Angus W. MacDonald - US grants

The Neurocognitive and Behavioral Core (NB Core) supports all three Projects. The Core will perform the development, provide training and supervise the collection and scoring of a common set of evaluations that will be done across the two Clinical Projects( 1 and 2). Based on the results and experiences with the proposed behavioral tasks, the NB Core will work to design tasks appropriate for future functional neuroimaging studies that would be part of a mature center. Additionally, the Core will organize and manage data from all three Projects, to allow the analysis of findings across species and Projects. This process will be facilitated by the involvement of Project and Core Pis, led by co-Pi of the Center, Dr. Carroll.

DESCRIPTION (provided by applicant): The objective of our transdisciplinary research team is to expand understanding about the neuroanatomical underpinnings of processing of media messages designed to prevent substance use among adolescents and young adults. The application builds upon established persuasion theories to guide two specific aims: the first aim proposes to identify messages that are effective and ineffective among adolescents and young adults, and the relationship between effectiveness and individual differences in personality and substance use history;the second aim proposes brain imaging techniques to determine the relationships among effectiveness, individual differences and brain activity associated with rewards and punishment. Neuroanatomical Basis of Anti-Drug Message Processing Narrative The objective of our transdisciplinary research team is to expand understanding about the neuroanatomical underpinnings of processing of media messages designed to prevent substance use among adolescents and young adults. The application builds upon established persuasion theories to guide two specific aims: the first aim proposes to identify messages that are effective and ineffective among adolescents and young adults, and the relationship between effectiveness and individual differences in personality and substance use history;the second aim proposes brain imaging techniques to determine the relationships among effectiveness, individual differences and brain activity associated with rewards and punishment.

