Imaging, EEG and Autopsy Studies

Advances in Autism Research
April 2010

Imaging studies are documenting structural differences among subgroups with autism and other autism-spectrum disorders (ASDs: eg, 1-2) and, as DSM-V is being invented, at least one study has reported indications of structural differences between Asperger's and autism (eg, 3). For more recent findings, the following Pubmed search is helpful:

(autis* OR Asperge*) AND (MRI OR fMRI OR EEG) AND 2010[dp]

1. Clinical and anatomical heterogeneity in autistic spectrum disorder: a structural MRI study
Toal F et al.
Psychol Med. 2009 Nov 6:1-11. [Epub ahead of print]
$ http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=6559412

BACKGROUND: Autistic spectrum disorder (ASD) is characterized by stereotyped/obsessional behaviours and social and communicative deficits. However, there is significant variability in the clinical phenotype; for example, people with autism exhibit language delay whereas those with Asperger syndrome do not. It remains unclear whether localized differences in brain anatomy are associated with variation in the clinical phenotype.MethodWe used voxel-based morphometry (VBM) to investigate brain anatomy in adults with ASD. We included 65 adults diagnosed with ASD (39 with Asperger syndrome and 26 with autism) and 33 controls who did not differ significantly in age or gender. RESULTS: VBM revealed that subjects with ASD had a significant reduction in grey-matter volume of medial temporal, fusiform and cerebellar regions, and in white matter of the brainstem and cerebellar regions. Furthermore, within the subjects with ASD, brain anatomy varied with clinical phenotype. Those with autism demonstrated an increase in grey matter in frontal and temporal lobe regions that was not present in those with Asperger syndrome. CONCLUSIONS: Adults with ASD have significant differences from controls in the anatomy of brain regions implicated in behaviours characterizing the disorder, and this differs according to clinical subtype.

2. The fMRI success rate of children and adolescents: typical development, epilepsy, attention deficit/hyperactivity disorder, and autism spectrum disorders
Yerys BE et al.
George Washington University School of Medicine
Hum Brain Mapp. 2009 Oct;30(10):3426-35.
http://www3.interscience.wiley.com/journal/122331286/abstract?CRETRY=1&SRETRY=0

Functional magnetic resonance imaging (fMRI) in children is increasingly used in clinical application and in developmental research; however, little is known how pediatric patient and typically developing populations successfully complete studies. We examined pediatric success rates with epilepsy, attention deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and typically developing children (TYP). We also examined the affect of age, and, for ADHD populations, medication status on success rates. We defined a successful fMRI individual run when the data were interpretable and included in group statistics. For unsuccessful runs, datasets with excessive motion or floor task performance were categorized when possible. All clinical groups scanned less successfully than controls; medication status did not affect ADHD success (epilepsy, 80%; ADHD (off methylphenidate), 77%; ADHD (on methylphenidate), 81%; ASD, 70%; TYP, 87%). Ten to 18-year-old had a significantly greater scan success rate than 4- to 6-year-old; adolescents (13- to 18-year-old) demonstrated greater scan success rates than 7- to 9-year-old. Success rate for completing an entire battery of experimental runs (n = 2-6), varied between 50-59% for patient populations and 69% for TYP (79% when excluding 4- to 6-year-old). Success rate for completing one run from a battery was greater than 90% for all groups, except for ASD (81%). These data suggest 20-30% more children should be recruited in these patient groups, but only 10-20% for TYP for research studies. Studies with 4- to 6-year-olds may require 20-40% additional participants; studies with 10- to 18-year-olds may require 10-15% additional participants.

3. Electrophysiological signs of supplementary-motor-area deficits in high-functioning autism but not Asperger syndrome: an examination of internally cued movement-related potentials
Enticott PG, Bradshaw JL, Iansek R, Tonge BJ, Rinehart NJ.
Monash University
Dev Med Child Neurol. 2009 Oct;51(10):787-91. Epub 2009 Mar 9.
$ http://www3.interscience.wiley.com/journal/122250795/abstract

AIMS: Motor dysfunction is common to both autism and Asperger syndrome, but the underlying neurophysiological impairments are unclear. Neurophysiological examinations of motor dysfunction can provide information about likely sites of functional impairment and can contribute to the debate about whether autism and Asperger syndrome are variants of the same disorder or fundamentally distinct neurodevelopmental conditions. We investigated the neurophysiology of internally determined motor activity in autism and Asperger syndrome via examination of movement-related potentials (MRPs). METHOD: We used electroencephalography to investigate MRPs, via an internally cued movement paradigm, in the following three groups: (1) individuals with high-functioning autism (14 males, one female; mean age 13 y 1 mo, SD 4 y 2 mo, range 7 y 8 mo to 20 y 9 mo; mean Full-scale IQ 93.40, SD 20.72); (2) individuals with Asperger syndrome (10 males, two females; mean age 13 y 7 mo, SD 3 y 9 mo, range 8 y 11 mo to 20 y 4 mo; mean Full-scale IQ 103.25, SD 19.37), and (3) a healthy control group (13 males, seven females; mean age 14 y 0 mo, SD 3 y 11 mo; range 8 y 4 mo to 21 y 0 mo; mean Full-scale IQ 114.25, SD 11.29). RESULTS: Abnormal MRPs can reflect disruption of motor-related neural networks involving the basal ganglia, thalamus, and supplementary motor area. There was evidence for abnormal MRPs in autism (e.g. increased post-movement cortical activity, abnormal peak time) but not in Asperger syndrome. INTERPRETATION: The results support basal ganglia, thalamus, and supplementary motor area involvement as a likely source of motor dysfunction in autism, and provide further evidence for the neurobiological separateness of autism and Asperger syndrome.

