Gabriel S. Dichter - US grants

[unreadable] DESCRIPTION (provided by applicant): The goal of the proposed research is to examine the neural correlates of depressive symptom reduction in individuals with major depressive disorder using functional magnetic resonance imaging (fMRI). Specifically, we propose to acquire functional imaging data from individuals with major depressive disorder at two points in time, both before and after an 8- to 15-week course of Brief Behavioral Activation Treatment for Depression, a structured and well-validated method of cognitive behavioral therapy designed to reduce sensitivity to loss and enhance sensitivity to reward (Hopko et al., 2003a). Imaging data will focus on activation of a reward network comprising the orbitofrontal and prefrontal cortices, the anterior cingulate, and, in particular, the ventral striatum, during anticipation of reward using the Wheel of Fortune Task, (Ernst et al., 2004). This previously validated task was designed to elicit responding to reward expectation and has been shown to activate this reward network in response to reward expectations in nonclinical samples (Ernst et al., 2005; Ernst et al., 2004). This reward network and the ventral striatum in particular, are critical for processing reward anticipation and cues of incentive motivation (e.g., Keedwell et al., 2005). Increased neural activation in this reward network in response to anticipation of reward after cognitive behavioral therapy will be evaluated in relation to symptom reduction in a number of domains, most notably symptoms of loss of pleasure (i.e., anhedonia). The proposed study has the potential to hone the targets of psychological interventions for major depressive disorder by identifying which components of therapy effect the anticipation of rewards, a central deficit in this psychiatric condition. The benefit to public health provided by this study would be a better understanding of how a specific form of psychotherapy may work to treat depression. The identification of brain markers of the effectiveness of a specific treatment for depression would enable future studies to evaluate a range of treatments, all with various costs and side-effect profiles, to determine optimum treatments for individuals suffering from major depressive disorder. Such a strategy is consistent with NIMH's mission to reduce the burden of psychiatric disorders. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This is an application for a Mentored Patient-Oriented Research Career Development Award. The candidate's prior training as a clinical psychologist and as a neuroimaging postdoctoral fellow has allowed him to develop expertise in clinical knowledge of symptom expression in autism spectrum disorders and the technical aspects of functional magnetic resonance imaging (fMRI). The candidate proposes a program of training and research with the goal of integrating: i) Applications of functional magnetic resonance imaging (fMRI) for intervention research, 2) Assessment of restricted and repetitive behaviors and executive function in autism, and 3) Autism treatment outcome research, including treatment study design, potential brain mechanisms of treatment response, and outcome assessment. To establish a career as a productive and independent autism investigator with a specialty in the use of fMRI to evaluate the putative mechanisms of action of autism treatments, the applicant is seeking support to obtain training in the disciplines listed above, The framework of this application is that symptom domains in autism are mediated by neurocognitive processes that may be ameliorated with targeted psychopharmacologic treatments and that may be assessed via fMRI. Building upon the training outlined in this award application, the candidate will use fMRI to investigate neurobiological links between neurocognitive processes mediating symptom expression and domain-specific symptom reductions induced by citalopram in high-functioning adults with autism. This study will extend the applicant's prior fMRI research and will represent an initial step in a program of mentored research with the goal of exploring the neural basis of autism symptom expression and their reduction via targeted treatments. This application is innovative because it would be the first to examine concurrently the neural, symptomatic, and neuropsychological profiles of treatment response in autism. PUBLIC HEALTH RELEVANCE: Brain imaging techniques allow for non-invasive investigations of neurodevelopmental disorders and how treatments may ameliorate symptoms. This study seeks to use measures of brain functioning to help understand how an effective intervention reduces symptoms in individuals with autism spectrum disorders. The findings of the study may lead to future research aimed at developing better interventions with the ultimate goal of reducing suffering for individuals with neurodevelopmental disorders.

DESCRIPTION (provided by applicant): The framework of this proposal is that the classic autism symptoms of social-cognitive deficits and restricted repetitive behaviors may both be characterized by dysregulated goal-directed responses to affective stimuli. Thus, we hypothesize that dysregulated neurobiological mechanisms mediating approach and withdrawal motivation may underlie these two seemingly disparate symptom domains. It has been argued that poorly modulated motivational responses are core features of other disorders, a conceptualization that has been fruitful because the neurobiological basis of goal-directed behaviors has been extensively studied in animal models, in human nonclinical contexts, and in human pathophysiological states. Additionally, because of established linkages between dysregulated motivational states and aberrant functioning of specific neurotransmitter systems, these lines of research have been successful in suggesting novel and effective treatment approaches in other disorders. We propose to leverage well-established psychophysiological measures of motivational states to assess the priming of neurobiologically-based defensive and appetitive systems in response to affective stimuli relevant to the autism behavioral phenotype. Specifically, we propose to measure affective modulation of psychophysiological responses to: (1) normative affective stimuli;(2) social stimuli, and (3) restricted interest stimuli in individuals with autism. Of prime relevance will be affective modulation of the startle eyeblink and postauricular reflex responses because, on theoretical grounds, they are ideally suited for assessing the response characteristics to social and restricted interest stimuli that are core features of autism. The project also represents an initial collaboration between two new members of NICHD Developmental Disabilities Research Centers (co-PI's Dr. Dichter at the University of North Carolina and Dr. Benning at Vanderbilt University) and brings together experts in the autism behavioral phenotype, psychophysiology, and child development to investigate a novel approach to characterizing the autism endophenotype. PUBLIC HEALTH RELEVANCE: This project seeks to better understand the pathophysiology of autism using painless and noninvasive psychophysiological measures. The information learned from this study would allow for future research that investigates whether these psychophysiological measures may have diagnostic utility and whether they may serve as biomarkers of treatment response.