[unreadable] DESCRIPTION (provided by applicant): This is a application in response to RFA-MH-08-090, titled "Adapting Basic Cognitive Measures for Clinical Assessment of Schizophrenia." Over the past decade there has been a growing awareness of the disabling effects of impaired cognition in individuals with schizophrenia. Along with this new awareness has come an increasing emphasis on the importance of developing new treatments that may positively impact these cognitive deficits. During this same period, the cognitive neuroscience field has seen an explosion of technical advances and new knowledge regarding the neural basis of cognition. Sadly, the translation and application of this cutting edge knowledge and paradigm development to new drug development in schizophrenia has lagged significantly behind the overall progress in the cognitive neuroscience field. The MATRICS initiative identified that the major barrier to this translation is a lack of data on the measurement properties of the behavioral tasks used in cognitive neuroscience. This concern spawned the Cognitive Neuroscience Research To Improve Cognition in Schizophrenia (CNTRICS) initiative, which conducted a series of conferences designed to bring together basic and clinical cognitive neuroscientists to develop consensus on the constructs and paradigms from cognitive neuroscience that are ripe for translation, and the validation and psychometric goals when translating such tasks for use in clinical trials contexts. The current application is a logical and much needed extension of the CNTRICS initiative that will begin the translation process for paradigms designed to assess four of the constructs identified as being ripe for translation in the first CNTRICS meeting. We have brought together a collaborative "translation" team that represents significant expertise from the many fields necessary for the success of this endeavor, including basic cognitive neuroscientists, clinical cognitive neuroscientists, psychometricians, statisticians, and clinical trials specialists. We have chosen to focus on four constructs that that allow us to illustrate the translation process with mechanisms that operate both early (e.g., gain control and visual integration in perception) and later (goal maintenance, relational encoding and retrieval) in human cognitive processing. By examining multiple mechanisms, we will be able to establish the generality of the translational approach we propose across different levels and types of cognitive mechanisms. Specific Aim 1 for this application is to validate (in both individuals with schizophrenia and comparison participants) optimized versions of the paradigms that assess our four constructs of interest (gain control, visual integration, goal maintenance and relational encoding/retrieval). By optimization, we mean examining modifications on already validated paradigms that are designed to: 1) minimize task length; 2) simplify task administration across multiple sites; 3) maximize sensitivity and selectivity in assessing the specific cognitive mechanisms of interesting; and 4) enhance reliability and minimize floor and ceiling effects. By validation, we mean ensuring that such optimizations designed to enhance the psychometric properties of the task do not alter its construct validity. Specific Aim 2 will be to assess and optimize test-retest reliability and practice effects for the task versions validated in Specific Aim 1. Project Narrative: 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. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): To reveal the effects of candidate genes on brain function in schizophrenia, we will employ a two-stage screening process to test genes for association with context processing deficits and prefrontal cortical dysfunction. Using an endophenotype-driven approach, we will determine whether mutations in glutamatergic genes underpin neural and cognitive risk for schizophrenia. 1) The first stage will test whether five glutamate moderating genes (RGS4, DTNBP1, GRM3, NRG1, and DAOA) are associated with individual differences in context processing in a large general population sample. We will also use resampling techniques to explore whether seven less established glutamate moderating genes (GRIA2, EPSIN 4, PPP3CC, GRIN, DAO, PRODH and YWHAH) contribute to context processing, and whether glutamate polymorphisms interact with the schizophrenia risk allele of COMT. 2) The second stage will evaluate whether glutamate modulating genes associated with context processing in the general population are related to context processing deficits in schizophrenia patients and their biological relatives. 3) Finally, to understand the relationship between glutamate polymorphisms and brain dysfunction, we will use functional magnetic resonance imaging (fMRI) to examine prefrontal cortical activity in healthy relatives of schizophrenia patients and controls during performance of a context processing task. This project falls within the scope of the R21 mechanism because studies in the general population and schizophrenia are established and funded. R21 funding will support behavioral phenotyping and genotyping, but not fMRI scanning, recruitment, or additional blood sampling costs. The current study has the potential to confirm the importance of glutamate modulating genes in the etiology of schizophrenia and highlight the intermediate mechanisms through which these genes lead to disease manifestation. PUBLIC HEALTH RELEVANCE: To reveal the effects of candidate genes on brain function in schizophrenia, we will employ a two-stage screening process to test genes for association with context processing deficits and prefrontal cortical dysfunction. The first stage will test whether glutamate moderating genes are associated with individual differences in context processing in a large general population registry. The second stage will evaluate whether positively screened glutamate genes are related to context processing deficits in schizophrenia patients and their biological relatives, and determine whether these genes are related to fMRI measures of brain function in relatives and controls. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Schizophrenia patients have difficulties with executive functioning including the domains of working memory, flexibility, and inhibiting planned motoric responses. Much of schizophrenia research has focused on the role of prefrontal cortex in executive functioning. This study plans to investigate the inhibition of planned responses using a stop-signal task developed to manipulate the number of motor cues before receiving an inhibition cue. This design allows for evaluation of traditional prefrontal regions as well as the striatum. Extensive research using multi-modal techniques have suggested a role for the striatum in schizophrenia, including animal models and structural and functional imaging. Most importantly, previous research indicated that the striatum plays an important role in both the inhibition of planned motoric responses and the anticipation of inhibition (Vink et al. 2005). A further goal of this study is to investigate whether the behavioral and imaging abnormalities in schizophrenia patients are related to the genes predisposing for schizophrenia or mostly to the disease process or other non-specific effects. To determine which processes are related to the genetic vulnerability to the disorder, this study will include the non-psychotic relatives of schizophrenia patients, as schizophrenia patients and their relatives share genes, but not the disease process. We anticipate that the striatum and regions of the prefrontal cortex will be found to be reduced in activity when inhibiting a response in schizophrenia patients and relatives of patients compared to controls. Lastly, we predicted that striatal functioning in controls will increase as these participants anticipate an inhibition cue, however this linear increase will be absent in schizophrenia patients and their relatives.

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.

