Biomedical subjects
Publications and source records attributed to Helen Tager-Flusberg.
The paper by Meyer-Lindenberg and colleagues in this issue of Neuron provides strong evidence that the absence of one or more genes in Williams syndrome leads to highly circumscribed pathology in the dorsal visual stream. This program of research demonstrates that neurocognitive architecture follows the same principles in typical and atypical development.
Autism is a neurodevelopmental disorder characterized by preserved visual abilities as well as a special profile for visual cognition. We examined the visual cortex of high-ability individuals with autism in order to assess whether the presence of abnormalities at the primary sensory level in autism could be the basis of their unusual pattern of visual cognitive abilities. We found that the early sensory visual areas are normally organized in individuals with autism, with a normal ratio between central versus peripheral visual field representation. We conclude that the differences observed in the visual capacities of individuals with autism are likely to arise from higher-level cognitive areas and functions, and are the result of top-down processes.
Language deficits are among the core impairments of autism. We previously reported asymmetry reversal of frontal language cortex in boys with autism. Specific language impairment (SLI) and autism share similar language deficits and may share genetic links. This study evaluated asymmetry of frontal language cortex in a new, independent sample of right-handed boys, including a new sample of boys with autism and a group of boys with SLI. The boys with autism were divided into those with language impairment (ALI) and those with normal language ability (ALN). Subjects (right-handed, aged 6.2-13.4 years) included 22 boys with autism (16 ALI and 6 ALN), 9 boys with a history of or present SLI, and 11 normal controls. MRI brain scans were segmented into grey and white matter; then the cerebral cortex was parcellated into 48 gyral-based divisions per hemisphere. Group differences in volumetric asymmetry were predicted a priori in language-related regions in inferior lateral frontal (Broca's area) and posterior superior temporal cortex. Language impaired boys with autism and SLI both had significant reversal of asymmetry in frontal language-related cortex; larger on the right side in both groups of language impaired boys and larger on the left in both unimpaired language groups, strengthening a phenotypic link between ALI and SLI. Thus, we replicated the observation of reversed asymmetry in frontal language cortex reported previously in an independent autism sample, and observed similar reversal in boys with SLI, further strengthening a phenotypic link between SLI and a subgroup of autism. Linguistically unimpaired boys with autism had similar asymmetry compared with the control group, suggesting that Broca's area asymmetry reversal is related more to language impairment than specifically to autism diagnosis.
Prior imaging studies have failed to show activation of the fusiform gyrus in response to emotionally neutral faces in individuals with autism spectrum disorder (ASD) [Critchley et al., Brain 124 (2001) 2059; Schultz et al., Arch. Gen. Psychiatry 57 (2000) 331]. However, individuals with ASD do not typically exhibit the striking behavioral deficits that might be expected to result from fusiform gyrus damage, such as those seen in prosopagnosia, and their deficits appear to extend well beyond face identification to include a wide range of impairments in social perceptual processing. In this study, our goal was to further assess the question of whether individuals with ASD have abnormal fusiform gyrus activation to faces. We used high-field (3 T) functional magnetic resonance imaging to study face perception in 11 adult individuals with autism spectrum disorder (ASD) and 10 normal controls. We used face stimuli, object stimuli, and sensory control stimuli (Fourier scrambled versions of the face and object stimuli) containing a fixation point in the center to ensure that participants were looking at and attending to the images as they were presented. We found that individuals with ASD activated the fusiform face area and other brain areas normally involved in face processing when they viewed faces as compared to non-face stimuli. These data indicate that the face-processing deficits encountered in ASD are not due to a simple dysfunction of the fusiform area, but to more complex anomalies in the distributed network of brain areas involved in social perception and cognition.
