National Institute of Mental Health Support for Cognitive Treatment Development in Schizophrenia: A Narrative Review.

For several decades the National Institute of Mental Health (NIMH) has supported basic and translational research into cognitive impairment in schizophrenia. This article describes the Institute's ongoing commitment to cognitive assessment and intervention research, as reflected by three signature initiatives-Measurement and Treatment Research to Improve Cognition in Schizophrenia; Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia; and Research Domain Criteria-and related funding announcements that span basic experimental studies, efficacy and comparative effectiveness trials, and implementation research designed to promote cognitive healthcare in real-world treatment settings. We discuss how trends in science and public health policy since the early 2000s have influenced NIMH treatment development activities, resulting in greater attention to (1) inclusive teams that reflect end-user perspectives on the utility of proposed studies; (2) measurement of discrete neurocognitive processes to inform targeted interventions; (3) clinical trials that produce useful information about putative illness mechanisms, promising treatment targets, and downstream clinical effects; and (4) "productive urgency" in pursuing feasible and effective cognitive interventions for psychosis. Programs employing these principles have catalyzed cognitive measurement, drug development, and behavioral intervention approaches that aim to improve neurocognition and community functioning among persons with schizophrenia. NIMH will maintain support for innovative and impactful investigator-initiated research that advances patient-centered, clinically effective, and continuously improving cognitive health care for persons with psychotic 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).

Revisiting the seven pillars of RDoC.

BACKGROUND: In 2013, a few years after the launch of the National Institute of Mental Health's Research Domain Criteria (RDoC) initiative, Cuthbert and Insel published a paper titled "Toward the future of psychiatric diagnosis: the seven pillars of RDoC." The RDoC project is a translational research effort to encourage new ways of studying psychopathology through a focus on disruptions in normal functions (such as reward learning or attention) that are defined jointly by observable behavior and neurobiological measures. The paper outlined the principles of the RDoC research framework, including emphases on research that acquires data from multiple measurement classes to foster integrative analyses, adopts dimensional approaches, and employs novel methods for ascertaining participants and identifying valid subgroups. DISCUSSION: To mark the first decade of the RDoC initiative, we revisit the seven pillars and highlight new research findings and updates to the framework that are related to each. This reappraisal emphasizes the flexible nature of the RDoC framework and its application in diverse areas of research, new findings related to the importance of developmental trajectories within and across neurobehavioral domains, and the value of computational approaches for clarifying complex multivariate relations among behavioral and neurobiological systems. CONCLUSION: The seven pillars of RDoC have provided a foundation that has helped to guide a surge of new studies that have examined neurobehavioral domains related to mental disorders, in the service of informing future psychiatric nosology. Building on this footing, future areas of emphasis for the RDoC project will include studying central-peripheral interactions, developing novel approaches to phenotyping for genomic studies, and identifying new targets for clinical trial research to facilitate progress in precision psychiatry.

Loss of growth hormone signaling in the mouse germline or in adulthood reduces islet mass and alters islet function with notable sex differences.

In the endocrine pancreas, growth hormone (GH) is known to promote pancreatic islet growth and insulin secretion. In this study, we show that GH receptor (GHR) loss in the germline and in adulthood impacts islet mass in general but more profoundly in male mice. GHR knockout (GHRKO) mice have enhanced insulin sensitivity and low circulating insulin. We show that the total cross-sectional area of isolated islets (estimated islet mass) was reduced by 72% in male but by only 29% in female GHRKO mice compared with wild-type controls. Also, islets from GHRKO mice secreted ∼50% less glucose-stimulated insulin compared with size-matched islets from wild-type mice. We next used mice with a floxed Ghr gene to knock down the GHR in adult mice at 6 mo of age (6mGHRKO) and examined the impact on glucose and islet metabolism. By 12 mo of age, female 6mGHRKO mice had increased body fat and reduced islet mass but had no change in glucose tolerance or insulin sensitivity. However, male 6mGHRKO mice had nearly twice as much body fat, substantially reduced islet mass, and enhanced insulin sensitivity, but no change in glucose tolerance. Despite large losses in islet mass, glucose-stimulated insulin secretion from isolated islets was not significantly different between male 6mGHRKO and controls, whereas isolated islets from female 6mGHRKO mice showed increased glucose-stimulated insulin release. Our findings demonstrate the importance of GH to islet mass throughout life and that unique sex-specific adaptations to the loss of GH signaling allow mice to maintain normal glucose metabolism.NEW & NOTEWORTHY Growth hormone (GH) is important for more than just growth. GH helps to maintain pancreatic islet mass and insulin secretion throughout life. Sex-specific adaptations to the loss of GH signaling allow mice to maintain normal glucose regulation despite losing islet mass.

