Cognitive predictors of language impairment in Down Syndrome

Principal Investigator:  Leonard Abbeduto, Ph.D.

People with Down syndrome (DS) are usually in the lowest 2% of the population in intellectual ability, yet their language ability is far lower than their intellectual ability. Although much work has been done to understand the pattern of language abilities in individuals with DS, little is known about the nature of the underlying processes or mechanisms that result in this pattern. This NIH-funded project is designed to identify the cognitive factors that contribute to the language impairments of people with DS, especially their impairments in syntax. We predict that impairments in implicit learning and phonological memory together lead to impairments in language.  We are using a combined comparative/longitudinal design in which people with DS, ages 10  to 21, and two control groups (CA and mixed etiology intellectual disability) are tested at Time 1 and the DS and mixed ID cohorts are tested again two years later at Time 2. We suggest that implicit learning affects language directly, because it limits the  acquisition  of  complex  rule  systems  and  covariations  necessary  for  language  acquisition,  but  also indirectly, through phonological memory. Poor implicit learning of covariations among phonologic units in one's native language leads to limitations in phonological memory, which constrain language acquisition.

Language development in Fragile X Syndrome

Principal Investigator:  Leonard Abbeduto, Ph.D.

Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability, affecting as many as 1 in 2500 people. This NIH-funded project is designed to examine the language development of males with FXS or autism during adolescence and young adulthood, the factors that affect that development, the consequences of language impairments for independent functioning in adulthood, and diagnostic differences of the language profile observed. The project involves a longitudinal design, with four annual assessments and participants entering between the ages of 15 and 22 years. We are measuring vocabulary, syntax, pragmatics, and atypical language behavior (i.e., perseveration) by using standardized tests, expressive language samples, and laboratory-based measures. We also are measuring factors that affect language development, including working memory, autism symptoms, social avoidance, and anxiety, as well as genetic factors (i.e., FMRP expression) and environmental factors (e.g., family climate). We also are investigating the impact of language impairments on adult outcomes reflective of independence participation in the community.  Participants have a documented diagnosis of full mutation (or mosaic) FXS or autism (without FXS).

Naturally hyposocial juvenile macaque monkeys:  A nonhuman primate model for autism spectrum disorder treatment discovery

Principal Investigator:  Melissa D. Bauman, Ph.D.

The overarching goal of the proposed research is to develop a nonhuman primate model that can be used to evaluate novel drugs that may mitigate the social and communication impairments that characterize ASD. We anticipate that novel therapeutic agents targeting social deficits will become available in the near future and will require sophisticated animal models to evaluate drug efficacy. Although there are currently no validated nonhuman primate models of autism, we believe that natural variation in sociability of rhesus monkeys can be used to evaluate pharmacological treatment(s) designed to improve social and communication deficits.  We propose to develop protocols that will be used to identify cohorts of endogenously hyposocial monkeys and to develop high throughput behavioral assays of sociability that will be used to confirm sociability status, establish baselines for both high and low-sociable populations and ultimately provide a sensitive assay of drug efficacy.

16p11.2 deletion mice:  autism-relevant phenotypes

Principal Investigators:  Jacqueline Crawley, Ph.D. and Ricardo Dolmetsch, Ph.D., Stanford University

Deletions and duplications within the 16p11.2 chromosomal locus are associated with autism spectrum disorders (ASDs), as well as with developmental delays, language impairments, intellectual disabilities, schizophrenia, motor deficits, seizures, macroencephaly and obesity.  The goal of this project is to understand the behavioral, anatomical, and cellular phenotypes caused by a heterozygous deletion of the mouse homolog of 16p11.2.  We are conducting comprehensive behavioral phenotyping of heterozygous 16p11.2 knockout mice and their wild type littermate controls on measures of social interaction, social communication, motor stereotypies, repetitive behaviors, developmental milestones, learning and memory, seizures, hyperactivity, anxiety, sensory sensitivity, sensorimotor gating, and motor functions, relevant to the human 16p11.2 syndrome.  Our collaborator Ricardo Dolmetsch is analyzing 16p11.2 knockout mice on measures of brain development, neuroanatomy, neurochemistry, electrophysiology, and downstream gene expression.

Engrailed2 regulates forebrain monoamines and behavior

Principal Investigators:  Jacqueline Crawley, Ph.D. and Emanuel DiCicco-Bloom, M.D., UMDNJ-Robert Woods Johnson Medical School

Engrailed2 is a homeodomain transcription factor that regulates embryonic hindbrain development.  Single nucleotide polymorphisms in EN2, the gene coding for Engrailed2, have been associated with autism in five independent genetic studies, implicated EN2 genetic variants as a likely autism susceptibility gene.   This project investigates monoamine levels and behavioral phenotypes relevant to the symptoms of autism in En2 knockout mice.   We are conducting behavioral assays relevant to sociability, cognition, and depression.  Pharmacological treatments that reverse the noradrenergic abnormalities discovered by our collaborator Manny DiCicco-Bloom are being evaluated for reversal of behavioral phenotypes in En2 knockout mice.

