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Identifying Cognitive Mechanisms Targeted for Treatment Development in Schizophrenia: An Overview of the First Meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia Initiative

Department of Psychiatry, University of California, Davis, CA 95817, USA.
Biological psychiatry (Impact Factor: 9.47). 08/2008; 64(1):4-10. DOI: 10.1016/j.biopsych.2008.03.020
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ABSTRACT This overview describes the generation and development of the ideas that led to the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative. It also describes the organization, process, and products of the first meeting. The CNTRICS initiative involves a series of three conferences that will systematically address barriers to translating paradigms developed in the basic animal and human cognitive neuroscience fields for use in translational research aimed at developing novel treatments for cognitive impairments in schizophrenia. The articles in this special section report on the results of the first conference, which used a criterion-based consensus-building process to develop a set of cognitive constructs to be targeted for translation efforts.

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Available from: Edward T Bullmore, Aug 24, 2015
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    • "This may be particularly true in studying the neurobiology of cognitive deficits, which remain the most difficult symptom cluster to treat in SZ yet hold the most promise for enhancing functional outcome (Green et al., 2000; Ibrahim and Tamminga, 2012). Indeed, the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative (Barch et al., 2008; Carter et al., 2008) has placed an emphasis on cognition as a core symptom of SZ, with the goal of assessing specific cognitive processes and their associated neural/psychological mechanisms in both animal models and humans in an effort to develop novel intervention strategies. We recently introduced chronic elevations of kynurenic acid (KYNA) as a naturalistic and translationally valid approach to experimentally study cognitive impairments seen in SZ. "
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    ABSTRACT: The levels of kynurenic acid (KYNA), an endogenous negative modulator of alpha7 nicotinic acetylcholine receptors (α7nAChRs), are elevated in the brains of patients with schizophrenia (SZ). We reported that increases of brain KYNA in rats, through dietary exposure to its precursor kynurenine from embryonic day (ED)15 to postnatal day (PD) 21, result in neurochemical and cognitive deficits in adulthood. The present experiments focused on the effects of prenatal exposure to elevated kynurenine on measures of prefrontal excitability known to be impaired in SZ. Pregnant dams were fed a mash containing kynurenine (100 mg/day; progeny = EKYNs) from ED15 until ED22. Controls were fed an unadulterated mash (progeny = ECONs). The dietary loading procedure elevated maternal and fetal plasma kynurenine (2223% and 693% above controls, respectively) and increased fetal KYNA (forebrain; 500% above controls) on ED21. Elevations in forebrain KYNA disappeared after termination of the loading (PD2), but KYNA levels in the prefrontal cortex (PFC) were unexpectedly increased again when measured in adults (PD56-80; 75% above controls). We also observed changes in several markers of prefrontal excitability, including expression of the α7nAChR (22% and 17% reductions at PD2 and PD56-80), expression of mGluR2 (31% and 24% reductions at ED21 and PD56-80), dendritic spine density (11-14% decrease at PD56-80), subsensitive mesolimbic stimulation of glutamate release in PFC, and reversal/extra-dimensional shift deficits in the prefrontally-mediated set-shifting task. These results highlight the deleterious impact of elevated KYNA levels during sensitive periods of early development, which model the pathophysiological and cognitive deficits seen in SZ. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Neuropharmacology 11/2014; 90C:33-41. DOI:10.1016/j.neuropharm.2014.10.017 · 4.82 Impact Factor
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    • "Analysis—To examine effects of cognitive control on DLPFC activation, we conducted an a priori region-of-interest (ROI) analysis with a functionally defined DLPFC ROI [Talairach coordinates Right: x=41, y=18, z=28, Left: x= −41, y=18, z=28, 36 voxels; (MacDonald et al., 2000)], previously shown to identify group differences under high cognitive control conditions in multiple FE studies (MacDonald and Carter, 2003; Snitz et al., 2005; Yoon et al., 2008). Beta weights for correct trials only were extracted from Cue A and Cue B contrast images separately. "
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    ABSTRACT: While structural abnormalities of the dorsolateral prefrontal cortex (DLPFC) may pre-date and predict psychosis onset, the relationships between functional deficits, cognitive and psychosocial impairments has yet to be explored in the at-risk period. An established measure of cognitive control (AXCPT) was administered to demographically matched clinical-high-risk (CHR; n=25), first-episode schizophrenia (FE; n=35), and healthy control (HC; n=35) participants during functional magnetic resonance imaging (fMRI) to investigate these relationships. CHR and FE individuals demonstrated impaired context processing and reduced DLPFC activation relative to HC individuals during increased cognitive control demands. FE and CHR individuals' ability to increase DLPFC activity in response to cognitive control demands was associated with better task performance. Task performance was also associated with severity of disorganization and poverty symptoms in FE participants. These findings support more extensive studies using fMRI to examine the clinical significance of prefrontal cortical functioning in the earliest stages of psychosis.
    10/2013; 221(1). DOI:10.1016/j.pscychresns.2013.09.001
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    • "A paradigmatic example of successful translation and back-translation focusing on a core cognitive dimension is described in Fig. 2. This approach to addressing effective translation underlies the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative (Carter et al., 2008). The job of experimental medicine then becomes one of focussing the clinical investigation of the chemical ligands, or hopefully medicines, across these same dimensions in a systematic way in both volunteers and in patients. "
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    ABSTRACT: There are many new advances in neuroscience and mental health which should lead to a greater understanding of the neurobiological dysfunction in neuropsychiatric disorders and new developments for early, effective treatments. To do this, a biomarker approach combining genetic, neuroimaging, cognitive and other biological measures is needed. The aim of this article is to highlight novel approaches for pharmacological and non-pharmacological treatment development. This article suggests approaches that can be taken in the future including novel mechanisms with preliminary clinical validation to provide a toolbox for mechanistic studies and also examples of translation and back-translation. The review also emphasizes the need for clinician-scientists to be trained in a novel way in order to equip them with the conceptual and experimental techniques required, and emphasizes the need for private-public partnership and pre-competitive knowledge exchange. This should lead the way for important new holistic treatment developments to improve cognition, functional outcome and well-being of people with neuropsychiatric disorders.
    Neuroscience & Biobehavioral Reviews 04/2013; 37(10). DOI:10.1016/j.neubiorev.2013.03.022 · 10.28 Impact Factor
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