Vijay A. Mittal, Ph.D. - US grants

DESCRIPTION (provided by applicant): Psychotic disorders such as schizophrenia have been associated with both frontal lobe dysfunction as well as abnormal regulation of subcortical regions. An innovative theory suggests that deficits in the system linking these two areas (the frontal-subcortical circuits; FSCs) may account for the wide range of symptoms and characteristics seen in psychotic disorders. Recent research detecting abnormal grey and white matter development in the frontal and medial temporal regions during the prodrome, a period proceeding formal onset of psychotic disorders, suggests that maturational changes are highly relevant in the etiology of psychotic disorders. Despite the evidence suggesting a prominent role of maturational factors in etiological conceptualizations of psychosis, it is unclear how neuromaturation in the FSC system may contribute to symptoms or characteristic behaviors of psychosis; to date no published studies have examined longitudinal grey and white matter changes in high-risk participants in this critical system. However, understanding the neural-reorganization preceding illness is integral as it stands to elucidate underlying pathogenic mechanisms prior to when widespread medication usage and neurotoxicity may confound clear understanding and further, within the context of detecting and treating high-risk adolescents, can lead to identifying biological markers of vulnerability- indicating which high-risk individuals are most likely to convert to psychosis. A strong line of evidence implicating that developmentally based FSC changes are tied to emerging psychosis, indicates that spontaneous movement abnormalities (SMAs) (i.e., dyskinesia and Parkinsonisms), presumed to reflect a compromised FSC system, become salient during adolescence, continue to progress in frequency/severity with age, are associated with symptoms, and predict eventual conversion to formal psychosis. However, to date it is unclear which particular maturational changes may underlie SMAs, or if these movements do indeed serve as a marker of progressive FSC dysfunction. Further, to date SMAs in high-risk populations have only been assessed with observer-based measures, and recent studies in psychotic populations, suggesting that instrumentally based measures of SMA are significantly more sensitive, hint at promise for a viable biomarker. The proposed study will test the hypothesis that irregular development in grey and connective white matter tracts among prodromal adolescents contributes to alterations in FSC, resulting in SMAs, prodromal symptoms, and eventually the onset of psychosis. We propose to utilize instrumental measures of SMAs (i.e., Force Variability and Velocity Scaling), magnetic resonance imaging (MRI), and diffusion tensor imaging (DTI), to examine structures and connective tracts comprising the FSC system, following groups of 75 adolescents with a prodromal syndrome (age 12-21), and 75 matched healthy controls over the period of one-year (baseline and on year follow-up) to determine the neurodevelopmental underpinnings of SMAs (if specific developmental patterns of grey and white matter in the FSC system characterize prodromal populations and result in dyskinesias and/or Parkinsonisms) and if developmental abnormalities in this system and SMAs (a potential biomarker that may directly reflect this pathology) predict a poorer course of illness.