DESCRIPTION (provided by applicant): During the previous funding cycle of this project (R01 MH073402) we identified distinct subtypes of repetitive behavior validated by the presence of subtype-specific clinical correlates. The potential impact of this finding is that these distinct repetitive behavior subtypes could be leveraged to help parse the biological, behavioral, and treatment-response heterogeneity that heretofore has constrained research on the etiology and treatment of autism. This idea is the focus of our next round of studies in this systematic program of research on repetitive behaviors: By focusing on specific subtypes of repetitive behaviors, can we identify unique pathophysiologic factors that could be used to guide the development of novel treatment strategies? Our focus in this application is on one of these distinct subtypes of repetitive behavior - unusual and intense interests, preoccupations, and attachments - that has received virtually no attention in autism. In recent studies we have found that these so-called Circumscribed Interests (CI) appear to impart significant added impairment in autism over and above other core deficits. Clinically, CI seem to be associated with strong positive affect and anticipatory motivation in contrast to repetitive behaviors in other disorders such as obsessive compulsive disorder (OCD) that seem to be associated with negative affect and anxiety-reduction (e.g. rituals, compulsions, insistence on sameness). The heightened interest and restricted focus that are characteristic of CI suggest that the functioning of neural circuitry that mediate reward processing may be altered in persons with autism. Consistent with this, we hypothesize that the development of CI in autism is mediated by an underlying cognitive-affective reward system that is biased away from social information and towards nonsocial information and thus that a unique cognitive-attentional phenotype may characterize CI. The goals of the proposed continuation of this project are to elucidate the clinical significance of CI in autism and to identify cognitive and neurobiological markers of this subtype. We propose to compare children (ages 12 - 18 years) with low-functioning (n = 40) and high-functioning autism (n = 40) to individuals with obsessive-compulsive disorder (n = 40), developmental delay (n=40) and typically developing controls (n = 40) on (a) a standardized assessment battery for measuring CI and the other varieties of repetitive behavior (Aim 1); (b) a passive visual exploration, eye-tracking task that measures differential attention to CI and non-CI images (Aim 2); and (c) to compare the HFA and TYP samples on two fMRI tasks comparing brain activation to CI versus non-CI images under conditions of reward anticipation and target detection (Aim 3).

DESCRIPTION (provided by applicant): Though there are many effective interventions for Major Depressive Disorder (MDD) available, there is significant heterogeneity in treatment response. One obstacle to improved treatment response rates is the lack of biomarkers to predict who will respond to a given treatment. Further, there is a lack of understanding of genetic mediators of both depressive symptoms and treatment response. In the attempt to form links from genes to depressive phenotype, brain activity is a key intermediate between genes and behavior. In MDD, dopamine (DA) systems are of particular interest, as they underlie reward responsivity (or its lack, anhedonia). This proposal will examine relations between neural response to rewards in MDD, allelic variations of candidate genes regulating functional output of DA systems, and response to psychotherapy. Imaging-genetics has been a fruitful approach in basic and clinical cognitive neuroscience but has not yet been applied to understand heterogeneity of psychotherapy response in MDD. Participants will undergo functional neuroimaging during a reward anticipation and feedback task (Monetary Incentive Delay) and will be genotyped for candidate dopamine genes (COMT, DAT1, and others) before initiating a course of Brief Behavioral Activation Treatment for Depression (BATD) psychotherapy. Candidate DA polymorphisms will be examined as predictors of both fronto-striatal reward network activation as well as psychotherapy treatment response. Fronto-striatal reward network activation will be examined further as a mediator of DA polymorphism effects on treatment response. This approach is an important step in a program of research with the ultimate goal of generating and validating imaging genetic models that may ultimately predict response to both pharmacological and psychotherapeutic antidepressant treatments in MDD. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because MDD is a leading cause of disability and is associated with increased risk of mortality. The proposed project will help to determine what patients are most likely to benefit from behavioral activation, an effective psychotherapy for MDD. The proposed research is relevant to the NIMH Strategic Plan to identify risk factors for mental illness across different phases of disease trajectory, especially the identification of predictors of intervention response.

