NIMH Research Domain Criteria Research Articles

Using Natural Language Processing to identify psychiatric symptoms related to Alzheimer’s disease: a novel tool to enhance molecular brain research in Alzheimer’s disease

AbstractBackgroundNeuropsychiatric symptoms (NPS), such as anxiety, depression, or agitation, are common across different stages of Alzheimer’s disease (AD). However, their molecular course is still poorly understood. While post‐mortem brain research provides a unique source to study brain‐specific molecular changes, clinical characterization of post‐mortem brain donors is challenging and primarily subject to case‐control designs. Here, we present a novel approach to post‐mortem brain donor characterization using natural language processing (NLP).MethodWe analyzed electronic health records (HER) of 92 brain donors (46 males, 46 females, mean age 81.9 years, B&B 0 ‐ VI) using NLP‐based NIMH Research Domain Criteria (RDoC) quantification. Individual RDoC scores were regressed to their neuropathological findings or RNAseq data from two independent brain regions, BA32 and insula.ResultNeuritic plaques (NP) in all four cortices show a high association with RDoC “cognition”, controlled for age and sex (frontal: ß = 0.38, p < 0.001; parietal: ß = 0.35, p < 0.001; temporal: ß = 0.37, p < 0.001; occipital: ß = 0.37, p < 0.001). These findings align with prior clinicopathological correlation studies where cognitive examinations were performed within one year before death (Nelson et al., J Neuropathol Exp Neurol, 2012). At pFDR<0.05, we identified 492 differentially expressed genes (DEGs) in the insula and 333 DEGs in the BA32. We have further built a model regressing individual RDoC levels against their DEGs in the two brain regions. In each domain, we observed a cluster of genes that is up‐ or downregulated in relation to their RDoC score (higher/lower domain burden). In addition, we saw that the majority of DEGs are RDoC‐specific. 223 DEGs were uniquely related to one domain (170 DEGs in the insula and 53 DEGs in BA32), while a total of 211 DEGs were associated with at least two domains (151 DEGs in the insula and 60 DEGs in BA32).ConclusionNLP‐based analysis of RDoC can be applied to post‐mortem case collections to phenotype brain donors and show promising associations with neuropathology or RNAseq data that can be used to discover novel molecular pathways related to psychiatric symptoms.

Reward Learning Through the Lens of RDoC: a Review of Theory, Assessment, and Empirical Findings in the Eating Disorders.

Reward-related processes may represent important transdiagnostic factors underlying eating pathology. Using the NIMH Research Domain Criteria as a guide, the current article reviews theories, behavioral and self-report assessments, and empirical findings related to reward learning in the eating disorders. Data from behavioral tasks suggest deficits in reinforcement learning, which may become more pronounced with increasing disorder severity and duration. Self-report data strongly implicate positive eating and thinness/restriction expectancies (an element of reward prediction error) in the onset and maintenance of eating pathology. Finally, self-report measures of habit strength demonstrate relationships with eating pathology and illness duration; however, behavioral task data do not support relationships between eating pathology and a propensity towards general habit development. Existing studies are limited, but provide preliminary support for the presence of abnormal reward learning in eating disorders. Continued research is needed to address identified gaps in the literature.

Comorbidity in Schizophrenia: Conceptual Issues and Clinical Management.

Schizophrenia is a complex psychiatric disorder that affects cognitive, perceptual, and emotional functioning. The currently available evidence suggests heterogenous intertwining of biological and psychosocial etio-pathogeneses. Clinical and research interests in the comorbidity issues of schizophrenia were borne out of the real-world clinical challenges that patients often present with multiple coexisting psychopathologies as well as comorbid medical conditions. The recent DSM-5 shift toward a symptom dimensional-based perspective, the NIMH Research Domain Criteria (RDoC) initiative to examine biopsychosocial pathogeneses in mental illness, and the FDA's emphasis on real world-based clinical trial criterion all have promoted a shift in clinical research that has facilitated understanding and treatment of comorbidity in schizophrenia. This emerging conceptual shift as well as pharmacological developments that address the multidimensional pathogeneses in schizophrenia may pave the way for a better understanding and treatment.

