Thursday, July 15, 2010

NIMH Research Domain Criteria Meeting

I spent the last two days in Bethesda at the first workshop of the NIMH RDoC project, which was one of the most interesting scientific meetings I've been to in quite a while.  This project is meant to address two major problems in psychiatry.  First, there is widespread dissatisfaction with the current categorical approaches to psychiatric diagnoses, and a growing realization that better understanding of these disorders requires a dimensional (rather than categorical) perspective (e.g., Kraemer, 2007).  Second, there is  an increasing realization of the need to ground psychiatric diagnoses in neuroscience (Miller, 2010). The goal of the RDoC project is to help determine what the best candidates are for neuroscientifically validated dimensions that are most likely to be relevant to mental disorders.


This workshop was the first of several, each of which will focus on a particular construct or domain.  This first meeting was focused on the concept of "working memory."  The group was quite broad, from researchers who study working memory in mental disorders to neurobiologists who study the molecular basis of sustained activity in rodents.  The first charge of the group was to come up with a definition of working memory.  Given how prevalent this concept is in the literature (more than 11,000 hits in PubMed), it might seem that a definition would be obvious, but it took the better part of an hour for each of the two  working groups to come up with a definition that most of us could agree on.  Remarkably, the definitions generated independently by each group were very similar!  A summary of the consensus definition (generated through additional discussion of the whole group) has been entered as the new definition of the "working memory" concept in the Cognitive Atlas and can be found here


Much of the remainder of the workshop focused on characterizing the tasks, neural systems, molecules, and genes that are relevant to working memory.  Although each group came up with lists of tasks that were thought to best capture the construct of working memory, there was some trepidation about publishing this list, lest it become a blessing for the uncritical use of these tasks as "working memory tasks".  Rather, the group focused more on discussing what task features are most important for ensuring construct validity of tasks meant to measure working memory.  These will be published soon as part of the output from the workshop.


Another interesting point of discussion centered around how to relate the different levels of analysis, from molecules to neuropsychological tests.  The challenge comes in thinking about how construct mechanistically realistic links between molecular constructs (such as allelic variation in the COMT gene) and behavior (such as performance on the N-back task).  Drawing from the approach that has been developed within the UCLA Consortium for Neuropsychiatric Phenomics, Bob Bilder and I argued that this should be thought of in terms of links between successive levels of structure. For example, we can establish links between cognitive processes and neural systems, between neural systems and cellular systems, and so on down to genes and environmental influences. These different levels can then be traversed to provide a sophisticated mechanistic understanding of how we can get from genes to cognitive function.


Finally, there was a good bit of interesting discussion about the need for measures of working memory that are better validated, both conceptually and psychometrically. There was a clear undercurrent of dissatisfaction with the degree to which the imaging literature has relied on tasks that are not well validated in either of these senses (the N-back task being the poster child for this).  There seems to be great interest in developing a battery of validated tests, and maybe even greater interest in the potential of using these for online testing of large groups across studies.  For example, this seems to be the only realistic way to get sample sizes large enough to make well-powered genome-wide association analyses feasible for cognitive phenotypes.


The RDoC meeting was particularly exciting because of how well it dovetails with the Cognitive Atlas Project.  Getting researchers involved in clarifying their concepts and specifying how they relate to tasks and other levels of analysis is exactly what this project was designed to do.  I have already entered a good bit of the knowledge that was generated in this first RDoC workshop into the system, and I hope that we can make the Cognitive Atlas a repository for all of the knowledge that is generated in the subsequent RDoC workshops as well.  It was heartening to see that the framework that we have developed for representing this kind of knowledge is so well aligned to the kinds of knowledge building that NIMH clearly sees as essential for progress.



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    I wondered if Russ and/or others know of other concrete demonstrations of this multi-level view with intermediate levels actually filled in with data, or even analyzed with multi-set techniques. Most of the example I am aware of cover only two levels (e.g., genes - neuroimaging) or occur at the same level (e.g., MRI - fMRI - EEG).

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