Over the past several decades, an increasingly comprehensive body of research in genetics, neuroscience, and behavioral science has transformed our understanding of how the brain produces adaptive behavior, and the ways in which normal functioning becomes disrupted in various forms of mental disorders. In order to speed the translation of this new knowledge to clinical issues, the NIMH included in its new strategic plan Strategy 1.4: “Develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures.” (For the full text, see http://www.nimh.nih.gov/about/strategic-planning-reports/index.shtml#strategic-objective1). The implementation of this strategy has been named the Research Domain Criteria Project (RDoC). The purpose of this document is to describe the RDoC project in order to acquaint the field with its nature and direction, and to facilitate commentary from scientists and other interested stakeholders regarding both general and specific aspects of the RDoC approach.
Across all areas of medicine, research in genomics, cell biology, and pathophysiology is revolutionizing diagnosis and treatment. In disorders as diverse as cancer, heart disease, diabetes, and inflammatory bowel disease, the discovery of identifiable subtypes within broad clinical phenotypes has led to more specific, more effective treatments or identification of new targets for prevention. Research in mental disorders is also developing quickly: Novel data about genomic factors and the role of particular brain circuits are reported almost monthly. However, new findings on mental disorders have had limited clinical impact, partly because they map only moderately onto current diagnostic categories for mental illness. Thus, some of the risk genes for psychotic disorders appear to be associated with both schizophrenia and bipolar disorder and the same prefrontal region has been implicated in depression and PTSD. In contrast to cancer and heart disease, where research has identified subtypes of common disease, it appears that the biological findings with mental disorders are relatively non-specific; could specificity in fact exist, but not for the currently recognized clinical categories? This question leads to a consideration of how current categories were derived.
Currently, diagnosis in mental disorders is based on clinical observation and patients’ phenomenological symptom reports. This system, implemented with the innovative Diagnostic and Statistical Manual-III (DSM-III) in 1980 and refined in the current DSM-IV-TR (Text Revision), has served well to improve diagnostic reliability in both clinical practice and research. The diagnostic categories represented in the DSM-IV and the International Classification of Diseases-10 (ICD-10, containing virtually identical disorder codes) remain the contemporary consensus standard for how mental disorders are diagnosed and treated, and are formally implemented in insurance billing, FDA requirements for drug trials, and many other institutional usages. By default, current diagnoses have also become the predominant standard for reviewing and awarding research grants.
However, in antedating contemporary neuroscience research, the current diagnostic system is not informed by recent breakthroughs in genetics; and molecular, cellular and systems neuroscience. Indeed, it would have been surprising if the clusters of complex behaviors identified clinically were to map on a one-to-one basis onto specific genes or neurobiological systems. As it turns out, most genetic findings and neural circuit maps appear either to link to many different currently recognized syndromes or to distinct subgroups within syndromes. If we assume that the clinical syndromes based on subjective symptoms are unique and unitary disorders, we undercut the power of biology to identify illnesses linked to pathophysiology and we limit the development of more specific treatments. Imagine treating all chest pain as a single syndrome without the advantage of EKG, imaging, and plasma enzymes. In the diagnosis of mental disorders when all we had were subjective complaints (cf. chest pain), a diagnostic system limited to clinical presentation could confer reliability and consistency but not validity. To date, there has been general consensus that the science is not yet well enough developed to permit neuroscience-based classification. However, at some point, it is necessary to instantiate such approaches if the field is ever to reach the point where advances in genomics, pathophysiology, and behavioral science can inform diagnosis in a meaningful way. RDoC represents the beginning of such a long-term project.
RDoC is intended as a framework to guide classification of patients for research studies, not as an immediately useful clinical tool. While the hope is that a new way forward for clinical diagnosis will emerge sooner rather than later, the initial steps must be to build a sufficient research foundation that can eventually inform the best approaches for clinical diagnosis and treatment. It is hoped that by creating a framework that interfaces directly with genomics, neuroscience, and behavioral science, progress in explicating etiology and suggesting new treatments will be markedly facilitated.
RDoC will follow three guiding principles, all diverging from current diagnostic approaches.
