Steven M. Silverstein - US grants

[unreadable] DESCRIPTION (provided by applicant): Despite pharmacologic treatment advances, there are many treatment-refractory schizophrenia patients remaining in state hospitals. Many of these patients are sufficiently cognitively impaired that they benefit little from psychosocial interventions and have little chance of returning to the community without the introduction of novel cognition-enhancing interventions. Moreover, many patients who have been discharged from state hospitals in the wake of recent census reductions also have attentional problems that preclude their ability to fully engage in, and benefit from, psychosocial interventions. Such patients can be considered at heightened risk for relapse and rehospitalization as long as their limited ability to benefit from treatment remains undressed. Compounding this problem is the inability of current cognitive rehabilitation interventions to improve attentional functioning in schizophrenia patients with the most severe attentional problems. For such patients, behaviorally oriented attention shaping procedures have demonstrated effectiveness in several small-scale studies. However, the lack of a user-friendly, standardized format for the delivery of this intervention has led to its almost complete nonuse outside of academic research centers. Therefore, the proposed study seeks to draw on the expertise of those investigators who have pioneered the use of shaping techniques to improve attention in treatment-refractory schizophrenia patients, in order to integrate these techniques into a standardized, manualized treatment intervention, along with an accompanying training videotape and therapist fidelity evaluation measure. The proposed project would develop this standardized treatment delivery format, and then refine it through a series of pilot treatment groups at three sites: Weill Medical College of Cornell University, Lincoln Regional Center, and Hawaii State Hospital. In addition, data would be collected and pooled regarding treatment-related changes in attentional functioning, skill acquisition in groups, and symptomatology. The expected results of this project include: 1) the development of a user-friendly set of materials to facilitate dissemination of the attention shaping intervention to real-world settings; 2) the collection of preliminary data on its effectiveness; and 3) the generation of estimates of power and subject variability which can serve as the foundation from which to design a large-scale controlled treatment study.

[unreadable] DESCRIPTION (provided by applicant): Despite pharmacologic treatment advances, there are many treatment-refractory schizophrenia patients remaining in state hospitals. Many of these patients are sufficiently cognitively impaired that they benefit little from psychosocial interventions and have little chance of returning to the community without the introduction of novel cognition-enhancing interventions. Moreover, many patients who have been discharged from state hospitals in the wake of recent census reductions also have attentional problems that preclude their ability to fully engage in, and benefit from, psychosocial interventions. Such patients can be considered at heightened risk for relapse and rehospitalization as long as their limited ability to benefit from treatment remains undressed. Compounding this problem is the inability of current cognitive rehabilitation interventions to improve attentional functioning in schizophrenia patients with the most severe attentional problems. For such patients, behaviorally oriented attention shaping procedures have demonstrated effectiveness in several small-scale studies. However, the lack of a user-friendly, standardized format for the delivery of this intervention has led to its almost complete nonuse outside of academic research centers. Therefore, the proposed study seeks to draw on the expertise of those investigators who have pioneered the use of shaping techniques to improve attention in treatment-refractory schizophrenia patients, in order to integrate these techniques into a standardized, manualized treatment intervention, along with an accompanying training videotape and therapist fidelity evaluation measure. The proposed project would develop this standardized treatment delivery format, and then refine it through a series of pilot treatment groups at three sites: Weill Medical College of Cornell University, Lincoln Regional Center, and Hawaii State Hospital. In addition, data would be collected and pooled regarding treatment-related changes in attentional functioning, skill acquisition in groups, and symptomatology. The expected results of this project include: 1) the development of a user-friendly set of materials to facilitate dissemination of the attention shaping intervention to real-world settings; 2) the collection of preliminary data on its effectiveness; and 3) the generation of estimates of power and subject variability which can serve as the foundation from which to design a large-scale controlled treatment study.

DESCRIPTION (provided by applicant): Among people with schizophrenia, attentional impairment is a major barrier to being able to engage in, and learn new skills in, psychosocial skills training interventions. Therefore, developing methods to promote attentiveness and learning during skills training is an important step in improving treatment outcomes. Prior case reports, one controlled study, and data from an ongoing R21 application indicate that attention shaping procedures (ASP) are highly effective methods to achieve these goals. ASP is a manualized, behavioral intervention that involves individualized goal-setting, and standardized observational rating, prompting, and reinforcement procedures to assist patients in increasing the duration and quality of their attentiveness in psychosocial interventions. To date, studies of ASP have been limited in their outcome evaluations to in- group attentiveness and learning of group material. Other cognitive outcomes, generalizability, functional outcomes and durability of gains have not been studied. This proposal, therefore, describes a controlled effectiveness study of ASP that would comprehensively assess relevant outcomes, generalizability, functional skills related to those taught in the intervention and maintenance of the gains over six months. ASP will be integrated within a standard form of social skills training [UCLA Basic Conversation Skills Module (BCS)], and compared to a BCS-alone condition. Specific aims of the study involve examinations of: 1) the generalizability of ASP's effects to relevant domains of non-study-group attentiveness, and standardized measures of neurocognition;2) functional outcomes involving social skills, as assessed through self-report, other-report, interview, and role-play based measures;and 3) the durability of ASP-associated gains, by conducting a 6-month follow-up assessment on all subjects. Statistical analyses will involve time-series and growth curve models that make use of daily in-group performance data to model treatment response. These data, plus more traditional analyses will determine whether, and to what extent, ASP confers advantages in attention, and learning and/or performance of behavioral skills to patients who receive it. The long-term objective of this project is to demonstrate that ASP can narrow the gap between the existence of potentially effective psychosocial interventions (such as skills training) and patients who, at present, cannot benefit from them due to attentional difficulties.