4. A Microscopic Study of Language-Related Cortex in Autism
Edith López-Hurtado and Jorge J. Prieto
American Journal of Biochemistry and Biotechnology 4(2): 130-145, 2008
http://www.scipub.org/fulltext/ajbb/ajbb42130-145.pdf

Impaired language function is a principle criterion for the diagnosis of autism. The present study of brain from age-matched autistic and control subjects compared brain regions associated with the production and processing of speech. Wernicke's area (Brodmann 22, speech recognition), Broca's area (Brodmann 44, speech production) andthe gyrus angularis (Brodmann 39, reading) from autistic subjects (7-44 years of age) and control subjects (8-56 years of age) were examined microscopically. Striking differences in the density of glial cells, the density of neurons andthe number of lipofuscin-containing neurons were observed in the autistic group compared with the control group. The mean density of glial cells was greater in the autistic cohort than controls in area 22 (p<0.001), area 39 (p<0.01) andarea 44 (p<0.05). The density of neurons was lesser in autism in area 22 (p<0.01) and area 39 (p<0.01). The autistic group exhibited significantly greater numbers of lipofuscin-containing cells in area 22 (p<0.001) and area 39 (p<0.01). The results are consistent with accelerated neuronal death in association with gliosis and lipofuscin accumulation in autism after age seven. Production of lipofuscin (a matrix of oxidized lipid and cross-linked protein more commonly associated with neurodegenerative disease) is accelerated under conditions of oxidative stress. Area 22 in autism evidenced the greatest glial increase, the greatest neuronal decrease andthe greatest increase of non-specific cells containing lipofuscin, which itself may contribute to greater free-radical generation in brain.

5. Rightward hemispheric asymmetries in auditory language cortex in children with autistic disorder: an MRI investigation
Gage NM et al.
J Neurodev Disord. 2009 Sep;1(3):205-214. Epub 2009 Apr 4.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758220/pdf/11689_2009_Article_9010.pdf

Purpose: determine if language disorder in children with autistic disorder (AD) corresponds to abnormalities in hemispheric asymmetries in auditory language cortex. Methods: MRI morphometric study in children with AD (n = 50) to assess hemispheric asymmetries in auditory language cortex. A key region of interest was the planum temporale (PT), which is larger in the left hemisphere in most healthy individuals. Results: (i) Heschl's gyrus and planum polare showed typical hemisphere asymmetry patterns; (ii) posterior Superior Temporal Gyrus (pSTG) showed significant rightward asymmetry; and (iii) PT showed a trend for rightward asymmetry that was significant when constrained to right-handed boys (n = 30). For right-handed boys, symmetry indices for pSTG were significantly positively correlated with those for PT. PT asymmetry was age dependent, with greater rightward asymmetry with age. Conclusions: results provide evidence for rightward asymmetry in auditory association areas (pSTG and PT) known to subserve language processing. Cumulatively, our data provide evidence for a differing maturational path for PT for lower functioning children with AD, with both pre- and post-natal experience likely playing a role in PT asymmetry. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11689-009-9010-2) contains supplementary material, which is available to authorized users.

6. Corpus callosum volume in children with autism
Hardan AY et al.
Stanford University
Psychiatry Res. 2009 Oct 30;174(1):57-61. Epub 2009 Sep 24.
http://www.ncbi.nlm.nih.gov/pubmed/19781917

The corpus callosum (CC) is the main commissure connecting the cerebral hemispheres. Previous evidence suggests the involvement of the CC in the pathophysiology of autism. However, most studies examined the mid-sagittal area and investigations applying novel methods are warranted. The goal of this investigation is to apply a volumetric method to examine the size of the CC in autism and to identify any association with clinical features. An MRI-based morphometric study of the total CC volume and its seven subdivisions was conducted and involved 22 children with autism (age range 8.1-12.7 years) and 23 healthy, age-matched controls. Reductions in the total volume of the CC and several of its subdivisions were found in the autism sample. Associations were observed between CC structures and clinical features including social deficits, repetitive behaviors, and sensory abnormalities. Volumetric alterations of the CC observed in this investigation are consistent with midsagittal area tracings of decreased CC size in autism. These findings support the aberrant connectivity hypothesis with possible decrease in interhemispheric communications.

