NIH ACE Grants

In September 2012, the National Institutes of Health (NIH) announced nine grant awards totaling $100 million for the Autism Centers of Excellence (ACE) research program. NIH created the ACE Program to “launch an intense and coordinated research program into the causes of ASD and to find new treatments”. Now in its sixth year, the program will continue to advance the field by funding much needed ASD research, including genetics studies and investigations focusing on understudied or underrepresented groups. In April 2013, the NIH announced funding for two additional ACE networks.

NIH summarized the research that each grant will fund in the announcement, but ASF was curious to learn more. We asked the awardees, several of whom serve on ASF’s Scientific Advisory Board, to tell us more about their research aims. Read their statements below.

 

Biomarkers of Developmental Trajectories and Treatment in

Autism Spectrum Disorders (ASD)

Principal Investigator: Susan Bookheimer, Ph.D., University of California, Los Angeles

The goal of the renewed ACE Center grant at the UCLA Center for Autism Research and Treatment (CART; www.autism.ucla.edu) is to continue research efforts to identify mechanisms by which risk genes affect developing brain structure and function in autism, to define pathways linking brain structure and function to core deficits in social communication, and to develop effective interventions based on basic experimental and clinical research findings that will change outcomes in autism spectrum disorders. In five new interdependent projects, the experienced and multidisciplinary team of UCLA CART investigators led by Bookheimer (and including Geschwind, McCracken, Kasari, Dapretto and Johnson) will integrate expertise in autism genetics, multimodal brain imaging, early detection and analysis of core autism features, psychopharmacology, and broad experience in implementing randomized control trials of novel interventions. Targeting core symptoms and with a focus on the underlying neurobiology, these projects will examine longitudinal neurodevelopmental trajectories in autism from infancy through adolescence, develop ways to alter these trajectories with treatments focused on altering developing autism symptoms in infants, intervene in nonverbal children combining behavioral and pharmacological intervention, and relate genetic risks and expression profiles to autism phenotypes and treatment outcomes.

The projects will utilize new technologies in genetics including high density SNP analysis and state of the art microarray facilities, new approaches to assessing developing brain function including resting state and activation-based functional connectivity with both EEG and fMRI, tractography to measure emerging structural connectivity, eye tracking and pupillometry, and new analytic approaches including graph theory and machine learning to model neural development, predict outcome, and identify mediators of treatment response.

The aims of the UCLA ACE center’s five new projects specifically address the research gaps detailed in the 2011 IACC Report: 1) Early identification of autism risk, developing a set of reliable biological and behavioral markers of emerging autism; 2) Early intervention, implementing a randomized control treatment in high risk infants and those with early ASD signs; 3) Intervention in non-verbal children, maximizing treatment efficacy in nonverbal children using combined language treatment and augmentative pharmacotherapy; 4) Longitudinal neuroimaging, aimed at linking early signs of autism to later brain abnormalities and tracking developmental trajectories in brain activity and connectivity; and 5) Genetics, identifying autism risk genes and analyzing gene expression in relation to neurobiological and behavioral phenotypes.

 

Adaptive Interventions for Minimally Verbal Children with ASD

in the Community (AIM-ASD) Study

Principal Investigator: Connie Kasari, Ph.D., University of California, Los Angeles

Current estimates are that 30-40% of children with autism spectrum disorder (ASD) remain minimally verbal, even after receiving years of interventions. Very little is known about individuals at this end of the autism spectrum. This is partly because it is a highly variable population with no single set of defining characteristics, and partly because these individuals are excluded from most research studies. Current interventions focus on children who are preverbal (preschool aged), and thus there are almost no rigorously tested interventions specifically for minimally verbal school-aged children despite their prevalence and severity of need. The Interagency Coordinating Council on Autism, National Institutes of Health, and Autism Speaks have placed a high priority on developing efficacious interventions for these children.