Mechanistic Trial Evaluating the Effect of Repetitive Transcranial Magnetic Stimulation on RDoC Constructs in Treatment-Resistant Depression

Remission rates for repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression (TRD) are as high as 43%, although the large-scale neural circuit mechanisms by which patients improve remain unclear. We assessed the effect of rTMS on neural circuits and concurrent changes in behaviors and symptoms within the NIMH's Research Domain Criteria (RDoC) constructs of reward responsiveness, rumination, attention, and cognitive control in a cohort of subjects with TRD and prominent anhedonia, encompassing loss of pleasure, interest, and/or motivation.

Image acquisition and quality assurance in the Boston Adolescent Neuroimaging of Depression and Anxiety study.

The Connectomes Related to Human Diseases (CRHD) initiative was developed with the Human Connectome Project (HCP) to provide high-resolution, open-access, multi-modal MRI data to better understand the neural correlates of human disease. Here, we present an introduction to a CRHD project, the Boston Adolescent Neuroimaging of Depression and Anxiety (BANDA) study, which is collecting multimodal neuroimaging, clinical, and neuropsychological data from 225 adolescents (ages 14-17), 150 of whom are expected to have a diagnosis of depression and/or anxiety. Our transdiagnostic recruitment approach samples the full spectrum of depressed/anxious symptoms and their comorbidity, consistent with NIMH Research Domain Criteria (RDoC). We focused on an age range that is critical for brain development and for the onset of mental illness. This project sought to harmonize imaging sequences, hardware, and functional tasks with other HCP studies, although some changes were made to canonical HCP methods to accommodate our study population and questions. We present a thorough overview of our imaging sequences, hardware, and scanning protocol. We detail similarities and differences between this study and other HCP studies. We evaluate structural-, diffusion-, and functional-image-quality measures that may be influenced by clinical factors (e.g., disorder, symptomatology). Signal-to-noise and motion estimates from the first 140 adolescents suggest minimal influence of clinical factors on image quality. We anticipate enrollment of an additional 85 participants, most of whom are expected to have a diagnosis of anxiety and/or depression. Clinical and neuropsychological data from the first 140 participants are currently freely available through the National Institute of Mental Health Data Archive (NDA).

Frustrative Non-reward and Lab-Based Paradigms for Advancing the Study of Aggression in Persons with Psychosis

Prior research and assessment of aggression in schizophrenia and other psychotic conditions has focused on one or two levels of measurement (third-party observation and self-report) identified by the NIMH Research Domain Criteria (RDoC), while frequently neglecting a third (laboratory behavioral paradigms). We review aggression in psychosis using the RDoC conceptualization of frustrative non-reward; describe how lab-based behavioral paradigms, particularly, the Point Subtraction Aggression Paradigm (PSAP), can help to better understand aggression in individuals with psychosis; and suggest directions for future research. Many studies of violence in psychosis focus on field observations of behavior and self-report. However, laboratory behavioral paradigms such as the PSAP, which have not been widely adopted, hold conceptual promise for the study of aggression in schizophrenia. The RDoC represent a neurobehavioral approach for advancing behavioral health research that recommends multilevel investigations to include laboratory behavioral paradigms. The PSAP is one such behavioral measure with particular relevance to a frustrative non-reward conceptualization of aggression. The PSAP and its adaptations offer a promising methodology for future research of aggression in schizophrenia and other psychotic conditions. The method may likewise prove useful in individual cases, to enhance the incremental validity of violence risk assessment.

The NIMH Research Domain Criteria (RDoC) Initiative and Its Implications for Research on Personality Disorder.