Although neurocognitive impairments in theory of mind and in executive functions have both been hypothesized to play a causal role in autism, there has been little research investigating the explanatory power of these impairments with regard to autistic symptomatology. The present study examined the degree to which individual differences in theory of mind and executive functions could explain variations in the severity of autism symptoms. Participants included 31 verbal, school-aged children with autism who were administered a battery of tests assessing the understanding of mental states (knowledge and false belief) and executive control skills (working memory, combined working memory and inhibitory control, and planning) and who were behaviorally evaluated for autism severity in the three core symptom domains. Whereas theory of mind and executive control abilities explained the significant variance beyond that accounted for by language level in communication symptoms, neither explained the significant variance in reciprocal social interaction or repetitive behaviors symptoms. These findings are discussed in terms of a proposed distinction between higher level, cognitive-linguistic aspects of theory of mind and related executive control skills, and more fundamental social-perceptual processes involved in the apprehension of mental state information conveyed through eyes, faces, and voices, which may be more closely linked to autistic deficits in social reciprocity.
Several different methodological approaches that have been used in studying language in children with autism are outlined. In classic studies, children with autism are compared to comparison groups typically matched on age, IQ, or mental age in order to identify which aspects of language are uniquely impaired in autism. Several methodological problems are noted with this approach including (a) heterogeneity of the autism population, (b) mental retardation, (c) developmental change with age, and (d) sample size and ascertainment. An alternative strategy is suggested which focuses on identifying the complex expression of the language phenotype in autism across the full range of the syndrome. This approach explores within-group individual differences in language functioning, and recently identified distinct language phenotypic subgroups within the autism population that are relevant to understanding the underlying genetic and neurobiological etiology of autism.
Recent structural and functional imaging work, as well as neuropathology and neuropsychology studies, provide strong empirical support for the involvement of frontal cortex in autism. The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a computer-administered set of neuropsychological tests developed to examine specific components of cognition. Previous studies document the role of frontal cortex in performance of two CANTAB subtests: the Stockings of Cambridge, a planning task, and the Intradimensional/Extradimensional Shift task, a measure of cognitive set shifting. To examine the integrity of frontal functions, these subtests were administered to 79 participants with autism and 70 typical controls recruited from seven universities who are part of the Collaborative Programs of Excellence in Autism network. The two groups were matched on age, sex, and full-scale IQ. Significant group differences were found in performance on both subtests, with the autism group showing deficits in planning efficiency and extradimensional shifting relative to controls. Deficits were found in both lower- and higher-IQ individuals with autism across the age range of 6 to 47 years. Impairment on the CANTAB executive function subtests did not predict autism severity or specific autism symptoms (as measured by the ADI-R and ADOS), but it was correlated with adaptive behavior. If these CANTAB subtests do indeed measure prefrontal function, as suggested by previous research with animals and lesion patients, this adds to the accumulating evidence of frontal involvement in autism and indicates that this brain region should remain an active area of investigation.
Autism is a complex disorder that is heterogeneous both in its phenotypic expression and its etiology. The search for genes associated with autism and the neurobiological mechanisms that underlie its behavioural symptoms has been hampered by this heterogeneity. Recent studies indicate that within autism, there may be distinct subgroups that can be defined based on differences in neurocognitive profiles. This paper presents evidence for two kinds of subtypes in autism that are defined on the basis of language profiles and on the basis of cognitive profiles. The implications for genetic and neurobiological studies of these subgroups are discussed, with special reference to evidence relating these cognitive phenotypes to volumetric studies of brain size and organization in autism.
This study compared the performance of 47 adolescents and adults with Williams syndrome to 39 age-matched controls on a face recognition task. Using the whole-part paradigm developed by Tanaka and his colleagues, we found that although performance overall was lower in the participants with Williams syndrome, both groups showed similar patterns of performance across the different conditions. Both groups performed significantly better in the whole-face than in the isolated-part test condition for upright faces, but not for inverted faces. The whole-face advantage only in the upright condition provides strong evidence that people with Williams syndrome encode and recognize faces holistically in the same way as normal controls, suggesting the use of similar underlying neurocognitive mechanisms. These findings contradict earlier reports in the literature that people with Williams syndrome process faces abnormally.