The goal of this ACE Network project is to construct an adaptive intervention that utilizes two interventions that have shown promise for optimizing the spoken language development of children with ASD. These interventions are discrete trial training for core ABA based learning (CORE-DTT; Smith et al., 2001), and an integrated behavioral and developmental intervention that focuses on prelinguistic gestures, joint engagement and spoken language (JASPER-EMT; Kaiser & Roberts, 2011; Kasari et al., 2006, 2008, 2010). The study utilizes a novel sequential multiple assignment-randomized trial (SMART) to evaluate and construct an optimal adaptive intervention. A total of 192 minimally verbal school aged children with an Autism spectrum disorder aged five to eight years of age will participate across four sites in Los Angeles, Nashville, New York City and Rochester. Children will be initially randomized to six weeks of JASP-EMT or CORE-DTT (first-phase treatment). After six weeks, children will be assessed for early response to intervention. Early responders will be randomized to staying the course on first-phase treatment with therapist intervention, or to therapist and parent training. Participants not demonstrating early response to intervention will be randomized to stay the course on first-phase treatment (granting more time to respond) or to receive both JASP-EMT and CORE-DTT in an attempt to maximize language outcomes. Children will receive intervention daily at school for four months total. Outcome assessments will occur at four and eight months and include the number of unique socially communicative and spontaneously spoken words.

Minimally verbal school aged children require an intervention approach that simultaneously (a) consolidates their early successes in intervention, (b) provides evidence-based interventions to accelerate development of spoken language, and (c) adapts such interventions to maximize their effects if there are not early indications of response to the treatment. Sequential adaptations of intervention protocols are needed to place all minimally verbal children on a positive, long-term course toward developing spoken language. This project unites a network of experienced researchers with complementary expertise to address this unmet priority including Connie Kasari, Ann Kaiser, Catherine Lord, Tristram Smith, and Daniel Almirall.

 

 

Mechanisms of Risk and Resilience in ASD: Ontogeny, Phylogeny and Gene Disruption

Principal Investigator: Ami Klin*, Ph.D., Emory University

In a collaboration between the Marcus Autism Center, the Yerkes National Primate Research Center and the Department of Human Genetics, the Emory University Autism Center of Excellence will investigate the instantiation of risk and resilience for autism within a highly synergistic systems social neuroscience research enterprise. It will focus on identification of factors associated with positive outcomes or social disability, starting in one-month-old infants, and will begin treatment in 12-month-olds in randomized clinical trials. Through parallel studies in model systems, the Emory ACE will chart brain development of neural networks involved in social interaction. The overarching goal of the Emory ACE is to increase understanding of how ASD unfolds across early development.

Seven laboratories join in four projects to probe the emergence of foundational mechanisms of socialization within a common conceptual and methodological framework. Project I (PI: Warren Jones, Ph.D.) focuses on predictors of risk and resilience in ASD through social visual engagement. A cohort of 330 infants at high and low risk for autism, densely sampled with 15 assessments before the age of 36 months, will complete an eye-tracking protocol that quantifies social visual engagement, prospectively and longitudinally. Project II (PI: Gordon Ramsay, Ph.D.) focuses on mapping out the developmental unfolding of social vocal engagement, monthly, in the same cohort. Based on automated acoustic analysis of day-long audio recordings of each child’s language environment, this project aims to test the hypothesis that derailment of emerging communication in infants with autism can be attributed to an earlier breakdown in mechanisms of social engagement. Project III (PI: Amy Wetherby, Ph.D.) will focus on a randomized control trial of a community-viable early treatment model beginning at the age of 12 months for infants identified to be at risk for autism from within the same cohort studied in Projects I and II. The central aim of this project is to identify individual child and family characteristics that predict responses to intervention. Clinical characterization assessments of all infants will be directed by Celine Saulnier, Ph.D. Project IV (PIs: Jocelyne Bachevalier, Ph.D.; Lisa Parr, Ph.D.; and Mar Sanchez, Ph.D.) will focus on the ontogeny and neural basis of social visual engagement in infant Rhesus monkeys from birth to six months, using eye-tracking protocols analogous to those deployed with human infants, as well as non-invasive neuroimaging methods (MRI, DTI, rs-fMRI) with the aim to map out the development of brain networks relevant to social visual engagement. 

 

Multimodal Developmental Neurogenetics of Females with

Autism Spectrum Disorder Study

Principal Investigator: Kevin Pelphrey*, Ph.D., Yale University

A highly collaborative team of researchers from Yale, UCLA, Harvard, and the University of Washington will investigate the poorly understood nature of autism in females. This team of researchers will study an unprecedented number of girls, focusing on genes, brain function, and behavior throughout childhood and into adolescence. The objectives are to identify causes of autism and develop novel treatments. The term Autism spectrum disorders (ASD) exemplifies the tremendous heterogeneity in this developmental disorder at both the phenotypic and underlying genetic levels.