DESCRIPTION (provided by applicant): This is a competitive revision in response to NOT-OD-09-058, the ARRA call for Competitive Supplement Applications. In the past decade there has been a growing awareness of the disabling effects of impaired cognition in individuals with schizophrenia and the importance of developing new treatments that target cognitive deficits. During this same period, the cognitive neuroscience field has seen an explosion of new knowledge regarding the neural basis of cognition. The application of this new knowledge to drug development in schizophrenia has lagged significantly behind overall progress in cognitive neuroscience, in large part due to the lack of data on the measurement properties of tasks used in cognitive neuroscience. This concern led to the Cognitive Neuroscience Research To Improve Cognition in Schizophrenia (CNTRICS) initiative, which conducted a series of conferences designed to develop consensus on the constructs and paradigms from cognitive neuroscience that are ripe for translation for use in clinical trials contexts. We were recently funded to start this translation process (Cognitive Neuroscience Task Reliability &Clinical Applications (CNTRACs) Consortium.") for behavioral paradigms. We brought together a collaborative team that represents significant expertise from the many fields necessary for the success of this endeavor. We are focusing on four constructs that span both early (gain control and visual integration in perception) and higher-level (goal maintenance, relational encoding and retrieval) components of human cognitive processing. Is this competitive revision we will extend this work in a highly critical and significant direction that the field has identified as a growing need - the development of well validated, and reliable functional neuroimaging paradigms that can serve as biomarkers for predicting and assessing drug and intervention response to treatments designed to enhance cognition. This focus meets one of the key topic areas for Competitive Supplements identified by the NIMH, namely Biomaterials and Biological Measures for the Study of Mental Disorders, which includes "Systematically collecting and analyzing biological measures (e.g., genetic polymorphisms, brain imaging indexes), which could be used, also in combination with clinically derived variables, to identify predictors of outcome, moderators of treatment response and adverse effects, or mediators and patterns of treatment effects." The end goal for these expanded aims will be to provide the field with: 1) easy to use imaging paradigms of these three cognitive functions that: 2) have been optimized for use in a clinical trials context (efficient, reliable, robust);while 3) maintaining their validity as specific measures of the cognitive and neural processes of interest. We believe that it is feasible to complete this added Aim in the time frame of the ARRA announcement, given that we have an established infrastructure. This set of collaborative R01 proposals meet the goals of the ARRA stimulus by providing for funding for 9 new positions, 3 positions that would allow us to retain staff that would otherwise need to be let go, and 1 position that we can increase from part to full time. PUBLIC HEALTH RELEVANCE: This project has high relevance for public health by significantly improving our ability to translate paradigms developed into the basic cognitive neuroscience literature for use in clinical trials aimed at improving cognition in schizophrenia. Cognitive deficits in schizophrenia are a major predictor of functional outcome in this debilitating illness. Thus, we need to improve our methods for detecting and enhancing cognitive function in schizophrenia in order to help individuals with this illness lead more productive and fulfilling lives.

