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OMMENTARY

ognitive Neuroscience and Schizophrenia:ranslational Research in Need of a Translator

onathan D. Cohen and Thomas R. Insel

t has now been more than half a century since the discovery ofeuroleptic medications as a treatment for schizophrenia. Theiriscovery marked the beginning of the biological revolution insychiatry. An understanding of their mechanisms of actionromised to shed light on the pathophysiologic processes thatre fundamental to schizophrenia. Furthermore, their efficacy inreating some of the most dramatic symptoms of schizophreniaincluding hallucinations and delusions) raised the promise thatdditional pharmacologic agents could be discovered to treat thether, equally debilitating disturbances associated with the ill-ess—loss of affect and cognitive disorganization. Unfortunately,either set of promises has been fully met. Although we haveearned much about neurobiological disturbances associatedith schizophrenia, we remain in the dark about the etiology andasic pathophysiology of this illness. At the same time, althoughhere have been refinements in antipsychotic medication, for theost part these have addressed the side effects of earlier agents,

nd little progress has been made in treating the other distur-ances associated with this illness. Most important among theses cognitive dysfunction—a treatment-refractory hallmark symp-om of schizophrenia, that may be the primary contributor to lossf social and occupational function (1). Cognitive dysfunctionan be clinically dissociated from the emotional and motivationisturbances associated with schizophrenia (2) and has beenound to be one of the most disabling dimensions of the illness,losely associated with inability to work and need for structurediving (3).

Recognizing the need for medications targeted at the cogni-ive deficits in schizophrenia, in 2002 the National Institutes ofealth sponsored the MATRICS Initiative (Measurement andreatment Research to Improve Cognition in Schizophrenia). Theoal of this initiative, led by Steve Marder, Keith Nuechterlein,nd Michael Green at the University of California—Los Angelesnd overseen by Wayne Fenton and Ellen Stover at the Nationalnstitute of Mental Health (NIMH), was to identify and standard-ze a battery of clinical instruments for assessing cognition inlinical trials of schizophrenia. An important purpose of this effortas to collaborate with the Food and Drug Administration (FDA) in

anctioning the use of such instruments as targets for the develop-ent and approval of new pharmacologic agents that improve

ognitive function in schizophrenia. This effort represented annprecedented collaboration between basic and clinical scientists incademia, the pharmaceutic industry, NIMH, and FDA. With re-arkable speed, the initiative produced the MATRICS Consensusognitive Battery (MCCB) (4), released in 2006, and had an instan-

aneous impact on pharmacologic research in schizophrenia.The MCCB was a landmark development, representing the

irst time that a measure of improvement in cognitive function in

rom the Department of Psychology and Neuroscience Institute (JDC),Princeton University, Princeton, New Jersey; and the National Institute ofMental Health (TRI), Bethesda, Maryland.

ddress reprint requests to Jonathan D. Cohen, M.D., Ph.D., Department ofPsychology, Center for Study of the Brain, Green Hall 3-N-8, PrincetonUniversity, Princeton, NJ 08544; E-mail: jdc@princeton.edu.

eceived April 30, 2008; accepted April 30, 2008.

006-3223/08/$34.00oi:10.1016/j.biopsych.2008.04.031

schizophrenia was recognized by the FDA as a legitimate indi-cation, unto itself, for the development of pharmacologic agents.Toward this end, two important factors governed the inclusion ofspecific instruments in the MCCB: psychometric validation andclinical practicality. That is, each instrument must provide arobust and reproducible measure of the dimension of cognitivefunction for which it was targeted, and its administration must bepractical and reliable in a clinical setting. These requirementsnaturally favored the inclusion of standard neuropsychologicinstruments that had been vetted by decades of intense evalua-tion and use in clinical settings.

For these same reasons, however, most of the neuropsycho-logic instruments included in the MCCB are based on psycho-logical theory and behavioral testing methods from the 1960s thathave changed little since that time. During the intervening 4decades, there have been revolutions in basic research on humancognition and its neural underpinnings, marked by the emer-gence of cognitive psychology in the early 1970s and cognitiveneuroscience in the late 1980s. Research in these fields hasproduced major advances in the precision with which cognitiveprocesses can be measured and related to underlying neuralmechanisms using modern electrophysiologic and neuroimagingtechniques.

Unfortunately, however, these developments in basic sciencehave seen little translation into clinical research or practice. Asthe authors of the MATRICS battery dutifully noted, a “priority forfuture research will be to subject these new instruments—emerging from basic cognitive neuroscientific research—to rig-orous psychometric testing, and translate the most promising ofthese into clinically useful instruments that may provide im-proved sensitivity for the evaluation of cognitive functioning inschizophrenia.” This is the focus of the NIMH sponsored Cogni-tive Neuroscience Treatment Research to Improve Cognitionin Schizophrenia (CNTRICS; http://cntrics.ucdavis.edu/index.shtml) and the subject of this special issue.