We discuss the implications of the Research Domain Criteria (RDoC) initiative for neuroscience research on personality disorder (PD). To organize our review, we construct a preliminary conceptual mapping of PD symptom criteria onto RDoC constructs. We then highlight recent neuroscience research, often built around concepts that correspond to RDoC elements, and discuss the findings in reference to the constructs we consider most pertinent to PD. PD symptoms were strongly conceptually tied to RDoC constructs within the Social Processes domain, implicating brain systems involved in interpersonal rejection, facial emotion perception, and self-referential processes. Negative and Positive Valence Systems were conceptually associated with many PD symptoms, with particular relevance ascribed to the latter's Reward Valuation construct, which could reflect a more widespread disruption of computational processes involved in estimating the probability and benefits of a future outcome. Within the Cognitive Systems domain, the Cognitive Control construct mainly related to PD symptoms associated with impulse control, suggesting a connection to neural circuits that underlie goal selection and behavioral control. Arousal and Regulatory Systems could only be conceptually mapped onto PD symptoms through the Arousal construct, with different symptoms reflecting either a higher or lower biological sensitivity to internal and external stimuli. The RDoC framework has promise to advance neuroscience research on PD. The Social Processes domain is especially relevant to PD, although constructs falling within the other RDoC domains could also yield important insights into the neurobiology of PD and its connections with other forms of psychopathology. Identifying RDoC constructs (e.g., habit formation) that subserve more fundamental processes relevant to personality functioning warrants further investigation.

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.

Toward Unraveling ADHD Pathophysiology: ADHD Endophenotypes, Research Domain Criteria (Rdoc) Measures, and Molecular Genetic Approaches

This Symposium will evaluate hypothesized mechanisms in cognition and brain for their role of genetic effects on ADHD, relating this to the endophenotype literature and the NIMH Research Domain Criteria (RDoC) approach in mental health research.

Unlocking Neurocognitive Substrates of Late-Life Affective Symptoms Using the Research Domain Criteria: Worry Is an Essential Dimension.

While investigations have sought to identify the distinct and shared contributions of anxiety and depression to neurocognitive processes in late life, less is known regarding the further contribution of worry, a unique and critical dimension of affective dysregulation. Capturing the full range of symptoms, as inspired by the NIH Research Domain Criteria (RDoC), may provide finer-grained information on inter-relationships among worry, anxiety and depression on neurocognitive processing in later life. The objective of this study was to determine if the dimensional trait of worry intensifies known negative associations of dimensional measures of anxiety and depressive symptoms with neurocognitive processes, specifically cognitive control and memory processes. Using a cross-sectional and observational design, this study was conducted within a translational research center located with a Veterans medical center in Northern California. One hundred and nineteen community-residing older adults ages 65–91 years participated, and were characterized with psychiatric and neurocognitive dimensional measures. Affective symptom severity was assessed with the Penn State Worry Questionnaire, the Beck Anxiety Inventory (BAI), and the Beck Depression Inventory-II. Primary neurocognitive outcomes were inhibitory control assessed using a Stroop paradigm and delayed verbal memory assessed with the Rey Auditory Verbal Learning Test. Secondary outcomes included other less frequently examined cognitive control mechanisms (working memory, information processing, and verbal fluency) and memory processes (visual delayed memory). Contrary to prediction, the dimensional trait of worry attenuated negative associations between anxiety and depressive symptoms and inhibitory control on the one hand, and between depressive symptoms and delayed verbal memory processes on the other. In the secondary models, symptom dimensions were not associated with other cognitive control or visual delayed memory processes. Our fine-grained approach, in line with the NIMH RDoC model, suggests the neurocognitive processes associated with dimensional measures of late-life affective symptoms are dissociable. Specifically, dimensional measures of worry operate independently from other anxiety and depression symptoms to reveal differential patterns of neurocognitive processes associated with affective dysregulation.

Presidential Symposium: Computational Neuroscience and Its Intersection With the NIMH Research Domain Criteria (RDoC) Initiative

PsychophysiologyVolume 54, Issue S1 p. S22-S23 Presidential Symposium Presidential Symposium: Computational Neuroscience and Its Intersection With the NIMH Research Domain Criteria (RDoC) Initiative First published: 12 November 2017 https://doi.org/10.1111/psyp.13034Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume54, IssueS1Special Issue: Society for Psychophysiological Research, Abstracts for the Fifty-Seventh Annual Meeting, The Hofburg, Vienna, Austria, October 11–15, 2017December 2017Pages S22-S23 RelatedInformation