It has repeatedly been observed that ASD disproportionately affects males relative to females. Although many hypotheses attempt to explain this bias, no clear answers have emerged because of inconsistent and incomplete phenotyping and small sample sizes. This team proposes to leverage the unprecedented interdisciplinary strengths and recruiting power of their network sites to study sex specific differences by deep phenotyping and genotyping ASD participants. The team will recruit a sex-balanced cohort of children with ASD (200 girls and 200 boys) and carefully matched typically developing (TD) comparison participants (200 girls and 200 boys), as well as a set of unaffected siblings (US; 100 girls and 100 boys). 

From there, researchers will quantitatively phenotype multiple behavioral domains and measure several key ASD-related neural systems at the level of brain structure (sMRI), connectivity (DTI and fMRI), function (task based and resting state fMRI), and temporal dynamics (EEG). Additionally, they will measure copy number variation (CNV) and single nucleotide variation (SNV) for these participants and their parents, allowing them to test sex- and circuit-specific genotype-phenotype hypotheses for five candidate ASD genes and ultimately extend their methods to a search for novel sex-specific and high-risk genes.

This project’s specific aims are to: 1) identify sex differences in brain structure, function, connectivity, and temporal dynamics in ASD, 2) characterize associations between DNA sequence and copy number variants, and brain structure and function in girls with ASD and TD girls versus boys with ASD and TD boys, and 3) relate brain differences in structure, function, and temporal dynamics to heterogeneity in ASD behavior and genetics. This team’s hypothesis is that advanced network methods can aid in understanding the tremendous heterogeneity in ASD by connecting different levels of phenotype with genetic variation. They will combine multiple levels of biology and endophenotypes – SNVs, CNVs, behavioral metrics, resting state imaging and electrophysiology measures – into one framework across affected and unaffected siblings and controls using a highly novel integrated network analysis.

 

The Infant Brain Imaging Study

Principal Investigator: Joseph Piven, M.D., University of North Carolina at Chapel Hill

This is study is aimed at describing the trajectories of brain and behavior development in infants at risk for autism. During the first five years of this study (IBIS-1), more than 350 infants at high familial risk for autism (i.e., younger siblings of older autistic children) and 150 infants at low familial risk for autism were enrolled for detailed brain imaging (brain volumes and DTI measurement of neural circuits) and behavioral assessments at 6, 12 and 24 months of age. Initial results demonstrated a gradual unfolding of autistic and associated behaviors over this period along with dynamic changes in brain development. Infants at high risk for autism who were later classified with Autism spectrum disorder at 24 months of age showed abnormalities in brain imaging by six months of age in comparison to high risk infants who did not show evidence of autism at two years of age (Wolff et al., American Journal of Psychiatry, 2012). 

Following these and other similar observations, the IBIS Network will study a new cohort of infants beginning at three months of age who are at high risk for autism to conduct even more refined assessments of brain changes (including functional connectivity MRI) and behavior changes (including eye tracking, measurement of the development of joint attention, and measurement of parent-child conversational turn taking) during this important period in the development of autism. Participating sites for clinical data collection include the University of North Carolina, Children’s Hospital of Philadelphia, Washington University in St. Louis, and the University of Washington. Additional contributing sites include the Data Coordinating Center at McGill University, as well the University of Utah and University of Alberta. Supplementary funding from Autism Speaks supports the additional study of environmental factors in early development as well as the potential molecular genetic underpinnings of brain and behavioral trajectories in children who develop autism as well as children at high familial risk for autism who do not later develop autism. Researchers welcome questions or comments from those who would like to learn more about the study. Visit IBIS Network website for contact information. 