DESCRIPTION (provided by applicant): Accumulating evidence from the animal literature, healthy populations, and schizophrenia studies suggests that regular exercise positively affects integral functions such as neurogenesis, synaptic plasticity and cognition. Likewise, preliminary evidence suggests that aerobic activity has been associated with improved quality of life and a lower level of symptoms in patients with schizophrenia. Because exercise has been found to stimulate human medial temporal neurogenesis, and related abnormalities have been widely observed in studies of schizophrenia, physical activity may be in an important intervention. During the psychosis prodrome, a period immediately preceding formal onset of psychotic disorders, adolescents experience subtle attenuated symptoms coupled with cognitive deterioration and a global decline in socio-occupational functioning and anywhere between 10-35% go on to transition to a psychotic disorder such as schizophrenia in a two-year period. Despite the promise of exercise interventions, and the critical role medial temporal lobe abnormalities play in etiological models of psychosis, there have been no experimental studies of aerobic exercise in ultra-high risk youth (UHR). Understanding the potential benefits of aerobic exercise in UHR youth is integral as the prodrome is a viable period of intervention in which considerable brain development is still occurring. Further, as there have been challenges associated with many of the available interventions, and an increasing level of potential found in neuroplasticity-based interventions, understanding the effect of exercise on respective brain-behavior holds considerable promise. Experimental research is sorely needed to determine if prescribed aerobic exercise can stimulate medial-temporal neurogenesis and ameliorate cognition and symptoms/functioning in this vital group. In the proposed study, an expert team of experienced prodromal and exercise investigators will follow a group of 15 UHR adolescent and young adults (ages 16-24) through a 12 week exercise trial to determine which level of exercise intensity/frequency is tolerable for participants and optimal for improving aerobic fitness (65% of VO2max and 2 sessions per week versus 85% intensity and 3 sessions per peek) and if improvements in aerobic fitness (i.e., VO2max, VO2peak, ventilatory threshold) are associated with increases in medial temporal structure volume (hippocampus and parahippocampal gyrus) and accompanying improvements in cognitive function (i.e., including tasks known to recruit heavily on medial temporal structures) as well as symptomatology and social/role functioning. If the benchmarks are met, this data will be used to streamline a three-year rater-blind controlled trial (15 UHR-exercise, 15 UHR waitlisted-control) to determine the efficacy of the intervention in promoting medial temporal health as well as accompanying cognitive, clinical, and socio-occupational function improvement. Participants will be followed up to 24-months to determine if the intervention has an affect on clinical course and transition to psychosis. Taken together, this study is important for understanding the lessons necessary for planning a future large-scale trial, and has the potential to shed light on a promising new treatment for UHR youth.

Project Summary/Abstract The proposed study aims to develop a brief, valid screening questionnaire to identify individuals at risk for psychosis in non-clinical populations across 3 large, community catchment areas with diverse populations. This is a needed study, as the current screening tools for at-risk psychotic populations have only been validated in clinical and/or treatment seeking samples, which likely do not generalize outside of these specialized settings. The proposed project will administer 3 well-known psychosis risk screeners, as well as additional symptom-based (e.g., depression, anxiety, etc.) and risk-factor based questionnaires (e.g., cannabis and other substance use, a family history of major mental disorders, trauma history) to 6,000 adolescents/young adults in local communities across 3 demographically diverse sites (Philadelphia, Baltimore, and the greater Chicago areas). Based on established cut-off scores from the 3 psychosis screeners, 1,560 subjects deemed as questionnaire higher risk (n=780; QHR) and questionnaire lower risk (n=780; QLR) for psychosis (estimated sample sizes based on pilot data) will be invited to complete semi- structured interviews to determine clinical high risk (CHR) for psychosis status based on the Structured Interview for Psychosis-Risk Syndromes (SIPS) and to assess current/past major mental disorders based on the Structured Clinical Interview for DSM-5 (SCID-5). Based on preliminary data and conservative estimates, we anticipate that 117 of the QHR group will be considered CHR for psychosis. The specific aims are as follows: 1) to determine norms and prevalence rates of attenuated positive psychotic symptoms across 3 diverse, community catchment areas and 2) to develop a questionnaire screener, using both symptom-based and risk factor-based questionnaires, that is validated against the SIPS to identify those at CHR for psychosis in the community. This is the first study in the U.S. to determine the rate of subthreshold psychotic symptoms across diverse non-help seeking samples, which is essential for investigations using dimensional approaches to psychotic disorders. Further, the proposed study will develop an essential screening tool that will identify which individuals have the greatest need for follow-up with structured interviews in CHR studies or clinical settings to determine psychosis-risk status. This tool is will be quite valuable given findings that those who develop psychotic disorders often do not seek treatment until after the onset of the disorder, and that duration of untreated psychosis is associated with more serious clinical outcomes. The proposed study has the potential for major contributions to the early detection and prevention of psychotic disorders.