Evolving Concepts of the Schizophrenia Spectrum: A Research Domain Criteria Perspective.

Several trends intersecting over the past two decades have generated increasing debate as to how the concepts of schizophrenia, the schizophrenia spectrum, and the psychotic disorders spectrum should be regarded. These trends are reflected in various areas of research such as genomics, neuroimaging, and data-driven computational studies of multiple response systems. Growing evidence suggests that schizophrenia represents a broad and heterogenous syndrome, rather than a specific disease entity, that is part of a multi-faceted psychosis spectrum. Progress in explicating these various developments has been hampered by the dependence upon sets of symptoms and signs for determining a diagnosis, and by the reliance on traditional diagnostic categories in reviewing clinical research grants. To address these concerns, the U.S. National Institute of Mental Health initiated the Research Domain Criteria (RDoC) project, a translational research program that calls for studies designed in terms of empirically-based functions (such as cognitive control or reward learning) rather than diagnostic groups. RDoC is a research framework rather than an alternative diagnostic system, intended to provide data that can inform future nosological manuals. This commentary includes a brief summary of RDoC as it pertains to schizophrenia and psychotic spectra, examples of recent data that highlight the utility of the approach, and conclusions regarding the implications for evolving conceptualizations of serious mental illness.

Comparative isotopic evidence from East Turkana supports a dietary shift within the genus Homo.

It has been suggested that a shift in diet is one of the key adaptations that distinguishes the genus Homo from earlier hominins, but recent stable isotopic analyses of fossils attributed to Homo in the Turkana Basin show an increase in the consumption of C4 resources circa 1.65 million years ago, significantly after the earliest evidence for Homo in the eastern African fossil record. These data are consistent with ingesting more C4 plants, more animal tissues of C4 herbivores, or both, but it is also possible that this change reflects factors unrelated to changes in the palaeobiology of the genus Homo. Here we use new and published carbon and oxygen isotopic data (n = 999) taken from large-bodied fossil mammals, and pedogenic carbonates in fossil soils, from East Turkana in northern Kenya to investigate the context of this change in the isotope signal within Homo. By targeting taxa and temporal intervals unrepresented or undersampled in previous analyses, we were able to conduct the first comprehensive analysis of the ecological context of hominin diet at East Turkana during a period crucial for detecting any dietary and related behavioural differences between early Homo (H. habilis and/or H. rudolfensis) and Homo erectus. Our analyses suggest that the genus Homo underwent a dietary shift (as indicated by δ13Cena and δ18Oena values) that is (1) unrelated to changes in the East Turkana vegetation community and (2) unlike patterns found in other East Turkana large mammals, including Paranthropus and Theropithecus. These data suggest that within the Turkana Basin a dietary shift occurred well after we see the first evidence of early Homo in the region.

Advancing Translational Research Using NIMH Research Domain Criteria and Computational Methods.

The NIMH Research Domain Criteria (RDoC) can aid in the translation of integrative neuroscience. We argue that the RDoC framework, with its emphasis on integration across units of analysis, leveraged with computational approaches, can organize intermediary treatment targets and clinical outcomes, augmenting the translational stream.

Psychophysiological science and the research domain criteria: A commentary.

