Helen L. Tager-Flusberg - US grants

The research is directed towards a clearer understanding of the delays and deficits in the syntactic development of retarded and autistic individuals. Research has demonstrated that some retarded and probably all autistic children are significantly more delayed in language development than would be predicted by their overall cognitive level. The purpose of this research is to investigate whether this significant language delay is related to the process by which these children acquire syntactic rules. Specifically, it is hypothesized that some retarded and all autistic children are particularly deficient in utilizing semantic constraints in the development of grammatical forms which are known to facilitate syntactic development in normal children. This hypothesis is derived from past research demonstrating that these children have difficulty making effective use of semantic information in cognitive tasks. The hypothesis will be addressed in two studies that are designed to investigate retarded and autistic children's ability to use semantic constraints in the acquisition and use of a number of grammatical constructions. In one study five retarded and five autistic children will be followed longitudinally, collecting regular samples of their spontaneous speech. The transcripts will be analyzed for the syntactic-semantic relationships in their utterances. The ability to use semantic information effectively in the acquisition of certain syntactic rules will be related to the amount of discrepancy between the subjects' mental age and language level. The second study is cross-sectional in design. Mentally retarded, autistic and normal children will participate in a series of experiments designed to test their comprehension and elicited production of a number of grammatical forms in a variety of semantic contexts. Again, the ability to make effective use of semantic constraints to understand or produce a particular form will be related to the degree of discrepancy between mental age and language level. The results from these studies will lead to an understanding of how different retarded and autistic children process various syntactic rules and to what extent their syntactic development follows the same route as in normal children. The findings will lead to the development of better diagnostic and screening instruments for language impairments, and training programs for teaching syntactic rules to language delayed children.

[unreadable] DESCRIPTION (provided by applicant): The main goals of our research program are to advance our understanding of the social phenotype of Williams syndrome (WS), and to define the cognitive mechanisms that underlie the unique social-affective features that define this neurodevelopmental disorder. Our current studies have demonstrated that adolescents and adults with WS are better than age and IQ matched learning disabled/mentally retarded controls oh standardized measures of face recognition, and in their ability to interpret prosodic cues to speakers' emotions in filtered speech, performing at similar levels to normal controls on these tasks. Moreover, they are more likely to notice subtle changes to social aspects of complex scenes, respond more empathically toward a person in distress, and on psychophysiological measures of arousal, appear to find social-affective stimuli less threatening than other people. In the next award period we plan to continue this line of research addressing the following questions: (1) Do people with WS show the same developmental changes during the early adolescent stage in face recognition as do controls? (2) Do people with WS interpret eye gaze information in the same way as controls? (3) Do people with WS show greater sensitivity to affective information in faces compared to controls using implicit tasks? (4) Do people with WS attend more than controls to social information in dynamic scenes, as evidenced by eye-tracking data? (5) Do people with WS find social stimuli differentially more rewarding than controls? (6) Do people with WS find social-affective stimuli less threatening, as evidenced by psychophysiological measures of arousal, than controls? We plan to investigate these questions in a series of experiments comparing adolescents and young adults with WS to age/IQ matched and normal age-matched controls, and predict that experiments addressing questions (1) - (2) will find comparable patterns of performance in the WS and control participants. In contrast, experiment addressing questions (3) - (6) will highlight unique performance patterns in WS, reflecting their greater attention and singular affective response to social information. This research program will not only advance our understanding of WS; it has the potential to influence developing theoretical models in the growing field of social cognitive neuroscience. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant) This application has been submitted as a request for continuing support for a program of projects that has been designed to better understand the neurobiology and genetics of autism. The central organizing theme of the project is on studies of processes associated with language and social deficits in this syndrome. In its initial funding cycle the program included 3 funded projects designed to: a) provide a longitudinal study of the relations between language and theory of mind; b) develop a battery of computer based tasks that would differentiate nonverbal children with autism from children with severe autism, and c) explore the neurobiological underpinnings of language and communication abnormalities in autism with MRI. Three new projects are described in this continuation proposal. Project I proposes a detailed comparison of face processing in children with autism and controls. Project II proposes to examine the similarities and differences in language impairments in children with autism versus those with and without specific language development. Project III has been designed to provide a morphometric and functional MRI exploration of the neural substrates of social and language impairments in autism. These projects are to be carried out as a collaborative effort across Boston University Medical School; Tufts / New England Medical Center, and Harvard Medical School / Massachusetts General Hospital. These projects will be coordinated by a clinical and administrative core.

