Research Abstracts from CPEA Investigators

The proposed project examines the basis of autism in the developing brain. The primary hypothesis of the Program Project is that developmental impairment of the orbitofrontal-limbic circuit of the brain, including the mesial-orbitofrontal cortex (M-ORB) and amygdala, is a biological marker for autism and that the characteristic socio-emotional deficits of persons with autism are related to developmental impairment of this circuit. A secondary hypothesis is also addressed that the mental retardation in individuals with autism results from impairment of the dorsolateral prefrontal-hippocampal circuit (DL/HIPPO) of the brain. Together, these hypotheses have the potential to help explain the clinical features of autism as well as the range of outcomes seen. The Program project includes three research projects and two core modules. Project I is using neuropsychological measures to determine whether developmental impairment is present in the hypothesized brain systems, and will relate performance on these measures to socioemotional development, and to clinical measures of autism. A group of children and adolescents with Autistic Disorder (DSM-IV) (N=72) aged 7 to 18 at entry and a comparison group of children and adolescents of comparable ages and IQs without autism (N=72) are being tested. Project II is using structural magnetic resonance neuroimaging to examine hypothesized differences in brain regions present in the participants seen in Project I as well as in rhesus monkeys tested in Project III. Comparisons between structural neuroimaging of monkeys and humans will be carried out. Project II is also using proton MR spectroscopic imaging of human participants to investigate regional brain differences associated with autism. Project III is examining the effects of early lesions of the orbitofrontal cortex or amygdaloid nuclei on development of cognition and social behavior in rhesus monkeys. Because these monkeys receive the same neuropsychological tasks as the human participants, comparison of results between humans and animals will be possible. Core A provides administrative oversight, scientific leadership and project coordination for the Program Project. Core B provides patient coordination and assessment for Projects I and II as well as methodology, statistics and data management support for Projects I, II, and III.

Project 1: Neurobehavioral Development and Dysfunction in Autism:
Principal Investigator: Katherine Loveland, Ph.D.

Project 1 brings together the Principal Investigator's previous research on development of communication and social behavior in autism with research by Co-PI Jocelyne H. Bachevalier on the developmental consequences of lesions on the medial temporal lobe in infant rhesus macaques. The primary hypothesis of the Program Project is that developmental impairment of the orbitofrontal-limbic circuit of the brain, including the medial-orbitofrontal cortex and amygdala, is a biological marker for autism and that the characteristic socio-emotional deficits of persons with autism are related to developmental impairment of this circuit. A secondary hypothesis derived from Dr. Bachevalier's research is also addressed: that the degree of intellectual impairment in individuals with autism is related to impairment of the dorsolateral prefrontal-hippocampal circuit of the brain, including the dorsolateral prefrontal cortex and the hippocampus. All components of the Program Project address these two hypotheses. Children and adolescents with Autistic Disorder (DSM-IV) (N=72) aged 7 to 18 years and a comparison group of comparable ages and IQs without autism are being compared cross-sectionally. Aims are as follows: Aim 1: to compare the performance of children and adolescents with and without autism, using neuropsychological tasks measuring the functioning of the orbitoprefrontal-amygdalar circuit of the dorsolateral prefrontal-hippocampal circuit. Aim 2: to compare performance on tasks measuring the functioning of the orbitoprefrontal-amygdalar circuit or the dorsolateral prefrontal-hippocampal circuit. Aim 2: to compare performance on tasks measuring the functioning of the orbitoprefrontal-amygdalar and dorsolateral prefrontal-hippocampal circuits of the brain with performance on tasks measuring socio-emotional cognition and behavior, and with clinical measures of the symptoms of autism. Aim 3:to carry out comparisons of Project I findings with those of other Program Project components. Because they share a common participant sample and design, direct comparisons between the neuroimaging data collected in Project II and neuropsychological and behavioral data collected in Project I will be possible. In addition, a core set of shared neuropsychological tasks will be given both to human participants in Project I and to rhesus monkeys in Project III that have received highly specific early lesions of the orbitoprefrontal cortex or amygdala, allowing exploratory comparisons between human and animal results. If confirmed, our hypotheses have the potential to help explain the neurodevelopmental disorder. As a component of the Program Project, Project I provides a necessary link between human behavior and a possible animal model of autism.

Project 2: Structural and Spectroscopic Brain MRI in Autism
Principal Investigator: Michael E. Brandt, Ph.D.

