2003 |
Hetrick, William P |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Erps in Schizophrenia and Alcohol Dependence @ Indiana University Bloomington
DESCRIPTION (provided by applicant): The estimated lifetime prevalence of alcohol dependence (AD) or abuse (AA) among schizophrenics (SZ) is alarmingly high (34%) compared to that of the US population (13%). In addition, people with SZ who are comorbid for AA or AD exhibit treatment complications and poor outcomes. However, it is unknown why the prevalence of alcohol disorders is nearly three times higher in SZ than in the general population; nor is it known whether these dually diagnosed (DD) patients show additional and more profound pathophysiological deficits compared to non-AD schizophrenics. It is possible that alcohol dependence in SZ patients reflects a specific vulnerability to develop AD and that this comorbidity is, in fact, associated with more pronounced pathophysiology than seen in AD or SZ alone. Findings from family studies indicate that SZ and AA/AD may share common vulnerabilities or that dual independent vulnerabilities may underlie this form of psychiatric comorbidity. Very little is known about functional pathophysiological substrates of this comorbidity. Among the vulnerabilities that these comorbid SZ patients may have are psychohysiological deficits (e.g., P50, and auditory & visual P300) that have been independently associated with either SZ or AD. The purpose of this study is to determine the psychophysiological deficits associated with this dual diagnosis using well characterized electrophysiological measures that are sensitive and specific to each illness. We predict that abstinent SZ patients with a recent comorbid diagnosis of AD will not only manifest psychophysiological deficits widely associated with SZ, but will also show the psychophysiological deficits frequently associated with AD. Characterizing functional deficits across these measures in these groups will contribute to the identification of phenotypic subtypes, etiological mechanisms, and potential targets of treatment.
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0.936 |
2006 — 2010 |
Hetrick, William P |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cerebellar Timing Dysfunction in Schizophrenia @ Indiana University Bloomington
DESCRIPTION (provided by applicant): A translational research program will investigate the integrity of cerebellar-mediated timing functions in schizophrenia and identify mechanisms that may modulate synaptic properties of cerebellar timing networks. Mounting theoretical and empirical evidence indicates that schizophrenia is associated with a fundamental disturbance in the timing of neural processes and behavior. This deficit in the temporal coordination of information processing, sometimes referred to as cognitive dysmetria, may lead to poor temporal coordination of perceptual, cognitive, affective, and motor processes. Abnormalities in a cortico-cerebellar-thalamic-cortical (CCTC) brain circuit, which is responsible for fluid, temporal coordination of sequences of behavior, are a likely source of the timing anomalies in schizophrenia. The proposed research will examine the functional integrity of the cerebellar mode of this circuit. Parallel and complementary human and non-human studies will be conducted primarily using cerebellar-dependent eye-blink conditioning tasks. The overarching aims are to: (1) comprehensively characterize the nature of the eyeblink conditioning (EEC) acquisition and timing abnormalities in schizophrenia and use a rabbit model to identify cerebellar mechanisms that may be responsible for the observed deficits;(2) examine the contribution of primary sensory processes associated with stimulus modality and intensity to the observed EBC acquisition and timing abnormalities in schizophrenia and a rabbit model;(3) systematically explore the effect of stable, antipsychotic medication treatment on EBC and other cerebellar-dependent measures of timing;and (4) determine the clinical, behavioral, and structural neuroanatomical correlates of EBC deficits in schizophrenia. Taken together, the studies will determine the functional integrity of the cerebellar node of the cortico-cerebellar-thalamic-cortical circuit in schizophrenia and test models of impaired cerebellar functioning that may give rise to timing deficits in the disorder. This research will result in knowledge about neural mechanisms associated with an extraordinarily debilitating psychological disorder, schizophrenia. A better understanding of these mechanisms will advance knowledge about the pathophysiology of schizophrenia, and may lead to the identification of neurobiological targets of treatment.
