NAMHC Minutes of the 247th Meeting

September 20, 2016

Department of Health and Human Services
Public Health Service
National Institutes of Health
National Institute of Mental Health

Introduction

The National Advisory Mental Health Council (NAMHC) convened its 247th meeting in open policy session at 9:00 a.m. on September 20, 2016, at the Neuroscience Center in Rockville, Maryland, and adjourned at approximately 12:40 p.m. In accordance with Public Law 92-463, the policy session was open to the public. The NAMHC reconvened for a closed session to review grant applications at 2:00 p.m. on May 26, 2016, at the Neuroscience Center in Rockville, Maryland, until adjournment at approximately 5:00 p.m. (See Appendix A: Summary of Primary MH Applications Reviewed). Bruce Cuthbert, Ph.D., Director of the Research Domain Criteria (RDoc) Unit, National Institute of Mental Health (NIMH) presided.

Council Members Present at the Grant Review and/or Open Sessions

(See Appendix B: Council Roster)

Chairperson

• Bruce Cuthbert, M.D.

Executive Secretary

• Jean Noronha, Ph.D.

Council Members

• Patricia Areán, Ph.D.
• Deanna M. Barch, Ph.D.
• David A. Brent, M.D.
• B.J. Casey, Ph.D.
• Benjamin G. Druss, M.D., M.P.H.
• Hakon Heimer, M.S.
• Michael F. Hogan, Ph.D.
• Richard L. Huganir, Ph.D.
• John Krystal, M.D.
• Gene E. Robinson, Ph.D.
• Mary Jane Rotheram, Ph.D.
• J. David Sweatt, Ph.D.
• Christopher A. Walsh, M.D.

Ex Officio Members

• John W. Davison, M.B.A., Ph.D. Department of Defense
• Theresa Gleason, Ph.D., Department of Veterans Affairs

Liaison Representative

• Anne Mathews-Younes, Ed.D., Center for Mental Health Services, Substance Abuse and Mental Health Services Administration (SAMSHA)

Others Present at the Open Policy Session

• Erin Cadwalader, Lewis-Burke Associates
• Noelle Corrado, Sign Language Interpreter
• Lynne Dahmen, Purdue University
• Alex Davies, Transcriber
• Craig Fisher, American Psychological Association
• Pamela Foote, SAMHSA
• Brad Joyce, Purdue University
• Perry Kirkham, Purdue University
• William Kochen, George Mason University
• Dytrea Langon, Synergy Enterprises, Inc.
• Alan Leshner, Retired, American Association for the Advancement of Science
• Kevin McNaught, Tourette Association of America, Inc.
• Christopher Ross, Johns Hopkins University
• Yumary Ruiz, Purdue University
• Angela Sharpe, Consortium of Social Science Associates
• Tanya Shuy, Public
• Paula Skedsvold, Federal Association of Behavioral and Brain Sciences
• Zoe Taylor, Purdue University
• Bridgett Townsend, Purdue University
• Daniel Vega, Sign Language Interpreter
• Tracy Waldeck, Association for Psychological Science
• A.J. Walker, National Association of State Mental Health Program Directors
• Philip Wang, American Psychiatric Association
• Lori Whitten, Science Writer
• Steve Wiggins, Purdue University
• TaRaena Yate, Synergy Enterprises
• Dennie Yu, Purdue University

Open Policy Session Call to Order and Opening Remarks

Dr. Cuthbert called the open policy session to order and welcomed all in attendance. He also welcomed members of the public attending via video cast.

Approval of Minutes of the Previous Council Meeting

Turning to the minutes of the May 2016 Council meeting, Dr. Cuthbert asked whether Council members had any comments, revisions, or questions. Receiving none, the Council unanimously passed the motion to approve the minutes.

NIMH Director’s Report

Dr. Cuthbert reported NIMH news:

Joshua Gordon, M.D., Ph.D., started as NIMH Director on September 12th. Dr. Gordon has already held two town hall meetings with NIMH staff members. Shelli Avenevoli, Ph.D., remains as Acting NIMH Deputy Director, and Dr. Cuthbert returns to his position as Director of the RDoC Unit. Gemma Weiblinger, Director of Office of Constituency Relations and Public Liaison (OCRPL) retired in July and Phyllis Quartey-Ampofo, M.P.H., is serving as Acting Director of OCRPL. Tracy Waldeck, Ph.D., Deputy Director of the Division of Extramural Affairs, who worked closely with Council, has moved to the Association for Psychological Science. New Intramural Research Program investigators have also joined NIMH, with Soohyun Lee, Ph.D., and Argyris Stringaris, M.D., Ph.D., taking up posts as Chief of the Functional Circuits Unit and Chief of the Mood, Brain, and Development Unit, respectively.

Turning to NIH news, $55 million was awarded to the Precision Medicine Initiative (PMI) in July for startup grants. Recruitment for the Adolescent Brain Cognitive Development (ABCD)  study began on September 13, 2016.  Additionally, the NIH Final rule for clinical trials registration was released on September 16, 2016. Finally, Diana Bianchi, M.D., will begin as Director of the National Institute of Child Health and Human Development on October 31, 2016. Dr. Cuthbert referred Council members to their packets for a copy of the revised NIMH Strategic Research Priorities.

Dr. Cuthbert noted that he provided a comprehensive update and additional news about the NIH Clinical Center at the May 2016 Council meeting. Andrew Griffith, M.D., Ph.D., NIDCD Scientific Director, will lead the NIH Office of Research Support and Compliance at the Clinical Center. John Gallin, M.D., will occupy the new dual position of NIH Associate Director for Clinical Research and Chief Scientific Officer for the Clinical Center. The Pharmaceutical Development Section is permanently closed, and the Clinical Center will move to an interim Intravenous Admixture Unit in October 2016.

The NIH fiscal year (FY) 2015 budget was $30.3 billion and the figure for FY 2016 is $32.3 billion. This represents a general increase of almost 4 percent, with additional increases for the NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative  and Precision Medicine  Initiative. For NIMH, the FY 2016 operating plan is $1.5 billion, which is a 5.9 percent increase. Dr. Cuthbert reviewed NIMH FY 2016 success rates for research project grant applications—which was 20 percent in 2015 and estimated to be 22 percent in 2016.  