DESCRIPTION (provided by applicant): The NIMH MATRICS and CNTRICS initiatives have clarified the domains of cognitive functioning that are most relevant to treatment development targeting improved cognition and functioning in people with schizophrenia. These projects also identified specific tasks that are psychometrically sound and well validated in patient populations, and that, in the case of CNTRICS, have well understood neurophysiology. More recently, interest has increased in identifying tasks that meet these criteria and that are sensitive to treatment effects. Identification of such tasks is important for grounding our understanding of illness progression and recovery processes within a cognitive neuroscience framework. This information would also allow for cognitive neuroscience-based indicators of treatment responsiveness, and therefore for more targeted drug development efforts and early prediction of medication response. Promising candidates for this type of task are measures of perceptual organization. Selected tests of perceptual organization meet the criteria of psychometric soundness (including avoidance of generalized deficit confounds), validation in patient studies, and known neurophysiology, although evidence regarding treatment effects at this point comes from very limited data. We now propose to conduct the first study in which schizophrenia patients are followed-up from the acute to stabilization to stable phases of illness, to determine whether perceptual organization dysfunction normalizes over the course of recovery. We will also determine if perceptual organization indices are most relevant for an illness subtype characterized by poor premorbid functioning, poor prognosis, and disorganized symptoms - relationships suggested by past studies. In addition, we will examine the course of perceptual organization in a first-episode population, which has not been previously described. Some evidence suggests that perceptual organization is normal or exaggerated at first episode. We will clarify whether the impairment is present at first episode or whether it develops within 15 months after initial hospitalization. For patients who begin to demonstrate impairment during the follow-up period, we will determine with what clinical and functioning changes the emerging abnormality is associated. We will explore these issues using a follow-up design in which we will enroll first-episode and later-episode schizophrenia patients (and a healthy control group), test them at hospital admission and discharge, and then again every 3 months, over a 15-month period. We will also examine covariation between changes in perceptual organization and changes in symptoms and level of functioning. The proposed project is consistent with two objectives from the NIMH Strategic Plan: 1) Strategy 1.3: Identify and integrate biological markers (biomarkers) and behavioral indicators associated with mental disorders;and 2) Strategy 2.1: Define the developmental trajectories of mental disorders. This study will determine the extent to which performance-based indices from promising perceptual organization tasks serve as biomarkers of illness processes for schizophrenia in general, or for a severely disabled illness subtype. PUBLIC HEALTH RELEVANCE: This project has high relevance for public health by identifying a biomarker of treatment responsiveness in a subtype of schizophrenia patient that is characterized by disorganized symptoms and poor prognosis. Examination of perceptual functioning longitudinally in first-episode patients will also allow for improved understanding of which patients decline in functioning over the first 1.25 years after initial hospitalization, and the associated cognitive mechanisms and markers of this decline. Identification of such markers may allow for identification of first episode patients who need more comprehensive and aggressive treatment to promote recovery. For first episode and older patients, identification of a biomarker of treatment responsiveness (or lack thereof) can aid new drug development efforts by helping to define, and improving our understanding of, a specific type of patient at high-risk for poor outcomes.

DESCRIPTION (provided by applicant): Clinical neuroscience is on the verge of a revolution. Traditional conceptualizations of disorders based on phenomenology are increasingly recognized as limited, but we have lacked a clear path toward a more valid approach. The Research Domain Criteria (RDoC) initiative has identified one such pathway; the examination of components of behavior linked to known neural systems that form the basis of core dimensions of psychopathology. This competing renewal will provide new insights into the cognitive and emotional processes underlying core symptom dimensions in major mental illness and provide a new set of valid and reliable tools to facilitate the aims of RDoC and Objective 1.4 of the NIMH Strategic Plan: Develop new ways of classifying disorders based on dimensions of observable behaviors and brain functions. This application will utilize the CNTRaC's infrastructure and expertise to optimize measures of WM capacity, positive and negative reinforcement learning (both implicit and explicit) and reversal learning, and then apply them together with previously validated measures. Specific Aim 1 is to validate (in individuals with schizophrenia, schizoaffective disorder and bipolar disorder, as well as comparison participants) optimized versions of the paradigms that assess our six constructs of interest, as well as to examine the relationship of task performance to clinical and functional outcomes in psychosis. Specific Aim 2 will be to assess and optimize test-retest reliability and practice effects for the task versions validated in Specific Aim 1. Specific Aim 3 will be to use these optimized measures of working memory capacity and reinforcement learning, along with our previously optimized measures of WM goal maintenance, relational encoding and retrieval, and visual integration to examine the relationship between performance on these measures of core constructs and dimensions of psychopathology across diagnoses (including medicated and un-medicated individuals with schizophrenia and schizoaffective disorders, as well as individuals with bipolar disorder). We hypothesize that impairments in the dorsal frontal- parietal and frontal-temporal systems supporting WM (capacity and goal maintenance) and relational encoding/retrieval contribute to disorganization symptoms and functional impairment and that these impairments and relationships cut across affective and non-affective disorder boundaries, forming a core dimension that helps explain the overlap in function and neurobiology across disorders. We also hypothesize that impairments in orbital frontal-striatal systems supporting reinforcement and reversal learning contribute to the negative symptoms of anhedonia/amotivation, which also cut across diagnostic boundaries. However, we hypothesize that anhedonia/amotivation may involve different aspects of reward processing and circuitry in primary mood versus non-mood disorders with our selection of measures motivated to test this hypothesis. We hypothesize that impaired visual integration, which is thought to reflect reduced horizontal and recurrent feedback, will be related to disorganized symptoms across disorders, but will not relate to mood pathology.