PROJECT SUMMARY The proposed project will examine emotional functioning in adolescents and young adults who are at heightened risk for imminently developing a psychotic disorder (i.e., ultra-high-risk [UHR] youth), focusing on interactions with their parental caregivers. While alterations in emotional functioning have been observed in individuals with psychosis and in UHR youth, the field has primarily focused on corroborative, self-report, and clinical interview-based measures, and as a result, currently has a limited understanding of how in-depth, dynamic interactions may play a pathogenic role. The current proposal is notable in linking across multiple modalities during experimental laboratory-based dyadic interactions to understand how emotional functioning in both UHR youth and caregivers predicts symptoms, social functioning, and clinical course over time. The first aim of the proposed research is to determine differences in emotional functioning during interaction between UHR-youth and caregivers compared to control youth and caregivers. This is of particular importance given that there are well-documented alterations in socioemotional functioning in UHR youth. Yet these alterations have rarely been examined in social contexts of key emotional significance, such as during interactions with their parental caregivers. Moreover, no studies have aimed to differentiate patterns of abnormality from developmentally normative emotional functioning during conflict interactions. The second aim is to determine which contexts reveal physiological vulnerability in UHR youth compared to control youth. Alterations in resting state autonomic physiology are a well-documented vulnerability factor in psychopathology, but have rarely been examined during negative (which put unique demands on the autonomic nervous system), neutral, and positive youth-caregiver interactions. The third aim is to evaluate whether emotional functioning during interactions in youth and caregivers predicts youth's symptoms and broader real-life social functioning concurrently and prospectively (over a period of 12 months). There is a large literature implicating caregivers' expressed emotions (EE) in psychosis, but no research has assessed emotional functioning in both youth and caregivers simultaneously during interaction. By delineating specific emotional qualities of UHR youth-caregiver interactions and identifying specific aspects of emotional functioning in both UHR youth as well as caregivers that put UHR youth further at risk, the proposed project will provide the foundation for identifying specific treatment targets for larger studies with both youth and caregivers.

Project Summary The overall objective of the current project is to examine the relationship between neural habituation, defined as a decrease in neural response to repeated visual stimuli (especially faces), and social processing deficits in ultra high-risk (UHR) youth, a group at imminent risk for psychosis. Although different aspects of social processing and neurobiology in UHR youth have been examined in relative isolation, the current proposal is notable in linking across multiple modalities from behavioral recognition abilities to perceptual processes to real-world functioning and clinical variables. The first aim of the proposed research is to utilize electroencephalography (EEG) to test the hypothesis that neural habituation deficits are present in UHR youth relative to healthy controls. This is of particular importance due to the association between habituation and learning and memory. Previous work has shown deficits in patients with schizophrenia, but whether these deficits are present prior to the onset of psychosis has yet to be examined. The second main aim will examine whether neural habituation is associated with face identity recognition, facial affect recognition, or general non- social object recognition. To do so, the proposed research will employ behavioral recognition tasks and examine the correlates between recognition abilities and neural habituation as tested in the first aim. Aim 3 will examine the degree to which neural habituation and behavioral recognition abilities (face identity, facial affect, and non-social object) are associated with symptom severity, cognitive measures, and clinical variables at initial assessment. Finally, an Exploratory Aim will examine which of the measures assessed in Aims 1 and 2 change over time and/or predict clinical status and social functioning 12-months later. Studying the mechanisms underlying social deficits in this population will provide a framework for future interventions, such as face-training remediations.