This longitudinal study investigated developmental change in theory of mind among 57 children with autism aged between 4 to 14 years at the start of the study. On an initial visit and one year later, each participant was administered a battery of tests designed to measure a broad developmental range of theory of mind abilities from early (e.g., desire) to more advanced (e.g., moral judgment) mental state understanding. Both group and individual data indicated significant developmental improvement in theory of mind ability, which was primarily related to the children's language abilities.
This study investigated the relationship between scores on standardized tests (Clinical Evaluation of Language Fundamentals [CELF], Peabody Picture Vocabulary Test-Third Edition [PPVT-III], and Expressive Vocabulary Test) and measures of spontaneous speech (mean length of utterance [MLU], Index of Productive Syntax, and number of different word roots [NDWR]) derived from natural language samples obtained from 44 children with autism between the ages of 4 and 14 years old. The children with autism were impaired across both groups of measures. The two groups of measures were significantly correlated, and specific relationships were found between lexical-semantic measures (NDWR, vocabulary tests, and the CELF lexical-semantic subtests) and grammatical measures (MLU, and CELF grammar subtests), suggesting that both standardized and spontaneous speech measures tap the same underlying linguistic abilities in children with autism. These findings have important implications for clinicians and researchers who depend on these types of language measures for diagnostic purposes, assessment, and investigations of language impairments in autism.
A group of adolescents with Williams syndrome (WS) was compared to matched groups of adolescents with Prader-Willi syndrome and nonspecific mental retardation on a task that tested the ability to distinguish different forms of nonliteral language. Participants listened to stories that ended in either a lie or an ironic joke. They were asked to decide the form of the nonliteral utterance and justify their responses. Almost none of the participants in any of the groups were able to correctly classify the ironic jokes, instead judging them to be lies because they did not correspond to reality. Their errors were similar to those made by younger normally developing children, but contrasted with those made by brain-damaged adults. These data are taken as further evidence that neurodevelopmental disorders are quite different from acquired brain disorders and require different neuropsychological models. The findings from this study also have important implications for considering the difficulties that adolescents with WS and other disorders will have in everyday social situations, especially among peers.
OBJECTIVE: To develop factors based on the Autism Diagnostic Interview-Revised (ADI-R) that index separate components of the autism phenotype that are genetically relevant and validated against standard measures of the constructs. METHOD: ADIs and ADI-Rs of 292 individuals with autism were subjected to a principal components analysis using VARCLUS. The resulting variable clusters were validated against standard measures. RESULTS: Six clusters of variables emerged: spoken language, social intent, compulsions, developmental milestones, savant skills and sensory aversions. Five of the factors were significantly correlated with the validating measures and had good internal consistency, face validity, and discriminant and construct validity. Most intraclass correlations between siblings were adequate for use in genetic studies. CONCLUSION: The ADI-R contains correlated clusters of variables that are valid, genetically relevant, and that can be used in a variety of studies.
This study investigated the role of language in the development of theory of mind. It was hypothesized that the acquisition of the syntactic and semantic properties of sentential complements would facilitate the development of a representational theory of mind. Sixty preschoolers who failed false belief and sentential complement pretests were randomly assigned to training on false belief, sentential complements, or relative clauses (as a control group). All the children were post-tested on a set of different theory of mind tasks, sentential complements and relative clauses. The main findings were that the group trained on sentential complements not only acquired the linguistic knowledge fostered by the training, but also significantly increased their scores on a range of theory of mind tasks. In contrast, false belief training only led to improved theory of mind scores but had no influence on language. The control group, trained on relative clauses, showed no improvement on theory of mind posttests. These findings are taken as evidence that the acquisition of sentential complements contributes to the development of theory of mind in preschoolers.