Abstract It is increasingly clear that people with schizophrenia have a range of visual perception impairments, including in low-level vision (e.g., acuity, contrast sensitivity) and mid-level vision (e.g., perceptual organization, coherent motion detection). These impairments are significantly related to poorer performance on cognitive (e.g., visual learning and memory) and social cognitive (e.g., facial emotion decoding) measures, and to worse functional outcomes. To date, there is no accepted technique for visual remediation for schizophrenia, and almost no work has been done in this area. However, visual remediation is a well-developed subfield within cognitive rehabilitation for TBI patients, and initial studies of short-term visual perceptual learning in schizophrenia indicate that plasticity exists that could support longer-term changes. Therefore, the overall goal of the proposed project is to test a visual remediation intervention for schizophrenia and determine its effects on specific visual targets with well-understood neurobiological mechanisms. The goal of the R61 is to determine the optimal intervention for improving the targets of contrast sensitivity (CS) and perceptual organization (PO). Extensive evidence exists for impaired CS and PO in schizophrenia. Moreover, these targets are prototypical examples of gain control and integration, respectively, which were identified by the NIMH-sponsored CNTRICS initiative as being the two core mechanisms involved in visual disturbances in the disorder. We will examine two computer-based interventions. One, ULTIMEYES (UE), targets CS. The other, contour integration training (CIT), targets PO. We will also examine the effects of combined treatment (UE&CIT). An active computer-based control treatment will be included. There will be 40 sessions, with assessments after every 10 sessions (N=20/group). The R61 Specific Aim is to evaluate the effects of UE and CIT on CS and PO targets, respectively, to determine if treatment effects meet a pre-specified effect-size criterion. Results of the R61 will be used to identify the treatment (UE, CIT, or UE&CIT) and duration (i.e., dose) that most effectively and efficiently improves the target(s). The goal of the R33 is to conduct an initial randomized controlled trial (RCT) of the optimal treatment identified in the R61. The R33 Specific Aims are to: 1) replicate and extend R61 results supporting visual target engagement in an adequately powered RCT (N=50/group); and 2) determine if visual target engagement is associated with improvements in cognition, social cognition, and functional capacity. If the R33 hypotheses are confirmed, results will inform the design of a later RCT to further explore mediators and moderators of treatment effects, and to move towards a precision medicine approach, wherein we determine which individuals are most likely to benefit from this intervention.

Advancements in computational psychiatry allow us to isolate multiple, specific cognitive mechanisms that determine human behavior. This formal modeling framework generates quantitative parameter estimates that can serve as bridges between pathophysiology and psychopathology. A major goal of computational psychiatry is to translate these laboratory tools so that they can be used in the clinic. Two critical hurdles need to be overcome. First, the enhanced validity and sensitivity of computational metrics needs to be established relative to standard behavioral performance metrics in key psychiatric and nonpsychiatric populations. We propose to do that by addressing a range of cognitive and motivational domains that have been strongly implicated in psychopathology, including working and episodic memory, visual perception, reinforcement learning, and effort based decision making. Second, we need to establish and optimize the psychometrics of these computational metrics so that they can be used as tools in treatment development, treatment evaluation, longitudinal, and genetic studies. These powerful metrics must have adequate test-retest reliability, and not be limited by ceiling and floor effects. We propose to develop these methods using an open, flexible, and scalable framework and demonstrate that they provide valid data both in the laboratory and in large-scale Internet-based data collection, facilitating ?big data? studies of cognitive processes. To this end, the current project will leverage the expertise of Cognitive Neuroscience Task Reliability and Clinical applications in Serious mental illness (CNTRACS) consortium, a multi-site research group with an established record of rapid cognitive tool development and dissemination. Aim 1 is to establish that model based parameters for the measurement of cognitive function are more sensitive than standard behavioral methods in assessing deficits across a range of common mental disorders, and have an enhanced capacity to predict clinical symptoms and real-world functioning, with a sample of 180 patients with psychotic and affective disorders (both medicated and unmedicated) and 100 healthy controls. Aim 2 is to measure and optimize the psychometric properties (test re-test reliability, internal validity, floor and absence of ceiling and practice effects) of computational parameters described in Aim 1, in a new sample of 180 psychiatric patients and 100 healthy controls. Aim 3 is to establish the feasibility and replicability of model-based analytic approaches outside the laboratory for assessing RDoC dimensions of interest, and to assess their relationships to variation in psychotic-like experience, depression and anhedonia, as well as real- world functioning in a community sample of 10,000 recruited over the Internet. Aim 4 is to validate key model based parameters against well-characterized neurophysiological measures acquired using EEG recordings during task performance. Successful completion of these Aims will significantly advance the field by providing easily administered and scalable web-based tools for estimating the integrity of key neural systems that underlie normal cognition and motivation and form the basis of common forms of cognitive and affective psychopathology.