The NAMHC Research Domain Criteria (RDoC) Tasks and Measures Workgroup evaluated the strength of evidence for measures of various constructs and will report on its findings at the meeting, followed by discussion. The RDoc Revisions to the Matrix Workgroup will be co-chaired by David Brent, M.D., and Greg Miller, Ph.D. It was noted by Dr. Cuthbert that this Workgroup will act as a screening and coordinating body for addressing proposals to change the RDoC matrix. The Workgroup will meet as needed to screen proposed changes to the matrix, recruit subject matter experts as needed, and provide a final report and recommendations. Minor changes (e.g., new elements) to the RDoC matrix will involve the Council and RDoC Workgroup members, while moderate changes (e.g., new or altered construct) will require a teleconference or email exchange with subject matter experts. For major changes (e.g., a new domain), the NAMHC will convene a full workshop. For example, approximately 40 subject matter experts will meet at a workshop to discuss the addition of a Motor Domain in November 2016. This new domain has been planned for many years, but only now is there a mechanism to advance it.

NIMH scientific highlights include work on the genomics of self-reported depression. A recent study identified 15 loci associated with risk for major depression (PMID 27479909 ). Research from the Human Connectome Project (HCP)  has revealed 180 cortical parcellation areas per hemisphere (e.g., auditory, sensory/motor, and visual). This work was conducted in individual subjects, involved multiple imaging techniques, and provides groundbreaking foundational work for precision medicine (PMID 27571196 ). Genomics research is testing the continuum model of Autism Spectrum Disorder (ASD) and found links between ASD and typical variation in social behavior and adaptive functioning (PMID 26998691 ).

As former Acting NIMH Director, Dr. Cuthbert commented that there is a need for balance across all the areas of NIMH science. The Institute is advancing the translation of basic science to psychopathology and treatment, which is urgently needed. He stated that research on services and interventions is critical and is of interest to Congress. In the push for more translational research, it is clear that the field is already working at full capacity. Therefore, to advance translational research, perhaps NIMH can determine a way to allocate more staff and effort to identify promising areas and move forward on them proactively. Quantitative prevention is a lofty goal; new technologies and the RDoC framework provide tools to examine prevention at the individual level, and identify dimensions of functioning before symptoms appear. Finally, Dr. Cuthbert thanked NIMH staff members and remarked that he enjoyed working with them as Acting Director. In all NIMH endeavors, staff members do a superlative job. Dr. Cuthbert reviewed the meeting agenda and introduced Dr. Gordon.

Dr. Gordon thanked Dr. Cuthbert for his work as Acting Director and acknowledged Dr. Avenevoli and other staff members who have been doing two jobs at once. He recognized their outstanding work in shepherding NIMH during the transition period and in implementing thoughtful changes to keep business progressing. Dr. Gordon remarked that he appreciated the documentation that staff prepared for his arrival, showing a well-functioning institute. He outlined his expectations from the Council. Dr. Gordon stressed that he appreciates the need for a broad NIMH research portfolio with short-, medium-, and long-term investments. He will rely on experts from clinical and services research to provide feedback on those areas, but would also like input on basic science. Council members should feel free to provide unfettered opinions and challenge him and NIMH staff, with the ultimate goal of making the Institute’s work better. Dr. Gordon asked Council members to think strategically about advancing NIMH’s work and commented that he was looking forward to working with the Institute’s excellent staff. NAMHC members welcomed Dr. Gordon. Jean Noronha, Ph.D., introduced Rebecca Wagenaar Miller, Ph.D., who is new to NIMH and will be assisting the Council in her role as NIMH Extramural Policy Branch Chief in the Division of Extramural Affairs.

NAMHC Workgroup on Tasks and Measures for Research Domain Criteria (RDoC)

Deanna Barch, Ph.D.
Chair, Department of Psychological & Brain Sciences and Gregory B. Couch Professor of Psychiatry Washington University

Dr. Barch identified the members of the Workgroup and listed those who worked on the Negative Valence, Positive Valence, Cognitive, Social Processes, and Arousal and Regulatory Systems domains. She thanked the chairs of the subgroups and acknowledged the valuable contributions of Co-Chair Maria Oquendo, M.D. Dr. Barch also thanked members of the NIMH staff who assisted the Workgroup, especially Jenni Pacheco, Ph.D., and Sarah Morris, Ph.D. Dr. Barch noted that although she is rotating off the Council, she will continue to be involved in RDoC activities.

Dr. Barch explained that she was presenting the Workgroup’s final report on Behavioral Assessment Methods for RDoC Constructs —which was made available to Council members—and would seek NAMHC approval of the document. The Workgroup’s charge was to recommend a set of two to four tasks for each construct that met all or many of a set of chosen criteria. Wherever possible, the measures should allow for behavioral assessment, as opposed to focused solely on biological signals. Generally, the Workgroup focused on identifying optimal tasks for domains and constructs as currently defined. The criteria for task selection were developed based on suggestions received in response to the Request for Information (RFI), a priori considerations, and discussions with the Workgroup. They were: validity; psychometric considerations; practicality, feasibility of use, and acceptability to people performing the tasks; ability to use with children or special populations; availability of adequate normative data, sensitivity to within-person change or normative developmental change; relationships between task performance and clinical features; and construct specificity.

The Workgroup aimed to produce a report that lists available tasks and measures that are recommended for inclusion in an RDoC battery. Another objective was to generate a report that listed tasks that could be appropriate for inclusion but needed further optimization (with a summary of work needed). Members also aimed to identify constructs for which no appropriate tasks are available and paradigms considered but not recommended (with rationale for exclusion). Finally, they also developed a rating for each task or proposed measurement tool on each criterion using a scale of 1 to 5 (1=no evidence, 3=some evidence, and 5=strong evidence) to facilitate direct comparisons among task characteristics. Ratings also made reasons for recommending each task more concrete. During the discussions, Workgroup members encountered various general issues. These included a lack of psychometric and normative data, as well as a lack of empirically derived standardized administration parameters. There was relatively little discussion of self-report measures. Dr. Barch explained that this was a strategic decision to focus on behavioral measures because of a limited time and does not imply that good self-report measures do not exist. The Workgroup members discussed emotional regulation a great deal. This domain requires further and more explicit discussion, as it is such a key aspect of psychopathology. Generally, RDoC domains and constructs need updating, and a new workgroup and revision approach is in process.

