Social and Affective Processes in Autism
- Primary Site: Boston University School of Medicine
- Helen Tager-Flusberg, Ph.D., Director
- Susan Folstein, Co-director
Development of Children with Autism and their Families
Principal Investigator: Carter; site: BUSM
The overarching goals of this project are to understand the early course of core features of autism, co-occurring symptoms, and temperament in the child in the context of maternal well-being, stress, and resources to inform parent-support and parent-child interventions. We plan to recruit a sample of 300 toddlers with autism between the ages of 18- to 33-months and to conduct a five-year, longitudinal study of their early course with respect to: (a) core features of autism, including social functioning, language and communication, and unusual behaviors; (b) co-occurring symptoms, including externalizing, internalizing and regulatory problems; (c) temperament, and (d) competencies. In addition, we plan to investigate stability and change in parental well-being, family climate and parental resources, from the period of initial diagnosis to school entry. Finally we are proposing to monitor the interventions that children and families receive through this period and to examine the role of treatment intensity (i.e., hours per week) and working alliance (i.e., parents' experience of providers as competent, responsive, and supportive) on both child and family outcomes.
- To investigate the early course of development in children with autism, examining the influence of specific child, family, and service factors on stability and change in the core symptoms of autism (i.e., social functioning, communication, and repetitive/stereotypical behaviors and interests).
- To investigate the course of psycholo.qical well-beinq of mothers and fathers of young children with autism, examining relations between child, family, and intervention service factors.
The Neuroanatomical Basis of Social-affective Deficits in Autism
Principal Investigator: Blatt; site: BUSM
In this project we plan investigate cerebral cortical areas that are directly interconnected with the two limbic subcortical areas, the hippocampus and amygdala that are known in normal individuals to play key roles in social-affective and memory processing in the brain. Lesion studies in monkeys directly implicate these limbic cortices in exacerbating the social-emotional phenotypic effects. To accomplish this, we will utilize immunocytochemical techniques to quantitatively determine the number and distribution of GABAergic interneuron types and neuroglia, and ligand binding techniques to determine the density, number and affinity of key GABAergic and serotonergic receptors in the autistic brain. From these quantitative studies, possible differences in cortical integrity and in selective modulatory neurotransmitter systems may emerge as a neuroanatomic basis for alterations in social-affective processing in the autistic brain.
- Survey our whole brain serial section material, looking specifically for cytoarchitectonic abnormalities and malformations in areas in the frontal lobe [orbital prefrontal cortex (area 13) and medial prefrontalcortex (area 25)], cingulate gyrus [anterior cingulate cortex (area 24), posterior cingulate cortex (area 23) and retrosplenial cortex (areas 29 & 30)], and the temporal lobe [fusiform face area (FFA) in the fusiform gyrus]. From these microscopic studies, we hypothesize that there is a selective and predictable pattern of anatomic abnormality involving limbic cortical areas that are essential to the core clinical features of autism and that these substrates will be characterized by alterations in cellular and laminar distribution and/or by anomalies in cell size, packing density and volume.
- With immunocytochemical techniques, determine the number and distribution of subpopulations of GABAergic interneurons utilizing calcium binding proteins (calbindin 28kD, parvalbumin and calretinin) in each lamina in the six limbic cortical areas in aim #1. We will also determine the density of each of the three GABA transporters (GAT-1, GAT-2 and GAT-3) which are functional markers for GABA activity. From this study, we hypothesize that there is an alteration in one or more subpopulations of intrinsic GABAergic neurons in the autistic limbic cortex and that there will be a change in the inhibitory modulation between GABAergic interneurons and pyramidal cells, disrupting information processing by these cortical centers.
- In the same six limbic cortical areas in the frontal, cingulate and temporal lobes as in the previous two aims, additional immunocytochemical staining will utilize adjacent sections to the interneuron studies, to determine if there is evidence for a progressive process in autism extending into adulthood, a hypothesis suggested by observations of changes in brain weight and nerve cell size and number with age. Evidence for an ongoing process will be sought by looking for the presence of reactive microglia and active gliosis using LN-3 and GFAP immunostains. We hypothesize in the autistic brains, that highly reactive gila accumulate in those brain areas with Nissl identifiable neuropathology, and that this represents an ongoing process leading to further changes in the cytoarchitecture of the affected neuronal populations, ultimately affecting neuronal function. Analysis will be conducted in both the gray and white matter in each limbic cortical region and in the gray/white matter border where reactive neuroglia tend to accumulate.