7. Neuroanatomical differences in brain areas implicated in perceptual and other core features of autism revealed by cortical thickness analysis and voxel-based morphometry
Hyde KL, Samson F, Evans AC, Mottron L.
McGill University
Hum Brain Mapp. 2009 Sep 29. [Epub ahead of print]
$ http://www3.interscience.wiley.com/journal/122611432/abstract

Autism spectrum disorder is a complex neurodevelopmental variant thought to affect 1 in 166 [Fombonne (2003): J Autism Dev Disord 33:365-382]. Individuals with autism demonstrate atypical social interaction, communication, and repetitive behaviors, but can also present enhanced abilities, particularly in auditory and visual perception and nonverbal reasoning. Structural brain differences have been reported in autism, in terms of increased total brain volume (particularly in young children with autism), and regional gray/white matter differences in both adults and children with autism, but the reports are inconsistent [Amaral et al. (2008): Trends Neurosci 31:137-145]. These inconsistencies may be due to differences in diagnostic/inclusion criteria, and age and Intelligence Quotient of participants. Here, for the first time, we used two complementary magnetic resonance imaging techniques, cortical thickness analyses, and voxel-based morphometry (VBM), to investigate the neuroanatomical differences between a homogenous group of young adults with autism of average intelligence but delayed or atypical language development (often referred to as "high-functioning autism"), relative to a closely matched group of typically developing controls. The cortical thickness and VBM techniques both revealed regional structural brain differences (mostly in terms of gray matter increases) in brain areas implicated in social cognition, communication, and repetitive behaviors, and thus in each of the core atypical features of autism. Gray matter increases were also found in auditory and visual primary and associative perceptual areas. We interpret these results as the first structural brain correlates of atypical auditory and visual perception in autism, in support of the enhanced perceptual functioning model [Mottron et al. (2006): J Autism Dev Disord 36:27-43]. Hum Brain Mapp, 2009. (c) 2009 Wiley-Liss, Inc.

8. Decreased Left Posterior Insular Activity during Auditory Language in Autism.
Anderson JS et al.
AJNR Am J Neuroradiol. 2009 Sep 12. [Epub ahead of print]
http://www.ajnr.org/cgi/reprint/ajnr.A1789v1

BACKGROUND AND PURPOSE: Individuals with autism spectrum disorders often exhibit atypical language patterns, including delay of speech onset, literal speech interpretation, and poor recognition of social and emotional cues in speech. We acquired functional MR images during an auditory language task to evaluate systematic differences in language-network activation between control and high-functioning autistic populations. MATERIALS AND METHODS: Forty-one right-handed male subjects (26 high-functioning autistic subjects, 15 controls) were studied by using an auditory phrase-recognition task, and areas of differential activation between groups were identified. Hand preference, verbal intelligence quotient (IQ), age, and language-function testing were included as covariables in the analysis. RESULTS: Control and autistic subjects showed similar language-activation networks, with 2 notable differences. Control subjects showed significantly increased activation in the left posterior insula compared with autistic subjects (P < .05, false discovery rate), and autistic subjects showed increased bilaterality of receptive language compared with control subjects. Higher receptive-language scores on standardized testing were associated with greater activation of the posterior aspect of the left Wernicke area. A higher verbal IQ was associated with greater activation of the bilateral Broca area and involvement of the prefrontal cortex and lateral premotor cortex. CONCLUSIONS: Control subjects showed greater activation of the posterior insula during receptive language, which may correlate with impaired emotive processing of language in autism. Subjects with autism showed greater bilateral activation of receptive-language areas, which was out of proportion to the differences in hand preference in autism and control populations.

9. Amygdala enlargement in toddlers with autism related to severity of social and communication impairments
Schumann CM, Barnes CC, Lord C, Courchesne E.
University of California, San Diego, La Jolla
Biol Psychiatry. 2009 Nov 15;66(10):942-9. Epub 2009 Sep 2.
http://www.journals.elsevierhealth.com/periodicals/bps/article/S0006-3223%2809%2900835-X/abstract

BACKGROUND: Autism is a heterogeneous neurodevelopmental disorder of unknown etiology. The amygdala has long been a site of intense interest in the search for neuropathology in autism, given its role in emotional and social behavior. An interesting hypothesis has emerged that the amygdala undergoes an abnormal developmental trajectory with a period of early overgrowth in autism; however this finding has not been well established at young ages nor analyzed with boys and girls independently. METHODS: We measured amygdala volumes on magnetic resonance imaging scans from 89 toddlers at 1-5 years of age (mean = 3 years). Each child returned at approximately 5 years of age for final clinical evaluation. RESULTS: Toddlers who later received a confirmed autism diagnosis (32 boys, 9 girls) had a larger right (p < .01) and left (p < .05) amygdala compared with typically developing toddlers (28 boys, 11 girls) with and without covarying for total cerebral volume. Amygdala size in toddlers with autism spectrum disorder correlated with the severity of their social and communication impairments as measured on the Autism Diagnostic Interview and Vineland scale. Strikingly, girls differed more robustly from typical in amygdala volume, whereas boys accounted for the significant relationship of amygdala size with severity of clinical impairment. CONCLUSIONS: This study provides evidence that the amygdala is enlarged in young children with autism; the overgrowth must begin before 3 years of age and is associated with the severity of clinical impairments. However, neuroanatomic phenotypic profiles differ between males and females, which critically affects future studies on the genetics and etiology of autism.