BACKGROUND: Individuals with Williams syndrome have good spontaneous language despite low levels of intelligence. This study explores the relationship between intelligence, word decoding and reading-related skills in 20 individuals with Williams syndrome. METHODS: In addition to the KBIT, the participants were administered standardized measures of reading, vocabulary, rapid naming, phonological skills and an experimental measure of rhyme judgement. RESULTS: There was wide variability in the reading achievement among the individuals with WS. While some participants were unable to recognize letters of the alphabet, others scored within the normal range of tests of single word reading and decoding. Reading scores were correlated with intelligence as measured on KBIT matrices but not with the vocabulary measures. Reading also correlated with phonological awareness tasks yet, surprisingly, not with rapid naming. CONCLUSION: It is suggested that in individuals with retardation, intelligence rather than language and language-related skills predict achievements in word reading.
Autism is a neurodevelopmental disorder affecting cognitive, language, and social functioning. Although language and social communication abnormalities are characteristic, prior structural imaging studies have not examined language-related cortex in autistic and control subjects. Subjects included 16 boys with autism (aged 7-11 years), with nonverbal IQ greater than 80, and 15 age- and handedness-matched controls. Magnetic resonance brain images were segmented into gray and white matter; cerebral cortex was parcellated into 48 gyral-based divisions per hemisphere. Asymmetry was assessed a priori in language-related inferior lateral frontal and posterior superior temporal regions and assessed post hoc in all regions to determine specificity of asymmetry abnormalities. Boys with autism had significant asymmetry reversal in frontal language-related cortex: 27% larger on the right in autism and 17% larger on the left in controls. Only one additional region had significant asymmetry differences on post hoc analysis: posterior temporal fusiform gyrus (more left-sided in autism), whereas adjacent fusiform gyrus and temporooccipital inferior temporal gyrus both approached significance (more right-sided in autism). These inferior temporal regions are involved in visual face processing. In boys with autism, language and social/face processing-related regions displayed abnormal asymmetry. These structural abnormalities may relate to language and social disturbances observed in autism.
BACKGROUND: Whether there is an unusual degree of unevenness in the cognitive abilities of children with autism spectrum disorder (ASD) and whether different cognitive profiles among children with ASD might index etiologically significant subgroups are questions of continued debate in autism research. METHOD: The Differential Ability Scales (DAS) and the Autism Diagnostic Observation Schedule (ADOS) were used to examine profiles of verbal and nonverbal abilities and their relationship to autistic symptomatology in 120 relatively high-functioning children with ADI-confirmed diagnoses of autism. RESULTS: Discrepancies between verbal and nonverbal ability scores occurred at a significantly higher rate than in the DAS normative sample (30%) in both a younger group of 73 children (56%) with a mean age of 5;5 and an older group of 47 children (62%) with a mean age of 8;11. Discrepancies were mainly in favor of nonverbal ability in the younger group, but occurred equally in favor of verbal and nonverbal abilities in the older group. Comparison of the two age groups suggested a growing dissociation between verbal and nonverbal (and particularly visual processing) skills with age. In the older group, children with discrepantly higher nonverbal abilities demonstrated significantly greater impairment in social functioning, as measured on the ADOS, independent of absolute level of verbal and overall ability. CONCLUSIONS: These findings demonstrate a high rate of uneven cognitive development in children with ASD. Indications of a dissociation between verbal and visual-perceptual skills among the older children, and the specific association of discrepantly high nonverbal skills with increased social symptoms suggest that the nonverbal > verbal profile may index an etiologically significant subtype of autism.
Autism involves primary impairments in both language and communication, yet in recent years the main focus of research has been on the communicative deficits that define the population. The study reported in this paper investigated language functioning in a group of 89 children diagnosed with autism using the ADI-R, and meeting DSM-IV criteria. The children, who were between 4- and 14- years-old were administered a battery of standardized language tests tapping phonological, lexical, and higher-order language abilities. The main findings were that among the children with autism there was significant heterogeneity in their language skills, although across all the children, articulation skills were spared. Different subgroups of children with autism were identified on the basis on their performance on the language measures. Some children with autism have normal language skills; for other children, their language skills are significantly below age expectations. The profile of performance across the standardized measures for the language-impaired children with autism was similar to the profile that defines the disorder specific language impairment (or SLI). The implications of this language impaired subgroup in autism for understanding the genetics and definition of both autism and SLI are discussed.