PROJECT SUMMARY/ABSTRACT The primary mission of the Administrative Core is to provide overall leadership and support for the ongoing research activities of our Clinical Research Center. Leadership will be provided by the Principal Investigators, Helen Tager-Flusberg (BU) and Connie Kasari (UCLA) who have both had extensive experience leading multi- site research programs and conducting research on minimally verbal ASD. The Core has three specific aims. Aim 1: Guide, support, and evaluate the programmatic and synergistic activities of the Center. This will be accomplished by setting up a communications system, an internal steering committee (Project and Core PIs), and an external advisory board. Activities to support this aim include the creation of a dedicated password protected Sharepoint account to facilitate communication, scheduling, file sharing and collaboration. In addition, there will be: regular biweekly teleconferences between the Center PIs; quarterly teleconferences with the steering committee; an annual meeting of all key personnel, trainees and the external board; a system for decision making about resource allocation; and support for fostering interchanges among the trainees and participating sites. Aim 2: Provide administrative support for the daily operations of the Center. The Center administrator at BU will coordinate and monitor the budgets for all projects and Cores, provide monthly updates to the PIs and oversee the annual progress reports. At each site (BU and UCLA), the Center administrators will be responsible for coordinating daily operations, including IRB and other regulatory requirements, personnel, supplies, other expenses, travel, meeting planning, etc. Aim 3: Center outreach and dissemination. We plan to create a website for the Center on which our accomplishments, publications and public talks will be made available to the broader community. We will coordinate with the PIs at each site to engage students at all levels in the research activities of the Center. The PIs both have extensive experience working closely with their local communities in activities related to their research programs. In addition, we have traveled widely to many countries around the world to present and train professionals and parents in furthering their understanding of ASD and disseminating intervention strategies tailored to the local resource environment and cultural frameworks. We plan to continue these activities with a particular focus on minimally verbal individuals with ASD to bring the work of the Center to a wide audience of professionals, families and other stakeholders. Taken together, the Administrative Core will be the hub for our unique multi-site center to enhance all our goals and ensure the smooth functioning and foster close collaborations among the projects and scientific core.

Impairments in social emotional reciprocity are among the core symptoms of autism spectrum disorders. Recent scientific and technological advances in the genetics of complex diseases and quantitative trait analysis, the emergence of the social and affective neurosciences, the measurement of heterogeneous behavioral phenotypes and quantitative traits associated with autism, and renewed attention to the developmental nature of neurodevelopmental disorders provide the foundation on which we have built our integrated, multidisciplinary research programs, addressing this defining feature of autism and potential treatments. This multi-site application for a STAART Center focuses on the central theme of social and affective processes in autism. Major institutions in Boston (Boston University School of Medicine, Tufts New England Medical Center, Harvard/Massachusetts General Hospital), northern New England (Dartmouth Medical Center) and Wisconsin (Waisman Center/University of Wisconsin) will collaborate on five projects that explore the early developmental course viewed within the context of family influences (Project I), underlying genetic causes using a quantitative trait approach (Project II), brain pathology and functioning (Projects III and IV), and treatment (Project V) of the core symptoms of social emotional impairment, and co-occurring affective disorder and problem behaviors in autism. The projects will be supported by a Clinical Core (Core B), which will collect diagnostic and phenotype data, DNA, and other biological information from children with autism and their first degree relatives; and a Data Management and Statistics Core (Core C), that will create and manage the database and provide major support for data entry, access, and statistical analyses for the projects. The Administrative Core (Core A) will coordinate the scientific components of the Center including the projects and other Cores, and will foster the development of new educational, clinical, training, and other outreach programs for the local, regional and national autism community. Our center brings together a team of leading scientists drawn from a broad geographical base who together create the infrastructure needed to fulfill the mission not only for our own scientific programs but also for the collaborative research that will be an important part of the NIH STAART Centers Program.

social psychology; mood disorders; behavior disorders; psychological models; family structure /dynamics; sign /symptom; language disorders; autism; quality of life; personality; parent offspring interaction; intelligence tests; racial /ethnic difference; gender difference; behavioral /social science research tag; clinical research; human subject;