10. Neural correlates of autistic traits in the general population: insights into autism
{editorial} Comment on: Am J Psychiatry. 2009 Aug;166(8):891-9.
Kennedy DP.
Am J Psychiatry. 2009 Aug;166(8):849-51.
http://tinyurl.com/ydfzz8y

11. Relationship between cingulo-insular functional connectivity and autistic traits in neurotypical adults
Di Martino A et al.
New York University Child Study Center
Am J Psychiatry. 2009 Aug;166(8):891-9.
http://ajp.psychiatryonline.org/cgi/content/full/166/8/891

OBJECTIVE: The Social Responsiveness Scale-Adult Version (SRS-A) measures autistic traits that are continuously distributed in the general population. Based on increased recognition of the dimensional nature of autistic traits, the authors examined the neural correlates of these traits in neurotypical individuals using the SRS-A and established a novel approach to assessing the neural basis of autistic characteristics, attempting to directly relate SRS-A scores to patterns of functional connectivity observed in the pregenual anterior cingulate cortex, a region commonly implicated in social cognition. METHOD: Resting state functional magnetic resonance imaging scans were collected for 25 neurotypical adults. All participants provided SRS-A ratings completed by an informant who had observed them in natural social settings. Whole brain-corrected connectivity analyses were then conducted using SRS-A scores as a covariate of interest. RESULTS: Across participants, a significant negative relationship between SRS-A scores and the functional connectivity of the pregenual anterior cingulate cortex with the anterior portion of the mid-insula was found. Specifically, low levels of autistic traits were observed when a substantial portion of the anterior mid-insula showed positive connectivity with the pregenual anterior cingulate cortex. In contrast, elevated levels of autistic traits were associated with negative connectivity between these two regions. CONCLUSIONS: Resting state functional connectivity of the pregenual anterior cingulate cortex-insula social network was related to autistic traits in neurotypical adults. Application of this approach in samples with autism spectrum disorders is needed to confirm whether this circuit is dimensionally related to the severity of autistic traits in clinical populations.

12. Acquired personality traits of autism following damage to the medial prefrontal cortex
Umeda S, Mimura M, Kato M.
Soc Neurosci. 2009 Jul 27:1-11. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/19637100

Recent neuroimaging studies on "theory of mind" have demonstrated that the medial prefrontal cortex (PFC) is involved when subjects are engaged in various kinds of mentalising tasks. Although a large number of neuroimaging studies have been published, a relatively small amount of neuropsychological evidence supports involvement of the medial PFC in theory of mind reasoning. We recruited two neurological cases with damage to the medial PFC and initially performed the standard neuropsychological assessments for intelligence, memory, and executive functions. To examine theory of mind performance in these two cases, four kinds of standard and advanced tests for theory of mind were used, including first- and second-order false belief tests, the strange stories test, and the faux pas recognition test. Both patients were also requested to complete the questionnaire for the autism-spectrum quotient. Neither case showed impairment on standard theory of mind tests and only mild impairments were seen on advanced theory of mind tests. This pattern of results is basically consistent with previous studies. The most interesting finding was that both cases showed personality changes after surgical operations, leading to characteristics of autism showing a lack of social interaction in everyday life. We discuss herein the possible roles of the medial PFC and emphasize the importance of using multiple approaches to understand the mechanisms of theory of mind and medial prefrontal functions.

13. Neural mechanisms of empathy in adolescents with autism spectrum disorder and their fathers
Greimel E, Schulte-Rüther M, Kircher T, Kamp-Becker I, Remschmidt H, Fink GR, Herpertz-Dahlmann B, Konrad K.
Neuroimage. 2010 Jan 1;49(1):1055-65. Epub 2009 Jul 30.
http://www.ncbi.nlm.nih.gov/pubmed/19647799

A deficit in empathy has been repeatedly described in individuals with autism spectrum disorder (ASD) and also, albeit less markedly, in their unaffected relatives. Here, we aimed to investigate the neural mechanisms of empathy in ASD, and to explore familial contributions to empathy correlates. Using functional magnetic resonance imaging, 15 boys with ASD, 11 fathers of adolescents with ASD, and two control groups comparable for age and IQ (n=15 typically developing boys and their fathers (n=9)) were investigated during an empathy task. Emotional faces were presented and participants were either asked to infer the emotional state from the face (other-task) or to judge their own emotional response to the face (self-task). When attributing emotions to self and other, the ASD group showed diminished fusiform gyrus activation compared to controls. Neural activity in the fusiform gyrus was inversely related to social deficits in ASD subjects. Moreover, when ASD subjects inferred their own emotional response to faces, they showed less congruent reactions and inferior frontal gyrus activity was decreased. Although fathers of ASD children scored higher on a self-rating scale for autistic symptoms compared to control fathers, their task performance was unimpaired. However, neurally, fathers of affected children also showed reduced fusiform gyrus activation when inferring others' emotions. Shared abnormalities in fusiform gyrus activation in affected adolescents and first-degree relatives suggest that this dysfunction constitutes a fundamental deviation in ASD. Moreover, the findings provide evidence that both aberrant neural face and mirroring mechanisms are implicated in empathy impairments in ASD.

