Cognitive Control Deficits in Schizophrenia: Mechanisms and Meaning

Department of Psychiatry, UC Davis Imaging Research Center, Davis School of Medicine, University of California, Sacramento, CA 95817, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 01/2011; 36(1):316-38. DOI: 10.1038/npp.2010.156
Source: PubMed


Although schizophrenia is an illness that has been historically characterized by the presence of positive symptomatology, decades of research highlight the importance of cognitive deficits in this disorder. This review proposes that the theoretical model of cognitive control, which is based on contemporary cognitive neuroscience, provides a unifying theory for the cognitive and neural abnormalities underlying higher cognitive dysfunction in schizophrenia. To support this model, we outline converging evidence from multiple modalities (eg, structural and functional neuroimaging, pharmacological data, and animal models) and samples (eg, clinical high risk, genetic high risk, first episode, and chronic subjects) to emphasize how dysfunction in cognitive control mechanisms supported by the prefrontal cortex contribute to the pathophysiology of higher cognitive deficits in schizophrenia. Our model provides a theoretical link between cellular abnormalities (eg, reductions in dentritic spines, interneuronal dysfunction), functional disturbances in local circuit function (eg, gamma abnormalities), altered inter-regional cortical connectivity, a range of higher cognitive deficits, and symptom presentation (eg, disorganization) in the disorder. Finally, we discuss recent advances in the neuropharmacology of cognition and how they can inform a targeted approach to the development of effective therapies for this disabling aspect of schizophrenia.

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Available from: Michael Minzenberg, Sep 30, 2015
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    • "cognitive disorganisation). While many aspects of cognition are impaired (Green, 1996; Lesh et al., 2011), it has been purported that memory processes in particular are severely affected (e.g. verbal memory: Toulopoulou and Murray, 2004; working memory: Manoach et al., 2000; see Aleman et al. (1999), for a meta- analysis). "
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    ABSTRACT: Overconfidence in false memories is often found in patients with schizophrenia and healthy participants with high levels of schizotypy, indicating an impairment of meta-cognition within the memory domain. In general, cognitive control is suggested to be modulated by natural fluctuations in oestrogen. However, whether oestrogen exerts beneficial effects on meta-memory has not yet been investigated. The present study sought to provide evidence that high levels of schizotypy are associated with increased false memory rates and overconfidence in false memories, and that these processes may be modulated by natural differences in estradiol levels. Using the Deese-Roediger-McDermott paradigm, it was found that highly schizotypal participants with high estradiol produced significantly fewer false memories than those with low estradiol. No such difference was found within the low schizotypy participants. Highly schizotypal participants with high estradiol were also less confident in their false memories than those with low estradiol; low schizotypy participants with high estradiol were more confident. However, these differences only approached significance. These findings suggest that the beneficial effect of estradiol on memory and meta-memory observed in healthy participants is specific to highly schizotypal individuals and might be related to individual differences in baseline dopaminergic activity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Psychiatry Research 08/2015; 229(3). DOI:10.1016/j.psychres.2015.08.016 · 2.47 Impact Factor
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    • "Combined with the orderly relationships between cost and purchasing decisions observed (Figure 1), this potentially suggests engagement in more deliberative, goal-directed decisions rather than habit-based responding. Use of higher-level cognitive processes is further supported by the bilateral dlPFC activation observed, given the central role of dlPFC in supporting cognitive control (Lesh et al, 2011), including during decision-making (Hare et al, 2009). "
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    ABSTRACT: Drug dependence may be at its core a pathology of choice, defined by continued decisions to use drugs irrespective of negative consequences. Despite evidence of dysregulated decision-making in addiction, little is known about the neural processes underlying the most clinically-relevant decisions drug users make: decisions to use drugs. Here, we combined functional Magnetic Resonance Imaging (fMRI), machine learning, and human laboratory drug administration to investigate neural activation underlying decisions to smoke cannabis. Non-treatment-seeking daily cannabis smokers completed an fMRI choice task, making repeated decisions to purchase or decline 1-12 placebo or active cannabis 'puffs' ($0.25-$5/puff). One randomly selected decision was implemented. If the selected choice had been bought, the cost was deducted from study earnings and the purchased cannabis smoked in the laboratory; alternatively, the participant remained in the laboratory without cannabis. Machine learning with leave-one-subject-out cross-validation identified distributed neural activation patterns discriminating decisions to buy cannabis from declined offers. Twenty-one participants were included in behavioral analyses; 17 purchased cannabis and were thus included in fMRI analyses. Purchasing varied lawfully with dose and cost. The classifier discriminated with 100% accuracy between fMRI activation patterns for purchased versus declined cannabis at the level of the individual. Dorsal striatum, insula, posterior parietal regions, anterior and posterior cingulate and dorsolateral prefrontal cortex all contributed reliably to this neural signature of decisions to smoke cannabis. These findings provide the basis for a brain-based characterization of drug-related decision-making in drug abuse, including effects of psychological and pharmacological interventions on these processes.Neuropsychopharmacology accepted article preview online, 12 May 2015. doi:10.1038/npp.2015.135.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 05/2015; DOI:10.1038/npp.2015.135 · 7.05 Impact Factor
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    • "In contrast, we could not replicate the finding of decreased prefrontal-thalamic connectivity. As this finding may be a highly relevant one, given the vast number of evidence reporting deficits of top-down functional control of prefrontal areas in schizophrenia, this issue might be worth highlighting (Lesh et al., 2011; Tu et al., 2013). The discrepancy might be based on the fact that disruption of functional connections in patients with schizophrenia is influenced by a number of endogenous disease-specific and treatment-associated molecular changes, whereas the present study included solely the modulation of the glutamatergic system . "
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    ABSTRACT: Schizophrenia has been associated with disturbances of thalamic functioning. In the light of recent evidence suggesting a significant impact of the glutamatergic system on key symptoms of schizophrenia, we assessed whether the modulation of the glutamatergic system via blockage of the NMDA-receptor might lead to changes of thalamic functional connectivity. Based on the "ketamine-model" of psychosis we investigated changes in cortico-thalamic functional connectivity by intravenous ketamine challenge during a 55 minutes resting-state scan. 30 healthy volunteers were measured with pharmacological functional magnetic resonance imaging (fMRI) using a double-blind, randomized, placebo-controlled, crossover design. Functional connectivity analysis revealed significant ketamine-specific changes within the "thalamus hub network", more precisely an increase of cortico-thalamic connectivity of the somatosensory and temporal cortex. Our results indicate that changes of thalamic functioning as described for schizophrenia can be partly mimicked by NMDA-receptor blockage. This adds substantial knowledge about the neurobiological mechanisms underlying the profound changes of perception and behaviour during the application of NMDA-receptor antagonists. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 04/2015; DOI:10.1093/ijnp/pyv040 · 4.01 Impact Factor
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