Summary This project is the next step in a research program designed to understand the pathophysiology and etiology of spite sensitivity, a theory-rich construct thought to underlie persecution and suspicious behaviors. We have developed a paradigm known as the Minnesota Trust Game that uses a parametric manipulation of risky decisions to quantify participants' suspicious behaviors. This game includes trials where the partner has an opportunity to be spiteful, that is lose their own money to cause the participant to lose even more money. Spite sensitivity, then, is reflected as an unwillingness to allow partners this opportunity. We have found across patient and healthy samples that this suspicious choice correspond to global judgments of persecution, paranoia and alienation. The project examines persecution in people receiving psychiatric services and twins from the general population using this game in a functional MRI scanner. The inclusion of psychiatric patients (n=50) and monozygotic twins (n=50 matched to patients and up to n=50 of their co-twins) allows us to examine the continuity of mechanisms across these populations. The inclusion of monozygotic twins also allows us to examine etiological factors and to evaluate causality. These tools therefore provide a robust test of the hypothesis that persecution is a form of spite sensitivity, a component the RDoC construct understanding others' mental states. Spite sensitivity, in turn, relates to a functional disconnection between executive control and valuation brain networks.

Non-invasive neuromodulation, such as transcranial direct current stimulation (tDCS), is emerging as an important therapeutic tool with documented effects on brain circuitry, yet little is understood about how it changes cognition. In particular, the challenge of how learning, or training, in one domain generalizes to unlearned or unpracticed domains has long been a focus of educational psychology. TDCS may have a critical role to play in generalization, previous studies have found: (i) Right prefrontal anodal tDCS with concurrent cognitive training enhances generalization of training in healthy controls that endures as much as 3-months later, (ii) Left prefrontal tDCS with concurrent cognitive training enhanced generalization of training in patients with schizophrenia compared to sham. Understanding how tDCS affects brain circuitry is critical to the design and application of effective interventions, especially if the effects are different for healthy vs. psychiatric populations. The premise of this proposal is that improvements in thalamocortical FC are associated with the generalization of cognitive training, and tDCS facilitates these improvements. The overarching goal of this proposal is to deploy neuroimaging and cognitive testing to understand how tDCS with cognitive training affects thalamocortical circuitry in individuals with and without psychopathology. Study 1 will compare right frontal, left frontal and sham tDCS during concurrent cognitive training over 10 weeks in 75 healthy controls (HC). Study 2 will be similar in all respects but will examine 75 patients with schizophrenia and include clinical assessments. Measures of learning rate, generalization and durability will be collected at regular intervals during the intervention period, including a mid-training scanning session and a 12-week follow-up assessment. These two studies will allow us to address the following specific aims: SA1. Compare the effect of right active-tDCS, left active-tDCS and sham (hemisphere), length of treatment and measured dosage on brain circuitry. In both HC and SZ, greater ipsilateral thalamocortical (prefrontal) FC increases are driven by H1.1 active tDCS in the ipsilateral hemisphere; H1.2 a longer length of treatment; and H1.3 higher modeled dosage. SA2. Establish the effects of hemisphere, length of treatment and modeled dosage on generalization and durability. In both HC and SZ, greater generalization and durability are driven H2.1 more by right tDCS compared to left tDCS or sham; H2.2 by a longer length of treatment; and H2.3 by higher modeled dosage. SA3. Examine how changes in thalamocortical FC in both hemispheres affect generalization and durability. In both HC and SZ, greater thalamocortical FC drives H3.1 greater generalization; and H3.2 greater durability. Impact. We propose the first experiments to examine tDCS-augmented cognitive training effects on brain circuitry and generalization in both health and psychosis, providing crucial information about location of stimulation, length of treatment, modeled dosage, trajectory and durability needed to guide future research and interventions for cognitive impairments.

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.