14. Autism is characterized by dorsal anterior cingulate hyperactivation during social target detection
Dichter GS, Felder JN, Bodfish JW.
University of North Carolina School of Medicine
Soc Cogn Affect Neurosci. 2009 Sep;4(3):215-26. Epub 2009 Jul 2.
$ http://scan.oxfordjournals.org/cgi/content/full/4/3/215

Though the functional neural correlates of impaired cognitive control and social dysfunction in autism spectrum disorders (ASD) have been delineated, brain regions implicated in poor cognitive control of social information is a novel area of autism research. We recently reported in a non-clinical sample that detection of 'social oddball' targets activated a portion of the dorsal anterior cingulate gyrus and the supracalcarine cortex (Dichter, Felder, Bodfish, Sikich, and Belger, 2009). In the present investigation, we report functional magnetic resonance imaging results from individuals with ASD who completed the same social oddball task. Between-group comparisons revealed generally greater activation in the ASD group to both social and non-social targets. When responses to social and non-social targets were contrasted, the ASD group showed relatively greater activation in the right and middle inferior frontal gyri and a region in dorsomedial prefrontal cortex that abuts the dorsal anterior cingulate (Brodmann's Area 32). Further, dorsal anterior cingulate activation to social targets predicted the severity of social impairments in a subset of the ASD sample. These data suggest that the dorsal anterior cingulate mediates social target detection in neurotypical individuals and is implicated in deficits of cognitive control of social information in ASD.

15. The anterior cingulate cortex in autism: heterogeneity of qualitative and quantitative cytoarchitectonic features suggests possible subgroups
Simms ML, Kemper TL, Timbie CM, Bauman ML, Blatt GJ.
Boston University School of Medicine
Acta Neuropathol. 2009 Nov;118(5):673-84. Epub 2009 Jul 10.
$ http://www.springerlink.com/content/6165g6n20j884368/

Autism is a behaviorally defined disorder with deficits in social interaction, communication, atypical behaviors, and restricted areas of interest. Postmortem studies of the brain in autism have shown a broad spectrum of abnormalities in the cerebellum and neocortex, involving limbic regions such as anterior cingulate cortex (ACC, Brodmann's area 24). Using stereological techniques, we analyzed quantitatively cytoarchitectonic subdomains of the ACC (areas 24a, b, c) with regard to cell packing density and cell size. Microscopic examination of the ACC was also done to identify any neuropathologies. Results showed a significant decrease in cell size in layers I-III and layers V-VI of area 24b and in cell packing density in layers V-VI of area 24c. Direct comparisons revealed irregular lamination in three of nine autism brains and increased density of neurons in the subcortical white matter in the remaining cases. Because previous studies have suggested that von Economo neurons (VENs) may be altered in autism, a preliminary study of their density and size was undertaken. VEN density did not differ between autism and control brains overall. However, among the nine autism cases, there were two subsets; three brains with significantly increased VEN density and the remaining six cases with reduced VEN density compared to controls. Collectively, the findings of this pilot study may reflect the known heterogeneity in individuals with autism and variations in clinical symptomotology. Further neuroanatomic analyses of the ACC, from carefully documented subjects with autism, could substantially expand our understanding of ACC functions and its role in autism.

16. The anterior insula in autism: under-connected and under-examined
Uddin LQ, Menon V.
Stanford University School of Medicine
Neurosci Biobehav Rev. 2009 Sep;33(8):1198-203. Epub 2009 Jun 16.
http://scsnl.stanford.edu/2009/Uddin_The_Anterior_Insula_09.pdf

Autism is a complex neurodevelopmental disorder of unknown etiology. While the past decade has witnessed a proliferation of neuroimaging studies of autism, theoretical approaches for understanding systems-level brain abnormalities remain poorly developed. We propose a novel anterior insula-based systems-level model for investigating the neural basis of autism, synthesizing recent advances in brain network functional connectivity with converging evidence from neuroimaging studies in autism. The anterior insula is involved in interoceptive, affective and empathic processes, and emerging evidence suggests it is part of a "salience network" integrating external sensory stimuli with internal states. Network analysis indicates that the anterior insula is uniquely positioned as a hub mediating interactions between large-scale networks involved in externally and internally oriented cognitive processing. A recent meta-analysis identifies the anterior insula as a consistent locus of hypoactivity in autism. We suggest that dysfunctional anterior insula connectivity plays an important role in autism. Critical examination of these abnormalities from a systems neuroscience perspective should be a priority for further research on the neurobiology of autism.