[unreadable] DESCRIPTION (provided by applicant): Autism spectrum disorders (ASD) and specific language impairment (SLI) are both complex disorders that involve primary impairments in language that are usually diagnosed on the basis of emerging behavioral symptoms during the toddler or preschool period. Twin and family studies have demonstrated high heritability estimates for both ASD and SLI and there is evidence from these studies for overlap among these disorders, suggesting partially shared etiology. For children diagnosed with ASD and SLI there is considerable variability in outcomes, especially in the severity of language and social-communication impairments. The main goal of the proposed exploratory research program is to develop a new methodological approach for identifying the earliest predictors of risk and early course of language and communication development for ASD and SLI between the ages of 6 and 12 months. A longitudinal prospective study of infants at high risk for ASD and SLI is proposed. 100 high risk infant siblings of probands with either ASD (N=50) or SLI (N=50), as well as low-risk sibling controls (N=30) will be recruited, and followed from 6 to 18 months of age, at which time provisional assessments of ASD and language delay will be conducted. Our goal is to acquire dense home-based diary records of the infants' development using novel structured parent data collection methods, including detailed diaries and video-tapes of the infants that will be coded for the emergence of early vocal, language and social-communicative behaviors. These diaries will be complemented by laboratory-based standard assessments at 6, 12 and 18 months. Analyses will focus on comparing the two high-risk sibling groups to one another and to the controls on the timing of emergence of key developmental milestones and the presence of unusual behaviors. The findings from this research program will lead to the development of new clinically useful methods for diagnosing and assessing ASD and SLI in infancy that could be implemented in community settings. Early diagnosis of high risk for these disorders is considered a crucial step in improving the prognosis for children with ASD and SLI, because this will open the doors for early entry into interventions that are known to lead to better outcomes. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Specific language impairment (SLI) and autism spectrum disorders (ASD) are complex, highly heritable disorders that involve primary impairments in language and communication. Both disorders are heterogeneous, longer-term outcomes vary considerably, and in families that have a diagnosed child, other relatives may share some behavioral features without meeting diagnostic criteria. At around 12 months, delays in major language and communication milestones are first reported for children later diagnosed with SLI or ASD, but thus far, relatively little is known about signs that may be detected during the first year of life. This research program is designed to address this important clinical and theoretical issue by investigating the early development of infants at risk for these disorders (with risk defined on the basis of an older sibling with a confirmed diagnosis). Building on earlier work by others and our own preliminary data, we propose that neurobehavioral markers of risk in fundamental processing systems (e.g., auditory/speech; visual/social) can be detected in the latter half of the first year of life. This is a highly significant stage because during this time development of both language and social perception depend on critical socially-embedded learning experiences. We hypothesize that infants at risk for SLI and ASD have risk markers that signal problems in speech/communication processing mechanisms; infants at risk for ASD have additional (non-shared) risk markers that signal problems in development that are grounded in socially-embedded experiences. These markers may result in altered developmental trajectories. The specific aims of the research are (1) to identify markers that distinguish between infants at risk for SLI or ASD and low risk controls; (2) to identify the predictors of later SLI and ASD diagnoses (at 36 months of age) from measures collected between 6 and 12 months of age; and (3) to compare developmental trajectories of key language and related social/cognitive measures between 6 and 36 months in infants with and without clinical outcomes. These aims will be pursued in a longitudinal prospective design following infants from 6 to 36 months of age. Data will be collected on language and social perception using behavioral, eye-tracking and neurophysiological measures as well as general measures of cognitive and brain development (head circumference; EEG). The findings from this research will have a significant impact on developing novel clinically useful methods for identifying infants at high risk for SLI and ASD; in turn this will improve their prognosis because it will open the doors for early entry into interventions that are known to lead to better outcomes.

DESCRIPTION (provided by applicant): This R13 application is a request for funds to provide partial support the biennial International Scientific and Professional Conference on Williams syndrome (WS), a well-characterized neurodevelopmental disorder caused by a chromosome microdeletion on 7q11.32 of several million base pairs. The impact of WS is far greater than its prevalence of ~1/7500 persons because it serves as a model disorder for drawing medical, cognitive and behavioral genotype-phenotype correlations. The parent organization, the Williams Syndrome Association (WSA), recognized more than 25 years ago that encouraging research would ultimately benefit their children with WS. To this end, they have sponsored a dozen small scientific/professional conferences since 1988. For several reasons, prime among which are recent advances in understanding and treating other genetically-based neurodevelopmental disorders, now is the right time for this conference to grow beyond what the parent group can sustain. The requested R13 funds will be used to expand the 2012, 2014, and 2016 WS International Scientific and Professional conferences beyond its existing foundation (which will continue to be supported with funds from the WSA). Specifically, these funds will enhance participation from: -keynote researchers leading scientific efforts in other disorders whose approaches and discoveries could inform WS; -trainees such as students and post-doctoral fellows, as well as promising young investigators; and -students, scientists, care providers, and research professionals who represent and serve minority communities or who have disabilities. The central goal of the meeting is to promote research and care pertaining to WS; accordingly, the meeting will be structured to achieve this goal by promoting cross-talk, exchange of ideas, and potential collaborations amongst all participants. R13 funds will allow a far greater range and diversity of meetings attendees. This will have both short term benefits (jump-starting research and possible therapeutic strategies) and also long term benefits (sustaining, even expanding, intellectual inquiry at the highest level).