Increasingly, clinical and non-human primate studies suggest that dysfunction in identified neural networks linking the limbic structures and the prefrontal cortex results in behavioral and emotional patterns that resemble autism. Neuroimaging techniques to date have not consistently identified brain abnormalities associated with autism. This likely due to heterogeneity of autistic populations, inadequate control populations and limitations of previous imaging techniques themselves. This project is using technological advances in structural and spectroscopic magnetic resonance imaging (sMRI and 1/H-MRSI and 1/H- MRSI) to investigate abnormalities in identified limbic-prefrontal neural networks and determine their association with autism. Seventy-two children and adolescents with autism aged 7;0 to 18;11 years and a group comparable in age, gender and IQ without autism receive high resolution sMRI. From the MR images, total and separate brain tissue (white matter/gray matter, cerebrospinal fluid) volume measurements will be performed (a) on the different structures of the limbic regions, i.e. the amygdala and hippocampus and (b) on two regions of the prefrontal cortex, i.e., the orbitofrontal and dorsolateral white/gray matter volume differences in orbitofrontal cortex of all autistic people as compared to control subjects; that volumetric differences in the structures of the M-ORB/AMYG circuit will correlate more strongly with neuropsychological test indices measuring functions of the amygdala and the orbitofrontal cortex, and clinical and behavioral measures of autistic symptoms (e.g. severity of autism), than with IQ measures; and that the dorsolateral prefrontal-hippocampal (DL/HIPPO) circuit will be more severely affected in low-functioning children and adolescents with autism than in high-functioning children and adolescents with autism and controls. In addition, a subgroup of subjects including 20 young high- functioning children and adolescents persons with autism, age 11; 0 to 18; 11 years and 20 controls matched for age, gender, IQ, and handedness receive 1/H-MRSI to assess the chemical composition for identified cerebral areas. In addition, all monkeys with infant and adult lesions in defined cerebral structures will be behaviorally tested (Project III) and imaged using the same technique to identify brain regions affected by the early versus late damage to the amygdala or orbitofrontal cortex. We hypothesize that abnormalities seen in higher-functioning children and adolescents with autism will be localized in the M-ORB/AMYG circuit, and those seen in the DL/HIPPO circuit will be associated with intellectual impairment; abnormalities of NAA reflecting alterations in neuronal integrity of the M-ORB-AMYG in autistic people will more strongly correlate with clinical and behavioral traits of autism as well as with scores on neuropsychological tasks measuring function of the M- ORB/AMYG circuit (Project I); in monkeys, we hypothesize that an early (infantile) lesion within the M-ORB/AMYG circuit (Project III) will have functional ramifications in other neural circuits (DL/HIPPO) and that the same lesion performed in adulthood will not have the same widespread impact.

Project 3: Orbitofrontal Limbic Circuit-Ontogeny and Early Dysfunction
Principal Investigator: Jocelyne H Bachevalier

One finding emerging from our research program is that insult to the medial temporal lobe in monkeys, and more specifically the amygdala, results in an array of behavioral changes that mimic in many ways the behavioral disturbances seen in autistic people. The goal of the present project is to pursue our investigation of this putative animal model of autism by testing the effects of early versus late lesions of a neural network that includes the amygdala and orbitofrontal cortex. For this purpose, using newly developed neurosurgical procedures and behavioral tasks, we are first evaluating the effects of selective bilateral lesions of the orbitofrontal cortex and amygdala in adult monkeys on cognitive tasks, fearful responses, and social bonds. Second, we will follow the long-term effects of early selective bilateral lesions of the orbitofrontal cortex and amygdala on cognitive tasks, fearful responses, and social bonds in the developing monkeys. These studies will provide the unique opportunity to examine in the same animals cognitive functions, regulations of emotions, and formation and maintenance of social bonds. Also, these studies will allow direct comparison between early versus late lesions that may indicate whether the early lesions he a beneficiary or a more debilitating behavioral effects. Impairment in monkeys with these early and late lesions will be compared to that of participants with autism (Project I). Finally, the monkeys will participate in Project II Aim 2 to establish the impact of these lesions on brain systems distant from the neural insult, such as prefrontal cortex and cingulate. Through such research, principles of the brain's response to damage will ultimately advance our understanding of the basic development processes that follow early dysfunction of the orbitofrontal-limbic circuit in primates, its implication for developmental disorders, such as autism, and will lead eventually to discovery of ways by which such effects can be alleviated or even eliminated.