The RDoC research framework can be considered as a matrix whose rows correspond to specified dimensions of function; these are explicitly termed “Constructs,” i.e., a concept summarizing data about a specified functional dimension of behavior (and implementing genes and circuits) that is subject to continual refinement with advances in science. Constructs represent the fundamental unit of analysis in this system, and it is anticipated that most studies would focus on one construct (or perhaps compare two constructs on relevant measures). Related constructs are grouped into major Domains of functioning, reflecting contemporary thinking about major aspects of motivation, cognition, and social behavior; the five domains are Negative Valence Systems (i.e., systems for aversive motivation), Positive Valence Systems, Cognitive Systems, Systems for Social Processes, and Arousal/Regulatory Systems. The columns of the matrix represent different classes of variables (or units of analysis) used to study the domains/constructs. Seven such classes have been specified; these are genes, molecules, cells, neural circuits, physiology (e.g. cortisol, heart rate, startle reflex), behaviors, and self-reports. Circuits represent the core aspect of these classes of variables – both because they are central to the various biological and behavioral levels of analysis, and because they are used to constrain the number of constructs that are defined. Investigators can select any level of analysis to be the independent variable for classification (or multiple levels in some cases, e.g., behavioral functioning stratified by a genetic polymorphism), and dependent variables can be selected from multiple columns. In addition, since constructs are typically studied in the context of particular scientific paradigms, a column for “paradigms” has been added; obviously, however, paradigms do not represent units of analysis.
Three criteria guided the selection of the draft list of candidate constructs presented here. First, the inclusion of a construct was constrained by whether a particular brain circuit or area could reasonably be specified that implements that dimension of behavior. Given the complexity of the brain and of behavior, this was more ambiguous in some cases than others; some constructs, such as attention, reflect activity spread relatively diffusely over many brain areas, while attachment behavior may similarly reflect neurotransmitter and hormonal functions (e.g., oxytocin) acting at disparate locations throughout the brain. Second, an attempt was made to maintain a reasonable “grain size” that would permit a tractable listing of the major functional dimensions of behavior. While it is recognized that there may be important and meaningful sub-constructs that could be considered (e.g., various types of aggression), an overly specified list could result in an unwieldy and excessively long listing. Third, the constructs are based on current literatures that have provided a neurobehavioral research base for each of the entries.
The draft RDoC matrix is listed in the table below, followed by examples of how the classification system might be used and several points of clarification. Dimensional constructs are listed in the rows. Below the matrix, several constructs are listed to provide examples of brain circuits and/or neurotransmitters that help define and constrain each one, along with a brief indication, where appropriate, of constructs representing the dimension’s opposite pole; note that listings of circuit components and neurotransmitters are meant to be illustrative, not exhaustive. Constructs are grouped into five major domain areas as listed above. It is important to emphasize that these particular domains and constructs are simply starting points that are not definitive or set in concrete. We expect these to change dynamically with input from the field, and as future research is conducted. The keys here are the overall framework that we are suggesting, and the process for its development.
Given that RDoC is a classification framework, how might the scheme work in actual practice, given the goals of (1) permitting widely differing independent variables and (2) implementing a dimensional system that allows variance extending down into what would be regarded as sub-threshold psychopathology? Two general approaches are as follows. The first is to include all patients presenting for treatment at a given type of treatment facility, as in the second example below; the statistical approach then becomes one of regression. The second approach is to specify a particular criterion for selecting multiple groups – e.g., patients who score more than one standard deviation below the mean on a cognitive task, patients who show significant activation in a specified brain area on a neuroimaging task – and compare these to other patients not meeting the criterion and/or to a non-clinical control group. In any case, exclusions for co-morbid conditions would be expected to be much less stringent (although the usual exclusions such as other medical or neurological disorders, extreme substance abuse, etc. could still apply). Manuscripts submitted under RDoC will be expected to state how many patients were screened for inclusion in the study, and the reasons for exclusion.
Two example studies are listed in order to illustrate the types of studies that might be conducted within the RDoC framework. For clarity, the variables used to classify subjects are reiterated at the end of each example.
The RDoC concept is organized around basic neural circuits, their genetic and molecular/cellular building blocks, and the dimensions of functioning that they implement. There are two highly important areas of mental disorders research that are thus not represented in the matrix per se, but are considered to be critical elements in research fostered by RDoC. These two areas are developmental aspects and interactions with the environment. The intent is that the RDoC matrix will enhance the study of both areas by promoting a systematic focus on their relationship to specific circuits and functions.