The Administration and Data Management Core Unit (A) will provide overall scientific and administrative leadership for the ACE. An advisory system, including internal and external advisory boards will guide the progress, planning and decision-making responsibilities for the research to be conducted in each of the 4 projects, as well provide cross-project integration. The boards will be composed of the senior investigators (Internal), national leaders, professionals from the community and parents (External). Communications and integration across the scientists, trainees, community members and families will be supported by a custom-designed Research Collaboration Platform that will connect research teams, families, training materials, scheduling systems and data transfer. The Core will be responsible for handling the day-to-day administrative needs of the ACE, oversee all IRB and other regulatory obligations, and manage resource allocations. The Data Coordinating Center will be responsible for creating project databases, data collection forms, tracking systems, data manuals, data cleaning and statistical support for the research conducted in the ACE.

The Research Training and Education Core will serve two primary constituencies: (1) The junior investigators, post-doctoral fellows, students and other trainees associated with the ACE; (2) The broader community of clinicians, educators, families and other stakeholders in our geographical region. For (1) a range of educational and training activities will be offered through the Core including: training in responsible and ethical conduct of research (through Boston University); a newly designed video-enriched web-based course on ASD; workshops on writing and grant applications; journal club focusing on ASD; training in major instruments and assessment techniques, especially for the minimally verbal population; seminars related to the disciplinary foundatons of the ACE scientific projects offered through the departments and Centers at BU associated with the ACE; seminars on ASD and related disorders in the Boston-area community; invited speakers; and an annual competition for small grant awards to stimulate novel research projects related to the goals of the ACE. Our goal is to provide a rich array of training opportunities for the next generation of researchers, the majority of whom will not have had an extensive background in ASD research. For (2), the senior investigators associated with the ACE will schedule regular speaking engagements to local schools serving children and adolescents with ASD, profesisonal groups (e.g., speech-language clinicians) and families through local ASD groups (e.g., Autism Speaks); organize an annual conference to be held at BU on our research findings related to minimally verbal children with ASD; and further disseminate our research in newsletters and publications (e.g., Exceptional Parent; Autism Spectrum Quarterly) that reach the wider community of stakeholders.

DESCRIPTION: A critical gap identified in the 2011 lACC Strategic Plan is the dearth of knowledge about older children and adults who fail to acquire spoken language. Little is known about these individuals because current assessment tools and practices are not adequate for this population. More significantly, there are no models that explain why about 30% of the ASD population remains minimally verbal and no interventions that specifically and uniquely target this population in promoting spoken language. The goals of our ACE are to address these issues, bringing tools, methods, and approaches have drawn from others areas of speech, auditory, clinical, and computational neurosciences. Our ACE, located at Boston University, brings together researchers from across the university and collaborators from Harvard Medical School, Northeastern University and Albert Einstein College of Medicine. The interconnected projects in the ACE include: a novel intervention to promote spoken language in school-aged children with ASD (Project I); investigation of biological markers of treatment response and outcome (Projects I, II, and III); investigation of mechanisms that might underlie the failure to speak including (a) structural and functional connectivity impairments in key nodes of the speech production network according to the DIVA model (Project 11); (b) abnormalities in the perception, organization and analysis of auditory scenes as indexed in electrophysiological responses and neural oscillatory patterns (Project III); disruptions in excitatory and inhibitory neuronal pathways in key prefrontal cortical areas associated with language using high resolution methods to investigate white matter and axonal growth proteins in tissue samples (Project IV). The projects are united and served by an Administration and Data Management Core (A), a Research Training and Education Core (B) and a Clinical Core (C), which will carry out comprehensive assessments using standard and novel experimental measures to capture the heterogeneous phenotypes of minimally verbal children with ASD, and that will be used to explain variability in treatment response and mechanistic factors identified in the Projects. Together, the research conducted in our ACE will significantly advance our understanding of this neglected end of the autism spectrum, provide innovative approaches to assessment and treatment, pave the way for identifying biological markers predict who will fail to acquire speech, and highlight potential molecular targets for therapeutic interventions.