The Research Domain Criteria framework: transitioning from dimensional systems to integrating neuroscience and psychopathology

ABSTRACTAlthough recent research in neuroscience and genetics is providing new insights into the etiology of psychiatric disorders, progress in treatment development has been hindered by reliance on diagnostic categories that are based primarily on presenting signs and symptoms. The NIMH Research Domain Criteria (RDoC) framework seeks to provide a neuroscience-based nosological background for future research on psychopathology, categorizing individuals for research purposes using a dimensional approach that benefit from significant progress in modern neuroscience. These scientific advances combined with new approaches to classification can inform the development of novel, circuit-based interventions and the personalization of treatments available. In this editorial, we describe the RDoC framework compared with Diagnostic and Statistical Manual/International Classification of Disease systems and highlight some of the emerging progress in RDoC-based research that is consistent with these developments.

Gender differences in the relationships of temperament and behavioral problems in Russian adolescents

Problems related to aggression in young people are traditionally subsumed under the header of conduct problems, which include conduct disorder and oppositional defiant disorder. Such problems in children and adolescents are an important societal and mental health problem. In this paper we present an evolutionarily informed developmental psychopathology view of conduct problems inspired by the NIMH Research Domain Criteria (RDoC) initiative. We assume that while there are many pathways to conduct problems, chronic or temporary impairments in the domain of social cognition or mentalizing are a common denominator. Specifically, we conceptualize conduct problems as reflecting temporary or chronic difficulties with mentalizing, that is, the capacity to understand the self and others in terms of intentional mental states, leading to a failure to inhibit interpersonal violence through a process of perspective-taking and empathy. These difficulties, in turn, stem from impairments in making use of a normally evolutionarily protected social learning system that functions to facilitate intergenerational knowledge transmission and protect social collaborative processes from impulsive and aggressive action. Temperamental, biological, and social risk factors in different combinations may all contribute to this outcome. This adaptation then interacts with impairments in other domains of functioning, such as in negative and positive valence systems and cognitive systems. This view highlights the importance of a complex interplay among biological, psychological, and environmental factors in understanding the origins of conduct problems. We outline the implications of these views for future research and intervention.

The genetics of anxiety-related negative valence system traits.

NIMH's Research Domain Criteria (RDoC) domain of negative valence systems (NVS) captures constructs of negative affect such as fear and distress traditionally subsumed under the various internalizing disorders. Through its aims to capture dimensional measures that cut across diagnostic categories and are linked to underlying neurobiological systems, a large number of phenotypic constructs have been proposed as potential research targets. Since "genes" represent a central "unit of analysis" in the RDoC matrix, it is important for studies going forward to apply what is known about the genetics of these phenotypes as well as fill in the gaps of existing knowledge. This article reviews the extant genetic epidemiological data (twin studies, heritability) and molecular genetic association findings for a broad range of putative NVS phenotypic measures. We find that scant genetic epidemiological data is available for experimentally derived measures such as attentional bias, peripheral physiology, or brain-based measures of threat response. The molecular genetic basis of NVS phenotypes is in its infancy, since most studies have focused on a small number of candidate genes selected for putative association to anxiety disorders (ADs). Thus, more research is required to provide a firm understanding of the genetic aspects of anxiety-related NVS constructs. © 2016 Wiley Periodicals, Inc.

An examination of the language construct in NIMH's research domain criteria: Time for reconceptualization!

The National Institute of Mental Health's Research Domain Criteria (RDoC) Initiative “calls for the development of new ways of classifying psychopathology based on dimensions of observable behavior.” As a result of this ambitious initiative, language has been identified as an independent construct in the RDoC matrix. In this article, we frame language within an evolutionary and neuropsychological context and discuss some of the limitations to the current measurements of language. Findings from genomics and the neuroimaging of performance during language tasks are discussed in relation to serious mental illness and within the context of caveats regarding measuring language. Indeed, the data collection and analysis methods employed to assay language have been both aided and constrained by the available technologies, methodologies, and conceptual definitions. Consequently, different fields of language research show inconsistent definitions of language that have become increasingly broad over time. Individually, they have also shown significant improvements in conceptual resolution, as well as in experimental and analytic techniques. More recently, language research has embraced collaborations across disciplines, notably neuroscience, cognitive science, and computational linguistics and has ultimately re‐defined classical ideas of language. As we move forward, the new models of language with their remarkably multifaceted constructs force a re‐examination of the NIMH RDoC conceptualization of language and thus the neuroscience and genetics underlying this concept. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

Reshaping clinical science: Introduction to the Special Issue on Psychophysiology and the NIMH Research Domain Criteria (RDoC) initiative.

