The NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty: Protocol and rationale for methods and measures.

Delineating the relationship between human neurodevelopment and the maturation of the hypothalamic-pituitary-gonadal (HPG) axis during puberty is critical for investigating the increase in vulnerability to neuropsychiatric disorders that is well documented during this period. Preclinical research demonstrates a clear association between gonadal production of sex steroids and neurodevelopment; however, identifying similar associations in humans has been complicated by confounding variables (such as age) and the coactivation of two additional endocrine systems (the adrenal androgenic system and the somatotropic growth axis) and requires further elucidation. In this paper, we present the design of, and preliminary observations from, the ongoing NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty. The aim of this study is to directly examine how the increase in sex steroid hormone production following activation of the HPG-axis (i.e., gonadarche) impacts neurodevelopment, and, additionally, to determine how gonadal development and maturation is associated with longitudinal changes in brain structure and function in boys and girls. To disentangle the effects of sex steroids from those of age and other endocrine events on brain development, our study design includes 1) selection criteria that establish a well-characterized baseline cohort of healthy 8-year-old children prior to the onset of puberty (e.g., prior to puberty-related sex steroid hormone production); 2) temporally dense longitudinal, repeated-measures sampling of typically developing children at 8-10 month intervals over a 10-year period between the ages of eight and 18; 3) contemporaneous collection of endocrine and other measures of gonadal, adrenal, and growth axis function at each timepoint; and 4) collection of multimodal neuroimaging measures at these same timepoints, including brain structure (gray and white matter volume, cortical thickness and area, white matter integrity, myelination) and function (reward processing, emotional processing, inhibition/impulsivity, working memory, resting-state network connectivity, regional cerebral blood flow). This report of our ongoing longitudinal study 1) provides a comprehensive review of the endocrine events of puberty; 2) details our overall study design; 3) presents our selection criteria for study entry (e.g., well-characterized prepubertal baseline) along with the endocrinological considerations and guiding principles that underlie these criteria; 4) describes our longitudinal outcome measures and how they specifically relate to investigating the effects of gonadal development on brain development; and 5) documents patterns of fMRI activation and resting-state networks from an early, representative subsample of our cohort of prepubertal 8-year-old children.

Attention-deficit/hyperactivity disorder: An integrated developmental psychopathology and Research Domain Criteria (RDoC) approach.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by heterogeneous behaviors and symptoms, developmental trajectories, and treatment response. Isolating intermediate phenotypes that are superior to current DSM-based nosology in order to explain such heterogeneity is integral to enhancing etiological theory, improving clinical assessment, predicting treatment response, and developing tailored treatments. To this end, this review provides an integrated developmental psychopathology and National Institute of Mental Health Research Domain Criteria (RDoC) approach to ADHD. In particular, associations between ADHD and RDoC domains of cognition (specifically working memory) and positive valence (reward anticipation/delay/receipt) are discussed. These domains are examined across behavioral and neurocircuitry levels of analysis and placed within a developmental context via examining associations among RDoC domains, relevant features of ADHD, and environmental correlates implicated across development. Limitations of the existing literature and proposed future directions are explored. Importantly, future work should focus on novel approaches that account for developmental shifts in functioning of relevant RDoC domains over time, as well as further examination of the interaction across RDoC domains and levels of analysis.

Future Research Directions in the Positive Valence Systems: Measurement, Development, and Implications for Youth Unipolar Depression.

The Positive Valence Systems (PVS) have been introduced by the National Institute of Mental Health as a domain to help organize multiple constructs focusing on reward-seeking behaviors. However, the initial working model for this domain is strongly influenced by adult constructs and measures. Thus, the present review focuses on extending the PVS into a developmental context. Specifically, the review provides some hypotheses about the structure of the PVS, how PVS components may change throughout development, how family history of depression may influence PVS development, and potential means of intervening on PVS function to reduce onsets of depression. Future research needs in each of these areas are highlighted.

NIMH perspectives on future directions in neuroimaging for mental health.

NIMH's mission is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure. New imaging techniques hold great promise for improving our understanding of the pathophysiology of mental illnesses, stratifying patients for treatment selection, and developing a personalized medicine approach. Here, we highlight emerging and promising new technologies that are likely to be vital in helping NIMH accomplish its mission, the potential for utilizing multimodal approaches to study mental illness, and considerations for data analytics and data sharing.

The role of RDoC in future classification of mental disorders
.

