important questions and future directions to integrate development and environment in RDoC-framed research. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Developmental patterning of irritability enhances prediction of psychopathology in preadolescence: Improving RDoC with developmental science.

The transdiagnostic importance of irritability in psychopathology has been demonstrated. However, the contribution of developmentally unfolding irritability patterns to specific clinical and neural outcomes remains an important and unanswered question. To address this gap in the literature, irritability patterns of 110 youth from a large, diverse cohort were assessed at preschool age and again at early school age (∼2.5 years later) with a dimensional irritability scale designed to capture the normal:abnormal spectrum. At preadolescence (∼6 years later), clinical outcomes (internalizing/externalizing symptoms) derived from a semistructured clinical interview and neural outcomes (characterized as gray-matter-volume abnormalities) were assessed. For clinical outcomes, preschool-age irritability alone was a transdiagnostic predictor of internalizing and externalizing symptoms at preadolescence. However, in a model including both preschool and early school age, irritability provided greater specificity, suggesting that higher irritability at early school age related to elevated preadolescent externalizing but not internalizing symptoms. In terms of neural outcomes, elevated preschool irritability did not predict preadolescent gray-matter-volume abnormality; however, irritability at early school age demonstrated an interactive effect among regions, with reduced volume in preadolescence emotional regions (e.g., amygdala, medial orbitofrontal cortex) and increased volume in other regions (e.g., cerebellum). These complex patterns highlight the contribution of a developmentally informed approach, the National Institute of Mental Health's Research Domain Criteria (RDoC) approach, to yield transdiagnostic phenotypes and multiple units of analysis. Capturing these individual differences and developmental heterogeneity can provide critical insight into the unfolding of mechanisms underlying emerging psychopathology. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Examining Research Domain Criteria (RDoC) constructs for anger expression and regulation in toddlers.

The present study is focused on anger expression and regulation within the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) construct of Frustrative Nonreward. Although previous studies have examined associations between child anger regulation and expression, these studies do not directly address the dynamic processes involved in Frustrative Nonreward using microlongitudinal methods. The current study used data from 561 adopted children, their adoptive parents, and birth parents and aimed to address gaps in the literature by examining: (a) temporal associations between anger expression during a frustrating situation, and behaviors thought to regulate emotions (e.g., attempt-to-escape, support-seeking, distraction, and focus-on-restraint) on a microlongitudinal scale during an arm restraint task assessed at 27 months; (b) birth parent externalizing problems and overreactive parenting by adoptive parents as predictors of child anger expression and moderators of the moment-to-moment associations estimated in Step 1; and (c) longitudinal associations (linear vs. quadratic) between anger expressions and externalizing behaviors at 4.5 years. Findings indicated that children's attempt-to-escape and support-seeking predicted an increase in anger expression in the following 3-s interval, whereas distraction and focus-on-restraint were not associated with changes in anger expression. Furthermore, we found that birth parents' externalizing problems were significantly associated with child anger expression, suggesting heritable influences. Anger expression showed a U-shaped longitudinal association with paternal report of externalizing behaviors at 4.5 years. Taken together, the findings emphasize the significance of integrating microlongitudinal analysis approaches into the RDoC framework, helping to advance our understanding of dynamic processes underlying reactions to Frustrative Nonreward. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Longitudinally stable, brain-based predictive models mediate the relationships between childhood cognition and socio-demographic, psychological and genetic factors.

Cognitive abilities are one of the major transdiagnostic domains in the National Institute of Mental Health's Research Domain Criteria (RDoC). Following RDoC's integrative approach, we aimed to develop brain-based predictive models for cognitive abilities that (a) are developmentally stable over years during adolescence and (b) account for the relationships between cognitive abilities and socio-demographic, psychological and genetic factors. For this, we leveraged the unique power of the large-scale, longitudinal data from the Adolescent Brain Cognitive Development (ABCD) study (n~ 11 k) and combined MRI data across modalities (task-fMRI from three tasks: resting-state fMRI, structural MRI and DTI) using machine-learning. Our brain-based, predictive models for cognitive abilities were stable across 2 years during young adolescence and generalisable to different sites, partially predicting childhood cognition at around 20% of the variance. Moreover, our use of 'opportunistic stacking' allowed the model to handle missing values, reducing the exclusion from around 80% to around 5% of the data. We found fronto-parietal networks during a working-memory task to drive childhood-cognition prediction. The brain-based, predictive models significantly, albeit partially, accounted for variance in childhood cognition due to (1) key socio-demographic and psychological factors (proportion mediated=18.65% [17.29%-20.12%]) and (2) genetic variation, as reflected by the polygenic score of cognition (proportion mediated=15.6% [11%-20.7%]). Thus, our brain-based predictive models for cognitive abilities facilitate the development of a robust, transdiagnostic research tool for cognition at the neural level in keeping with the RDoC's integrative framework.