Objective-Impaired verbal memory in schizophrenia is a key rate-limiting factor for functional outcome, does not respond to currently available medications, and shows only modest improvement after conventional behavioral remediation. The authors investigated an innovative approach to the remediation of verbal memory in schizophrenia, based on principles derived from the basic neuroscience of learning-induced neuroplasticity. The authors report interim findings in this ongoing study.Method-Fifty-five clinically stable schizophrenia subjects were randomly assigned to either 50 hours of computerized auditory training or a control condition using computer games. Those receiving auditory training engaged in daily computerized exercises that placed implicit, increasing demands on auditory perception through progressively more difficult auditory-verbal working memory and verbal learning tasks.Results-Relative to the control group, subjects who received active training showed significant gains in global cognition, verbal working memory, and verbal learning and memory. They also showed reliable and significant improvement in auditory psychophysical performance; this improvement was significantly correlated with gains in verbal working memory and global cognition.Conclusions-Intensive training in early auditory processes and auditory-verbal learning results in substantial gains in verbal cognitive processes relevant to psychosocial functioning in schizophrenia. These gains may be due to a training method that addresses the early perceptual impairments in the illness, that exploits intact mechanisms of repetitive practice in schizophrenia, and that uses an intensive, adaptive training approach.One of the greatest challenges for 21st-century bio-medicine is to develop an effective treatment for the cognitive dysfunction of schizophrenia. Antipsychotic medications and adjunctive cognitive-enhancing agents show little benefit thus far (1)(2)(3)(4)(5). Cognitive remediation trials demonstrate some efficacy (6), but a recent meta-analysis revealed a "glass ceiling" of low to medium effect sizes across a large variety of methods (7). Clearly, a fresh approach to the treatment of cognitive dysfunction in this illness is warranted. Verbal learning and memory are among the most robustly abnormal cognitive functions in schizophrenia and are key targets for treatment (8). Impaired verbal memory is associated with poor community functioning and poor response to psychosocial rehabilitation programs (9-11); it may be the principal reason why the gains provided by such programs are lost once the intervention ends (12)(13)(14). We wondered whether it is possible to develop a novel approach to the remediation of verbal memory deficits in schizophrenia based on recent developments in clinical and basic neuroscience.In schizophrenia, abnormalities are observed in fronto-temporal cortical networks during verbal working memory, word encoding, and word recognition (15,16). However, disturbances are also present at the earliest stages of...

SUMMARY Schizophrenia patients suffer from severe cognitive deficits, such as impaired reality monitoring. Reality monitoring is the ability to distinguish the source of internal experiences from outside reality. During reality monitoring tasks, schizophrenia patients make errors identifying “I made it up” items, and even during accurate performance, they show abnormally low activation of the medial prefrontal cortex (mPFC), a region that supports self-referential cognition. We administered 80 hours of computerized training of cognitive processes to schizophrenia patients and found improvement in reality monitoring that correlated with increased mPFC activity. In contrast, patients in a computer games control condition did not show any behavioral or neural improvements. Notably, recovery in mPFC activity after training was associated with improved social functioning six months later. These findings demonstrate that a serious behavioral deficit in schizophrenia, and its underlying neural dysfunction, can be improved by well-designed computerized cognitive training, resulting in better quality of life.

Neuropsychiatric illnesses are associated with dysfunction in distributed prefrontal neural systems that underlie perception, cognition, social interactions, emotion regulation, and motivation. The high degree of learning-dependent plasticity in these networksFcombined with the availability of advanced computerized technologyFsuggests that we should be able to engineer very specific training programs that drive meaningful and enduring improvements in impaired neural systems relevant to neuropsychiatric illness. However, cognitive training approaches for mental and addictive disorders must take into account possible inherent limitations in the underlying brain 'learning machinery' due to pathophysiology, must grapple with the presence of complex overlearned maladaptive patterns of neural functioning, and must find a way to ally with developmental and psychosocial factors that influence response to illness and to treatment. In this review, we briefly examine the current state of knowledge from studies of cognitive remediation in psychiatry and we highlight open questions. We then present a systems neuroscience rationale for successful cognitive training for neuropsychiatric illnesses, one that emphasizes the distributed nature of neural assemblies that support cognitive and affective processing, as well as their plasticity. It is based on the notion that, during successful learning, the brain represents the relevant perceptual and cognitive/affective inputs and action outputs with disproportionately larger and more coordinated populations of neurons that are distributed (and that are interacting) across multiple levels of processing and throughout multiple brain regions. This approach allows us to address limitations found in earlier research and to introduce important principles for the design and evaluation of the next generation of cognitive training for impaired neural systems. We summarize work to date using such neuroscience-informed methods and indicate some of the exciting future directions of this field.

