Antonio Hardan - US grants

DESCRIPTION (provided by applicant): The career development and research plans outlined in this Mentored Patient-Oriented Research Career Development Award application are designed to enable the candidate to independently design and conduct neuroimaging studies investigating the neurobiology of autism by examining increased brain size and the involvement of the cerebelo-thalamo-frontal circuit in the pathophysiology of this neurodevelopment disorder. Autism is a severe disorder characterized by marked social and communication deficits, restricted and stereotyped patterns of behaviors and interests. A wide range of abnormalities has been reported and studies of brain structure have implicated several aspects of brain development involved in neuronal organization including the elaboration of dendritic and axonal ramifications, the establishments of synaptic connection, and cell death. Recent neuropathologic and neuroimaging studies have reported increased brain size in autism, and evidence supporting the underdevelopment of the circuitry of neural networks that involve cerebral cortex, limbic system and cerebellum. The proposed longitudinal study will use the combination of volumetric measurements obtained from magnetic resonance imaging scans and chemical shift imaging proton spectroscopy obtained at 30 months intervals from a group of children with autism (8-12 years of age) and individually-matched controls to characterize the developmental changes of brain enlargement, and the involvement of the cerebello-thalamo-frontal circuit in autism. It will also provide the candidate with the experience necessary to apply advanced neuroimaging techniques and a solid foundation from which to conduct longitudinal studies investigating the developmental neurobiology of autism and possibly identifying clinical, prognostic and therapeutic correlates. The candidate is certified in psychiatry, and child and adolescent psychiatry with four years of post-graduate clinical experience. Drs. Nancy Minshew, and Matchery Keshavan will serve as preceptors. Course work and directed reading in biostatistcs, data management, research ethics, neuroanatorny, neuroimaging and developmental neuroscience will complement the research training.

DESCRIPTION (provided by applicant): Autism is a severe neurodevelopmental disorder characterized by marked social and communication deficits, restricted and stereotyped patterns of behaviors and interests with evidence supporting its neurobiologic and polygenic basis. The proposed study will build on an ongoing NIMH-funded study (R01 MH 067005 "A population-based twin study of autism in California" PI: Joachim Hallmayer). The existence of this population-based study of twins, with at least one twin with autism, will provide unprecedented opportunities to examine the relative impact of genetic and nongenetics factors on brain anatomy and chemistry in autism. Specifically, from this sample of more than 120 twin pairs who completed the genetic study to date, we will randomly recruit 80 same-sex autism twin pairs, 40 MZ and 40 DZ. We will also recruit 40 typically developing same-sex twin pair controls, 20 MZ and 20 DZ, group-matched to the sample comprised by the 80 autistic (twin) probands for age, gender, and socioeconomic status. High resolution anatomical, diffusion tensor and proton spectroscopy scans will be obtained from all participants. All new data collected in this study will be evaluated in the context of extensive cognitive and behavioral measures available from the ongoing NIMH study described above. We also will collect additional clinical measures at the time of the proposed imaging investigation to provide more specific covariates for neuroanatomical and neurochemical variables. The overarching goal is to develop a better understanding of linkages among clinical features and neurobiological measures in individuals affected by autism, thus allowing the identification of clinical or biological endophenotypes that will lead to a better characterization and understanding of this disorder. Twin studies in autism are particularly informative for examining the relative contribution of genetic and environmental risk factors to neurobiologic variations observed in this disorder. Improving our understanding of the neurobiology of autism and brain behavior correlations will help in the development of better procedures for predicting outcome and the design and implementation of more targeted therapeutic approaches. PUBLIC HEALTH RELEVANCE: Autism and autism spectrum disorders are very heterogeneous and disabling conditions with recent estimates suggesting that the prevalence of this class of disorders may be considerably higher than previously thought (NINDS, 1983;Fombonne, 2003). Adult outcome studies indicate that about two thirds of autistic adults remain severely handicapped and live in complete dependence or semi-dependence, with only 1 to 2 percent acquiring a normal and independent status with gainful employment, and 5 to 20 percent achieving a borderline normal status (Young et al., 1989). Therefore, the quest continues to identify innovative strategies that will allow us to better understand the neurobiology of this disorder. Twin studies in autism are very informative since they facilitate the examination of the relative contribution of genetic and environmental risk factors to the neurobiologic changes observed in this disorder. A better understanding of the pathophysiology of autism will be instrumental in the development of effective therapeutic strategies that aim at targeting the core symptoms of social and communication deficits.