 

Early Biomarkers of Autism Spectrum Disorders in infants with Tuberous Sclerosis

Principal Investigator: Mustafa Sahin, M.D., Ph.D., Harvard University

A network of five leading pediatric hospitals, led by Boston Children’s Hospital and Cincinnati Children’s Hospital Medical Center, and including University of Alabama at Birmingham, University of Texas at Houston, and University of California at Los Angeles, will study infants with tuberous sclerosis complex (TSC), a rare genetic disorder that causes autism in about 50 percent of patients. TSC is marked by tumors in the brain and other organs and can be diagnosed even before birth, making it possible to observe prospectively the natural history of ASD and develop better tools for early detection. Through the newly formed TSC Autism Center of Excellence Research Network (TACERN), and in close collaboration with the national Tuberous Sclerosis Alliance, researchers will follow brain development in infants with TSC using advanced brain imaging called Diffusion Tensor Imaging. Brain wiring will also be analyzed with EEG techniques, and the infants will undergo frequent developmental assessments from 3 months to 3 years of age, when a clinical diagnosis of autism can be made. Additionally, collaboration with Leadership Education in Neurodevelopmental and Related Disabilities (LEND) programs at each hospital will provide additional research training and education expertise in ASD and TSC. The results of this study will further elucidate brain connectivity and its relationship to ASD in TSC and will pave the way for new interventions for this and related causes of autism.

 

Minimally Verbal ASD Study: From Basic Mechanisms to Innovative Interventions

Principal Investigator: Helen Tager-Flusberg, Ph.D., Boston University

ASD research has flourished during the past two decades yet almost all studies on children and adults have focused on the higher end of the spectrum and theories have primarily addressed the core deficits associated with higher functioning ASD. For too long the other end of the spectrum has been virtually ignored by researchers. A significant minority of children with ASD remain severely impaired, and, most importantly, fail to acquire spoken language, even after years of access to high quality intensive interventions. Researchers know almost nothing about the estimated 30% of children with ASD who remain minimally verbal into the school years. There is a dearth of novel treatments to address the specific and unique needs of this population. Yet no theories have been proposed that might explain why these children fail to acquire spoken language. The goal of this ACE project is to address these critically important issues. During the next five years this team of investigators, in partnership with primary stakeholders in the community (schools, major autism organizations, and families of minimally verbal children) will complete a series of investigations that will:

Advance knowledge of the heterogeneous phenotypes associated with minimally verbal ASD; Develop and disseminate novel methods of assessing cognitive, linguistic and behavioral domains; Propose and evaluate several mechanisms to explain why some children remain nonverbal; Complete randomized clinical trials (RCT) of a novel intervention specifically designed for this population, which has shown great promise in pilot studies; Develop neurobiological markers that predict response to treatment in the RCTs, and that serve as measures of outcome success.

This ACE project will be the first systematic integrated approach to address the gaps in knowledge about minimally verbal school-aged children with ASD. This project brings together innovative ideas, conceptual models, and experimental paradigms that will answer the central question of why these children fail to acquire spoken language. This team of researchers views children with minimally verbal ASD and their families as the most neglected in the field. This population is the highest priority because they have multiple behavioral and medical needs; they bear the most significant emotional and financial burdens; they are most at risk for safety concerns; they are the most vulnerable, often receiving non-evidence based treatments; and they are most in need of lifetime care with no possibility of independence. This team has developed a combination of basic and clinical projects that they hope will have an important impact on the autism community and pave the way for other research that focuses on the many problems faced by this group of children and families.
 
 

Study of Oxytocin in Autism for Reciprocal

Social Behaviors (SOARS-B)

Principal Investigator: Linmarie Sikich, M.D., University of North Carolina at Chapel Hill

Oxytocin is the brain’s most abundant hormone. Previous studies have shown that oxytocin plays a critical role in social behaviors in both animals and people. Specifically, in animal models including primates, oxytocin has been demonstrated to increase eye contact, social approach, social recognition, social memory, and generosity and to reduce stress responses. All of those typical social behaviors are usually diminished in individuals with an autism spectrum disorder.  Oxytocin is currently approved for use in the United States to induce labor in women.  It is also sometimes being used “off label” in people with ASD without knowing if it really helps and if it is safe for long-term use.  Intranasal oxytocin has shown promise in reducing some of the social deficits that are common in autism spectrum disorders in a small pilot study that was recently completed at the University of North Carolina at Chapel Hill (UNC-CH) and funded by Autism Speaks. 