Developmental aspects. Mental disorders are increasingly viewed as neurodevelopmental disorders in one way or another. Therefore, addressing development issues across various phases of the life span represents a critical consideration that is implicit to the RDoC framework, and might be considered as a third dimension in the matrix. The types of constructs typically found in the child temperament literature are (not coincidentally) similar to the RDoC domains, and many areas of the child psychopathology literature (e.g., broadly addressed to Internalizing or Externalizing problems) serve as a more compatible model for a dimensionally-based approach compared to the highly specified categories of adult psychopathology. Four brief examples might be given of life-span goals that could be addressed within the RDoC framework: (1) Further explicate the longitudinal course of adolescent brain maturation and synaptic pruning to identify genes and circuit development factors associated with departures from normal developmental functioning, and points in prodromal stages where intervention might particularly be targeted; (2) Evaluate the extent to which the recruitment of additional cortical areas during task performance or emotional challenge in elderly subjects predicts resilience against onset or deterioration of course in mental disorders; (3) Generate improved explication of the construct of cognitive control (or effortful control), relative to disentangling current controversies regarding ADHD, juvenile bipolar disorder, conduct disorder, etc.; (4) Specify the mechanisms regarding developmental changes in systems for fear and distress across puberty (including the effects of the social environment), that could explain clinical data indicating that adolescent anxiety disorders often precede depression.
Environmental aspects. The central nervous system is exquisitely sensitive to interactions with various elements of its environment virtually from the moment of conception. The social and physical environment comprises sources of both risk and protection for many different disorders occurring at all points along the life span, and methods for studying such phenomena as gene expression, neural plasticity, and various types of learning are rapidly advancing. As with developmental aspects, environmental influences may thus be considered as another critical dimension of the RDoC matrix. The effects of a particular interaction with the environment, e.g., the effects of early child abuse, may pose risk for a wide variety of disorders. As another example, illicit drug use may cause sensitization of mesolimbic dopamine circuits that generalizes to other drugs of abuse and addictive behaviors. Thus, it is hoped that a research program organized around the relevant circuit-based dimensions that are affected, independent of a particular disorder, will accelerate knowledge regarding such environmental influences along the entire range of analysis from genes to behavior.
The NIMH intends that the RDoC process be as transparent as possible. An internal NIMH steering group, advised by a small group of external experts, has created the initial RDoC framework and devised the list of candidate domains, constructs, and classes of variables. NIMH issued a companion Request for Information (RFI) in the NIH Guide to seek input about all aspects of this first draft of the RDoC matrix and process. These comments were taken into account in further refining the initial version of the matrix.
A series of workshops is currently in progress as an initial step in defining the specifications for each construct. At a minimum, one workshop will be held for each of the five domains. However, in order to gain experience with the process, the first workshop focused on the construct of working memory. Each workshop involves experts from various areas that span the RDoC’s units of analysis. Participants are asked to discuss and decide upon current findings, paradigms, and procedures relevant to each level of analysis, along with critical research questions. Proceedings of each workshop are posted on the RDoC page of the NIMH web site for continuing commentary and suggestions for changes. Depending on the nature and extent of comments, a second workshop may be held to achieve consensus on final specifications.
The final specification for each construct will consist of:
The intent of the RDoC is to accelerate the pace of new discoveries by fostering research that translates findings from basic science into new treatments addressing fundamental mechanisms that cut across current diagnostic categories. The research specifications are intended to guide investigators in conducting such integrative research by including cutting-edge variables in research applications. However, since RDoC is a research framework, use of such variables is not required; indeed, one goal is to speed the pace of new information at all levels of analysis. For this reason, RDoC will incorporate a mechanism for continual evaluation of new findings, and inclusion into the domain/construct specifications. While the exact procedures remain to be worked out, it is anticipated that the NIMH steering group will work together with subject-area experts from each of the relevant domains to accept nominations (from the evaluation team or from scientists in the field) for modifications and additional listings.
Although the formal period for commenting under the RFI has terminated, NIMH welcomes continuing commentary regarding any aspect of the RDoC project, including, but not limited to, the following points. Comments may be emailed to rdoc@mail.nih.gov.
NIMH staff look forward to working with all groups of interested stakeholders as the RDoC project is developed.