DESCRIPTION (provided by applicant): Autism is characterized by core social impairments which limit patients' ability to form and maintain meaningful social relationships. At present, antipsychotic medications are the only pharmacotherapeutic option approved to treat autism. However, these agents mainly target associated symptoms (e.g., irritability), have unfavorable side-effects (e.g., lethargy, weight gain), and remain ineffective in treating the social features f this disorder. Developing new medications that specifically target social functioning thus will address a critical unmet need. A large body of research has shown that the closely related neuropeptides arginine-vasopressin (AVP) and oxytocin (OT) play critical roles in adaptive social functioning. For instance, AVP or OT impairments induced pharmacologically or transgenically produce a variety of social deficits in animals. Importantly, single-doses of intranasally administered OT improve several complex social functions (e.g., processing of social information, emotion recognition) in people with autism. Although intranasally administered AVP improves social cognition and memory in neurotypical individuals, and has been used safely for years to treat diabetes insipidus and nocturnal enuresis, no studies have tested the effects of AVP treatment on social functioning in individuals with autism. However, preclinical research has shown that in an OT receptor null (Oxtr-/-)mouse model of autism, social behavior is modulated selectively through brain AVP V1a receptors and that AVP administration rescues social deficits in these animals. Moreover, in other preclinical models, AVP, acting via V1a receptors, more selectively enhances male social behavior than does OT. In contrast, OT, acting via OT receptors, more selectively enhances female social behavior. Given that autism is a predominantly male-biased disorder, that in animals AVP is more important than OT for male social behavior, and that even so, acute OT does help male autistic patients, we hypothesize that AVP will be particularly effective in treating social symptoms in autism. The first step is to test whether AVP ameliorates social impairments in autism and whether males respond more robustly to AVP than females. We will test the effects of single-dose (20 IU) and 4-week (20 IU BID) intranasal AVP administration on social deficits in 50 high functioning males and females with autism aged 6 to 12 years using a double-blind, randomized, placebo controlled, parallel design. Study outcome measures are improvements on parent ratings of the Social Responsiveness Scale (SRS) and laboratory-based assessments of social behavior and cognition (i.e., facial emotion recognition, eye gaze to social cues, social memory, and social perceptual abilities). Consistent with preclinical evidence, we predict that AVP will improve social functioning in individuals with autism. Data from this study will be leveraged to secure additional funding to initiate head-to-head comparisons of AVP and OT treatment in a larger autism cohort. This research has high potential to lead to the development of the first effective treatments and earlier interventions for social impairments in individuals wth autism.

DESCRIPTION (provided by applicant): Over the last decade, considerable progress has been made to increase our understanding of the pathophysiology of autism spectrum disorder (ASD), but limited progress has been made in identifying effective interventions. The goal of this investigation is to build on our preliminary findings and conduct a randomized controlled 24-week pilot trial to examine the efficacy of a pivotal response treatment package (PRT-P) in improving language expression in young children with ASD. Pivotal response treatment (PRT) is a naturalistic behavioral intervention based on the principles of applied behavior analysis. While some evidence has emerged suggesting the effectiveness of PRT, no randomized well-controlled trials have been published to date examining the efficacy of this intervention in ASD. The proposed treatment model will focus on teaching parents PRT strategies in combination with in-home therapy for 24 weeks and will be compared to families in a delayed treatment group (DTG). To achieve these goals, 48 children with autism (age range: 2-5.11 years) with severe communication deficits will be recruited to participate in this study and will be stratified according to gender. Twenty-four children will be randomized to the PRT-P and 24 to the DTG. The PRT-P will consist of a combination of parent training sessions and in-home therapy for a total of 10 weekly treatment hours for the first 12 weeks, and 5 hours per week for the following 3 months. Standardized and video-taped assessments will be conducted at baseline, week 6, 12, and 24 and will be rated by a blind investigator. In addition, full-day audio recordings of the child's natural language environment will be analyzed using the Language ENvironment Analysis System (LENA), which involves digital language recording and software analysis. Finally, a social attention and word-learning eye tracking task will be used to monitor the effectiveness of treatment on social and communication deficits. This research will show that parents of children with autism can learn pivotal response training procedures and their children will benefit with improved language skills. Additionally, we are interested in exploring whether response to treatment will vary according to any clinical or cognitive factors at baseline (moderators). 1