For each of the domains—the Negative Valence, Positive Valence, Cognitive, Social Processes, and Arousal and Regulatory Systems—Dr. Barch reviewed general issues and task recommendations. For Negative Valence Systems, several of the construct definitions do not lend themselves easily to a laboratory measurement model that would elicit the individual differences of interest (i.e., loss). The domain is lacking some coverage across the topic area and should more explicitly dovetail with Positive Valence Systems. There is a great deal of overlap in the tasks and measures that could be used. The Workgroup supports the addition of construct of “emotional lability,” “pain,” and “affective decision making.” Task recommendations for Negative Valence Systems include those in the areas of acute, potential, and sustained threat, as well as loss and frustrative nonreward. The Workgroup recommended specific tests and self-report measures for each area. For loss and sustained threat, the Workgroup could not recommend tasks due to ethical and practical considerations, particularly for young children.  

For Positive Valence Systems, the Workgroup proposed a slight regrouping and renaming of the constructs to match more clearly the existing empirical literature and reduce redundancies across the constructs. Constructs included reward responsiveness (initial response to reward, reward anticipation, and reward satiation), reward learning (habit, probabilistic and reinforcement learning, and reward prediction error), and reward valuation (reward probability, delay, and effort). The Workgroup recommended specific tasks in each area and drew on literature about paradigms that are useful but which have not typically been used to understand psychopathology (e.g., reward satiation).

For Cognitive Systems, many constructs overlap; this is the nature of cognition and to some extent, is unavoidable. Some key cognitive constructs were not currently represented in the matrix (e.g., reasoning and inference). The Workgroup suggested an update of the Attention construct in light of current work in cognitive neuroscience. It suggested three subconstructs: Controlled versus autonomic attention; Capacity and interference control; and vigilance (sustained attention). The construct “language behavior” was less well elaborated than other constructs. Given the specialized nature of the field of linguistics and the interactions between linguistic and cognitive systems, a new subgroup with expertise in the area should identify subconstructs and paradigms from this construct. The Workgroup recommended tasks in the areas of cognitive control (goal selection, updating, representation and maintenance; response selection, response inhibition/suppression; and performance monitoring) and working memory (active maintenance; flexible updating; limited capacity; and interference control).

In the Social Processes domain, the Workgroup suggested adding “rejection sensitivity” and “social motivation” as subconstructs under the Affiliation and Attachment construct. Members of the Workgroup also recommended development of the “Social Communication – production of facial communication” construct. Both methods of eliciting emotions and measuring facial expressions are ripe for additional research. Beyond facial communication, there is a significant need to develop techniques and instruments that capture the dimensionality of functioning across the life span, as well as instruments that optimize ecological validity. The Workgroup recommended tasks in the areas of affiliation and attachment, social communication, perception and understanding of self, and perception and understanding of others.

For the Arousal and Regulatory Systems domain, many of the constructs and subconstructs under this domain are actually part of another construct—for example, reactivity to social motivation or threat. The Workgroup recommended physiological measures in the areas of arousal, sleep/wakefulness, and circadian rhythms.

In addition to Council approval of the Workgroup report, the next steps are for the NIMH RDoC Unit to review the recommendations regarding tasks and measures and to update the matrix accordingly. 

The NAMHC Workgroup on Revisions to the RDoC Matrix was announced at the May 26, 2016 meeting. This Workgroup will consider proposals for modifications to the matrix and, where warranted, organize an appropriate process for evaluating the proposed changes. Meetings and workgroup rosters will be coordinated in an on-going and as-needed basis to handle proposed changes to the matrix and the approach for evaluating such changes.

Discussion

Dr. Brent thanked Dr. Barch and acknowledged the amazing amount of work done by the Workgroup. The report provides a great snapshot of the RDoC enterprise as well as a map of what the initiative has accomplished and its future directions. A review of all RDoC domains revealed that the Positive and Negative Valence System domains require harmonization.

Generally, there is a paucity of evidence about the reliability of measures, particularly those that test domains and constructs across the lifespan or that span animal and human research.  A key question for NIMH is: What steps should be taken to encourage work that can fill in these gaps? Additionally, the Workgroup recognized that new domains and constructs may be needed. What should be the criteria for the creation of new domains and constructs and what steps should be taken to launch them? Some of the proposed domains and constructs may involve the intersection of existing domains/constructs. Is it better to err on the side of parsimony? How should RDoC accomplish the harmonization between the Negative Valence and Positive Valence domains? There is a need for self-report measures that fit into the RDoC framework. What is the priority of this issue? How should these efforts intersect with PhenX and PROMIS? Scientists know very little about the within-person relationship among domains/constructs. Relatively little is known about the combination of characteristics across RDoC domains that constitute meaningful clinical entities.
What are the best ways to utilize the extant RDoC database?

Dr. Barch focused on the steps that NIMH might take to encourage research to fill these gaps. Although there has been some progress, more work is needed. Often, grants on methodological development are scored poorly. It takes effort and resources to develop something like the NIH Toolbox , but that level is needed to advance RDoC measures. Research progress is limited when scientists do not have tools and measures. The Human Connectome Project (HCP)  developed standard tools and measures, and people are using them in the field.

Dr. Cuthbert commented that the criteria for adding new domains to RDoC are rigorous and set a high bar. First, there must be good evidence for the functional construct. Second, there must be evidence for a neural system or circuit for implementing the construct. Third, a putative relationship with psychopathology must be demonstrated. Dr. Brent added that with the establishment of criteria, the Workgroup must decide whether the matrix is capturing unique or overlapping constructs and which domains should remain or be deleted.

Regarding the harmonization of Negative and Positive Valence Systems, Dr. Barch remarked that overlapping domains or constructs might have some dissociable mechanisms. Dr. Brent clarified that he meant harmonization at the meta-level. B.J. Casey, Ph.D., expressed reservations about separating Negative and Positive Valence Systems. The interaction of these two systems influences psychopathology and normative behavior. Dr. Casey added that it was positive that RDoC is attending to developmentally sensitive measures, as it is critical to capture the neurodevelopmental perspective. She and Dr. Brent agreed on the importance of a research portfolio that moves fluently from molecule to circuit to behavior.