With support from the National Institute of Child Health and Development (NICHD), a branch of the National Institute of Health, researcher Linmarie Sikich, MD of the ASPIRE Research Program at UNC-CH has established the ACE SOARS Network, which is composed of leaders in the field of autism research involving medication treatments and genetic influences to treatment. Dr. Sikich will lead the ACE SOARS Network and work closely with the other members of the network including Simon Gregory, PhD (Duke University); Christopher McDougle, MD (Harvard University); Alex Kolevzon, MD (ICON School of Medicine); Alice Kau, PhD (NICHD); Katerina Tsilou (NICHD), Latha Soorya, PhD (Rush University); Robert M. Hamer PhD (UNC-CH); Jacqueline Johnson, PhD (UNC-CH); Bryan King, MD (University of Washington), Jeremy Veenstra-Vander Weele, MD (Vanderbilt University) and Geraldine Dawson, PhD (Autism Speaks).  UNC-CH will serve as the lead site by providing overall project coordination, data management and data analysis for the ACE SOARS Network.  The ACE SOARS Network’s primary objective is to provide the infrastructure necessary to meet the needs of the autism community across the continental United States by developing novel treatments to help with core ASD symptoms on an ongoing basis. 

The first step of the ACE SOARS network is a 5 year study of oxytocin nasal spray in children and adolescents (ages 3-17) with an autism spectrum disorder called SOARS-B.  The SOARS-B study will determine if oxytocin improves social functioning in ASD, evaluate oxytocin’s safety in children, and identify factors that influence a child’s response to oxytocin.  Study participants will receive either active medicine (oxytocin) or inactive medicine (placebo) for the first 6 months and then all participants will receive the active medicine (oxytocin) for an additional 6 months. The study is unique because it is the largest treatment study to date as it will ultimately include 300 individuals with an autism spectrum diagnosis. Another distinctive feature of this study is that it is one of the first studies that will focus equally on both verbal and nonverbal individuals. In addition, Duke University researcher Simon Gregory, PhD will play a vital role as his laboratory will be examining samples collected from this project by looking look at how non-DNA based variation predicts response to treatment and the types of genes that are produced during treatment. Participants will be enrolled at the ASPIRE program at UNC-CH, NC; the Lurie Center for Autism of Massachusetts General Hospital, MA; the Seaver Autism Center at Mount Sinai School of Medicine, NY; Seattle Children’s Research Institute, WA and the Vanderbilt Treatment and Research Institute for Autism Spectrum Disorders (TRIAD), TN. 

The overarching purpose of the ACE SOARS Network is to develop and optimize safe, personalized treatments that improve functioning and reduce disability for individuals with autism spectrum disorders. The network seeks to translate the most current understanding of the underlying mechanisms of autism spectrum disorders into widely accessible and tolerable treatments. Our hope is that this network will not only examine oxytocin as a possible treatment option, but also will establish a solid foundation to examine other novel treatments that directly address the core symptoms of autism. 

 

Early Intervention in ASD: How Do Intensity and Approach

Affect Short-term Outcomes?

Principal Investigator: Sally Rogers, Ph.D., University of California, David MIND Institute

Early childhood appears to be particularly important for learning due to plasticity of early neural development, impact of early social learning experiences, and unique preparedness for language learning. It is likely for these reasons that high quality, intensive early intervention is a powerful treatment for ASD, improving IQ and language abilities markedly, at least in the short term. While several different types of approaches have demonstrated efficacy, there are direct contradictions among them, two of which involve (1) the delivery style of intervention – play-based versus direct, discrete trial teaching, and (2) the intensity, or dosage, of intervention. Neither has been tested in a rigorously controlled comparative study; yet both have major policy, practice, and funding implications for public intervention delivery systems, for professional training and practice, for parental choice and learning, and for children’s lives. Further, since almost no studies of very early autism intervention have reported longer term outcomes, it is unknown if short term outcomes are sustained. 

In the next five years, this new ACE Treatment Network will conduct two rigorously controlled randomized trials (RCTs) to answer two main questions: (1) study 1: what is the effect of two core ingredients: dosage and style, on developmental progress of toddlers with ASD enrolled in a rigorous intensive and empirically supported early intervention trial: and (2) study 2: do toddlers previously enrolled at ages 12-24 months in a two year randomized controlled trial of intensive early intervention continue to demonstrate treatment effects and stable growth patterns 2-3 years later, at ages 6-7 

For study 1, a new sample of 108 young children with ASD, ages 15-30 months, will be enrolled for 12 months of intensive intervention in three national sites and randomized into one of four treatment cells that vary on two dimensions: greater or lesser dosage – 15 or 25 hours per week of 1:1 treatment; and discrete trial or play-based teaching. All other aspects of intervention will be held constant, including use of the principles of applied behavior analysis, staff, and parent curriculum. 