Project Summary This grant seeks to evaluate striatal dopaminergic functioning during reward processing in autism spectrum disorder (ASD) through the use of simultaneous positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Preclinical research strongly implicates impaired mesolimbic dopamine functioning in the etiology of ASD. Additionally, fMRI evidence suggests that ASD is characterized by striatal hypoactivation during reward processing. However, since fMRI is sensitive only to blood oxygen level dependent signals, it is not known whether striatal hypoactivation during reward processing in ASD observed with fMRI is associated with impaired striatal dopamine functioning. Additionally, it is not known whether striatal hypoactivation during reward processing in ASD is linked to reduced phasic dopamine release or to reduced background dopamine tone that inhibits phasic dopamine release. Finally, whether impaired dopamine functioning in ASD is related to ASD symptom severity is poorly understood. These are critical gaps in our understanding of ASD pathophysiology given that studies of ASD model organisms are starting to pinpoint the specific molecular mechanisms that are implicated in ASD, whereas not a single molecular imaging study to date has targeted the mesolimbic dopamine system in ASD. PET imaging is ideally suited to bridge this gap between preclinical ASD research and clinical neuroimaging studies of reward processing in ASD. We propose to collect simultaneous PET and fMRI from a cohort of young adults with ASD and matched typically developing young adults during a reward processing task using the D2/D3 dopamine receptor antagonist [11C]raclopride. The use of a bolus+infusion radiotracer administration protocol will provide increased sensitivity towards measuring dopamine release, a critical feature of this project. We will evaluate background dopaminergic tone and phasic dopaminergic release in response to incentives in ASD (Aim 1), correlations between PET-derived measures of D2/D3 striatal receptor occupancy and fMRI-derived measures of striatal activation (Aim 2), and relationships between PET-derived measures of D2/D3 striatal receptor occupancy and symptom severity in the ASD group (Aim 3). This project represents the first step of our long- term goal to establish a program of PET ASD research that is positioned to translate findings of novel compounds that rescue receptor binding potentials in preclinical ASD models to clinical ASD studies of target engagament by these same compounds. This pipeline of preclinical drug discovery to clinical drug evaluation is ideally suited to PET neuroimaging because of its capacity to measure classes of receptors targeted by specific ligands.

Project Summary Deficits in motivation and pleasure, together referred to as anhedonia, are implicated in a number of psychiatric illnesses, including mood and anxiety disorders, substance-use disorders, schizophrenia, and attention- deficit/hyperactivity disorder. As a result, constructs related to anhedonia are central to the NIMH Research Domain Criteria (RDoC) project. Anhedonia is often one of the most difficult psychiatric symptoms to treat and thus represents a critical endophenotype and vulnerability factor for a range of psychiatric disorders. Given the centrality of anhedonia to a large number of psychiatric disorders, improved interventions to treat motivation and pleasure are critical for these disorders. The overall goal of this R61/R33 project is to develop a novel transdiagnostic treatment for anhedonia, called Behavioral Activation Treatment for Anhedonia (BATA). This new intervention is designed to treat anhedonia by emphasizing supported engagement with personally relevant goals and reducing avoidance behaviors. Consistent with the objectives and milestones outlined in RFA-MH-16-406 (?Exploratory Clinical Trials of Novel Interventions for Mental Disorders?), in the R61 phase of this trial we propose to use an experimental therapeutics approach to first evaluate mesocorticolimbic target engagement by this treatment in a transdiagnostic sample characterized by clinically impairing anhedonia (Aim 1). Specifically, we will examine the effects of this treatment, relative to an active comparison treatment, on caudate nucleus activation during reward anticipation and rostral anterior cingulate cortex activation during reward outcomes using ultra-high field (7T) functional magnetic resonance imaging. In this phase of the project, we will also use fMRI to determine the optimal dose of the intervention (Aim 2). If quantitative milestones for target engagement are achieved, in the R33 phase of this proposal we plan to evaluate the effects of the optimal does of this new treatment, versus an active comparison treatment, on anhedonic symptoms and functional outcomes (Aim 3), behavioral indicators of reward sensitivity (Aim 4), and neural indicators of reward processing (Aim 5). If hypotheses are supported, the results of this project will change real-world clinical practice given that there are currently no empirically-validated treatments, psychosocial or otherwise, that target anhedonia transdiagnostically. Given the high rates of clinically impairing anhedonia across a range of psychiatric disorders, as well as the relative ease with which BATA can be disseminated, this novel intervention has the potential to rapidly and meaningfully impact patient care in clinics that specialize in a range of disorders and conditions, including mood disorder clinics, anxiety disorder clinic, and general outpatient psychiatry services. The application proposed here cuts across multiple NIMH priorities and initiatives, including an experimental therapeutics approach to treatment development (NOT-MH-14-007: Policy for Submission of Applications Containing Clinical Trials), the use of standardized phenotype measures (NOT- MH-15-009: Data Harmonization for NIMH Human Subjects Research via the PhenX Toolkit), rigor and transparency in research (NOT-OD-16-011: Rigor and Transparency in NIH & AHRQ Research Grant Applications), and data sharing with the scientific community (NOT-MH-14-015: Data Sharing Expectations for NIMH-funded Clinical Trials and NOT-MH-15-012: Data Sharing Expectations for Clinical Research Funded by NIMH).