John Krystal, M.D., commented that the impact of RDoC work could be increased if it incorporated all stakeholders in the research. He suggested that NIMH partner with other NIH institutes around constructs of mutual interest, perhaps developing an NIH-wide matrix. Similarly, partnerships with groups interested in translational processes (e.g., basic behavioral neuroscience and the pharmaceutical industry) could be fruitful. It is difficult to develop medications for conditions without animal models, and pharmaceutical researchers need biomarkers to advance this field. Engaging both basic neuroscience and pharmaceutical researchers in the Workgroup’s logic will sharpen the questions these investigators examine. Hakon Heimer, M.S., suggested that NIMH should explain the RDoC approach to different basic science groups. Dr. Cuthbert agreed, and noted that papers have been written on applying the RDoC model in animal systems. 

Patricia Areán, Ph.D. added that there is work to translate the RDoC framework into treatments. The constructs discussed are amenable to behavioral interventions developed in industry. Technology startups can quickly disseminate targeted behavioral treatments to communities (e.g., real-time coaching modules).

Dr. Brent asked whether there is a parallel RDoC process in other NIH brain institutes. Dr. Cuthbert responded that the National Institute on Alcohol Abuse and Alcoholism has developed and implemented a similar process in its intramural clinical trials. The National Institute on Drug Abuse is considering an RDoC-like process. For the NIH-wide Adolescent Brain Cognitive Development (ABCD)  study, NIMH staff members have participated in formative meetings on the inclusion of RDoC-compatible tasks. At NIH’s Office of Behavioral and Social Sciences Research, Bill Reilly, Ph.D. is assembling a compendium of tasks and is in communication with NIMH regarding this project. NIH BRAIN institutes are communicating to achieve some standardization in this area.

Bettina Buhring, Ph.D., noted that that NIMH has released two Requests for Applications related to this topic. One focuses on translating EEG biomarkers from animals to humans (RFA-MH-16-220 ). The other focuses on the basic science of temporal dynamics, but includes translation from animals to humans (PAR-14-153 ).

Mary Jane Rotheram, Ph.D., remarked that RDoC provides an opportunity to transform how researchers design treatments and to identify the core elements common across interventions. She asked whether there is an initiative to determine the core elements of evidence-based interventions and whether RDoC principles are utilized. Reframing treatments in this way could offer a new generation of interventions. Dr. Cuthbert responded that NIMH has not examined the core elements of existing behavioral interventions.  Yet, NIMH now asks clinical trials researchers to focus on mechanisms and demonstrate that interventions affect mechanisms in such a way as to influence outcomes. RDoC is one approach to address these issues, but the Institute is not prescriptive. RDoC grants are not yet completed, but moving forward with approaches that attend to mechanism should bear fruit. Dr. Cuthbert added that NIMH encourages clinical trials researchers to determine whether particular groups of patients will respond to an evidence-based treatment.

Dr. Areán noted that many evidence-based behavioral interventions are based on animal models, so most would be straightforward to translate. The recent National Academies report, Psychosocial Interventions for Mental and Substance Use Disorders: A Framework for Establishing Evidence-Based Standards , pointed out the need for research on which patients respond to particular therapies. She encouraged NIMH to support more work in this area. Dr. Gordon asked whether there are good examples of research on personalized or idealized therapies. Dr. Areán replied that there is some work on distilling the common therapeutic elements of behavioral treatments for the purposes of training. Her research addresses the treatment of late-life depression with a behavioral-activation strategy. For non-responders, researchers determine the barrier and implement a streamlined intervention that addresses it. Dr. Rotheram added that most child and family interventions use constructs similar to RDoC. When therapeutic strategies are matched to these constructs, it results in better outcomes.

Dr. Cuthbert called for a motion to accept the Workgroup report, which was moved and seconded. The Council unanimously passed the motion to approve the RDoC Workgroup report.

NAMHC Workgroup on Opportunities and Challenges of Developing Information Technologies on Behavioral and Social Science Clinical Research

Patricia Areán, Ph.D., Professor, Department of Psychiatry and Behavioral Sciences, Director of Targeted Treatment Development University of Washington

Dr. Areán commented that her presentation was an update rather than a final report. NAMHC initiated the Workgroup in light of concerns about the future of behavioral science during the next 5 years. Council decided to focus on leveraging technology to facilitate behavioral science. The decision was informed by exciting work in industry on the measurement of emotion and the development of behavioral applications, which have received press coverage despite not being widely validated. Council wanted to identify current technologies and determine their usefulness to understand mental illness in the context of treatment and improvement of therapies.

The Workgroup charge was to identify opportunities and directions for using emerging technologies that can facilitate innovative, efficient, and nimble clinical research. Members of the Workgroup also considered technologies to improve the reach, accuracy, efficiency, effectiveness, and quality of assessment, intervention, and service delivery. During two previous Workgroup meetings, the members focused on the following questions:

1. What technologies need to be developed to understand the life course/etiology of mental disorders?
2. How can new technologies be used to predict/prevent mental illness?
3. How can new technologies be used to achieve more efficient and effective diagnosis and treatment?
4. How can these new technologies be used to improve quality in MH practice?
5. How can new technologies enable more rapid and nimble research?

The Workgroup’s overarching recommendation is to fund science that tests principles, not products or applications. Therefore, efforts should focus on how tools measure psychopathology and useful treatment delivery platforms. For the first question, the Workgroup suggests that NIMH consider and encourage the development of research platforms and databanks to collect and compile data from multiple sources (e.g., the Precision Medicine Initiative and Arivale). Crowdsourcing can identify predictive algorithms for the prevention and early identification of illnesses. It is possible to collect behavioral data from mobile technologies, given their ubiquity. Digital markers could be used with other information to better understand mental disorders. This work will require collaboration with experts in other fields.

For the second question, multi-modal, real-time data collection can yield information that can be used to develop and guide personalized approaches for changing behavior over time. An individual’s data—particularly deviation from the usual pattern—may be a better predictor than averaged group data. The Workgroup suggests that NIMH consider and encourage research using “real-time” data collection of behavioral and self-reported predictors. This research might use coupling technologies to improve assessment/prediction. NIMH can also support the improvement of analytic approaches to facilitate idiographic prediction (e.g., to identify patterns within the same individual over time).

For the third question, it is critical to take advantage of the mobile health platform, which presents unique opportunities for developing intervention content/formats. Mobile technology also provides new ways to collect information on illnesses. Some companies are already conducting research in this area. Researchers are moving away from self-report to behavioral data collected from mobile devices, and patients are using mobile telephones for as-needed interventions. In this context, the field needs new paradigms for developing, refining, and testing behavioral intervention technologies. These paradigms must go beyond randomized controlled trials. The field also needs new analytic strategies for informing decision rules and algorithms for stepped interventions and for personalized approaches.