The current special issue, devoted to the Research Domain Criteria (RDoC) initiative of the US National Institute of Mental Health, showcases a variety of empirical and review articles that address issues related to this dimensional and multi-method approach to research on mental disorders. Here, we provide an integrative perspective on various aspects of these articles, focused around the primary principles of the RDoC approach and the practical and methodological issues related to conducting RDoC-informed research. The chief point we wish to highlight is that these articles demonstrate the ways in which the field of psychophysiology already thinks along the lines of RDoC in terms of using biobehavioral constructs, looking for convergence among constructs using various methodologies, and utilizing dimensional measurements in studies. In this sense, RDoC is not novel; however, by specifying a formal research platform it provides explicit encouragement and guidance for using such principles in understanding psychiatric phenomena, rather than continuing to focus research efforts on traditional diagnostic categories alone.

Informed consent in the psychosis prodrome: ethical, procedural and cultural considerations.

Research focused on the prodromal period prior to the onset of psychosis is essential for the further development of strategies for early detection, early intervention, and disease pre-emption. Such efforts necessarily require the enrollment of individuals who are at risk of psychosis but have not yet developed a psychotic illness into research and treatment protocols. This work is becoming increasingly internationalized, which warrants special consideration of cultural differences in conceptualization of mental illness and international differences in health care practices and rights regarding research participation. The process of identifying and requesting informed consent from individuals at elevated risk for psychosis requires thoughtful communication about illness risk and often involves the participation of family members. Empirical studies of risk reasoning and decisional capacity in young people and individuals with psychosis suggest that most individuals who are at-risk for psychosis can adequately provide informed consent; however ongoing improvements to tools and procedures are important to ensure that this work proceeds with maximal consideration of relevant ethical issues. This review provides a discussion of these issues in the context of international research efforts.

Studying hallucinations within the NIMH RDoC framework.

We explore how hallucinations might be studied within the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) framework, which asks investigators to step back from diagnoses based on symptoms and focus on basic dimensions of functioning. We start with a description of the objectives of the RDoC project and its domains and constructs. Because the RDoC initiative asks investigators to study phenomena across the wellness spectrum and different diagnoses, we address whether hallucinations experienced in nonclinical populations are the same as those experienced by people with psychotic diagnoses, and whether hallucinations studied in one clinical group can inform our understanding of the same phenomenon in another. We then discuss the phenomenology of hallucinations and how different RDoC domains might be relevant to their study. We end with a discussion of various challenges and potential next steps to advance the application of the RDoC approach to this area of research.

Rethinking mental disorders: the role of learning and brain plasticity.

Recent research in neurodevelopment, neuroplasticity and genetics is providing new insights into the etiogenesis of psychopathology, but progress in treatment development has been hampered by reliance on diagnostic categories that are characterized by heterogeneity and based primarily on phenomenology. The NIMH Research Domain Criteria (RDoC) initiative seeks to provide a neuroscience-based nosological framework for future research on psychopathology, categorizing individuals for research purposes using a dimensional approach that capitalizes on advances in modern neuroscience. These scientific advances and new approaches to classification can inform the development of novel, circuit-based interventions and the personalization of treatment. In this paper, we review key advances areas in clinical neuroscience, describe the RDoC project and highlight some emerging treatment approaches that are consistent with these developments.

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.

Response activation impairments in schizophrenia: evidence from the lateralized readiness potential.

Previous research has demonstrated deficits in preresponse motor activity in schizophrenia, as evidenced by a reduced lateralized readiness potential (LRP). The LRP deficit could be due to increased activation of the incorrect response (e.g., failure to suppress competition) or to reduced activation of the correct response (e.g., a low-level impairment in response preparation). To distinguish these possibilities, we asked whether the LRP impairment is increased under conditions of strong response competition. We manipulated the compatibility of stimulus-response mappings (Experiment 1) and the compatibility of the target with flankers (Experiment 2). In both experiments, the patient LRP was reduced as much under conditions of low response competition as under high competition. These results are incompatible with a failure of patients to suppress competition and are instead consistent with a deficit in activating the correct response.