Gene discovery and neurodevelopmental analysis in a mouse model of autism

Principal Investigators:  Jacqueline Crawley, Ph.D..and Elliott Sherr, M.D., UC San Francisco

This project is a genetic investigation of BTBR mice, an inbred strain that displays low sociability, high repetitive behaviors, and corpus callosum absence.  We are conducting behavioral assays of sociability and repetitive behaviors in 400 F2 mice from the BTBR x B6 intercross, to identify significant quantitative trait loci (QTL) and generate a list of high probability candidate genes within those chromosomal loci.   Our collaborator Elliott Sherr is simultaneously conducting corpus callosum assays in the same F2 mice, to identify genetic loci mediating the acallosal syndrome in BTBR.  20x sequencing coverage of the BTBR genome is being employed to identify candidate genes for both commissural anatomy and autism-relevant behaviors revealed by the QTL screen.  The overarching aim of these studies is to identify background genes mediating biological pathways that regulate autism-relevant behaviors in mice, which may inform the search for susceptibility and protective genes in autism.

Characterization of brain and behavior in 7q11.23 duplication syndrome

Principal Investigators:  Jacqueline Crawley, Ph.D. and Lucy Osborne, Ph.D., University of Toronto

Duplication of the Williams syndrome region on chromosome 7q11.23 (Dup7q11.23) has recently been identified as a possible autism-associated copy number variant.  Four Dup7q11.23 de novo cases of autism were identified during screening of the Simons Simplex Collection.  We are characterizing a Dup7q11.23 mouse model, employing our constellations of behavioral assays relevant to the diagnostic and associated symptoms of autism.  Our collaborator Lucy Osborne is characterizing the biological properties of mouse and human Dup7q11.3 cell reprogrammed to become neurons.   Collaborators Jacob Ellegood and Mark Henkelman are conducting brain morphology and diffusion tensor imaging of this mouse model of 7q11.23 duplication syndrome.

A cognitive test battery for intellectual disabilities

Principal Investigator:  David Hessl, Ph.D.

There is a rapidly growing translational neuroscience effort to understand the brain mechanisms of dysfunction in neurodevelopmental disorders (NDs) such as fragile X syndrome (FXS), Down syndrome (DS), and others. After development and validation of mechanistically-targeted treatments that modify underlying disease processes in animal models, empirically-supported clinical trials to translate these findings to humans with ND need to be carried out. Although most human treatment studies have focused on maladaptive behavior, the animal studies (e.g. Fmr1 knockout mouse models of FXS, Ts65Dn mouse model of DS) suggest that substantial gains in cognitive function and even reversal of disability are possible, even in adults with lifelong cognitive deficits. However, virtually no developmentally appropriate, well-validated and reliable cognitive measures suitable for tracking treatment response are available for individuals with intellectual disability. The goal of this NIH-funded, multi-site project is to develop and validate an assessment battery to measure cognitive outcomes in clinical trials of individuals with intellectual disabilities. The project critically leverages efforts by the NIH Neuroscience Blueprint Toolbox consortium which recently validated a computer administered cognitive battery (NIH Toolbox Cognitive Battery – NIH-TCB, normed in the general population for the ages of 3 to 89 years. The cognitive battery will be piloted, refined and adapted if needed, and then formally validated utilizing groups of individuals with fragile X syndrome, Down syndrome, and idiopathic intellectual disability. The proposed research will benefit a wide range of studies aiming to assess or improve specific domains of cognition and general intellectual functioning in persons with ID. More generally, it will critically extend the utility of the NIH-TCB to populations of individuals with developmental and intellectual disabilities.

Extending autism behavioral intervention to young children with Fragile X Syndrome

Principal Investigator:  David Hessl, Ph.D.

Current treatment regimens for patients with Fragile X syndrome (FXS) rely heavily on medications to manage behavior and psychiatric symptoms, and the animal models of the disorder have given rise to multiple additional pharmacological targets now under intense study in various clinical trials.  In contrast, although early intervention for this disorder is heavily emphasized, currently there is no comprehensive and developmentally appropriate behavioral treatment that has been empirically validated for young children with FXS.  As such, the evaluation of the best available behavioral interventions is a critical unmet need in the field.  This pilot project will evaluate, in a single subject multiple baseline design, the efficacy of the Early Start Denver Model, a parent training curriculum originally developed for autism, for families of young children with FXS. This type of intervention may be especially suited for FXS because these children have high rates of autism symptoms, including problems with communication, reciprocal social interaction and repetitive behaviors and intense interests.  The first cohorts of families will receive direct, or “in-person”, training at our center.  In anticipation of the need to disseminate effective therapy to geographically isolated families affected by FXS, the next cohort will be treated using telehealth or communication technology systems. The results of the study will provide critical pilot data in support of a future application for funding for a larger controlled trial.