For the fourth question, NIMH should consider and encourage strategies for coupling patient data from personal devices with electronic health records (EHRs). Predictive analytics can be used with EHR data to identify individuals at risk for illness or relapse. Health information exchanges and all-payer databases can facilitate population-level approaches. It is important to develop deployment-focused approaches that anticipate the needs of providers who are on the receiving end of devices. Finally, NIMH might support research to demonstrate technology’s return of value.

For the fifth question, it is critical to understand that digital platforms develop rapidly and that researchers can conduct large-scale recruitment quickly over the internet. In this context, data collection is iterative. But there are ethical questions and issues with Institutional Review Boards (IRB).  There is great variability in the acceptance of digitally based research by IRBs, so ethicists and researchers need to educate IRBs about these technologies. Researchers must be clear about data security and what participant information is uploaded to the Internet. The Workgroup encourages NIMH to collect lessons from investigators to inform IRB practices in this area. It should encourage testing strategies for using technology to enhance the consent process and explore consenting strategies that allow participants to select the information they choose to share. NIMH might also disseminate best practices for safety monitoring and management. NIMH should also encourage researchers to leverage ongoing projects and existing infrastructure. It might supplement existing studies to embed mobile technology and engage small businesses using SBIR/STTR funds. It will be important to identify funding mechanisms to rapidly test ideas and conduct exploratory research.  Perhaps T32 programs and K awards might be used to encourage researchers to work in this area.

Additionally, NIMH should develop or identify training mechanisms for clinicians and researchers, who need to know how to use and visualize the data. Investigators need to use study designs that allow technology to evolve during the research lifecycle. It is important for NIMH to develop linkages between researchers and large provider organizations. NIMH should encourage investigators to use the principles of behavioral science and user-centered design when designing technology and research to test it.

The Workgroup’s next step is to complete a draft Workgroup Report for Council input and approval. Once approved, NIMH will disseminate the Workgroup Report recommendations on its website and through outreach to the field via conferences and review groups. The Institute should implement the recommendations through its guidance to applicants and through potential future initiatives. In conclusion, Dr. Areán thanked all members of the Workgroup and acknowledged NIMH staff members who have facilitated efforts.

Alan Leshner, Ph.D., thanked Dr. Areán and the NIMH staff members who assisted the Workgroup. He commented that technology is being used in the mental health arena, albeit in a non-focused and incoherent way. Therefore, NIMH must decide its goals in the area of technology. At a minimum, the Institute can bring some order and cohesiveness to the development of research and clinical tools. A focused research agenda would be helpful to the field. The Workgroup has provided a great deal of detail on this area, and NIMH should determine the major questions to be answered. Dr. Leshner suggested that NIMH develop a training framework and agenda, as using technology is not simple for everyone. Researchers and practitioners will require training in these technologies: Who will do that? Like current research in this area, training efforts are also not coherent. NIMH might sponsor meetings or conferences to increase the coherence of training efforts. Finally, there is a great need for a directed policy for technology and mental health. What kind of research should be conducted to frame activities? How might technologies be used in real-life settings? The Council could help articulate the important questions and issues that must be resolved.

Discussion

Dr. Cuthbert thanked Dr. Areán, Dr. Leshner, Workgroup members, and NIMH staff involved in this effort. Dr. Brent asked whether technologies related to mental health could be incorporated into the NIMH Intramural Research Programs. Technology offers an opportunity to deliver new treatment approaches. For example, for people who self-harm, a game can reinforce not paying attention to this behavior and having positive self-regard.

Dr. Areán commented that by the time a grant is funded, the technology has changed, so NIMH needs to fast track this type of research. The gaming industry would like to use its technology to enhance cognition, which could be a useful tool for children (e.g., cognitive training games). This educational strategy might be supported by other Federal agencies. She encouraged the field to consider innovative ways of thinking about interventions beyond one-on-one therapies.

Regarding the challenges in the area of participant consent and database security, Dr. Cuthbert noted that Gregory Farber, Ph.D., directs NIMH’s Office of Technology Development and Coordination and leads efforts in this area. Dr. Farber and Robert Heinssen, Ph.D., are working on an innovative initiative within the EPINet Program so that its research centers transmit data at high frequency to NIMH while protecting participant confidentiality. This represents a groundbreaking advance, and the same strategies could be applied to this area.

NAMHC Workgroup on Mental Health Genomics

Thomas Lehner, M.D. Director, Office for Genomics Research Coordination; Senior Genomics Advisor, Office of the Scientific Director, NIMH Division of Intramural Research Programs

Dr. Cuthbert commented on the explosion of exciting research in genomics generally and in mental health genomics. In response, an update on efforts in this area, and a Council Workgroup on mental health genomics seems warranted.

Thomas Lehner, Ph.D., remarked on the complexity of mental health genomics. Psychiatry is moving from descriptive diagnoses to dimensions that relate more closely to neurobiological functioning. Genetic variation influences biological systems, which in turn affect the domains of psychopathology and clinical symptoms. Although scientists understand some of these elements, integration of knowledge across different levels is mostly lacking. Doing so presents a huge challenge to the field.

A confluence of key developments in psychiatric genomics—including technological advances, team science, genomics resources, and a policy framework for sharing of samples and data – have made possible the progress of recent years. There has been an explosion of collaboration in genomics, and NIMH has made significant investments in all these areas (e.g., NRGR – NIMH Repository and Genomics Resource ).

Across the allelic spectrum, many genetic factors lead to brain dysfunction, and a very broad range of alleles confer risk. Key questions include: What is the appropriate sample size for this work? For gene discovery, sample size and power are still limitations. Even for the best case scenarios (i.e., genes with known strong effect of rare variants on phenotype), the numbers of samples currently examined in exome studies do not easily achieve genome-wide significance (PMID 22641211 ). However, there are now some novel statistical tools and approaches that can assist in these analyses.

A systems level approach, which determines the molecular networks in brain function and dysfunction, is needed. Although scientists can discover factors that affect molecules, cells, circuits and behaviors, the challenge is to integrate knowledge across these levels of analysis. It is also crucial to consider genetics beyond traditional diagnostic boundaries. There is overlap of genetic loci found in cross-disorder analyses, but it can be difficult to parse the genetic architecture of a mental disorder. Parsing of phenotypes is advancing scientific understanding in this area.