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0.936 |
2012 — 2016 |
Hetrick, William P |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cerebellar Dysfunction in Schizophrenia @ Indiana University Bloomington
DESCRIPTION (provided by applicant): This project began with compelling theoretical evidence and intriguing empirical hints to support our innovative hypothesis that schizophrenia (SZ) is associated with learning and temporal processing deficits linked to dysfunction of the cerebellum (CB) and related circuits. In the intervening years we found striking empirical evidence in SZ of behavioral dysfunction on several CB-dependent tasks, including associative learning (eyeblink conditioning), motor timing (finger tapping), and time perception (temporal bisection). Moreover, we found that 1st-degree relatives of SZ patients and individuals with schizotypal personality disorder also exhibit associative learning deficits. Finally, correlations between performance on CB-dependant tasks and cognitive functioning support contemporary models of the role of the CB in cognition. Taken together, our findings of learning and temporal processing deficits dovetail elegantly with emerging evidence of structural and functional CB abnormalities in SZ, and warrant further investigation for several important reasons. First, we must determine whether the observed behavioral deficits are associated with direct evidence of functional and structural CB abnormalities. We will use fMRI to investigate whether task-related CB activation predicts behavioral performance deficits in SZ across three tasks: eyeblink conditioning, finger tapping, and temporal bisection. Second, it is critical to determine whether SZ is associated with impaired cortico-CB connectivity. We will use MRI to examine resting-state functional connectivity and DTI-based structural connectivity between the CB and select cerebral regions that normally have strong neuroanatomical connections with the CB-though it is not known if this is the case in SZ-and are thought to be involved in temporal processing. Task-related fMRI dynamic causal modeling will be used to study directional influences between brain regions. Third, it is critical to understand whether neuroimaging dependent variables predict cognitive performance, so we have selected a battery of tasks with strong evidence of CB involvement. Fourth, our preliminary evidence that CB-dependent eyeblink conditioning is impaired in 1st-degree relatives of SZ patients and in schizotypal personality disorder begs the question of whether CB abnormalities represent endophenotypes of SZ. Forty individuals with SZ and 40 of their 1st-degree relatives will complete a battery of tasks to address these questions. Their performance will be compared to age- and sex-matched non-psychiatric control subjects (N=80). Successfully completing the proposed research will determine: (1) whether CB dysfunction underlies behavioral abnormalities observed in SZ on associative learning and temporal processing tasks; and (2) whether CB abnormalities represent endophenotypes of SZ. Our data will critically inform models of CB involvement in cortical cognitive processing in psychiatric illness and yield insights about potential novel mechanisms of illness and targets of treatment.
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0.936 |
2015 — 2021 |
Hetrick, William P |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Training in Clinical Translational Science: Maximizing the Public Health Impact @ Indiana University Bloomington
Project Summary/Abstract This program is focused on leveraging two innovative developments in medicine and clinical science to enhance the predoctoral training of psychological and brain scientists to make breakthroughs in understanding, preventing, and treating severe psychopathology. One development, the NIH initiative to foster clinical translational science (CTS), is motivated by the unmet critical need to move clinically-relevant scientific discoveries along the translational pipeline?from basic science to controlled research with clinical populations to dissemination and implementation?in order to make a substantive public mental health impact. A second development, the NIMH Research Domain Criteria (RDoC) initiative, is motivated by the critical need to develop multi-dimensional, multi-unit of analysis approaches to understanding psychopathology. Advances in clinical psychological science will come from a new generation of investigators with expertise at the intersection of these two NIH-driven developments. The ultimate goal of this training program is to maximize the likelihood of producing independent clinical research scientists and leaders with expertise in cutting-edge translational research designs, frameworks, and methodologies that will usher in breakthroughs in the identification of mental illness mechanisms, prevention, and treatment. Following a successful initial training period (years 1?4; 13 trainees), federal funds are requested to continue supporting six predoctoral trainees per year, along with two new institutionally supported trainees, for up to two years. Training opportunities center around four basic aims for each trainee: (1) to gain exposure to foundational concepts, theories, and methodologies, as well as exemplars of both CTS and multiple units of analysis informed by the RDoC; (2) apply this integrated framework to research addressing a public health issue; (3) to learn to foster collaborative opportunities that stretch the boundaries of research both along the CTS continuum and across multiple units of analysis; and, (4) develop professionally to continue this line of research as an independent clinical scientist. Trainees begin their intensive training by identifying a public health issue on which to focus their research efforts. These aims are then realized through: (a) structured research activities under the dual mentorship of a primary and a ?stretch? mentor (designed to extend the research either along the CTS continuum or across a unit of analysis); (b) dual research mentoring of the trainee leading to submission of an NRSA application; (c) peer, advanced trainee, and expert guidance and feedback on their research through participation in a year- long seminar; (d) tailored doctoral qualifying examinations; (e) coursework and advanced seminars focused on addressing mental health issues within the CTS and RDoC frameworks; (f) workshops in professional development, responsible conduct of research, and grant writing; and (g) colloquia series and conference attendance to encourage networking and collaborative opportunities. Trainees work with their dual mentors to design an individualized program of study in combination with the activities listed above.