Both scientific and sociological obstacles have impeded thetranslation of advances in cognitive psychology and cognitiveneuroscience to clinical research and practice. Scientifically,instruments emerging from behavioral and cognitive neuro-science laboratories are not always suitable “off the shelf” forclinical application: they may not be sufficiently robust toproduce reliable results in clinical populations while havingsufficient sensitivity to detect changes in clinical state necessaryto assess the effects of treatment. They may also lack practicality,involving procedures that are too long or too complex to beperformed by patients with psychiatric illness or relying onapparatus or procedures that require specialized training toadminister. Although in many instances it may be possible toovercome these obstacles, doing so also faces sociologicalchallenges. On one hand, the basic scientists responsible fordeveloping these measures often are not interested in, nor arethey rewarded for, translating these paradigms into clinicallyuseful instruments (tenure is rarely given for methods develop-ment). On the other hand, the clinical researchers and practitio-ners who could make productive use of such instruments rarely

have the relevant training in behavioral and neuroscientific

BIOL PSYCHIATRY 2008;64:2–3© 2008 Society of Biological Psychiatry

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J.D. Cohen and T.R. Insel BIOL PSYCHIATRY 2008;64:2–3 3

ethods to pursue such work. In other words, translationalesearch in cognitive neuroscience is in need of a translator.

This is the express purpose of CNTRICS: to provide mecha-isms for, incentives that motivate, and instructive examples ofhe translation of modern cognitive psychological and cognitiveeuroscientific measures into clinically useful instruments. Underhe leadership of Cameron Carter at the University of California,avis and Deanna Barch at Washington University, and theuidance of Robert Heinssen at the NIMH, three internationaleetings have been planned to initiate this effort. These are

ponsored by the NIMH and designed to sustain the collaborativeomentum built by the MATRICS Initiative, engaging basic and

linical scientists from academic and industry laboratories, asell as representatives from the NIMH and FDA. The goal of

hese meetings is to generate consensus on three critical issues:hich cognitive processes and corresponding neural mecha-isms are most important to target (first meeting), what stepsust be taken to adapt methods for studying these to use in

linical settings (second meeting), and what specific tasks andeuroscientific methods measure the relevant cognitive pro-esses and are suitable for such adaptation (third meeting). Theverview article by Carter et al. in this special issue (pages 4–10)escribes the agendas for each of these three meetings in greateretail, as well as future directions for the CNTRICS initiative. Theemaining articles report on the significant progress that wasade at the first of these meetings, held in February 2007 inashington, DC, and focusing on the selection of cognitive

ystems to be targeted.Over the past 5 years, the NIMH has increasingly focused on

ranslating neuroscience discoveries to solve problems in publicealth. In some areas, this has meant understanding the devel-pmental expression of candidate genes or the search for newolecular targets, a translational task that can be accomplished

hrough traditional research grant mechanisms. Translatingreakthroughs in cognitive neuroscience is a greater challenge,equiring NIMH to exert its convening authority to bridge theociological and intellectual gaps among the academic world ofognitive science, the regulatory constraints of the FDA andndustry, and the needs of clinical investigators working withcutely ill patients. The goal is ambitious: to redefine schizophre-ia as a cognitive disorder, with psychosis as a late and poten-ially preventable consequence. If CNTRICS can identify cognitivearkers of schizophrenia that precede and predict psychosis, this

ffort could transform our approach to the treatment of schizophre-

nia from ameliorative antipsychotic medications to the developmentof preemptive interventions that could forestall or even preventpsychosis. With the encouragement of the National Mental HealthAdvisory Council and the leadership of NIMH program staff, andespecially Robert Heinssen, CNTRICS is already on its way totransforming the next generation of research studies of schizo-phrenia.

The CNTRICS Initiative represents the second milestone in abold new mission for the field of schizophrenia research. TheMATRICS Initiative broke ground by establishing improvementsin cognition as a legitimate target for drug development and byestablishing the precedent of consensus measures for the field.CNTRICS now seeks to modernize the instruments used to assesscognitive processes and the neural mechanisms on which theyrely. Success in this effort will yield many important dividends,including progress in our understanding of the pathophysiologyof schizophrenia and the generation of more refined methods fordiagnosis and treatment of schizophrenia, including the devel-opment and approval of new drugs. These efforts promise also tohave an impact on other domains of psychiatric research byproviding a new generation of methods for studying cognitivedisturbances in illnesses such as depression, bipolar disorder,and attentional-deficit disorder. We applaud the vision andcommitment of the many investigators who have worked tomove this effort forward and eagerly anticipate the progress theirwork will bring.

Dr. Cohen reports having research funding from the NationalInstitute of Mental Health, the National Institute on Drug Abuse,and the Air Force Office of Scientific Research. Dr. Insel reportshaving no biomedical financial interests or potential conflicts ofinterest.

1. Green MF (1996): What are the functional consequences of neurocogni-tive deficits in schizophrenia? Am J Psychiatry 153:321–330.

2. Barch DM, Yodkovik N, Sypher-Locke H, Hanewinkel M (in press): Intrinsicmotivation in schizophrenia: Relationships to cognitive function, depres-sion, anxiety and personality. J Abnorm Psychol.

3. Green MF, Kern RS, Heaton RK (2004): Longitudinal studies of cognitionand functional outcome in schizophrenia: Implications for MATRICS.Schizophr Res 72:41–51.

4. Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, et al.

(2008): The MATRICS Consensus Cognitive Battery, part 1: Test selection,reliability, and validity. Am J Psychiatry 165:203–213.

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