Sophia Vinogradov - US grants

Recent research suggests that a defect in language information processing may be pathognomic of schizophrenia; however, no single explanatory model of abnormal cognition has been able to encompass the clinical and biological heterogeneity of this illness. Indeed, current reports which examine structural and processing aspects of semantic memory reveal that there are significant differences in the language information processing performance of various schizophrenic subgroups. These approaches derive from the field of cognitive psychology, which has witnessed a formidable explosion over the past fifteen years both in terms of experimental data and models which illuminate thought processes in normal subjects. In this project, we will systematically investigate semantic priming effects in schizophrenia and their relationship to clinical phenomenology and neuropsychological performance. We will compare and contrast both automatic and controlled levels of information processing, with an emphasis on distinguishing the performance of subgroups of schizophrenics on these tasks. We hypothesize that: A subgroup of schizophrenics shows virtually no semantic priming effects in tasks which rely mainly on automatic information processing, but shows normal (or greater-than-normal) priming in experiments which evoke controlled processes. This subgroup manifests paranoid/delusional features, less of a negative symptom/deficit syndrome, normal performance on neuropsychological testing which examines mainly executive functions, and abnormal performance in neuropsychological tasks examining aspects of working memory. A second subgroup of schizophrenics shows greater-than-normal semantic priming ("hyperpriming") in automatic information processing conditions plus evidence of impaired strategic/controlled priming mechanisms. This subgroup is characterized by disorganized and undifferentiated features, a negative symptom/deficit syndrome, and impairment on executive functions.

Recent research suggests that a defect in language information processing may be pathognomic of schizophrenia; however, no single explanatory model of abnormal cognition has been able to encompass the clinical and biological heterogeneity of this illness. Indeed, current reports which examine structural and processing aspects of semantic memory reveal that there are significant differences in the language information processing performance of various schizophrenic subgroups. These approaches derive from the field of cognitive psychology, which has witnessed a formidable explosion over the past fifteen years both in terms of experimental data and models which illuminate thought processes in normal subjects. In this project, we will systematically investigate semantic priming effects in schizophrenia and their relationship to clinical phenomenology and neuropsychological performance. We will compare and contrast both automatic and controlled levels of information processing, with an emphasis on distinguishing the performance of subgroups of schizophrenics on these tasks. We hypothesize that: A subgroup of schizophrenics shows virtually no semantic priming effects in tasks which rely mainly on automatic information processing, but shows normal (or greater-than-normal) priming in experiments which evoke controlled processes. This subgroup manifests paranoid/delusional features, less of a negative symptom/deficit syndrome, normal performance on neuropsychological testing which examines mainly executive functions, and abnormal performance in neuropsychological tasks examining aspects of working memory. A second subgroup of schizophrenics shows greater-than-normal semantic priming ("hyperpriming") in automatic information processing conditions plus evidence of impaired strategic/controlled priming mechanisms. This subgroup is characterized by disorganized and undifferentiated features, a negative symptom/deficit syndrome, and impairment on executive functions.