The genomics of mental health faces a number of challenges. Obtaining samples that are representative of the general population and representing ethnic diversity is critical, yet most studies fall short on that metric.

Dr. Lehner described the charge to the Council Workgroup. This Council Workgroup will advise the NAMHC on future directions in psychiatric genetics and functional genomics, including how best to address the gap in knowledge between gene discovery and mechanistic models of disease that transcend categorical DSM disease classification. He presented the following questions that map onto the challenges for Psychiatric Genetics:

1. With hundreds of replicated genetic factors now robustly associated with disease, what are the best strategies for prioritizing which genetic/genomic signals and gene(s) to pursue for functional analysis to gain a deeper understanding of the molecular processes underlying mental disorders?
2. What are currently the most tractable and cost-effective experimental paradigms and computational tools to interrogate the biology of these genetic risk factors at different levels of functional analysis?
3. How can NIMH stimulate the discovery of suspected “missing heritability” in mental disorders and leverage large diverse population based cohorts to enable population scale genomic discovery?
4. While there is now ample evidence of molecular overlap in the genetic risk factors across mental disorders, today’s disease gene discovery results are based on large samples with categorical disease classifications. What is the role of dimensional phenotypes in further delineating the genetic architecture of mental disorders? How should such strategies be deployed?

Discussion

Gene Robinson, Ph.D., asked how genetic efforts integrate with the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative . Dr. Lehner replied that the BRAIN Initiative does not focus on phenotypes, but NIMH staff members involved in genetic efforts consider its goals.

Christopher Walsh, M.D., commented that NIMH has done amazing work in this area. He volunteered to serve on the Workgroup and noted that it would be addressing tough questions. 

Mr. Heimer asked about partnerships for this work. Dr. Lehner explained that this research involves an interconnected network of international scientific groups. NIMH is at the center of the network and tries to integrate all the work into a cohesive effort that is not redundant. Many groups working in the initiative are public-private partnerships, as such research-intensive endeavors require collaboration.

Richard Huganir, Ph.D., remarked that this is a turning point in psychiatric disorders. He asked: When should researchers stop sequencing genes and turn their attention to biology? Dr. Lehner agreed that this is a key issue, and noted that there are a few examples where genes have been followed through to biology. Dr. Huganir volunteered to serve on the Workgroup.

David Sweatt, Ph.D., wondered about the question of missing heritability. He commented that the epigenome is as yet untapped. MicroRNAs are the low hanging fruit, and may be a key component of missing heritability. Dr. Barch asked NIMH to consider mapping genetic efforts to RDoC, as this will be critical to advancing the field. RDoC has not yet contacted other groups working to restructure the conceptualization of psychopathology. There was suggestion for NIMH to convene a meeting of such groups. The Hierarchical Taxonomy of Psychopathology (HiTOP ) consortium argues for the use of symptom counts, self-report, and other measures to determine the underlying structure of psychopathology. There is evidence to support this idea, but she was unaware of efforts to connect that work to genetic research. Dr. Barch asked whether genetic work was examining childhood risk factors. Dr. Lehner responded that this is not studied to a great extent, as it is difficult to conduct such research. Team science can help address this question, but longitudinal data are lacking.

Dr. Krystal suggested that NIH address the proliferation of large DNA collections and superficial phenotypes. He offered to participate in the Workgroup and especially focus on this difficult issue. Dr. Gordon commented that researchers would probably not be able to obtain RDoC measures with huge sample sizes. So the Workgroup should consider the right way to identify the best gene candidates, perhaps with animal models. Other questions to consider include: What is the best way to focus efforts in this area and to connect genetics with phenotypes? Do we need phenotypes that are quantitative and dimensional?  Can we achieve that?  At what cost?  Or do we focus on genes for which we can delve deeply into the biology?

Dr. Krystal asked whether data exist to answer this question. New technologies may help to achieve deep phenotyping at a reasonable cost. NIMH should build in this kind of feature from the start. Dr. Lehner commented that some efforts are conceptualizing phenotype data using the RDoC framework and integrating genetic data. Dr. Huganir remarked that NIMH should encourage research in this area.

Dr. Cuthbert noted that that NAMHC will go ahead with the Workgroup and that Council members who want to join should email Jean Noronha, Ph.D.

Big Data to Knowledge (BD2K) Multi-Council Workgroup Update

Gene Robinson, Ph.D. Director, Institute for Genomic Biology Swanlund Chair, Center for Advanced Study Professor in Entomology and Neuroscience University of Illinois at Urbana-Champaign

Dr. Cuthbert explained that Dr. Robinson represents the NAMHC on the Multi-Council Working Group on Big Data to Knowledge (BD2K). As Dr. Robinson is rotating off of the NAMHC, another Council member will need to take on this role.

Dr. Robinson commented that BD2K is a NIH-wide initiative and that the Multi-Council Working Group provides oversight. He highlighted two interesting developments for BD2K. The first is a movement to institute cloud-based (the Commons) datasets, which is in the early stages. The idea is to co-locate large datasets and computing power, which will improve access, use, re-use, and sharing of data and tools. The BD2K initiative aims to kick-start The Commons  with compliant data and tools that adhere to Findable, Accessible, Interoperable and Reusable (FAIR) principles. A major issue is addressing commercial ownership and security issues for the cloud.

The second BD2K development is a new initiative to bring together the six model organism databases, which would be of tremendous value to the scientific community. Currently, model organism databases are facing sustainability challenges. Additionally, there is user confusion because of a lack of homogeneity and redundancy of operations in these databases. The Multi-Council Working Group is discussing how to move forward. It is proposing a federated approach to bring the databases together with all existing services, called the Alliance of Genomic Resources (AGR). The AGR will embrace Cloud-based technologies and ensure its data and sharing practices conform to FAIR principles for research resources. Dr. Robinson reviewed AGR’s aims:

1. Federate participating resources via standardized programmatic interfaces driving a unified web portal.
2. Standardize the acquisition, curation, and display of shared data types.
3. Design a unified data model and modern scalable information architecture.
4. Support the scientific community in fully leveraging Alliance resources by creating a common Scientific Advisory Board and establishing a “central office” for consortium communications, user support, training, and outreach.