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0.936 |
2019 — 2021 |
Hetrick, William P |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cerebellar Biobehavioral Markers in Cannabis Users @ Indiana University Bloomington
Cannabis use represents a significant and increasing public health concern as social acceptance accompanies legalization of this drug for medicinal and recreational purposes. These factors make understanding the health consequences of cannabis (CB) urgent and critical. For example, a recent study found university students age 19-22 had the highest rate of CB use in the last 30 years, with 39% having used in the last year. The prevailing view is that CB is a significant public health risk factor because (1) use is associated with increased risk for health and accidents, (2) adolescent use likely disturbs crucial brain maturation processes; (3) chronic use has been associated with cognitive deficits and (4) people who use CB are at increased risk for psychotic and mood disorders. However, the assessment of risks associated with cannabis is currently incomplete and equivocal. The proposed research strongly advocates that understanding the risks (or lack thereof) depends critically on a neural circuit-informed approach to testing the integrity of brain systems known to be richly endowed with CB-relevant receptors that are altered in response to CB exposure. The principal psychoactive ingredient of CB is delta-9-tetrahydrocannabinol (THC), which acts as a ligand for widely distributed CB1 receptors in the human brain. CB1R density in cerebellum is one of the highest in the brain. Although measures of cerebellar function could provide sensitive probes for the neurobehavioral effects of CB use, they have rarely been tested in CB users, nor have they been explicitly linked to behavioral deficits. Specific Aim 1 will measure resting state functional connectivity (rsFC) between cerebellum sub-regions and established cortical resting state brain networks (RSNs). Specific Aim 2 will test: a) whether cerebellar fMRI activation during cerebellar-dependent delay eyeblink conditioning (dEBC) is reduced in CB users; and b) whether task-based cerebellar activations produce different patterns of RSN connectivity (using the 10 RSNs from Aim 1) that are differentially sensitive to CB use. Specific Aim 3 will test the sensitivity of a set of cerebellar-dependent behavioral tasks to CB use. Findings from the proposed research will likely identify the cerebellar paradigms and measures which are most affected in current CB users. If the strongly founded predictions are borne out, this set of measures could then be utilized in a wide range of studies, including 1) longitudinal studies of high risk groups and CB users which would be critical for future research projects, 2) direct administration of cannabis compounds in humans, 3) studies of comparable measures in animal models of cannabis use and consequences, 4) genetically informed familial and twin studies and 5) field studies of cannabis intoxication. Additionally, these protocols could be highly informative in parsing cerebellar circuits which have been implicated in a broad range of addictive behaviors.
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0.936 |
2019 — 2020 |
Hetrick, William P |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Cerebellar Dysfunction in Autism @ Indiana University Bloomington
ABSTRACT Converging findings from diverse levels of analysis provide compelling evidence of cerebellar (CB) abnormalities in autism spectrum disorder (ASD), including decreased Purkinje cell numbers, neurochemical abnormalities, and increased glial cell activation. However, little is known about in vivo CB structure and function, nor the behavioral consequences of CB abnormalities. The proposed research tests a novel theoretical model using cutting-edge brain connectivity approaches to explore pathophysiological mechanisms associated with ASD and explicitly targets the CB, a brain area known to be abnormal in ASD. We will recruit 40 high functioning individuals with ASD and 40 neurotypical controls. Specific Aim 1 will determine how CB functional and structural abnormalities contribute to documented CB-dependent task-related deficits in the disorder. Specifically, we will determine if CB fMRI activation and CB gray matter volumes predict CB- dependent delay eyeblink conditioning (dEBC) behavioral abnormalities in ASD. Regression analyses will quantify the CB's specific contribution over and above other contributing regions (e.g., middle frontal, temporal & parietal cortices, basal ganglia). Specific Aim 2 will determine CB task-related (dEBC) effective connectivity and resting state functional connectivity to brain regions with which it has strong neuroanatomical connections, and the extent to which connectivity is disrupted in ASD. Path analysis will be used to determine CB effective connectivity and directionality. Resting state functional connectivity will be quantified using seed- based and ROI-based approaches. These functional analyses will explore CB connectivity and directional influence in the context of a network and rule out models where the deficit is systemic or due to extra-CB areas. Specific Aim 3 will determine whether core ASD symptom domains correlate with functional connectivity within specific closed-loop CB-cortical circuits. We hypothesize the following with respect to ASD functional connectivity: 1) CB anterior lobe and lobules VII-VIII to somatosensory/motor cortex will be inversely correlated with dEBC timing impairment and with Repetitive Behaviors Scale Revised (RBS-R) scores; 2) Posterior CB (including Crus I/II) to temporal and prefrontal cortex will be positively correlated with the social cognition scale of the Social Responsiveness Scale (SRS); 3) Crus I & II with cortical language regions will be inversely correlated with receptive language processing. The proposed research could identify critical mechanisms underlying ASD by re-shaping ideas about the role of the CB in the disorder's fundamental motor, social, and cognitive deficits. Moreover, these aims are consistent with NIMH priorities including developing an integrative understanding of basic brain-behavior processes that provide the foundation for understanding mental disorders and probing the connectivity of brain networks.
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0.936 |