[unreadable] DESCRIPTION (provided by applicant): The purpose of this Supplemental Application is to study how the brain changes in response to intensive cognitive training in schizophrenia. We will extend upon our original cognitive remediation project and perform a set of neurobiological assessments on a subsample of schizophrenic subjects before, during, and after training. We hypothesize that we will obtain direct evidence for plasticity: improvements in the brain's information processing capabilities at the neural level in response to neuroadaptive cognitive remediation exercises in schizophrenia. [unreadable] [unreadable] The Original Study: We are employing a set of novel, intensive, computer-based cognitive training exercises that specifically target processing efficiency and attention/working memory using an adaptive training procedure. We are examining the effects of this neuroscience-guided targeted cognitive training (TCT) on cognitive performance, symptom profile, quality of life, and social cue recognition in subjects with schizophrenia, as compared to subjects who undergo a control intervention (graphics-based computer games). [unreadable] [unreadable] The Supplement: We propose to perform magnetoencephalography (MEG) to examine changes in early cortical event-related responses and in working memory responses, as a function of TCT. We also propose to perform functional magnetic resonance imaging (fMRI) studies of changes in cortical activation patterns during a working memory task and an episodic memory task in response to TCT. [unreadable] [unreadable] What the Supplement Adds: The overall general design and methods of our study will remain intact. The supplemental funding will be used to acquire, process, manage, and analyze the neurobiological data. We thus will be able to accomplish several innovative goals that make use of the unique subject sample in our study and that greatly enhance the behavioral assessments. We will demonstrate that, in response to TCT, schizophrenic subjects show: [unreadable] [unreadable] 1. Improvements in the brain's fidelity (amplitude of neuronal response) and efficiency (deployment of neuronal resources) in the processing of early auditory information, via MEG. [unreadable] [unreadable] 2. Improvements in the brain's efficiency during working memory tasks (via MEG and fMRI). [unreadable] [unreadable] 3. "Normalization" of fMRI brain activation patterns during verbal memory processing. [unreadable] [unreadable] 4. Correlation of "normalized" brain activation patterns with behavioral improvements in neurocognitive performance. [unreadable] [unreadable] To the public: We are conducting a research study to find out whether computerized training might help people with schizophrenia or schizoaffective disorder lessen their symptoms and learn new thinking and problem-solving skills. We will also study how the brain changes in people with schizophrenia as they undertake this training. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The purpose of this study is to explicitly and aggressively drive an optimal response to neuroplasticity- based cognitive remediation in schizophrenia in order to maximize treatment response. We will investigate factors that have generally been ignored in computer-based cognitive remediation programs-those related to social cognition-- and will delineate their relationship to motivation, functional outcome, and the neural substrates of reward anticipation and emotion processing. Current research indicates that, unless we fully understand and harness these factors, we will not achieve meaningful treatment gains for individuals with schizophrenia. Our specific aims are: 1. To perform an RCT in which 100 schizophrenia subjects are assigned to either 60 hours of neuroplasticity- based computerized targeted cognitive training (TCT) that focuses exclusively on cold cognition (a program which trains early sensory processing, attention, working memory and cognitive control in auditory and visual domains), or to 60 hours of training that combines the TCT program with 20 minutes per day of adaptive computerized social cognition training (SCT) exercises. 2. To compare the outcomes of these two groups of subjects on measures of neurocognition, social cognition, motivation, and functional outcome. 3. To assess subjects six months after the intervention to determine the durability of training effects. 4. To identify changes in brain activation patterns in key neural regions as a result of TCT alone vs. TCT+SCT: during reward anticipation, and during emotion recognition. The timeliness of this approach is supported by recent evidence demonstrating only weak associations between traditional cognitive remediation approaches and functional outcome in schizophrenia, but a strong, direct relationship between social cognition and functional outcome. Thus we must now examine the clinical, functional, and neural effects of a well-designed state-of-the-art cognitive training program that combines neurocognition with social cognition training. Public Health Relevance Statement (Narrative) This research is relevant to public health in that it will: 1) determine whether the addition of social cognition training exercises to neuroplasticity-based cognitive training of auditory and visual processing improves outcome for people with schizophrenia; 2) help to identify neuroplasticity-based cognitive remediation strategies for schizophrenia that provide the maximal benefit in terms of helping patients to achieve meaningful improvements in motivation and social and occupational functioning.

DESCRIPTION (provided by applicant): The goals of this project are: 1) to develop research expertise and a sustainable research infrastructure among psychiatrists in a developing country (Brazil) in the study of cognition in schizophrenia; 2) to modify a neuroscience-based computerized cognitive training program for schizophrenia so that it is adapted for the language and cultural milieu of Brazil; 3) to perform a clinical trial of cognitive training in the context of a developing country. In Latin America, schizophrenia is the second contributor to the burden of psychiatric illness, and there is a growing interest in finding treatments that can reduce the psychosocial burden and improve quality of life. In this project, we will examine whether a promising neuroscience-based computerized cognitive training program under investigation in the U.S. can be successfully adapted for a clinical trial in a developing country. This will give insights about the potential worldwide impact of this approach to cognitive training in schizophrenia. Study co-PI Dr. Vinogradov has been investigating the effects of computerized auditory/verbal learning training to enhance cognitive function in schizophrenia, an approach that is based on principles of learning-induced neuroplasticity. Study co-PI Dr. Panizzutti has been a Visiting Scientist at the University of California, San Francisco for the past three years and has been involved in this research in Dr. Vinogradov's laboratory. This project will support an active collaboration in which, during Year 1, Dr. Panizzutti will implement his new knowledge and skills at the Universidade Federal do Rio de Janeiro to build research infrastructure and to develop a culturally appropriate computerized cognitive training program for schizophrenia that can be studied in the network of outpatient clinics run by the Brazilian public health service. In Years 2 and 3, a randomized controlled trial will take place.

