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Post by Former NIMH Director Thomas Insel: Three Principles for Clinical Research

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During the week of July 12, NIMH hosted two meetings with broad implications for our clinical research portfolio. The first was a progress report on Cognitive Neuroscience Approaches to the Treatment of Impaired Cognition in Schizophrenia (CNTRICS), the NIMH initiative to develop tools for defining the cognitive deficits in schizophrenia. The second was the inaugural meeting of the Research Domain Criteria (RDoC), the NIMH initiative to build a new framework for classification for research purposes. This meeting focused on working memory, exploring the idea of cognitive science as a potential tool for defining clinical categories independent of our current classification system. While it may sound as if the two meetings were mostly academic discussions of esoteric topics, both led to important conversations about how we support clinical research.

One implication was the need for standardized, web-based cognitive measures. In the early 2000s, the Institute supported the creation of the Measurement and Treatment of Research to Improve Cognition in Schizophrenia (MATRICS) battery as a neuropsychological toolbox for assessing cognitive deficits in schizophrenia. This standardized assessment has been widely adopted. But the measures, most of which predate modern cognitive neuroscience, appear to be less sensitive and less specific than current assays.1 And because the battery is not web-based, there is no opportunity for integrating data seamlessly from many sites.

More recently, the NIH Blueprint for Neuroscience Research supported the development of the NIH Toolbox, a collection of web-based measures. While this will be useful for standardizing tests of sensory and motor function, it does not have the capacity to probe cognitive control, working memory, and other aspects of what is often called executive function. It also lacks measures of affective regulation. A third effort, the Cognitive Atlas project , is creating a knowledge base or ontology on the web for the entire community, linking cognitive tools to the emerging database on genes, cells, and circuits.

The success of each of these three projects points to the need for a new initiative: a neurocognitive toolbox that includes standardized, web-based assessments of the many aspects of executive function and affective regulation that can be assessed efficiently in clinical practice as well as in the research lab. "Standardized" refers to consistency in the way the tests are administered as well as how they are used. The actual items can be adapted by the computer according to the testing situation or the performance. Web-based approaches allow tests of reaction time as well as accuracy. Most importantly, the implementation of a panel of validated tests, as currently being developed by the CNTRICS group, will ensure that our funding supports research that can be integrated across research sites, rather than resulting in a collection of non-comparable results.

Of course, a standardized battery must not stifle innovation. Ultimately, NIMH might expect all grantees to use a specific panel for neurocognitive assessment, but this is not a limit to developing new and better tools beyond this core group.

For me, what emerged from these meetings were three core principles: standardization, integration, and sharing. While these principles have been adopted already in the world of genomics, they have not become part of the wider culture of clinical research. The lesson from genomics is clear: There is strength in numbers.

Going forward, to increase the impact of our clinical research, NIMH hopes to instill these principles in the studies we support: standardized measures (including standardized protocols), integration across sites (and, in a different sense, across levels of analysis), and broad sharing of data. The first step will be the development of the core battery of tests, as currently being done by the CNTRICS team for cognition. This effort can be expanded to other domains under the auspices of RDoC.

1 Cohen JD and Insel TR. Cognitive neuroscience and schizophrenia: translational research in need of a translator. Biological Psychiatry. 2008 July. 64(1):2-3.

Carter CS, Barch DM, Gur R, Pinkham A, Ochsner K. CNTRICS final task selection: social cognitive and affective neuroscience-based measures. Schizophrenia Bulletin. 2009 Jan.35(1):153-162.