? DESCRIPTION (provided by applicant): Neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), are characterized by abnormalities in baseline cortical excitability that are believed to be caused by an abnormal, system-wide balance between excitation and inhibition. Mounting evidence has linked baseline cortical excitability to abnormalities in the sensory systems. as manifested by both over- and hypo- reactivity to sensory stimuli and by the high prevalence of epileptiform EEG activity in the majority of neurodevelopmental disorders including ASD and ADHD. Sensory systems rely on a set of well-characterized network of mechanisms whose functioning directly depends on a precise balancing of excitation and inhibition. The aim of this investigation is to use sensory evoked responses as a means to quantitatively assess baseline cortical excitability in two common neurodevelopmental disorders, ASD and ADHD. These measurements will be made via Steady-State Visual and Auditory Evoked Potentials. Patterns sensory responses measured electrophysiologically will be compared to patterns of behavioral hyper/hyposensitivity measured via a well- characterized parental questionnaire and examiner-administered performance evaluations. These measurements will be obtained from 40 children with ASD, 40 children with ADHD and 40 matched controls. The immediate goal of the project is to determine whether specific patterns of sensory evoked potentials are associated with behavioral indices of disturbed sensory processing. The long-term goal of this proposal is to develop sensitive and objective measures of cortical excitability for use in classifying neurodevelopmental disorders. An ability to detect and quantify underlying alterations in cortical excitability in infancy and ealy childhood would be of significant value in the diagnosis, classification and treatment management of common neurodevelopmental disorders. The present proposal is a fundamental step toward the achievement of this purpose and this approach is consistent with the NIMH Strategic Plan for the development of new ways of classifying psychopathology based on dimensions of observable behavior and neurobiological measures.

Abstract NIMH Research domain criteria (RDoC) are a guiding framework for etiologic research in psychopathology. The RDoC Social Communication (SC) construct represents an important component of several forms of developmental psychopathology, including autism spectrum disorder (ASD). A key next step in the application of RDoC SC criteria toward understanding developmental psychopathology will be to identify, differentiate, and measure SC sub-constructs. The over-arching long-term goal of this application is to develop brief, quantitative, subjective parent report and clinician observation measures of RDoC SC sub- constructs relevant to developmental psychopathology. To achieve this goal, we will first empirically identify and differentiate broad and specific RDoC-relevant SC sub-constructs using de-identified clinical and behavioral data from samples an order of magnitude larger than all previous studies (Aim 1). This approach will identify a generalizable structure of SC behavior by combining data across datasets and applying advanced statistical methods that simultaneously extract SC dimensions from multiple measures and information sources (parent report, parent interview, and clinician observation). Next, using the results of aim 1 and an exhaustive review of the social communication literature, we will fill in the SC map by conducting additional quantitative and qualitative analyses focused on identifying SC facets that were not adequately represented by existing item sets (Aim 2). Finally, using the results of Aims 1 and 2, we will develop and pilot test parent report and clinician observation measures of RDoC-relevant SC sub- constructs. To accomplish these aims, the proposed project will analyze data from eight large-sample sources that include measures of social behavior on more than 30,000 children (ages 2-18) with a range of social communication abilities - from severe ASD to other psychiatric disorders to healthy controls. After SC sub-structure is identified, we will write parent-report and clinician observation measures and pilot test these measures for content validity, readability, and parent acceptability. If the above aims are achieved, the proposed project will represent a critical first step toward the development and dissemination of RDoC- relevant SC measures that can linked to other RDoC levels of analysis (genetic, cellular, neural systems, etc.), applied in future research to improve our understanding of developmental psychopathology, and implemented in clinical practice to enhance patient care.