The Research Domain Criteria (RDoC) project constitutes a translational framework for psychopathology research, initiated by the National Institute of Mental Health in an attempt to provide new avenues for research to circumvent problems emerging from the use of symptom-based diagnostic categories in diagnosing disorders. The RDoC alternative is a focus on psychopathology based on dimensions simultaneously defined by observable behavior (including quantitative measures of cognitive or affective behavior) and neurobiological measures. Key features of the RDoC framework include an emphasis on functional dimensions that range from normal to abnormal, integration of multiple measures in study designs (which can foster computational approaches), and high priority on studies of neurodevelopment and environmental influences (and their interaction) that can contribute to advances in understanding the etiology of disorders throughout the lifespan. The paper highlights key implications for ways in which RDoC can contribute to future ideas about classification, as well as some of the considerations involved in translating basic behavioral and neuroscience data to psychopathology.
.

El proyecto Research Domain Criteria (Criterios de Dominio de Investigación, CDI) constituye un marco traslacional para la investigación en psicopatología y fue iniciado por el Instituto Nacional de Salud Mental en un intento por proporcionar nuevas alternativas de investigación para sortear los problemas que surgen del uso de categorías diagnósticas basadas en síntomas para el diagnóstico de los trastornos mentales. La propuesta CDI se centra en la psicopatología basada en dimensiones, las cuales se definen simultáneamente por el comportamiento observable (incluyendo las mediciones cuantitativas del comportamiento cognitivo o afectivo) y las mediciones neurobiológicas. Las características clave de los CDI incluyen un énfasis en las dimensiones funcionales que van de lo normal a lo anormal, la integración de múltiples mediciones en los diseños de estudio (que pueden fomentar enfoques computacionales) y una alta prioridad en los estudios del neurodesarrollo y de las influencias ambientales (y de su interacción), todo lo cual puede contribuir a los avances en la comprensión de la etiología de los trastornos a lo largo de la vida. Este artículo destaca las consecuencias clave de las formas en que los CDI pueden contribuir a futuras ideas acerca de la clasificación, así como a algunas de las consideraciones involucradas en la traducción de datos básicos del comportamiento y de la neurociencia para la psicopatología.

Le National Institute of Mental Health a créé le projet des Critères de domaines de recherche (RDoC, Research Domain Criteria) comme cadre de recherche en psychopathologie, dans le but d'ouvrir les champs de recherche en contournant les problèmes issus des catégories diagnostiques basées sur les symptômes des maladies. Le RDoC est centré sur la psychopathologie et s'appuie sur un comportement observable (y compris des données quantitatives de comportement cognitif ou affectif) comme sur des données neurobiologiques. Structuré autour de caractéristiques essentielles, le RDoC valorise les dimensions fonctionnelles (de normales à anormales), les études de conceptions différentes (pouvant favoriser les méthodes numériques), et prioritairement les études de neurodéveloppement, les influences environnementales et leurs interactions qui peuvent améliorer la compréhension de l'étiologie des maladies au cours de la vie. Cet article souligne les principaux messages concernant les apports du RDoC aux nouvelles méthodes de classification, ainsi que certaines observations en lien avec la traduction des données fondamentales neuroscientifiques et comportementales en psychopathologie.

Capacity-building and training opportunities for implementation science in mental health.

This article traces efforts over the past decade by the National Institute of Mental Health, of the US National Institutes of Health, and other US organizations to build capacity for mental health researchers to advance activities in implementation science. Authors briefly chronicle the antecedents to the field's growth, and describe funding opportunities, workshop and conferences, training programs, and other initiatives that have collectively engaged hundreds of mental health researchers in the development and execution of implementation studies across the breadth of contexts where mental health care and prevention programs are delivered to those in need. The authors summarize a number of key initiatives and present potential next steps to further build the capacity for a new generation of implementation studies in mental health.

Child psychiatry branch of the National Institute of Mental Health longitudinal structural magnetic resonance imaging study of human brain development.

The advent of magnetic resonance imaging, which safely allows in vivo quantification of anatomical and physiological features of the brain, has revolutionized pediatric neuroscience. Longitudinal studies are useful for the characterization of developmental trajectories (ie, changes in imaging measures by age). Developmental trajectories (as opposed to static measures) have proven to have greater power in discriminating healthy from clinical groups and in predicting cognitive/behavioral measures, such as IQ. Here we summarize results from an ongoing longitudinal pediatric neuroimaging study that has been conducted at the Child Psychiatry Branch of the National Institute of Mental Health since 1989. Developmental trajectories of structural MRI brain measures from healthy youth are compared and contrasted with trajectories in attention-deficit/hyperactivity disorder (ADHD) and childhood-onset schizophrenia. Across ages 5-25 years, in both healthy and clinical populations, white matter volumes increase and gray matter volumes follow an inverted U trajectory, with peak size occurring at different times in different regions. At a group level, differences related to psychopathology are seen for gray and white matter volumes, rates of change, and for interconnectedness among disparate brain regions.