DESCRIPTION (provided by applicant): The purpose of this study is to perform a double-blind randomized controlled trial (RCT) in young patients with recent-onset (RO) schizophrenia to target improvement in cognitive functioning within real-world treatment settings. This multi-site study will be performed in 3 community mental health centers with specialized Early Intervention Services (EIS). We will compare the effects of web-based targeted cognitive training (TCT) vs. web-based general cognitive exercises (GCE), both delivered via portable laptop computers. We will investigate the behavioral and functional changes seen immediately after the intervention as well as at 6-month follow-up, compared to a no-training control group (NTC). This will be the first study to investigate cognitive enhancement for young RO schizophrenia patients in community mental health settings, using scalable interactive neurotechnology, and the first to compare two distinct cognitive training approaches. This study will generate high impact data on the potential for targeted pre-emption of the downward spiral of in cognitive and functional disability that often characterizes psychotic illness. It will also generate valuable daa on the relative effects of two distinct cognitive training approaches in schizophrenia, each derived from a very different theoretical rationale, providing much-needed information on the efficacy of a targeted distributed neural system training model derived from systems neuroscience vs. a general cognitive stimulation training model derived from neuropsychological rehabilitation approaches. The aims of this project are based on the current state of early psychosis research, as well as our own experience successfully applying neuroscience-informed cognitive training in schizophrenia. It is now abundantly clear that cognitive/neural system dysfunction represents a significant risk factor for schizophrenia as well as a poor prognostic indicator. Functional outcome in RO schizophrenia is predicted by level of cognitive impairment and baseline cognitive reserve, and recent findings suggest that specialized EIS programs focusing only on symptom reduction and psychosocial support may not robustly improve long-term outcomes- indicating that critical treatment targets are not being addressed at present in early psychosis interventions. Cognitive dysfunction and underlying neural system inefficiency should therefore be one of the primary targets for pre-emptive intervention in early psychosis. In this study, we will determine whether we can achieve this goal using cognitive training delivered via a portable computer, in order to improve functional outcome in young individuals with RO schizophrenia.

The purpose of this study is to perform longitudinal high-resolution 7T MRI in participants with first-episode psychosis (FEP) enrolled in our ongoing randomized controlled clinical trial (RCT) of cognitive training. Despite the recent explosion in treatment programs for FEP, many patients still do not experience optimal outcomes, with impaired cognition in particular being a poor prognostic indicator. Indeed, we now know that the early phases of psychotic illness are characterized by progressive neural system dysfunction, including accelerated frontal and temporal gray matter loss, as well as white matter changes and neuroinflammation. In this innovative high-risk project, we seek to determine whether a 12-week course of intensive cognitive training of auditory processing in young FEP patients delivered remotely as a stand-alone treatment is neuroprotective against neural tissue loss in auditory cortex (superior temporal gyrus, STG), and possibly in other cortical regions. We will also investigate the effects of training on white matter integrity. Our prior work has shown that intensive cognitive training of auditory processing drives significant cognitive improvement in FEP patients; our unpublished data indicate that improved positive symptoms are seen 6 months later. In studies with persistently ill patients, we have demonstrated significant functional plasticity in prefrontal and auditory cortex after this form of training. Here, we integrate our findings with emerging data from basic science and ask a high-risk/ high-gain research question: Can a short course of intensive cognitive training not only improve cognition, but prevent accelerated gray matter loss in left STG, and possibly in other regions, such as prefrontal cortex? Additionally, does it mitigate white matter changes? Finally, we will explore its possible effects on a putative marker of neuroinflammation. We will answer these questions by acquiring state-of-the-art high-resolution 7T MRI longitudinal imaging data in a subset of young FEP patients who are enrolled in our current NIMH-funded RCT of cognitive training in community mental health centers. The goal of the original RCT is to investigate the clinical and cognitive effects of 30 hours of cognitive training delivered via iPads, as compared to treatment-as-usual. This R21 Exploratory/Developmental grant will permit us to leverage our unique subject population and research infrastructure in order to obtain sophisticated imaging data at two time points 12 months apart in a highly informative preliminary sample of young FEP individuals. The data we obtain will contribute to our understanding of how to develop scalable, optimally effective personalized treatments that pre-empt cognitive and neural system deterioration and promote recovery in the early phases of psychotic illness.