? DESCRIPTION (provided by applicant): Searching for biomarkers and behavioral signs of early risk for neurodevelopmental disorders has emerged as an important line of clinical research in an effort to improve diagnosis and develop the most effective treatments and preventive interventions. In our current award period we identified several significant differences between infants at high familial risk for ASD (defined as having an older sibling with the disorder) and low risk control infants, including alterations in EEG, atypical lateralization for speech and faces, and reduced cortical connectivity all of which might serve as early risk markers. These differences were not only identified during the first year of life, their developmental trajectories were also atypical; a finding that appears to be a hallmark of risk for ASD. Our findings open up important questions about whether these risk markers extend to other infants later diagnosed with ASD, particularly infants from the general population, and whether they might also serve as risk markers for other related disorders, particularly language and social communication delay. In the next award period we address these questions by adding a new group of infants who fail a developmental screener (the CSBS) at 12 months. This group will be drawn from general pediatric practices, and will be compared to high-risk infant siblings and low risk controls on a battery of electrophysiological and behavioral measures that will be administered at 12-14 months, and again at 18, 24 and 36 months, at which time diagnostic outcomes will be evaluated. The project will address two specific aims. First, Do neural and behavioral risk markers (and their developmental trajectories) that distinguish infants at familial risk for ASD from low risk controls extend to infants at risk based on early behavioral differences detected on a 12-month screening instrument? We hypothesize that some risk markers will be shared across both high-risk groups, though for the screened group this may only hold for infants with clinical outcomes and show different developmental trajectories. Other risk markers may be unique to infants at familial risk. Our second aim addresses the question: Do the developmental profiles of neural and behavioral risk markers we identify predict only to later diagnoses of ASD or do they extend to other non-ASD neurodevelopmental outcomes at 36 months, including language or social communication delay? We hypothesize that some of our risk markers will be shared across these non-ASD related (and overlapping) clinical outcomes, while others will be unique to ASD outcomes. As research progresses on identifying behavioral and neural markers in infants that are at risk for neurodevelopment disorders, it is critical that we extend our research beyond familial risk to the general population and to evaluate risk markers across several diagnostic outcomes. In this way our goal is to advance knowledge of the shared and unique mechanisms that can ultimately be the focus of more targeted interventions at a time when there is greatest plasticity and opportunity for preventing adverse outcomes.

PROJECT SUMMARY/ABSTRACT A significant number of children with ASD remain minimally verbal even after receiving quality interventions. Recent studies have highlighted the heterogeneity of this group confirming that no single mechanism can explain the underlying causes of their severe communication deficits. At the same time, innovative targeted behavioral interventions can lead to improvements in speech and social communication in some minimally verbal children. The goals of this Center, located at Boston University and University of California Los Angeles, are to build on our earlier work addressing a central theme: Which young minimally verbal children with ASD make gains acquiring language during the early school years and how can we facilitate such progress? We approach these questions from a multidisciplinary perspective, employing tools, methods, and approaches drawn from communication disorders, speech and motor science, developmental neuroscience, genetics and interventions research. The four interconnected projects address the following aims. Aim 1: To identify motor and neural mechanisms underlying the profound spoken language impairments that define minimally verbal children with autism. In two projects on the same group of young minimally verbal children we plan to characterize oral and general motor functioning using state-of- the-art technologies, and electrophysiology to probe neural functioning (Project 1, 2). Aim 2: To advance our understanding of how to optimize the language outcomes of young minimally verbal children with ASD. We address this by carrying out a randomized controlled trial of a behavioral intervention that combines social communication and oromotor targets (Project 3) and by following the children studied in Aim 1 for two years to explore how changes in motor and neural functioning may predict diverse language pathways (Projects 1, 2). Aim 3: To investigate genetic risk factors associated with minimally verbal ASD, including both common and rare variants (Project 4). We plan to leverage the children enrolled in all the projects to explore the relationship between the quantitative load for common polygenic risk for ASD and language, motor, and neural phenotypes as well as genetic predictors of response to treatment and more optimal developmental outcomes (all Projects). The projects are united and served by an Administrative Core (A) and a Clinical and Data Management Scientific Core (B) that will carry out comprehensive assessments using available and novel measures to capture the heterogeneous phenotypes of minimally verbal children with ASD. Together, the research conducted in our Center will significantly advance our understanding of the profound communication deficits at this neglected end of the autism spectrum, develop behavioral and neural biomarkers that predict different developmental pathways for language, and may highlight potential molecular targets for future novel therapeutic interventions.