17. Brief report: inhibitory control of socially relevant stimuli in children with high functioning autism
Geurts HM, Begeer S, Stockmann L.
University of Amsterdam
J Autism Dev Disord. 2009 Nov;39(11):1603-7.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759869/pdf/10803_2009_Article_786.pdf

The current study explored whether inhibitory control deficits in high functioning autism (HFA) emerged when socially relevant stimuli were used and whether arousal level affected the performance. A Go/NoGo paradigm, with socially relevant stimuli and varying presentation rates, was applied in 18 children with HFA (including children with autism or Asperger syndrome) and 22 typically developing children (aged 8-13 years). Children with HFA did not show inhibitory control deficits compared to the control group, but their performance deteriorated in the slow presentation rate condition. Findings were unrelated to children's abilities to recognize emotions. Hence, rather than a core deficit in inhibitory control, low arousal level in response to social stimuli might influence the responses given by children with HFA.

18. Mapping brain abnormalities in boys with autism
Brun CC et al.
UCLA School of Medicine
Hum Brain Mapp. 2009 Dec;30(12):3887-900.
$ http://www3.interscience.wiley.com/journal/122465290/abstract

Children with autism spectrum disorder (ASD) exhibit characteristic cognitive and behavioral differences, but no systematic pattern of neuroanatomical differences has been consistently found. Recent neurodevelopmental models posit an abnormal early surge in subcortical white matter growth in at least some autistic children, perhaps normalizing by adulthood, but other studies report subcortical white matter deficits. To investigate the profile of these alterations in 3D, we mapped brain volumetric differences using a relatively new method, tensor-based morphometry. 3D T1-weighted brain MRIs of 24 male children with ASD (age: 9.5 years +/- 3.2 SD) and 26 age-matched healthy controls (age: 10.3 +/- 2.4 SD) were fluidly registered to match a common anatomical template. Autistic children had significantly enlarged frontal lobes (by 3.6% on the left and 5.1% on the right), and all other lobes of the brain were enlarged significantly, or at trend level. By analyzing the applied deformations statistically point-by-point, we detected significant gray matter volume deficits in bilateral parietal, left temporal and left occipital lobes (P = 0.038, corrected), trend-level cerebral white matter volume excesses, and volume deficits in the cerebellar vermis, adjacent to volume excesses in other cerebellar regions. This profile of excesses and deficits in adjacent regions may (1) indicate impaired neuronal connectivity, resulting from aberrant myelination and/or an inflammatory process, and (2) help to understand inconsistent findings of regional brain tissue excesses and deficits in autism. 2009 Wiley-Liss, Inc

19. White matter fractional anisotrophy differences and correlates of diagnostic symptoms in autism
Cheung C et al.
University of Hong Kong
J Child Psychol Psychiatry. 2009 Sep;50(9):1102-12. Epub 2009 Mar 31.
$ http://www3.interscience.wiley.com/journal/122295689/abstract?CRETRY=1&SRETRY=0

BACKGROUND: Individuals with autism have impairments in 3 domains: communication, social interaction and repetitive behaviours. Our previous work suggested early structural and connectivity abnormalities in prefrontal-striato-temporal-cerebellar networks but it is not clear how these are linked to diagnostic indices. METHOD: Children with autism (IQ > 70) aged 6 to 14 years old and matched typically developing controls were studied using diffusion tensor imaging. Voxel-based methods were used to compare fractional anisotrophy (FA) measures in each group and to correlate FA measures in the autism group with the diagnostic phenotype described by the Autism Diagnostic Interview - Revised (ADI-R) algorithm for ICD-10. RESULTS: After controlling for the effects of age and white matter volume, we found that FA in the autism group was significantly lower than controls in bilateral prefrontal and temporal regions, especially in the right ventral temporal lobe adjacent to the fusiform gyrus. FA was greater in autism in the right inferior frontal gyrus and left occipital lobe. We observed a tight correlation between lower FA and higher ADI-R diagnostic algorithm scores across white matter tracts extending from these focal regions of group difference. Communication and social reciprocity impairments correlated with lower FA throughout fronto-striato-temporal pathways. Repetitive behaviours correlated with white matter indices in more posterior brain pathways, including splenium of the corpus callosum and cerebellum. CONCLUSIONS: Our data support the position that diagnostic symptoms of autism are associated with a core disruption of white matter development.

20. Decreased brain coordinated activity in autism spectrum disorders during executive tasks: reduced long-range synchronization in the fronto-parietal networks
Perez Velazquez JL et al.
Hospital for Sick Children, Toronto
Int J Psychophysiol. 2009 Sep;73(3):341-9. Epub 2009 May 22.
http://www.ncbi.nlm.nih.gov/pubmed/19465065

Current theories of brain function propose that the coordinated integration of transient activity patterns in distinct brain regions is the essence of brain information processing. The behavioural manifestations of individuals with autism spectrum disorders (ASD) suggest that their brains have a different style of information processing. Specifically, a current trend is to invoke functional disconnection in the brains of individuals with ASD as a possible explanation for some atypicalities in the behaviour of these individuals. Our observations indicate that the coordinated activity in brains of children with autism is lower than that found in control participants. Disruption of long-range phase synchronization among frontal, parietal and occipital areas was found, derived from magnetoencephalographic (MEG) recordings, in high-functioning children with ASD during the performance of executive function tasks and was associated with impaired execution, while enhanced long-range brain synchronization was observed in control children. Specifically, a more significant prefrontal synchronization was found in control participants during task performance. In addition, a robust enhancement in synchrony was observed in the parietal cortex of children with ASD relative to controls, which may be related to parietal lobe abnormalities detected in these individuals. These results, using synchronization analysis of brain electrical signals, provide support for the contention that brains of individuals with autism may not be as functionally connected as that of the controls, and may suggest some therapeutic interventions to improve information processing in specific brain areas, particularly prefrontal cortices.