Study 2 will extend a previous ACE Network multisite treatment trial begun when the children were 12-24 months. The sample of 78 children with ASD will be followed up at 6-7 years of age to examine longer-term treatment effects on child factors (diagnostic severity, degree of intellectual disability, adaptive functioning), family factors (parenting stress, parent sense of competence, SES) and treatment group. 

Primary aims of the proposed studies: 

1. To examine the effect of intensity of treatment, or “dosage”, on child progress and outcomes. 

2. To examine the effect of intervention delivery style – play-based or discrete trial teaching, on child progress and outcomes. 

3.To examine effects of quality and quantity of parent-provided learning opportunities at home on child progress and outcomes. 

4. To test the moderating effects of initial pre-linguistic phonemic patterns, initial developmental rates, and autism severity on child treatment outcomes. 

5. To examine effect of treatment group assignment, and stability of intellectual, linguistic ,adaptive functioning, and severity of core ASD symptoms from age 3-4 to age 6-7, for subjects previously enrolled in a ACE Treatment Network RCT. 

6. To support the scientific development of graduate and postgraduate trainees, and junior faculty members, with specific interest and expertise in autism-related science.

 
 

Autism Genetics, Phase II:

Increasing Representation of Human Diversity 

Principal Investigator: Daniel H. Geschwind, M.D., Ph.D., University of California, Los Angeles

Genetic research for ASD over the last 10 years has been remarkably productive, identifying major genetic risk factors in between 10-20% of ASD cases.  However, the vast majority of genetic advances in ASD have been derived from samples that are drawn from European populations.  There are significant disparities in ASD diagnosis and prevalence in under-represented populations, including African Americans. The reasons for this are only partially understood and may be confounded by actual differences in causation, incidence, and severity of phenotypic expression.  Despite representing about 11% of the US population and an equivalent fraction of ASD subjects, African-American children represent fewer than 5% of subjects in genetic research, have poorer access to services, and are diagnosed years later than white children from similar geographic regions.  

Our project fills a significant gap in autism research by recruiting and evaluating genetic risk for ASD in underserved subjects of self-reported African ancestry (African-Americans). Our recruitment plan includes an embedded health disparities project that will evaluate access to care for African-Americans with ASD and clarify factors influencing participation of African-American individuals in genetic research.

The ACE Network involves six research sites (UCLA, Washington University, Emory University, Albert Einstein/Yeshiva University, Yale University, Johns Hopkins University) and the AGRE Data Coordinating Center collaborating in a systematic, comprehensive investigation of ASD genetics in order to identify rare mutations, chromosomal abnormalities, and common variation contributing to ASD susceptibility in the African-American population. We will employ novel methods to define the ancestral origin of specific chromosomal segments and cutting-edge technologies in genetics including whole-exome sequencing, analyses of copy number variation, gene expression profiling and network analyses.  Through these approaches, we seek to identify new ASD susceptibility factors and prioritize variants for additional study in African Americans and other other populations.  Genetic risk factors identified in the mostly European samples examined to date will also be tested for association in the African-American sample to determine whether these cohorts share the same genetic risk factors. The observation of new forms or different population frequencies of ASD-related variation in African-Americans as well as the sharing of most CNV and single nucleotide variants with other cohorts are both outcomes that will have great significance for future studies and clinical care. 

Our project responds directly to at least five areas of the ACE RFA’s research objectives as outlined in the IACC 2011 strategic plan: 1) Addressing heterogeneity by identification of biological signatures; 2) Identifying genetic risk factors; 3) Understanding health disparities; 4) Making progress towards the inclusion of under-represented groups in research on ASD; and 5) Informing clinical genetic testing. 

 

 
Additional awardees:
  • Abraham Reichenberg, Ph.D., Mount Sinai School of Medicine, New York City

 

*Kevin Pelphrey and Ami Klin serve on the Autism Science Foundation Scientific Advisory Board

 

Watch Dr. Alice Kau's presentation on the ACE projects at the April 9 IACC full committee meeting: