No abstract

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.

Attentional control involves the ability to allocate preparatory attention to improve subsequent stimulus processing and response selection. There is behavioral evidence to support the hypothesis that increased expectancy of stimulus and response conflict may decrease the subsequent experience of conflict during task performance. We used a cued Flanker and event-related fMRI design to separate processes involved in preparation from those involved in resolving conflict, and to identify the brain systems involved in these processes as well as the association between preparatory activity levels and activity related to subsequent conflict processing. Our results demonstrate that preparatory attentional allocation following a cue to the upcoming level of conflict is mediated by a network involving Dorsolateral Prefrontal Cortex (DLPFC) and the Intraparietal Sulcus (IPS). Informed preparation for conflict processing was associated with decreased Anterior Cingulate Cortex/preSupplementary Motor Area (ACC/preSMA) and IPS activity during the flanker target presentation, supporting their roles in conflict processing and visuospatial attention during the flanker task. Ventrolateral Prefrontal Cortex/Orbitofrontal Cortex (VLPFC/OFC) was active when specific strategic task rule and outcome information was available.

BACKGROUND: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure. METHODS: Using voxel-and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV. RESULTS: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion . control . duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion . control; Cohen's d . 1), the superior and middle temporal gyri (deletion , control; Cohen's d , 21), and the caudate and hippocampus (control . duplication; 20.5 . Cohen's d . 21). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results. CONCLUSIONS: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria. Autism spectrum disorder (ASD) and related neurodevelopmental disorders are defined behaviorally and characterized by a significant clinical and etiologic heterogeneity. As a consequence, investigating ASD under the assumption of an underlying homogeneous condition has resulted in controversial findings in the field of neuroimaging (1). Increased brain growth early in development (2-4) and alterations of many regional brain volumes (5) have been implicated in ASD, but results have proven difficult to replicate (1,(6)(7)(8).To mitigate some of these issues, cohorts of individuals with shared genetic risk factors have been assembled to minimize the noise introduced by etiologic and biological heterogeneity (9). Such a "genetic-first" study design provides the opportunity to investigate a given neurodevelopmental risk (and associated mechanism) shared by individuals who carry the same genetic etiology irrespective of the psychiatric diagnosis.Copy number variants (CNVs) at the 16p11.2 (breakpoints 4-5, 29.6-30.2 Mb-hg19) (10) are among the most frequent risk factors for neurodevelopmental and psychiatric conditions.

Schizophrenia is characterized by dysfunction in basic auditory processing, as well as higher-order operations of verbal learning and executive functions. We investigated whether targeted cognitive training of auditory processing improves neural responses to speech stimuli, and how these changes relate to higher-order cognitive functions. Patients with schizophrenia performed an auditory syllable identification task during magnetoencephalography before and after 50 hours of either targeted cognitive training or a computer games control. Healthy comparison subjects were assessed at baseline and after a 10 week no-contact interval. Prior to training, patients (N = 34) showed reduced M100 response in primary auditory cortex relative to healthy participants (N = 13). At reassessment, only the targeted cognitive training patient group (N = 18) exhibited increased M100 responses. Additionally, this group showed increased induced high gamma band activity within left dorsolateral prefrontal cortex immediately after stimulus presentation, and later in bilateral temporal cortices. Training-related changes in neural activity correlated with changes in executive function scores but not verbal learning and memory. These data suggest that computerized cognitive training that targets auditory and verbal learning operations enhances both sensory responses in auditory cortex as well as engagement of prefrontal regions, as indexed during an auditory processing task with low demands on working memory. This neural circuit enhancement is in turn associated with better executive function but not verbal memory.