Project Summary Major depressive disorder (MDD) is a serious public health problem that has, at best, modest treatment response. One reason for this mixed efficacy is that MDD has a very heterogeneous clinical presentation. One way to parse the heterogeneity is to investigate the role of particular features of MDD, an endeavor that can also help identify novel and focal targets for treatment and prevention efforts. Psychomotor disturbance (e.g., psychomotor agitation [PmA] and retardation [PmR]) has long been viewed as a particularly pernicious feature of MDD, and yet we know surprisingly little about these behaviors. For example, it is unknown if motor disturbance occurs only in active depression, or whether it also continues into remission (potentially signaling vulnerability for relapse). There also has been little work (a) linking PmA & PmR with abnormal neural circuitry mediating these motor behaviors, (b) examining how motor symptoms change over the course of illness, and (c) investigating whether PmR & PmA represent a single underlying process, or reflect distinct mechanisms. The present proposal seeks to test these questions and also identify powerful and easy to administer tools to assess these behaviors in clinical practice. The proposed project will recruit those with current MDD (n = 100), remitted MDD (n = 100) and controls (n = 50) and take a Research Domain Criteria (RDoC) approach by comparing the three groups on multiple indicators of PmR and PmA (Aim 1). Specifically, we will assess PmR and PmA with self and observer- based reports, behavioral assessments in the laboratory (Velocity Scaling [PmR] and Force Variability [PmA]), and behavioral assessments in subjects' natural environment (actigraphy and daily typing behavior on one's smartphone [texting, emailing, etc.]). These behavioral measures are particularly critical as they yield more fine-grained and objective assessments of PmR and PmA that may be missed by traditional diagnostic assessments. Aim 2 seeks to examine the structural (diffusion tensor) and functional (resting state fMRI) connectivity of motor circuitry of the three groups as well as the relation between motor circuitry and the proposed indicators of PmR and PmA. For this aim, we will utilize innovative graph theory metrics of connectivity of the three primary motor circuits identified in animal and human studies (specifically, basal ganglia, cerebellar and cortico-cortical motor circuits) which will provide a comprehensive examination of motor system organization in MDD. Aim 3 seeks to follow-up subjects three times over 18 months to evaluate whether motor symptoms change in tandem with overall depressive symptoms and functioning over time and/or whether baseline PmR/PmA predicts course of depression an functoining. Aim 3 is particularly clinically significant. Finding that motor and overall depression severity co- vary over time, or that motor variables predict subsequent change in overall depression severity, would support the potential clinical utility of the proposed novel, reliable, and easily administered motor assessments.

Project Summary Negative symptoms are a core feature of schizophrenia defined as the loss of normative motivation and/or expression. This dimension of psychopathology is distinct from other aspects of the illness and highly predictive of poor community-based functional outcomes. However, pharmacological and psychosocial treatments for negative symptoms have demonstrated limited effectiveness. To address this critical unmet need in schizophrenia therapeutics, the NIMH sponsored a consensus development conference to delineate research priorities for the field and stimulate treatment development. The primary conclusion of this meeting was that next-generation negative symptom rating scales should be developed to address methodological and conceptual limitations of existing instruments. Two next-generation clinical rating scales resulted from the NIMH consensus development conference that were intended for use with adult populations presenting with established psychotic illnesses. However, the consensus conference did not discuss development of assessments specific to youth at ultra-high risk (UHR) for developing psychosis (i.e. adolescents/young adults meeting criteria for a prodromal syndrome). Given that negative symptoms are highly predictive of the transition to diagnosable psychotic illness, enhancing our ability to detect negative symptoms in UHR youth is paramount. Existing scales designed to assess negative symptoms in UHR youth have conceptual and methodological limitations and scales designed for adults with diagnosable illness do not meet the unique needs of the UHR population. New scales specifically designed to assess negative symptoms in UHR youth are needed to accurately chart mental illness trajectories and determine when, where, and how to intervene. The current study aims to extend the scale development aims of the NIMH consensus development conference to the UHR population by taking an iterative, data-driven approach to creating a new measure, the Prodromal Inventory for Negative Symptoms (PINS). A beta version of the PINS was developed that displayed promising psychometric properties. Two studies will be conducted to refine the beta version and arrive at a final scale based on state-of-the-art statistical methods, with data collected at 3 sites with ongoing UHR research programs. Study 1 will include a large, representative, and diverse sample of UHR youth (n = 180) and evaluate the psychometric properties of the beta version. To determine how the beta version should be revised, analyses will be conducted to determine item selection, modification, and retention, including Item Response Theory, confirmatory factor analysis, item-level analyses, within- and between-site inter-rater reliability, and analyses of convergent and discriminant validity. In study 2, psychometric properties of the revised scale will be evaluated in a sample of UHR youth (n = 120) who will be followed longitudinally. Analyses of the final scale will evaluate measurement stability, internal consistency, inter-rater reliability, prediction of the transition to diagnosable psychotic illness, factor structure, convergent validity, and discriminant validity. This iterative, data-driven scale development process will provide the field with a next-generation negative symptom scale that meets the unique assessment needs of the UHR population.

Project summary The goal of this project is to investigate the feasibility of using speech acoustics as a clinical biomarker in individuals at clinical high risk (CHR) for developing psychosis. There is evidence that disruptions to cortico-cerebellar circuits in individuals experiencing attenuated psychosis symptoms impact motor control of the face and limbs. This proposal would be the first study to examine whether these motor disruptions in high-risk populations also affect the complex motor control required for speech. In Aim 1 an instrumental approach will be used to investigate the acoustic correlates of psychosis risk. Specifically, speech data will be collected to investigate fine-grained acoustic properties of vowels and consonants in simple repetition tasks as well as during more naturalistic conversational speech. The speech of CHR young adults will be compared to age-matched healthy controls to discover if there are group differences in the speech acoustics that allow us to classify speech samples into healthy and clinical groups. To enable fast, reliable analysis, machine learning-based algorithms will be used to measure the acoustics speech properties of interest. In Aim 2, the speech properties measured in Aim 1 will be compared to other behavioral measures, in order to discover if they correlate with several measures of cerebellar dysfunction (posture control, procedural learning, and motor timing) that are known to occur in CHR individuals. These measures will provide convergent validity for these novel speech measures. Cognitive capabilities which are related and unrelated to speech and motor control will also be assessed, to provide specificity and divergent validity to these measures. In Aim 3, the links between speech features and changes in symptom severity will be assessed at two time points, connecting changes in speech motor control to longitudinal changes in the progression of the symptoms over 12 months. These investigations may reveal speech as a novel and easily-collected biomarker enabling early detection of psychosis risk.

Summary Research suggests that early identification of individuals at clinical high risk (CHR) for psychosis may be able to improve illness course. Studies suggest that early identification of CHR using specialized interviews with help-seeking individuals (with attenuated psychosis symptoms) is a useful approach. This work has two major limitations: 1) interview methods have limited specificity as only 20% of CHR individuals convert to psychosis, and 2) the expertise needed to make CHR diagnosis is only accessible in a few academic centers. We propose to develop a new psychosis symptom domain sensitive (PSDS) battery, prioritizing tasks that show correlations with the symptoms that define psychosis and are tied to the neurobiological systems and computational mechanisms implicated in these symptoms. To promote accessibility, we utilize behavioral tasks that could be administered over the internet; this will set the stage for later research testing widespread screening that would identify those most in need of in-depth assessment. To reach that goal we first need determine which tasks are effective for predicting illness course and how this strategy compares to published prediction methods. We propose to recruit 500 CHR participants, 500 help-seeking individuals, and 500 healthy controls across 5 sites with the following Aims: Aim 1A) To develop a psychosis risk calculator through the application of machine learning (ML) methods to the measures from the PSDS battery. In an exploratory ML historical analysis, we will determine the added value of combining the PSDS with self-report measures and predicators;Aim 1B) We will evaluate group differences on the risk calculator score and hypothesize that the risk calculator score of the CHR group will differ from help-seeking and healthy controls. We further hypothesize that the risk calculator score of the CHR converters will differ significantly from groups of CHR nonconverters, help-seeking and healthy controls. The inclusion of a help-seeking group is critical for translating the risk-calculator into clinical practice, where the goal is to differentiate those at greatest risk for psychosis from those with other forms of psychopathology; Aim 1C): Evaluate how baseline PSDS performance relates to symptomatic outcome 2 years later examining: 1) symptomatic worsening treated as a continuous variable, and 2) conversion to psychosis. We hypothesize that the PSDS calculator: 1) will predict symptom course and, 2) that the differences observed between converters and nonconverters will be larger on the PSDS calculator than on the NAPLS calculator. Aim 2) Use ML methods, as above, to develop calculators that predict: 2A) social, and, 2B) role function deterioration, both observed over two years. Because negative are more strongly linked to functional outcome than positive symptoms, we predict that negative mechanism tasks will be the strongest predictor of functional decline in both domains.This project will provide a next-generation CHR battery, tied to illness mechanisms and powered by cutting-edge computational methods that can be used to facilitate the earliest possible detection of psychosis risk.