PROJECT SUMMARY Autism spectrum disorder (ASD) is characterized by core social impairments which limit patients? ability to form and maintain meaningful relationships. At present, antipsychotics are the only medication approved to treat ASD, but they target associated symptoms, have unfavorable side-effects, and do not treat ASD?s core social deficits. Developing new medications that specifically target social functioning will thus address an important unmet need. A large body of research has shown that the neuropeptide arginine vasopressin (AVP) plays a critical role in promoting social behavior and that experimental dysregulation of the AVP signaling pathway produces social deficits in animal models. Although intranasal AVP administration improves social cognition and memory in neurotypical individuals, no published research has tested the effects of AVP treatment in ASD patients. Several lines of evidence underscore the necessity of such research. For example, we recently reported that blood AVP levels predict theory of mind ability in children with ASD, such that children with the lowest AVP levels have the most marked theory of mind deficits. This finding is consistent with our preclinical research showing that socially impaired monkeys have significantly diminished cerebrospinal fluid AVP levels compared to control monkeys. Similarly, data from the first neuropeptide receptor mapping study of postmortem primate brain tissue revealed that AVP V1a receptors are widely distributed throughout the extended neural amygdala pathway, suggesting that AVP administration can target directly neural pathways known to regulate social functioning. Interestingly, AVP?s pharmacological effects are especially evident in male animals, and given ASD?s male-biased prevalence, AVP deficits may be particularly relevant to understanding the risk for, and treatment of, ASD. We recently tested the effects of 4-week intranasal AVP treatment in children with ASD in a double-blind randomized placebo- controlled pilot trial (R21 MH100387; MPI: Parker & Hardan). AVP was overall well tolerated in this small sample, and importantly, AVP treatment improved social abilities in children with ASD as assessed by parent ratings on the Social Responsiveness Scale, 2nd Ed (SRS-2). This result was more pronounced when we accounted for pre-treatment blood AVP levels. Here we seek to extend these findings in a larger ASD study cohort (N=100), aged 6 to 17 years, in this double-blind randomized placebo-controlled 8-week trial. Our primary outcome measure is improvement in child social abilities as assessed by parent ratings on the SRS-2. We will also test the safety and tolerability of AVP treatment, and whether pre-treatment blood AVP levels are a personalized predictor of treatment efficacy. Finally, we will test whether AVP treatment improves ASD symptoms as assessed by clinician impression, additional parent report measures, and child performance on laboratory tests of social cognition and communication. We predict that AVP treatment will improve social abilities in children with ASD, and that AVP will be well tolerated, in keeping with our preliminary data. This research has high potential to lead to development of the first effective medication to treat ASD?s currently intractable social deficits.

Project Summary/Abstract Autism spectrum disorder (ASD) is an exceedingly heterogeneous disorder with limited empirically validated behavioral and biological interventions. The goal of this pilot investigation is to apply a biologically-based approach to identify predictors of treatment response in children with ASD who are receiving Pivotal Response Treatment (PRT), an evidence-based behavioral intervention. Specifically, we propose to identify neuroimaging biomarkers of treatment response to a PRT program (PRT-P) targeting language deficits in young children with ASD who will be randomized to either PRT-P or to a delayed treatment group (DTG). At the end of the controlled phase, families randomized to the DTG will be invited to participate in a PRT in an open-label trial. PRT-P will consist of 4 months of parent-training sessions to teach parents how to apply PRT in the natural environment. Standardized and video-taped assessments will be conducted at baseline, week 8, and post- treatment and will be rated by an investigator blinded to treatment group. Neuroimaging data will be obtained at baseline and at the end of the trial and will include anatomical MRI, diffusion tensor imaging (DTI), resting state functional magnetic resonance imaging (rs-fMRI), and 1H magnetic resonance spectroscopy. Based on the established evidence and our previous trials, we expect that parents participating in PRT-P will demonstrate evidence of targeted skills at post-treatment and that their children will show significant benefits in language abilities, relative to those in the DTG. We also hypothesize, based on our preliminary data, that baseline neuroimaging measures from the frontal and temporal language areas will predict treatment response to PRT-P. This investigation will be an important step towards identifying potential biosignatures of treatment response, which are critical for young children with ASD, and permit the examination of whether improvements in language abilities are associated with neurobiological changes in the brain. Findings from this pilot study will also be instrumental in designing larger trials that will help in the dissemination of parent-delivered early interventions to children with ASD and will lay the foundation for a research program focused on the discovery of neuroimaging biomarkers of treatment response.