PROJECT SUMMARY The Recovery After an Initial Schizophrenia Episode (RAISE) Early Treatment Program (ETP) is an exciting new evidence-based intervention for schizophrenia spectrum disorders. However, several questions arise from this study. Why are benefits in Quality of Life seen primarily during the first 6 months of treatment, and only for individuals whose duration of untreated psychosis is <74 weeks? Does a deeper understanding of treatment trajectories lead to new insights about prognosis or about novel leverage points to refine and optimize the treatment approach? The purpose of this project is to answer these questions by performing state-of-the-art computational analyses on data from RAISE-ETP and from our own cognitive training trial. Our interdisciplinary team of clinical investigators and data scientists will use data-driven predictive, causal clustering, and causal discovery analyses to examine clinical and cognitive response patterns in the RAISE-ETP data set. We will then validate the baseline causal model(s), describing the mechanistic relationship among patients' baseline characteristics derived from the RAISE-ETP data, against our own early psychosis data set, and explore the effects of cognitive training on key predictive variables identified in the RAISE-ETP analyses. We seek to understand whether data from our experimental neuroscience-informed cognitive training studies in recent-onset schizophrenia can suggest ways of enriching the RAISE-ETP approach in order to optimize outcomes for as many individuals as possible, not just those with a shorter duration of untreated psychosis. One of our main areas of focus will be cognition, since cognitive deficits predict psychosocial dysfunction even when symptoms are in remission and are unresponsive to current medications. In an exploratory Causal Graph Analysis performed on RAISE-ETP data, we find that baseline Cognition Composite performance is causally associated with Quality of Life (QLS) Total Score at 6 months, which in turn predicts the two-year QLS trajectory. Baseline Cognition Composite is also related to Positive and Negative Syndrome Scale (PANSS) Total Symptoms score at 6 months, via an unidentified latent variable linking QLS and PANSS Total Symptoms. Consistent with these causal relationships, exploratory growth curve modeling in our cognitive training data show that individuals assigned to training demonstrate a linear improvement in PANSS Total Symptoms 6 months after the intervention, while those control condition subjects show no such change. Our goal is to examine these findings in depth in order to inform the design of the next generation of ?first episode? treatments.

PROJECT SUMMARY: PROJECT 4 The purpose of PROJECT 4 is to investigate computationally-informed precision treatments to improve two forms of state representation dysfunction in early psychosis: 1) State estimation processes at the perceptual input level, which we will target through auditory discrimination training; 2) State representation stability of auditory information, which we will target through auditory working memory training. Participants will be drawn from PROJECT 3, where they will have been assessed with behavioral and EEG-fMRI measures at baseline and after 6 months of usual care, so that their initial characteristics and clinical trajectory will be known. Participants will be stratified on an EEG index of state estimation processes (fronto-parietal theta power at DPX encoding), which we posit to be present in ~60% of subjects, and randomly assigned to one of the two training strategies. Our goal is not to perform a treatment efficacy study comparing these two interventions. Rather, we seek to use predictions derived from attractor network models to test the effects of neuroplasticity-based precision treatments targeting two distinct information processing pathologies in early psychosis, with the ultimate goal of improving state representation processes and cognition. In Aim 1, we will investigate parameter changes in the fit attractor network models in each subject group, fit to DPX and Bandit Task behavioral data immediately after training and 3 months later, and we will assess whether parameter changes reflect restorative or compensatory modifications. We will also test the hypothesis that state representation processes and cognitive performance show greater improvement in subjects who received training tailored to their state estimation parameter. In Aim 2, we will examine how specific parameter changes in attractor network models relate to neurophysiological changes in measures indexing activity timing, excitatory-inhibitory balance, and system noise, in order to identify which changes are the most predictive of improved cognition. Causal discovery analyses will be employed to identify causal relationships among computational parameters, behavioral data, neurophysiologic indices, treatment assignment, and one- year clinical trajectories.

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