- To determine quantitatively the ligand binding density, distribution, number and binding affinity of key GABAergic [benzodiazepine, GABAA, and GABAB] and serotoninergic receptor types [5-HTU (serotonin uptake sites or transporter), 5-HT1A and 5-HT2 receptors] in the same six limbic cortical areas in the frontal, cingulated and temporal lobes. Ligand binding autoradiography will be utilized to conduct multiple concentration saturation binding studies to quantify any differences in laminar binding and whether such differences are due to altered number of receptors or to binding affinity of the ligand to receptor sites. From these studies, we hypothesize that in the autistic brain there will be alterations in both the distribution and number of binding sites in at least one or more of the GABA receptor types as well as in serotonergic uptake sites. Previous studies have identified such GABA alterations in the hippocampus of adult autistic individuals (e.g., Blatt et al., 2001a) and abnormalities in the GABAergic system are also evident in the cerebellum. Thus, the neurochemical abnormalities may be widespread, targeting specific limbic and cerebellar structures that may in part, underlie the behavioral phenotype of the autism disorder.
Dysfunction of Affective Circuitry in Autism
Principal Investigator: Davidson; site: Waisman Center/University of Wiscosin
The broad goal of this project is to examine the brain circuitry underling emotion in autistic and comparison subjects. All studies will involve functional magnetic resonance imaging (fMRI) during tasks designed to probe different aspects of affective function. In addition, all studies will also use eye tracking to ascertain precisely where subjects are fixating during stimulus presentation since some of the extant neuroimaging data in autistic subjects is assumed to be a function of the fact that autistic subjects are exhibiting gaze aversion and not foveating the stimuli to the same degree as controls. In each of the proposed studies, analyses will be conducted on all trials, as well as restricted to only those trials during which subjects are fixating on the stimuli. We will also test a small sample of children with childhood separation anxiety disorder or social phobia to use a second comparison group to ascertain the extent to which the deficits observed for autistic subjects are specific to this population. Finally, structural MR scans will be used in an exploratory effort with deformation-based voxel-wise morphometry to examine regionally-specific morphometric variations in autism.
- To investiqate the hypothesis that at least some autistic individuals have excessive activation in the amygdala and increased electrodermal activity in response to social stimuli compared with non-autistic control subjects when they are attendinq to the stimuli in question.
- To compare the neural circuitry associated with reactivity to positive and neqative, social and nonsocial affective stimuli.
- To probe the functions of the anterior cingulate cortex (ACC) in autistic and control subjects.
Citalopram Treatment in Children with Autism Spectrum Disorders and High Levels of Repetitive Behavior
Principal Investigator: King; sites: Dartmouth, UCLA, Mt. Sinai, Long Island Jewish Hospital, UNC-Chapel Hill, & Yale Unversity
For persons with autism spectrum disorders (ASD, also known as Pervasive Developmental Disorders - PDDs), repetitive behaviors are common and frequently interfere with functioning in the home as well as in social and educational settings. These symptoms may involve stereotypic movements, repetition of routine behaviors, repetitive play and preservative speech. High levels of repetitive behaviors in individuals with ASD may be associated with high levels of anxiety, dysphoria, self-injury, and tantrums when caretakers interrupt these behaviors. The primary aim of this study is to determine the efficacy in improving global functioning, tolerability, and safety of citalopram, a selective serotonin reuptake inhibitor (SSRI) as compared to placebo in the acute treatment of children with a diagnosis of an autism spectrum disorder. The primary outcome measure of efficacy will be improvement in functioning as reflected by the Clinical Global Impressions- Improvement score (CGI-I); positive response will be defined as a score of 1- (Very Much Improved) or 2-(Much Improved). Secondary aims are to evaluate the effect of citalopram on repetitive behavior and to evaluate longer-term safety and tolerability of citalopram for up to 28 weeks of exposure. We will also examine the association between subject characteristics, serotonin genotypes, hepatic enzyme genotypes, and whole blood serotonin levels with clinical response (i.e., both improvement and adverse events) to citalopram in children and adolescents with ASD. This will involve examination of specific genetic polymorphisms of serotonin system and drug metabolism as well as changes in basal and post-treatment platelet serotonin uptake.