Autism spectrum disorder (ASD) is a very heterogeneous disorder with limited empirically validated behavioral and biological interventions. The goal of this pilot investigation is to apply a biologically-based approach to identify predictors of treatment response in children with ASD (age 3 to 5 years) who are receiving Pivotal Response Treatment (PRT), an evidence-based behavioral intervention. Specifically, we propose to identify neuroimaging biomarkers of treatment response to a PRT program (PRT-P) targeting language deficits in young children with ASD who will be randomized to either PRT-P or to a delayed treatment group (DTG). At the end of the controlled phase, families randomized to the DTG will be invited to participate in a PRT in an open-label trial. PRT-P will consist of 4 months of parent-training sessions to teach parents how to apply PRT in the natural environment. Standardized and video-taped assessments will be conducted at baseline, week 8, and post-treatment and will be rated by an investigator blinded to treatment group. Neuroimaging data will be obtained at baseline and at the end of the trial and will include anatomical MRI, diffusion tensor imaging (DTI), resting state functional magnetic resonance imaging (rs-fMRI), and 1H magnetic resonance spectroscopy. Based on the established evidence and our previous trials, we expect that parents participating in PRT-P will demonstrate evidence of targeted skills at post-treatment and that their children will show significant benefits in language abilities, relative to those in the DTG. We also hypothesize, based on our preliminary data, that baseline neuroimaging measures from the frontal and temporal language areas will predict treatment response to PRT-P. This investigation will be an important step towards identifying potential biosignatures of treatment response, which are critically needed for young children with ASD, and permit the examination of whether improvements in language abilities are associated with neurobiological changes in the brain. Findings from this pilot study will also be instrumental in designing larger trials that will help in the dissemination of parent-delivered early interventions to children with ASD and will lay the foundation for a research program focused on the discovery of neuroimaging biomarkers of treatment response.

Project Summary Restricted and repetitive behaviors (RRB) are a core feature of autism spectrum disorder (ASD) and also occur across a range of other neurodevelopmental disorders. RRB present a major barrier to learning and adaptation, interfere with family functioning and present a source of considerable stress for parents. Despite their clinical significance, underlying mechanisms behind this complex behavioral domain are poorly understood and effective, targeted, individually tailored treatment options are currently lacking. One of the major barriers to moving the RRB research agenda forward has been the lack of clarity around the structure and conceptualization of RRB and the limitations of the currently available measures, particularly in terms of their (i) inability to comprehensively capture the full range of RRB and (ii) lack of sensitivity to treatment-related change. Therefore, the overarching aim of this project is to develop a parent report measure for comprehensive and quantitative RRB assessment applicable across clinical populations and across the life- span and useful in both etiological- and treatment-related research. In order to achieve this goal, we will first conduct advanced statistical analyses of multiple, large, high-quality datasets containing a range of currently available measures in order to achieve fine-grained differentiation between distinct RRB domains (Specific Aim 1) and to identify domains not adequately captured by the current measures (Specific Aim 2). The implementation of this initial phase of the project will ensure that robustness and generalizability of the factor structures for each individual measure across age, developmental level, gender, and diagnostic status, is established and that generalizable core RRB structure across the currently available RRB instruments is identified. Neither of these two different aspects have been comprehensively addressed before. Robust derived RRB factor structure, together with the identification of potential RRB domains that might be under- represented and not adequately depicted by the current instruments, together with the systematic review of the literature will inform the development of items of the new scale to capture the full range of RRB. The pilot version of the new scale will be psychometrically evaluated online within a large sample of children and adolescents with ASD (Specific Aim 3). This project will lay the foundation for future investigations aimed at further refinement of the newly developed informant-based scale and the development of a clinician interview and objective instrument, as well as their validation across ASD ansd neurodevelopmental disorders, and the testing of their utility as a clinical outcome measure.