Revolutionizing the Study of Mental Disorders

March 27, 2024 • Feature Story • 75th Anniversary

President George H. W. Bush proclaimed the 1990s “The Decade of the Brain ,” urging the National Institutes of Health, the National Institute of Mental Health (NIMH), and others to raise awareness about the benefits of brain research.

“Over the years, our understanding of the brain—how it works, what goes wrong when it is injured or diseased—has increased dramatically. However, we still have much more to learn,” read the president’s proclamation. “The need for continued study of the brain is compelling: millions of Americans are affected each year by disorders of the brain…Today, these individuals and their families are justifiably hopeful, for a new era of discovery is dawning in brain research.”

Still, despite the explosion of new techniques and tools for studying the brain, such as functional magnetic resonance imaging (fMRI), many mental health researchers were growing frustrated that their field was not progressing as quickly as they had hoped.

For decades, researchers have studied mental disorders using diagnoses based on the Diagnostic and Statistical Manual of Mental Disorders (DSM)—a handbook that lists the symptoms of mental disorders and the criteria for diagnosing a person with a disorder. But, among many researchers, suspicion was growing that the system used to diagnose mental disorders may not be the best way to study them.

“There are many benefits to using the DSM in medical settings—it provides reliability and ease of diagnosis. It also provides a clear-cut diagnosis for patients, which can be necessary to request insurance-based coverage of healthcare or job- or school-based accommodations,” said Bruce Cuthbert, Ph.D., who headed the workgroup that developed NIMH’s Research Domain Criteria Initiative. “However, when used in research, this approach is not always ideal.”

Researchers would often test people with a specific diagnosed DSM disorder against those with a different disorder or with no disorder and see how the groups differed. However, different mental disorders can have similar symptoms, and people can be diagnosed with several different disorders simultaneously. In addition, a diagnosis using the DSM is all or none—patients either qualify for the disorder based on their number of symptoms, or they don’t. This black-and-white approach means there may be people who experience symptoms of a mental disorder but just miss the cutoff for diagnosis.

Dr. Cuthbert, who is now the senior member of the RDoC Unit which orchestrates RDoC work, stated that “Diagnostic systems are based on clinical signs and symptoms, but signs and symptoms can’t really tell us much about what is going on in the brain or the underlying causes of a disorder. With modern neuroscience, we were seeing that information on genetic, pathophysiological, and psychological causes of mental disorders did not line up well with the current diagnostic disorder categories, suggesting that there were central processes that relate to mental disorders that were not being reflected in DMS-based research.”

Road to evolution

Concerned about the limits of using the DSM for research, Dr. Cuthbert, a professor of clinical psychology at the University of Minnesota at the time, approached Dr. Thomas Insel (then NIMH director) during a conference in the autumn of 2008. Dr. Cuthbert recalled saying, “I think it’s really important that we start looking at dimensions of functions related to mental disorders such as fear, working memory, and reward systems because we know that these dimensions cut across various disorders. I think NIMH really needs to think about mental disorders in this new way.”

Dr. Cuthbert didn’t know it then, but he was suggesting something similar to ideas that NIMH was considering. Just months earlier, Dr. Insel had spearheaded the inclusion of a goal in NIMH’s 2008 Strategic Plan for Research to “develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures.”

Unaware of the new strategic goal, Dr. Cuthbert was surprised when Dr. Insel's senior advisor, Marlene Guzman, called a few weeks later to ask if he’d be interested in taking a sabbatical to help lead this new effort. Dr. Cuthbert soon transitioned into a full-time NIMH employee, joining the Institute at an exciting time to lead the development of what became known as the Research Domain Criteria (RDoC) Framework. The effort began in 2009 with the creation of an internal working group of interdisciplinary NIMH staff who identified core functional areas that could be used as examples of what research using this new conceptual framework looked like.

The workgroup members conceived a bold change in how investigators studied mental disorders.

“We wanted researchers to transition from looking at mental disorders as all or none diagnoses based on groups of symptoms. Instead, we wanted to encourage researchers to understand how basic core functions of the brain—like fear processing and reward processing—work at a biological and behavioral level and how these core functions contribute to mental disorders,” said Dr. Cuthbert.

This approach would incorporate biological and behavioral measures of mental disorders and examine processes that cut across and apply to all mental disorders. From Dr. Cuthbert’s standpoint, this could help remedy some of the frustrations mental health researchers were experiencing.

Around the same time the workgroup was sharing its plans and organizing the first steps, Sarah Morris, Ph.D., was a researcher focusing on schizophrenia at the University of Maryland School of Medicine in Baltimore. When she first read these papers, she wondered what this new approach would mean for her research, her grants, and her lab.

She also remembered feeling that this new approach reflected what she was seeing in her data.

“When I grouped my participants by those with and without schizophrenia, there was a lot of overlap, and there was a lot of variability across the board, and so it felt like RDoC provided the pathway forward to dissect that and sort it out,” said Dr. Morris.

Later that year, Dr. Morris joined NIMH and the RDoC workgroup, saying, “I was bumping up against a wall every day in my own work and in the data in front of me. And the idea that someone would give the field permission to try something new—that was super exciting.”