PROJECT SUMMARY/ABSTRACT A significant number of children with ASD remain minimally verbal even after receiving quality interventions. Recent studies have highlighted the heterogeneity of this group confirming that no single mechanism can explain the underlying causes of their severe communication deficits. At the same time, innovative targeted behavioral interventions can lead to improvements in speech and social communication in some minimally verbal children. The goals of this Center, located at Boston University and University of California Los Angeles, are to build on our earlier work addressing a central theme: Which young minimally verbal children with ASD make gains acquiring language during the early school years and how can we facilitate such progress? We approach these questions from a multidisciplinary perspective, employing tools, methods, and approaches drawn from communication disorders, speech and motor science, developmental neuroscience, genetics and interventions research. The four interconnected projects address the following aims. Aim 1: To identify motor and neural mechanisms underlying the profound spoken language impairments that define minimally verbal children with autism. In two projects on the same group of young minimally verbal children we plan to characterize oral and general motor functioning using state-of- the-art technologies, and electrophysiology to probe neural functioning (Project 1, 2). Aim 2: To advance our understanding of how to optimize the language outcomes of young minimally verbal children with ASD. We address this by carrying out a randomized controlled trial of a behavioral intervention that combines social communication and oromotor targets (Project 3) and by following the children studied in Aim 1 for two years to explore how changes in motor and neural functioning may predict diverse language pathways (Projects 1, 2). Aim 3: To investigate genetic risk factors associated with minimally verbal ASD, including both common and rare variants (Project 4). We plan to leverage the children enrolled in all the projects to explore the relationship between the quantitative load for common polygenic risk for ASD and language, motor, and neural phenotypes as well as genetic predictors of response to treatment and more optimal developmental outcomes (all Projects). The projects are united and served by an Administrative Core (A) and a Clinical and Data Management Scientific Core (B) that will carry out comprehensive assessments using available and novel measures to capture the heterogeneous phenotypes of minimally verbal children with ASD. Together, the research conducted in our Center will significantly advance our understanding of the profound communication deficits at this neglected end of the autism spectrum, develop behavioral and neural biomarkers that predict different developmental pathways for language, and may highlight potential molecular targets for future novel therapeutic interventions.

PROJECT SUMMARY/ABSTRACT A significant number of children with ASD remain minimally verbal even after receiving quality interventions. Recent studies have highlighted the heterogeneity of this group confirming that no single mechanism can explain the underlying causes of their severe communication deficits. At the same time, innovative targeted behavioral interventions can lead to improvements in speech and social communication in some minimally verbal children. The goals of this Center, located at Boston University and University of California Los Angeles, are to build on our earlier work addressing a central theme: Which young minimally verbal children with ASD make gains acquiring language during the early school years and how can we facilitate such progress? We approach these questions from a multidisciplinary perspective, employing tools, methods, and approaches drawn from communication disorders, speech and motor science, developmental neuroscience, genetics and interventions research. The four interconnected projects address the following aims. Aim 1: To identify motor and neural mechanisms underlying the profound spoken language impairments that define minimally verbal children with autism. In two projects on the same group of young minimally verbal children we plan to characterize oral and general motor functioning using state-of- the-art technologies, and electrophysiology to probe neural functioning (Project 1, 2). Aim 2: To advance our understanding of how to optimize the language outcomes of young minimally verbal children with ASD. We address this by carrying out a randomized controlled trial of a behavioral intervention that combines social communication and oromotor targets (Project 3) and by following the children studied in Aim 1 for two years to explore how changes in motor and neural functioning may predict diverse language pathways (Projects 1, 2). Aim 3: To investigate genetic risk factors associated with minimally verbal ASD, including both common and rare variants (Project 4). We plan to leverage the children enrolled in all the projects to explore the relationship between the quantitative load for common polygenic risk for ASD and language, motor, and neural phenotypes as well as genetic predictors of response to treatment and more optimal developmental outcomes (all Projects). The projects are united and served by an Administrative Core (A) and a Clinical and Data Management Scientific Core (B) that will carry out comprehensive assessments using available and novel measures to capture the heterogeneous phenotypes of minimally verbal children with ASD. Together, the research conducted in our Center will significantly advance our understanding of the profound communication deficits at this neglected end of the autism spectrum, develop behavioral and neural biomarkers that predict different developmental pathways for language, and may highlight potential molecular targets for future novel therapeutic interventions.