21. A failure to grasp the affective meaning of actions in autism spectrum disorder subjects
Grèzes J, Wicker B, Berthoz S, de Gelder B.
Neuropsychologia. 2009 Jul;47(8-9):1816-25. Epub 2009 Feb 21.
http://www.ncbi.nlm.nih.gov/pubmed/19428413

The ability to grasp emotional messages in everyday gestures and respond to them is at the core of successful social communication. The hypothesis that abnormalities in socio-emotional behavior in people with autism are linked to a failure to grasp emotional significance conveyed by gestures was explored. We measured brain activity using fMRI during perception of fearful or neutral actions and showed that whereas similar activation of brain regions known to play a role in action perception was revealed in both autistics and controls, autistics failed to activate amygdala, inferior frontal gyrus and premotor cortex when viewing gestures expressing fear. Our results support the notion that dysfunctions in this network may contribute significantly to the characteristic communicative impairments documented in autism.

22. Psychosis and autism: magnetic resonance imaging study of brain anatomy
Toal F et al.
Royal College of Surgeons in Ireland
Br J Psychiatry. 2009 May;194(5):418-25.
$ http://bjp.rcpsych.org/cgi/content/full/194/5/418

BACKGROUND: Autism-spectrum disorder is increasingly recognised, with recent studies estimating that 1% of children in South London are affected. However, the biology of comorbid mental health problems in people with autism-spectrum disorder is poorly understood. AIMS: To investigate the brain anatomy of people with autism-spectrum disorder with and without psychosis. METHOD: We used in vivo magnetic resonance imaging and compared 30 adults with autism-spectrum disorder (14 with a history psychosis) and 16 healthy controls. RESULTS: Compared with controls both autism-spectrum disorder groups had significantly less grey matter bilaterally in the temporal lobes and the cerebellum. In contrast, they had increased grey matter in striatal regions. However, those with psychosis also had a significant reduction in grey matter content of frontal and occipital regions. Contrary to our expectation, within autism-spectrum disorder, comparisons revealed that psychosis was associated with a reduction in grey matter of the right insular cortex and bilaterally in the cerebellum extending into the fusiform gyrus and the lingual gyrus. CONCLUSIONS: The presence of neurodevelopmental abnormalities normally associated with autism-spectrum disorder might represent an alternative 'entry-point' into a final common pathway of psychosis.

23. The neural substrates of cognitive control deficits in autism spectrum disorders
Solomon M, Ozonoff SJ, Ursu S, Ravizza S, Cummings N, Ly S, Carter CS.
University of California, Davis
Neuropsychologia. 2009 Oct;47(12):2515-26. Epub 2009 May 4.
http://www.ncbi.nlm.nih.gov/pubmed/19410583

Executive function deficits are among the most frequently reported symptoms of autism spectrum disorders (ASDs), however, there have been few functional magnetic resonance imaging (fMRI) studies that investigate the neural substrates of executive function deficits in ASDs, and only one in adolescents. The current study examined cognitive control - the ability to maintain task context online to support adaptive functioning in the face of response competition - in 22 adolescents aged 12-18 with autism spectrum disorders and 23 age, gender, and IQ matched typically developing subjects. During the cue phase of the task, where subjects must maintain information online to overcome a prepotent response tendency, typically developing subjects recruited significantly more anterior frontal (BA 10), parietal (BA 7 and BA 40), and occipital regions (BA 18) for high control trials (25% of trials) versus low control trials (75% of trials). Both groups showed similar activation for low control cues, however the ASD group exhibited significantly less activation for high control cues. Functional connectivity analysis using time series correlation, factor analysis, and beta series correlation methods provided convergent evidence that the ASD group exhibited lower levels of functional connectivity and less network integration between frontal, parietal, and occipital regions. In the typically developing group, fronto-parietal connectivity was related to lower error rates on high control trials. In the autism group, reduced fronto-parietal connectivity was related to attention deficit hyperactivity disorder symptoms.