The National Institute of Mental Health's (NIMH) Research Domain Criteria (RDoC) initiative seeks to establish new dimensional conceptions of mental health problems, through the investigation of clinically relevant "process" constructs that have neurobiological as well as psychological referents. This special issue provides a detailed overview of the RDoC framework by NIMH officials Michael Kozak and Bruce Cuthbert, and spotlights RDoC-oriented investigative efforts by leading psychophysiological research groups as examples of how clinical science might be reshaped through application of RDoC principles. Accompanying commentaries highlight key aspects of the work by each group, and discuss reported methods/findings in relation to promises and challenges of the RDoC initiative more broadly.

Psychophysiology of threat response, paradigm shifts in psychiatry, and RDoC: Implications for genetic investigation of psychopathology.

Two articles in this issue seek to further the goal of NIMH's Research Domain Criteria (RDoC) initiative to develop new approaches for investigating mental disorders, using fundamental dimensions that cut across traditional disorder categories and align more closely with mechanisms that underlie psychopathology. One article, by Lang, McTeague, and Bradley, describes the construction of such a disorder cross-crossing dimension of fear response. The other, by Kozak and Cuthbert, expounds upon the basis and conceptualization of research targets under RDoC. Possible implications of these developments for psychiatric genetics research are discussed.

Psychobiological operationalization of RDoC constructs: Methodological and conceptual opportunities and challenges.

NIMH's Research Domain Criteria (RDoC) project seeks to advance the diagnosis, prevention, and treatment of mental disorders by promoting psychobiological research on dimensional constructs that might cut across traditional diagnostic boundaries (Kozak & Cuthbert, ). At the core of this approach is the notion that these dimensional constructs can be assessed across different units of analysis (e.g., genes, physiology, behavior), enriching the constructs and providing more complete explanations of clinical problems. While the conceptual aspects of RDoC have been discussed in several prior papers, its methodological aspects have received comparatively less attention. For example, how to integrate data from different units of analysis has been relatively unclear. Here, we discuss one means of psychobiologically operationalizing RDoC constructs across different units of analysis (the psychoneurometric approach; Yancey et al., ), highlighting ways in which this approach might be refined in future iterations. We conclude that there is much to be learned from this technique; however, greater attention to scale-development methods and to psychometrics will likely benefit this and other methodological approaches to combining measurements across multiple units of analysis.

The RDoC initiative and the structure of psychopathology.

The NIMH Research Domain Criteria (RDoC) project represents a welcome effort to circumvent the limitations of psychiatric categories as phenotypes for psychopathology research. Here, we describe the hierarchical and dimensional structure of phenotypic psychopathology and illustrate how this structure provides phenotypes suitable for RDoC research on neural correlates of psychopathology. A hierarchical and dimensional approach to psychopathology phenotypes holds great promise for delineating connections between neuroscience constructs and the patterns of affect, cognition, and behavior that constitute manifest psychopathology.

Neuroethology as a translational neuroscience strategy in the era of the NIMH Research Domain Criteria.

The article by Latzman et al. in the current special issue utilizes a novel dataset consisting of behavioral, brain, and genomic data from a sample of 76 captive chimpanzees to make the case that negative affective expression is influenced by variation in the gene coding for arginine vasopressin receptor 1A (AVPR1A), in a sex-linked manner. A novel feature of this study is the ethological approach employed by the authors, i.e., the use of scratching as a behavioral indicator of negative affective state. I comment on conceptual and methodological aspects of this work, and consider how it interfaces with the Research Domain Criteria (RDoC) framework as described by Kozak and Cuthbert in their article for this issue.