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A total of 50 hours of neuroplasticity-based computerized cognitive training appears sufficient to drive improvements in verbal learning/memory and cognitive control that endure 6 months beyond the intervention, but a higher "dose" and more "broad-spectrum" training may be necessary to drive enduring gains in processing speed and global cognition. Training-induced cognitive improvement is related to enhanced functioning at 6 months. These data suggest that (1) higher and "broader" doses of cognitive training may confer the most benefits for schizophrenia patients; (2) the posttraining period opens a critical window for aggressive adjunctive psychosocial rehabilitation.

Background Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and plasticity; decreased BDNF functioning may contribute to the pathogenesis of schizophrenia. However, BDNF levels are not static; in animal experiments, brain BDNF increases during spatial learning, and in clinical depression, successful antidepressant treatment raises serum BDNF. We asked: would neuroplasticity-based cognitive training in schizophrenia result in increased serum BDNF? Methods Fifty-six schizophrenia outpatients and 16 matched healthy comparison subjects were assessed on baseline cognitive performance and serum BDNF. Schizophrenia subjects were randomly assigned to either 50 hours (10 weeks) of computerized auditory training or a computer game control condition, followed by reassessment of cognition and serum BDNF. Results At baseline, schizophrenia participants had significantly lower-than-normal serum BDNF. Schizophrenia subjects who engaged in computerized cognitive training designed to improve auditory processing showed significant cognitive gains and a significant increase in serum BDNF compared with subjects who played computer games. This increase was evident after 2 weeks of training, and after 10 weeks in the active condition, subjects “normalized” their mean serum BDNF levels, whereas the control group showed no change. In the active condition, change in BDNF was significantly associated with improved quality of life. Conclusions Serum BDNF levels are significantly increased in clinically stable, chronically ill schizophrenia subjects after neuroplasticity-based cognitive training, but not after computer games. Serum BDNF levels may serve as a peripheral biomarker for the effects of intensive cognitive training and may provide a useful tool for the evaluation of cognitive enhancement methods in schizophrenia.

A critical research priority for our field is to develop treatments that enhance cognitive functioning in schizophrenia and thereby attenuate the functional losses associated with the illness. In this article, we describe such a treatment method that is grounded in emerging research on the widespread sensory processing impairments of schizophrenia, as described elsewhere in this special issue. We first present the rationale for this treatment approach, which consists of cognitive training exercises that make use of principles derived from the past 2 decades of basic science research in learning-induced neuroplasticity; these exercises explicitly target not only the higher order or "top-down" processes of cognition but also the content building blocks of accurate and efficient sensory representations to simultaneously achieve "bottom-up" remediation. We then summarize our experience to date and briefly review our behavioral and serum biomarker findings from a randomized controlled trial of this method in outpatients with long-term symptoms of schizophrenia. Finally, we present promising early psychophysiological evidence that supports the hypothesis that this cognitive training method induces changes in aspects of impaired bottom-up sensory processing in schizophrenia. We conclude with the observation that neuroplasticity-based cognitive training brings patients closer to physiological patterns seen in healthy participants, suggesting that it changes the brain in an adaptive manner in schizophrenia.

Objective-A burgeoning area of research has focused on motivational deficits in schizophrenia, producing hypotheses about the role that motivation plays in the well-known relationship between neurocognition and functional outcome. However, little work has examined the role of motivation in more complex models of outcome that include social cognition, despite our increased understanding of the critical role of social cognition in community functioning in schizophrenia, and despite new basic science findings on the association between social cognitive and reward processing in neural systems in humans. Using path analysis, we directly contrasted whether motivation 1) causally influences known social cognitive deficits in schizophrenia, leading to poor outcome or 2) mediates the relationship between social cognitive deficits and outcome in this illness.Method-Ninety one patients with schizophrenia or schizoaffective disorder completed interviewbased measures of motivation and functional outcome as well as standardized measures of neurocognition and social cognition in a cross-sectional design.Results-In line with recent research, motivation appears to mediate the relationship between neurocognition, social cognition and functional outcome. A model with motivation as a causal factor resulted in poor fit indicating that motivation does not appear to precede neurocognition.Conclusions-Findings in the present study indicate that motivation plays a significant and mediating role between neurocognition, social cognition, and functional outcome. Potential psychosocial treatment implications are discussed, especially those that emphasize social cognitive and motivational enhancement.