Implications of RDoC for the research and practice of psychotherapy.

The field of psychotherapy is at an important juncture. Recent changes in the field include (a) the skeptical reception of the fifth edition of the Diagnostic and Statistical Manual and (b) NIMH's prioritization of an alternative classification system to guide translational and intervention research. Moreover, (c) the field continues to be held accountable to governmental agencies and third-party payers to demonstrate its empirical basis. Thus, psychological research as it relates to the practice of psychotherapy is at a crossroads. In this article, we provide a brief overview of several generations of psychotherapy outcome research, including the consequences that followed in the 1980s as psychotherapy research moved toward randomized controlled trials for clinical disorders. We delineate the inherent strengths and limitations of this movement and address how the NIMH has recently responded with the Research Domain Criteria (RDoC). We then address philosophical and practical implications of the emphasis on a neuroscientific conceptualization of psychological problems. Finally, we discuss opportunities for a next generation of convergent science that incorporates, rather than replaces, psychosocial variables across stages of translational research and treatment development.

Twenty-five years of progress: the view from NIMH and NINDS.

As directors of two NIH institutes supporting neuroscience research, we explore the gap between 25 years of stunning progress in fundamental neuroscience and the persistent needs of those with brain disorders. We conclude that closing this gap will require a more detailed comprehension of brain function, a rethinking of how we approach translational science, a focus on human neurobiology, and a continuing commitment to build a diverse, innovative neuroscience workforce. In contrast to many other areas of medicine, we lack basic knowledge about our organ of interest. The next phase of progress on brain disorders will require a significantly deeper understanding of fundamental neurobiology.

Aims and results of the NIMH systematic treatment enhancement program for bipolar disorder (STEP-BD).

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was funded as part of a National Institute of Mental Health initiative to develop effectiveness information about treatments, illness course, and assessment strategies for severe mental disorders. STEP-BD studies were planned to be generalizable both to the research knowledge base for bipolar disorder and to clinical care of bipolar patients. Several novel methodologies were developed to aid in illness characterization, and were combined with existing scales on function, quality of life, illness burden, adherence, adverse effects, and temperament to yield a comprehensive data set. The methods integrated naturalistic treatment and randomized clinical trials, which a portion of STEP-BD participants participated. All investigators and other researchers in this multisite program were trained in a collaborative care model with the objective of retaining a high percentage of enrollees for several years. Articles from STEP-BD have yielded evidence on risk factors impacting outcomes, suicidality, functional status, recovery, relapse, and caretaker burden. The findings from these studies brought into question the widely practiced use of antidepressants in bipolar depression as well as substantiated the poorly responsive course of bipolar depression despite use of combination strategies. In particular, large studies on the characteristics and course of bipolar depression (the more pervasive pole of the illness), and the outcomes of treatments concluded that adjunctive psychosocial treatments but not adjunctive antidepressants yielded outcomes superior to those achieved with mood stabilizers alone. The majority of patients with bipolar depression concurrently had clinically significant manic symptoms. Anxiety, smoking, and early age of bipolar onset were each associated with increased illness burden. STEP-BD has established procedures that are relevant to future collaborative research programs aimed at the systematic study of the complex, intrinsically important elements of bipolar disorders.

Research Domain Criteria: cognitive systems, neural circuits, and dimensions of behavior.

Current diagnostic systems for mental disorders were established before the tools of neuroscience were available, and although they have improved the reliability of psychiatric classification, progress toward the discovery of disease etiologies and novel approaches to treatment and prevention may benefit from alternative conceptualizations of mental disorders. The Research Domain Criteria (RDoC) initiative is the centerpiece of NIMH's effort to achieve its strategic goal of developing new methods to classify mental disorders for research purposes. The RDoC matrix provides a research framework that encourages investigators to reorient their research perspective by taking a dimensional approach to the study of the genetic, neural, and behavioral features of mental disorders, RDoCs integrative approach includes cognition along with social processes, arousal/regulatory systems, and negative and positive valence systems as the major domains, because these neurobehavioral systems have all evolved to serve the motivational and adaptive needs of the organism. With its focus on neural circuits informed by the growing evidence of the neurodevelopmental nature of many disorders and its capacity to capture the patterns of co-occurrence of behaviors and symptoms, the RDoC approach holds promise to advance our understanding of the nature of mental disorders.