Dr. Robinson noted that these aims are complex. For example, the notion of “curation” involves many different, complex activities. He added that the future of BD2K is unclear, as there are questions about where its home will be in the upcoming years.

Discussion

Dr. Sweatt requested that NIH add rat genome data, as this is a widely used model for NIMH researchers, perhaps building upon on the mouse data. Dr. Robinson agreed and asked which other genetic databases would be helpful to NIMH researchers. Dr. Sweatt noted that genomic data for small, non-human primates would be useful. Dr. Cuthbert noted that Council members who want to participate in a new genetics Workgroup should contact Dr. Noronha.

Comments from Retiring Members

Dr. Areán commented that she felt fortunate to have had the chance to work with so many smart and wonderful people on the Council. She added that she has learned a great deal and was honored to serve. Dr. Areán remarked that the RDoC approach to identifying and underlying mechanisms over illness with an eye towards personalized medicine is an exciting for clinical research. However, she noted that the matrix does not specifically call out environmental risk factors—such as exposures to toxins, poverty, maltreatment, and neglect. She encouraged NIMH to include this information, as it is essential to understand the nuances of mental illnesses. Dr. Areán encouraged NIMH to fund more research that combines data sources from across all the domains in the matrix, and adds to it information about the social and physical environment.

In her opinion, there have been positive changes in the treatment, development, and clinical trial arena. Particularly positive has been requiring investigators to determine what the effective treatment component is for a given problem and studying who responds to specific treatments. She also thought creating new RFAs that allow investigators to ask for what they need to conduct a study has been positive. However, she noted that the proportion of the budget towards clinical trials continues to decrease, particularly so for behavioral interventions. This is significant, because most people prefer psychosocial treatments, and rarely do effective treatment programs work without the inclusion of a behavioral intervention. She encouraged NIMH to release more RFAs that directly address the development of behavioral interventions.

Dr. Areán stressed the importance of getting new treatments out into the community, which will require more hybrid effectiveness implementation studies. She encouraged NIMH to support more R01- level RFAs in the spirit of the ALACRITY Centers, as well as implementation contracts in the future. She highlighted the importance of adequate research on geriatric mental health, which is lacking, and encouraged NIMH to support work in this area.

Dr. Barch thanked NIMH for the opportunity and a great intellectual journey. It was most informative to get to know NIMH program staff better, as well as learn about the work it takes to run programs. She also thanked other Council members, who have taught her so much. Dr. Barch focused on the need for quantified targeted prevention—an area for which investments are needed. The area of prevention should be re-thought from this perspective. Generally, the risk factors with the most evidence are often not targeted, so the field needs to address broader characteristics related to risk that operate early in childhood. NIMH might re-think the focus on specific mental health risk factors and concentrate on early childhood and development. Although research in this area can be difficult, longitudinal studies are needed on the targets of intervention during different stages of development.

Dr. Casey commented that it has been an honor to serve on the Council and that she has enjoyed the opportunity to emphasize the neurodevelopmental perspective. She stressed that there are many windows of opportunity to recognize that we are treating the biological state of the developing brain across the lifespan. Important aspects are missed when investigations do not consider the developmental perspective. For example, a child is not a little adolescent or adult. Dr. Casey also spoke about the importance of early intervention and treatment. She encouraged a focus on factors that might boost resiliency and mental health. Dr. Casey suggested that work build on the importance of the environment and best opportunities for youth, as this is the foundation of a healthy society. Of course, large initiatives featuring big data and team science are important, but it is also critical not to lose sight of hypothesis generating research questions to discover mechanisms. Such research should be aligned with team science and big data. Dr. Casey is involved with the ABCD study, and is excited by the many opportunities that will come out of this work, but in order to understand the most basic mechanisms of environmental influences that impact brain development, there will need to be controlled concomitant experiments, supported across many institutes.   She suggested that NIMH recognize the dynamic nature of measures on brain and behavior when recommending tasks or developing toolboxes.

Mr. Heimer thanked other members of the Council and NIMH staff members. He suggested that NIMH post slide presentations from Council meetings on its website. Mr. Heimer also recommended mentoring new Council members. He commented that serving on NAMHC has been a valuable opportunity to see how science happens. It can be difficult to predict where better treatments come from. He suggested more research on treatments for those with mental illness now and those who will develop these disorders in the future.

Dr. Robinson commented that this has been the most educational of all his service experiences. He has appreciated the opportunity to learn. He suggested a focus on neurogenomic research. He highlighted the privacy and security issues inherent in big data, especially in mental health, and the importance of computing in analyzing data. Council will be dealing with these issues more in the future, and he suggests including engineering and computing experts on the NAMHC. Dr. Robinson expressed appreciation to NIMH staff and for the opportunity to learn about the effort needed to develop new initiatives and program priorities. He admires staff members’ deep knowledge of specific proposals and the larger context and their dedication.

Dr. Rotheram thanked all involved with the Council for a great experience. She appreciated the hard work of NIMH staff members and commented that the Institute provides strategic leadership in the field that benefits society. Dr. Rotheram observed that the research portfolio has a narrower focus on the basic science area and advocated for a diversified portfolio.

Dr. Sweatt suggested that more research is needed on epigenetics as well as on pharmacology and drug development. Many candidate drugs die in clinical trials, particularly in psychopharmacology. NIMH should track this issue and lead and invest in efforts to repurpose drugs. On a personal note, everyone associated with Council has been great, especially the staff and leadership of NIMH. The intellectual caliber and creativity at NIMH is underappreciated.

Dr. Cuthbert thanked outgoing Council members for their kind comments. This is a large graduating class of Council members, but also one of the most eminent. He added that this group has made outstanding contributions that are greatly appreciated. NIMH will be in touch with outgoing Council members on new and different roles in the future.

Public Comment

Dr. Cuthbert invited members of the audience to make any comments to the Council.

Christopher Ross, M.D., Ph.D., from the Department of Psychiatry and Behavioral Sciences at Johns Hopkins University commented on his concerns about the dominance of the RDoC approach. In his opinion, the RDoC framework is difficult to apply to major mental illnesses. He wondered about their organization and meaning because the RDoC constructs and domains seem arbitrary. He stated that the approach assumes that psychiatric diseases are extremes of normal behavior, but that may not be correct. A categorical rather than dimensional point of view may be more appropriate in some cases. Although the dimensional approach is important, ultimately physicians make a categorical diagnosis and offer a treatment. Finally, RDoC is a top-down approach, but most other areas of medicine are having success with a bottom-up (i.e., molecular) approach. In conclusion, RDoC has strengths and may be relevant to some conditions (e.g., anxiety), but Dr. Ross is concerned that excessive application of RDoC principles distract from research on etiology, pathogenesis, and treatment.