The five original RDoC domains of functioning were introduced to the broader scientific community in a series of articles published in 2010 .

To establish the new framework, the RDoC workgroup (including Drs. Cuthbert and Morris) began a series of workshops in 2011 to collect feedback from experts in various areas from the larger scientific community. Five workshops were held over the next two years, each with a different broad domain of functioning based upon prior basic behavioral neuroscience. The five domains were called:

• Negative valence (which included processes related to things like fear, threat, and loss)
• Positive valence (which included processes related to working for rewards and appreciating rewards)
• Cognitive processes
• Social processes
• Arousal and regulation processes (including arousal systems for the body and sleep).

At each workshop, experts defined several specific functions, termed constructs, that fell within the domain of interest. For instance, constructs in the cognitive processes domain included attention, memory, cognitive control, and others.

The result of these feedback sessions was a framework that described mental disorders as the interaction between different functional processes—processes that could occur on a continuum from normal to abnormal. Researchers could measure these functional processes in a variety of complementary ways—for example, by looking at genes associated with these processes, the brain circuits that implement these processes, tests or observations of behaviors that represent these functional processes, and what patients report about their concerns. Also included in the framework was an understanding that functional processes associated with mental disorders are impacted and altered by the environment and a person’s developmental stage.

Preserving momentum

Over time, the Framework continued evolving and adapting to the changing science. In 2018, a sixth functional area called sensorimotor processes was added to the Framework, and in 2019, a workshop was held to better incorporate developmental and environmental processes into the framework.;

Since its creation, the use of RDoC principles in mental health research has spread across the U.S. and the rest of the world. For example, the Psychiatric Ratings using Intermediate Stratified Markers project (PRISM) , which receives funding from the European Union’s Innovative Medicines Initiative, is seeking to link biological markers of social withdrawal with clinical diagnoses using RDoC-style principles. Similarly, the Roadmap for Mental Health Research in Europe (ROAMER)  project by the European Commission sought to integrate mental health research across Europe using principles similar to those in the RDoC Framework.;

Dr. Morris, who has acceded to the Head of the RDoC Unit, commented: “The fact that investigators and science funders outside the United States are also pursuing similar approaches gives me confidence that we’ve been on the right pathway. I just think that this has got to be how nature works and that we are in better alignment with the basic fundamental processes that are of interest to understanding mental disorders.”

The RDoC framework will continue to adapt and change with emerging science to remain relevant as a resource for researchers now and in the future. For instance, NIMH continues to work toward the development and optimization of tools to assess RDoC constructs and supports data-driven efforts to measure function within and across domains.

“For the millions of people impacted by mental disorders, research means hope. The RDoC framework helps us study mental disorders in a different way and has already driven considerable change in the field over the past decade,” said Joshua A. Gordon, M.D., Ph.D., director of NIMH. “We hope this and other innovative approaches will continue to accelerate research progress, paving the way for prevention, recovery, and cure.”

Publications

Cuthbert, B. N., & Insel, T. R. (2013). Toward the future of psychiatric diagnosis: The seven pillars of RDoC. BMC Medicine, 11, 126. https://doi.org/10.1186/1741-7015-11-126 

Cuthbert B. N. (2014). Translating intermediate phenotypes to psychopathology: The NIMH Research Domain Criteria. Psychophysiology, 51(12), 1205–1206. https://doi.org/10.1111/psyp.12342 

Cuthbert, B., & Insel, T. (2010). The data of diagnosis: New approaches to psychiatric classification. Psychiatry, 73(4), 311–314. https://doi.org/10.1521/psyc.2010.73.4.311 

Cuthbert, B. N., & Kozak, M. J. (2013). Constructing constructs for psychopathology: The NIMH research domain criteria. Journal of Abnormal Psychology, 122(3), 928–937. https://doi.org/10.1037/a0034028 

Garvey, M. A., & Cuthbert, B. N. (2017). Developing a motor systems domain for the NIMH RDoC program. Schizophrenia Bulletin, 43(5), 935–936. https://doi.org/10.1093/schbul/sbx095 

Kozak, M. J., & Cuthbert, B. N. (2016). The NIMH Research Domain Criteria initiative: Background, issues, and pragmatics. Psychophysiology, 53(3), 286–297. https://doi.org/10.1111/psyp.12518 

Morris, S. E., & Cuthbert, B. N. (2012). Research Domain Criteria: Cognitive systems, neural circuits, and dimensions of behavior. Dialogues in Clinical Neuroscience, 14(1), 29–37. https://doi.org/10.31887/DCNS.2012.14.1/smorris 

Sanislow, C. A., Pine, D. S., Quinn, K. J., Kozak, M. J., Garvey, M. A., Heinssen, R. K., Wang, P. S., & Cuthbert, B. N. (2010). Developing constructs for psychopathology research: Research domain criteria. Journal of Abnormal Psychology, 119(4), 631–639. https://doi.org/10.1037/a0020909 

Learn more

• Presidential Proclamation 6158 (The Decade of the Brain) 
• Research Domain Criteria Initiative website
• Psychiatric Ratings using Intermediate Stratified Markers (PRISM)