Dissociation of response and feedback negativity in schizophrenia: electrophysiological and computational evidence for a deficit in the representation of value.

Contrasting theories of schizophrenia propose that the disorder is characterized by a deficit in phasic changes in dopamine activity in response to ongoing events or, alternatively, by a weakness in the representation of the value of responses. Schizophrenia patients have reliably reduced brain activity following incorrect responses but other research suggests that they may have intact feedback-related potentials, indicating that the impairment may be specifically response-related. We used event-related brain potentials and computational modeling to examine this issue by comparing the neural response to outcomes with the neural response to behaviors that predict outcomes in patients with schizophrenia and psychiatrically healthy comparison subjects. We recorded feedback-related activity in a passive gambling task and a time estimation task and error-related activity in a flanker task. Patients' brain activity following an erroneous response was reduced compared to comparison subjects but feedback-related activity did not differ between groups. To test hypotheses about the possible causes of this pattern of results, we used computational modeling of the electrophysiological data to simulate the effects of an overall reduction in patients' sensitivity to feedback, selective insensitivity to positive or negative feedback, reduced learning rate, and a decreased representation of the value of the response given the stimulus on each trial. The results of the computational modeling suggest that schizophrenia patients exhibit weakened representation of response values, possibly due to failure of the basal ganglia to strongly associate stimuli with appropriate response alternatives.

Dopamine uptake inhibitors but not dopamine releasers induce greater increases in motor behavior and extracellular dopamine in adolescent rats than in adult male rats.

Most life-long drug addiction begins during adolescence. Important structural and functional changes in brain occur during adolescence and developmental differences in forebrain dopamine systems could mediate a biologic vulnerability to drug addiction during adolescence. Studies investigating age differences in psychostimulant responses have yielded mixed results, possibly because of different mechanisms for increasing extracellular dopamine. Recent research from our laboratory suggests that adolescent dopamine systems may be most affected by selective dopamine uptake inhibitors. We investigated age-related behavioral responses to acute administration of several dopamine uptake inhibitors [methylphenidate, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR12909), and nomifensine] and releasing agents [amphetamine and methylenedioxymethamphetamine (MDMA)] in adolescent and adult male rats. Methylphenidate and amphetamine effects on stimulated dopamine efflux were determined using fast-scan cyclic voltammetry in vivo. Dopamine uptake inhibitors but not dopamine releasing agents induced more locomotion and/or stereotypy in adolescent relative to adult rats. MDMA effects were greater in adults at early time points after dosing. Methylphenidate but not amphetamine induced much greater dopamine efflux in periadolescent relative to adult rats. Periadolescent male rats are particularly sensitive to psychostimulants that are DAT inhibitors but are not internalized and do not release dopamine. Immaturity of DAT and/or DAT associated signaling systems in adolescence specifically enhances behavioral and dopaminergic responses in adolescence.

Reward processing in schizophrenia: a deficit in the representation of value.

Patients with schizophrenia demonstrate deficits in motivation and learning that suggest impairment in different aspects of the reward system. In this article, we present the results of 8 converging experiments that address subjective reward experience, the impact of rewards on decision making, and the role of rewards in guiding both rapid and long-term learning. All experiments compared the performance of stably treated outpatients with schizophrenia and demographically matched healthy volunteers. Results to date suggest (1) that patients have surprisingly normal experiences of positive emotion when presented with evocative stimuli, (2) that patients show reduced correlation, compared with controls, between their own subjective valuation of stimuli and action selection, (3) that decision making in patients appears to be compromised by deficits in the ability to fully represent the value of different choices and response options, and (4) that rapid learning on the basis of trial-to-trial feedback is severely impaired whereas more gradual learning may be surprisingly preserved in many paradigms. The overall pattern of findings suggests compromises in the orbital and dorsal prefrontal structures that play a critical role in the ability to represent the value of outcomes and plans. In contrast, patients often (but not always) approach normal performance levels on the slow learning achieved by the integration of reinforcement signals over many trials, thought to be mediated by the basal ganglia.