Limbic system function in carriers of the Fragile X premutation

Principal Investigator: David Hessl, Ph.D.

Individuals with the Fragile X premutation are “carriers” – they can transmit an expansion of the gene to their children, who may become affected by Fragile X syndrome (FXS), the leading inherited cause of intellectual disability and a common cause of autism.  Until recently, these “carriers” were believed to be clinically unaffected.  However, recent evidence has emerged demonstrating that a proportion of these individuals have significant social, emotional, and cognitive problems, even autism and intellectual disability in the most affected patients.  In addition, we have discovered that male and rare female carriers are at significant risk for a neurodegenerative disease in later adulthood primarily characterized by intention tremor and gait ataxia called Fragile X-Associated Tremor Ataxia Syndrome.  This disease is not seen in FXS and has a different genetic mechanism.  This project does not involve FXTAS patients but rather younger men and women with the premutation who demonstrate psychiatric disturbances and are at risk for later neurodegeneration.   The project, using structural and functional brain imaging, neuropsychological assessment and genetic measures, examines the hypothesis that dysfunction of the limbic area of the brain, especially the hippocampus and amygdala, are involved in memory, emotional and social problems in premutation carriers. This research related to the premutation that may provide insight into other disorders involving memory, social-emotional dysfunction, and the broader autism phenotype.

Brain structure and connectivity in young children with autism

Principal Investigator: Christine Wu Nordahl, Ph.D.

The goal of this project is to use structural and functional neuroimaging techniques to investigate abnormalities in brain structure and connectivity in preschool-aged children with autism. Although previous structural imaging studies have provided some insight into the neuropathology of autism, the vast majority of studies have focused on older adolescents and adults with autism. Since autism emerges in the first years of life, during critical periods of brain development, it is critical to study children as close in time as possible to the clinical diagnosis and prior to intensive behavioral and medical interventions. Children are enrolled through the UC Davis MIND Institute’s Autism Phenome Project. Neuroimaging data is acquired at three annual time points, beginning at 3 years of age. All longitudinal imaging is carried out during natural nocturnal sleep, without the use of sedation or anesthesia. We will evaluate brain maturation trajectories in association with behavioral development over this critical period. Understanding the neural underpinnings of ASD is a critical step towards developing effective interventions and optimizing treatment outcomes.

Neural phenotypes of females with autism spectrum disorder

Principal Investigator: Christine Wu Nordahl, Ph.D.

Autism spectrum disorder (ASD) affects 1 in 88 children in the United States, but the disorder is much less common in girls than in boys. The prevalence of ASD in girls is 5 times lower than in boys, with a rate of 1 in 54 for boys and 1 in 252 for girls. Although this difference in prevalence rates is among the most highly replicated findings in studies of ASD, sex differences in ASD remain poorly understood. Because ASD is so much more common in males, females with ASD remain understudied. The goal of this study is to evaluate a large, sex-balanced cohort of preschool-aged children with ASD in order to elucidate the neural phenotypes of females with ASD and to identify sex-differences in the neuropathology of ASD. Children will be enrolled at the time of diagnosis (2-3 years of age) and followed longitudinally for two years. Imaging will be carried out at study enrollment and then at two additional annual time points and behavioral testing will be conducted twice, in conjunction with the first and third MRI time points. Imaging will include structural, diffusion-weighted and resting state functional connectivity in order to accomplish the following aims: 1) to evaluate sex differences in the neural systems that underlie core deficits in ASD 2) to investigate sex differences in brain growth trajectories in these neural systems and 3) to identify associations between distinct neural phenotypic subgroups and etiologic factors or behavioral outcomes.

Autism in infancy

Principal Investigator:  Sally J. Ozonoff, Ph.D.

This study tracks the early development of younger siblings of children with autism, children with other developmental delays, and children with typical development. Through this study, we hope to learn more about the early warning signs of later developmental problems and possible genetic markers for speech and language delay. Studies have indicated a 5-10% risk of having a second child with an autism spectrum disorder, with the risk potentially rising to as high as 35% for a third child. Babies are followed for three to four years and their social, communicative, cognitive, physical, and motor development is studied using a combination of behavioral methods, eye tracking paradigms, and gene assays. Once the participants have passed through the window of risk for the development of autism, we will be able to examine which behaviors differentiate the children who are affected from those who develop typically. The goal of this investigation is to develop a set of behavioral criteria that predict which infants will be later diagnosed with autism. Early recognition and intervention are very important in order to achieve the best long-term outcomes for children with autism.