The overall goal of this project is the development and validation of parametric mathematical assays of human decision-making, based on an online information-foraging task (WebSurf). Decisional impairments in general are common in mental illnesses, but the exact pattern of deficits varies within and between diagnostic categories. Those deficits often involve multiple decision-making systems and the interactions between those systems. For instance, patients with obsessive-compulsive disorders rely overly on habitual/procedural action (leading to ritualizing behavior), but also show impairment in change-of-mind systems (inability to interrupt rituals) and deliberation (?analysis paralysis? in the face of uncertainty and a chance of negative outcomes). A major challenge in computational psychiatry is the need for tasks/paradigms that measure these multi- system dysfunctions, including interactions between systems. A further need is tasks that are viable for clinical settings, i.e. that are valid for repeated-measures use, sensitive to clinical-level impairment, and usable without highly trained experimenters present. We propose to address these needs with WebSurf, an information-foraging task developed by co-PIs MacDonald and Redish. These investigators and their colleagues have used WebSurf (and its rodent version, Restaurant Row) to demonstrate a common ?sunk costs? fallacy across rodents and humans, to identify the neural basis of regret, and to quantify differences in rule-based decision making in patients with eating disorders. Those studies have demonstrated WebSurf?s general utility as a cross-species paradigm and shown the richness of parametric descriptions that can be extracted from task behavior. They have also identified difficulties with the base version of the task, including needs for greater subject engagement and higher trial counts. As importantly, although Restaurant Row appears to elicit stable day-to-day behavior in mice, we do not yet know if the same is true for humans. We will close these gaps in task validation by assessing the performance of multiple variants using Amazon?s Mechanical Turk platform. Data from those variants, as well as ongoing data collection with the baseline task in our psychiatric clinics, will validate newer and more robust approaches to decision parameter estimation (Aim 1), grounded in Bayesian hierarchical modeling. They will demonstrate repeated- measures stability (Aim 2) and ability to describe variation between and within clinical populations (Aim 3). Executing these Aims will build on WebSurf?s success as a (reverse) translatable experimental paradigm, demonstrating a tool for clinical computational psychiatry. Our team?s broad experience includes computational science, experimental psychology and neuroscience, and clinical psychiatry, making us well-suited both to perform the Aims and apply the results in future psychiatric neuroscience studies.

PROJECT SUMMARY: PROJECT 3 The purpose of PROJECT 3 is to determine how failures in information processing that supports state representation in neural circuits relate to clinical heterogeneity in early psychosis. To this end, we will: (a) Recruit people with early psychosis (N=125) and demographically similar healthy controls (N=125) aged 16-30 years; (b) Determine test-retest reliability of the DPX and Bandit tasks as assessments of state representation processes; (c) Characterize behavioral performance and neurophysiology at baseline using the DPX and Bandit tasks during simultaneous EEG-fMRI; (d) Follow patients for 6 months while they receive usual care, to delineate their clinical trajectories; (e) Repeat the behavioral and EEG-fMRI assessments after six months (N=100 retained per group). The data we acquire will allow us to examine the baseline relationships between clinical and experimental measures, and also to investigate how changes in clinical and experimental measures are related over a 6-month time period during a critical phase of illness. The overall goal of PROJECT 3 is to permit neural macro-circuit links in humans to the behavioral and neurophysiology experiments in monkeys and mice (PROJECTS 1 & 2). This will allow us to examine how state representation dysfunctions observed in early psychosis -- along with EEG and fMRI-derived neurophysiologic indices of activity timing, excitatory-inhibitory (E-I) balance, and noise -- relate to clinical heterogeneity at baseline, and to heterogeneity in 6-month clinical trajectories. In Aim 1, we compute the retest reliability of state representation measures. In Aim 2, we characterize and compare the features of behavior, EEG and fMRI in early psychosis and healthy controls during state representation processes. In Aim 3,we re- assess performance on the DPX and Bandit tasks during simultaneous EEG-FMRI, in order to characterize the course of state representation dysfunctions in early psychosis during the critical first 6 months of treatment. We will determine the extent to which changes in computational parameters derived from the COMPUTATIONAL CORE, and neurophysiologic measures related to activity timing, E-I balance, and noise (see TRANSLATIONAL NEUROPHYSIOLOGY CORE), map to distinct trajectories in quality of life using causal discovery analyses. We will also test whether trajectories can be predicted from baseline features. Additionally, our healthy control data set will permit us to explore normal patterns of stability vs. change as observed over 6 months in adolescents and young adults.