Dr. Cuthbert thanked Dr. Ross for his remarks. Hearing no further comments from the public, Dr. Cuthbert adjourned the meeting at approximately 12:40 p.m.

Appendix A

Summary of Primary MH Applications Reviewed

Council: September 2016

Category	IRG Recommendation
	Scored #	Scored Direct Cost $	Not Scored (NRFC) #	Not Scored (NRFC) Direct Cost $	Other #	Other Direct Cost $	Total #	Total Direct Cost $
Research	605	$733,659,990.00	498	$562,777,978.00	6	$1,448,767.00	1109	$1,297,886,735.00
Research Training	0	$0.00	0	$0.00	0	$0.00	0	$0.00
Career	55	$40,275,721.00	33	$25,616,810.00	0	$0.00	88	$65,892,531.00
Other	0	$0.00	0	$0.00	0	$0.00	0	$0.00
Totals	660	$773,935,711.00	531	$588,394,788.00	6	$1,448,767.00	1197	$1,363,779,266.00

Appendix B

Department of Health and Human Services
National Institutes of Health
National Institute of Mental Health
National Advisory Mental Health Council

(Terms end 9/30 of designated year)

Chairperson

• Bruce N. Cuthbert, Ph.D.
  Acting Director
  National Institute of Mental Health
  Bethesda, MD

Executive Secretary

• Jean Noronha, Ph.D.
  Director
  Division of Extramural Activities
  National Institute of Mental Health
  Bethesda, MD

Members

• Patricia A. Areán, Ph.D. (16)
  Professor
  Director of Targeted Treatment Development
  University of Washington
  Department of Psychiatry and Behavioral Sciences
  Seattle, WA
• Deanna M. Barch, Ph.D. (16)
  Gregory B. Couch Professor of Psychiatry
  Department of Psychology, Psychiatry and Radiology
  Washington University
  St. Louis, MO
• David A. Brent, M.D. (17)
  Academic Chief
  Child & Adolescent Psychiatry
  Endowed Chair in Suicide Studies
  Professor of Psychiatry, Pediatrics and Epidemiology
  Director, Services for Teens at Risk
  University of Pittsburgh School of Medicine
  Pittsburgh, PA
• BJ Casey, Ph.D. (16)
  Sackler Professor
  Department of Psychiatry and Neuroscience
  Sackler Institute for Developmental Psychobiology
  Weill Medical College of Cornell University
  New York, NY
• Benjamin G. Druss, M.D., M.P.H. (18)
  Rosalynn Carter Chair in Mental Health and Professor
  Department of Health Policy and Management
  Rollins School of Public Health
  Emory University
  Atlanta, GA
• Hakon Heimer, M.S. (16)
  Founding Editor
  Schizophrenia Research Forum
  Brain and Behavior Research Foundation
  Providence, RI
• Michael F. Hogan, Ph.D. (18)
  Consultant and Advisor
  Hogan Health Solutions LLC
  Delmar, NY
• Richard L. Huganir, Ph.D. (17)
  Professor and Director
  Department of Neuroscience
  Investigator, Howard Hughes Medical Institute
  Co-Director, Brain Science Institute
  The Johns Hopkins University School of Medicine
  Baltimore, MD
• John H. Krystal, M.D. (19)
  Robert L. McNeil, Jr. Professor of Translational Research
  Chair, Professor of Neurobiology
  Chief of Psychiatry, Yale-New Haven Hospital
  Department of Psychiatry
  Yale University School of Medicine
  New Haven, CT
• Marsha M. Linehan, Ph.D. (17)
  Professor and Director
  Behavioral Research and Therapy Clinics
  Department of Psychology
  University of Washington
  Seattle, WA
• Maria A. Oquendo, M.D. (17)
  Vice Chair for Education
  Professor of Psychiatry
  Department of Psychiatry
  Columbia University
  New York State Psychiatric Institute
  New York, NY
• Gene E. Robinson, Ph.D. (16)
  Director, Institute for Genomic Biology
  Swanlund Chair
  Center for Advanced Study Professor in Entomology And Neuroscience
  University of Illinois at Urbana-Champaign
  Urbana, IL
• Rhonda Robinson Beale, M.D. (19)
  Senior Vice President and Chief Medical Officer
  Blue Cross of Idaho
  Meridian, ID
• Mary Jane Rotheram, Ph.D. (16)
  Bat-Yaacov Professor of Child Psychiatry And Behavioral Sciences
  Director, Global Center for Children and Families
  Director, Center for HIV Identification Prevention And Treatment Services (CHIPTS)
  Semel Institute and the Department of Psychiatry, University of California, Los Angeles
  Los Angeles, CA
• J. David Sweatt, Ph.D. (16)
  Professor
  Evelyn F. McKnight Endowed Chair
  Department of Neurobiology
  Director, McKnight Brain Institute
  University of Alabama at Birmingham
  Birmingham, AL
• Hyong Un, M.D. (17)
  Head of EAP & Chief Psychiatric Officer
  AETNA
  Blue Bell, PA

Ex Officio Members

Office of the Secretary, DHHS

• Sylvia M. Burwell
  Secretary
  Department of Health and Human Services
  Washington, DC

National Institutes of Health

• Francis Collins, M.D., Ph.D.
  Director
  National Institutes of Health
  Bethesda, MD

Department of Veterans Affairs

• Theresa Gleason, Ph.D.
  Deputy, Chief Research & Development Officer
  Office of Research & Development
  Department of Veterans Affairs
  Washington DC

Department of Defense

• John W. Davison, M.B.A., Ph.D.
  Chief, Conditioned-Based Specialty Care Section
  Clinical Support Division
  Defense Health Agency
  Department of Defense
  Office of the Chief Medical Officer (OCMO)
  TRICARE Management Activity, OASD (HA)
  Falls Church, VA

Liaison Representative

• Paolo del Vecchio, M.S.W.
  Director
  Center for Mental Health Services
  Rockville, MD