Effective intervention for toddlers with autism

Principal Investigator:   Sally Rogers, Ph.D.

Children with autism are now being diagnosed as early as 12-18 months of life. We have very little information on how to intervene effectively with children so young. This five year, multisite, randomized controlled study, funded by NIMH and NICHD, will examine the outcomes after 27 months of treatment for 108 children ages 12-24 months at enrollment in three sites: University of Washington, University of Michigan, and UC Davis M.I.N.D. Institute. Children will be diagnosed at the university clinics and randomized into one of two groups, those who will be referred for the interventions available in their community through public resources, and a specific intervention developed by Sally Rogers and Geraldine Dawson, formerly at the University of Washington. The intervention, called the Early Start Denver Model, uses a play based, relationship based developmental approach in which social, communicative, and play interactions are carried out via naturalistically applied teaching procedures derived from applied behavior analysis, first developed in an intervention known as Pivotal response Training (PRT). This intervention approach thus fuses developmental, relationship, and behavioral approaches into an integrated and developmentally appropriate approach for infants and toddlers. Parents are coached to deliver the intervention, and therapists also visit children in their homes to deliver 20 hours of intervention each week. The main questions of interest involve the efficacy of the intervention approach, and identification of child, family,a nd biological mediators and moderators of treatment effects.

Girls with autism spectrum disorders

Principal Investigator:  Marjorie Solomon, Ph.D.

Autism spectrum disorders (ASDs), including autism, high functioning autism, Asperger's disorder, and pervasive developmental disorder NOS (PDDNOS) have a prevalence of one in 150. Male predominance of these disorders is four to one, although prevalence in females may be underestimated. Studies of gender differences in ASDs have reported that girls are more severely impaired than boys on measures of social skills and executive functions, however most of these studies did not adequately control for IQ. The goal of the current study is to use behavioral measures and functional magnetic resonance imaging (fMRI) to test hypotheses about gender differences in the manifestation of social and cognitive deficits and symptoms of psychopathology in a high functioning sample of girls with ASDs.

Non-social rewards and autism

Principal Investigator:  Marjorie Solomon, Ph.D.

Autism involves dysregulated motivation in interpersonal relationships, goal-directed behavior, and learning. Theories about social aspects of motivation impairments, including those found in joint attention and face processing, recently have been articulated, however, there has been little study of non-social forms of motivation that also can create profound problems in adaptive functioning. The behavioral intervention literature also suggests that learning is dysregulated in autism spectrum disorders (ASDs) since acquisition of new skills may require multiple discrete learning trials with very explicit reinforcement schedules. Paradoxically, while some rewards are not motivating enough, some are too attractive to children with ASDs. For example, engagement in repetitive behavior may be self-reinforcing and circumscribed interests can be so seductive that adaptive functioning is disrupted when the person with ASD becomes absorbed in them.

Predictors of cognitive development in autism spectrum disorders

Principal Investigator:  Marjorie Solomon, Ph.D.

Existing studies of middle childhood suggest that some children with ASD show significant improvements in IQ and other aspects of cognitive functioning during this period, while others stabilize or fall further behind. With the increased availability of intensive early intervention, it is not clear that findings from these older studies are applicable to children with ASD now. Given that cognitive abilities developed through early and middle childhood provide a critical foundation for later competencies, and are the strongest predictors of adolescent and adult outcomes, the lack of clarity about cognitive development during middle childhood constitutes a significant gap in our understanding of ASD. To close this gap we will conduct a longitudinal study of individuals with ASD that focuses on middle childhood in a well-characterized cohort of children from the UC Davis MIND Institute Autism Phenome Project (APP). We will reassess the original cohort of 279 when they reach middle childhood (at 8-10 years). We will examine cognitive functioning; identify distinct developmental trajectories of intellectual functioning/IQ between early and middle childhood; and identify predictors of membership in these trajectories. We also will test 2 mechanistic models of how intensive early intervention might promote positive middle childhood functioning in individuals with ASD. These include the “Hippocampal Compensation Model,” which proposes that in some children intervention promotes neuroplasticity of the hippocampus which then leads to improvements in memory, IQ, and academic functioning in middle childhood and the “Social Attention Model,” which suggests that in children with better academic, social, and adaptive functioning at ages 8-10 years there will be a positive association between intensity of early intervention, and executive attentional control and social communication development.