24. Brain serotonin and dopamine transporter bindings in adults with high-functioning autism
Nakamura K et al.
Hamamatsu University School of Medicine
Arch Gen Psychiatry. 2010 Jan;67(1):59-68.
http://www.ncbi.nlm.nih.gov/pubmed/20048223

CONTEXT: Autism is a neurodevelopmental disorder that is characterized by repetitive and/or obsessive interests and behavior and by deficits in sociability and communication. Although its neurobiological underpinnings are postulated to lie in abnormalities of the serotoninergic and dopaminergic systems, the details remain unknown. OBJECTIVE: To determine the occurrence of changes in the binding of serotonin and dopamine transporters, which are highly selective markers for their respective neuronal systems. DESIGN: Using positron emission tomography, we measured the binding of brain serotonin and dopamine transporters in each individual with the radioligands carbon 11 ((11)C)-labeled trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([(11)C](+)McN-5652) and 2beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane ([(11)C]WIN-35,428), respectively. Statistical parametric mapping was used for between-subject analysis and within-subject correlation analysis with respect to clinical variables. SETTING: Participants recruited from the community. PARTICIPANTS: Twenty men (age range, 18-26 years; mean [SD] IQ, 99.3 [18.1]) with autism and 20 age- and IQ-matched control subjects. RESULTS: Serotonin transporter binding was significantly lower throughout the brain in autistic individuals compared with controls (P < .05, corrected). Specifically, the reduction in the anterior and posterior cingulate cortices was associated with the impairment of social cognition in the autistic subjects (P < .05, corrected). A significant correlation was also found between repetitive and/or obsessive behavior and interests and the reduction of serotonin transporter binding in the thalamus (P < .05, corrected). In contrast, the dopamine transporter binding was significantly higher in the orbitofrontal cortex of the autistic group (P < .05, corrected in voxelwise analysis). In the orbitofrontal cortex, the dopamine transporter binding was significantly inversely correlated with serotonin transporter binding (r = -0.61; P = .004). CONCLUSIONS: The brains of autistic individuals have abnormalities in both serotonin transporter and dopamine transporter binding. The present findings indicate that the gross abnormalities in these neurotransmitter systems may underpin the neurophysiologic mechanism of autism. Our sample was not characteristic or representative of a typical sample of adults with autism in the community.

25. Serotonin transporter genotype and neuroanatomy in autism spectrum disorders
Raznahan A et al.
Psychiatr Genet. 2009 Jun;19(3):147-50.
http://www.ncbi.nlm.nih.gov/pubmed/19369912

There is increasing evidence that people with autism spectrum disorders (ASDs) have abnormalities in the serotonergic system. For example, a functional polymorphism of the serotonin transporter gene promoter region (5HTTLPR long/short polymorphism) has been reported to confer risk for ASDs, and to affect cortical grey matter volume in young children. However, the persistence of this association later in development is unknown. Hence, we investigated whether variation in the 5HTTLPR long/short polymorphism modulates brain anatomy in older people with ASD. We related 5HTTLPR long/short polymorphism in 43 adolescents and adults with ASD to brain anatomy using structural magnetic resonance imaging and voxel-based morphometry. There were no significant associations between brain anatomy and genotype. When considered alongside evidence of a relationship between 5HTTLPR genotype and brain volume amongst children with autism, our findings raise the possibility that the relationship between 5HTTLPR polymorphism and brain anatomy in ASDs anatomy may differ as a function of age and/or ASD subdiagnosis.

26. Alterations in Frontal Lobe Tracts and Corpus Callosum in Young Children with Autism Spectrum Disorder
Kumar A, Sundaram SK, Sivaswamy L, Behen ME, Makki MI, Ager J, Janisse J, Chugani HT, Chugani DC.
Cereb Cortex. 2009 Dec 17. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/20019145

Major frontal lobe tracts and corpus callosum (CC) were investigated in 32 children with autism spectrum disorder (ASD, mean age: 5 years), 12 nonautistic developmentally impaired children (DI, mean age: 4.6 years), and 16 typically developing children (TD, mean age: 5.5 years) using diffusion tensor imaging tractography and tract-based spatial statistics. Various diffusion and geometric properties were calculated for uncinate fasciculus (UF), inferior fronto-occipital fasciculus (IFO), arcuate fasciculus (AF), cingulum (Cg), CC, and corticospinal tract. Fractional anisotropy was lower in the right UF, right Cg and CC in ASD and DI children; in right AF in ASD children; and in bilateral IFO in DI children, compared with TD children. Apparent diffusion coefficient was increased in right AF in both ASD and DI children. The ASD group showed shorter length of left UF and increased length, volume, and density of right UF; increased length and density of CC; and higher density of left Cg, compared with the TD group. Compared with DI group, ASD group had increased length, volume, and density of right UF; higher volume of left UF; and increased length of right AF and CC. Volume of bilateral UF and right AF and fiber density of left UF were positively associated with autistic features.

27. Electroencephalogram Discharges in Atypical Cognitive Development.

Frye RE, Butler I, Strickland D, Castillo E, Papanicolaou A.
J Child Neurol. 2010 Mar 18. [Epub ahead of print]


28. Dopaminergic functioning and preschoolers' theory of mind.

Lackner CL, Bowman LC, Sabbagh MA.
Neuropsychologia. 2010 Mar 4. [Epub ahead of print]

29. Neural circuitry of emotional face processing in autism spectrum disorders.
Monk CS, Weng SJ, Wiggins JL, Kurapati N, Louro HM, Carrasco M, Maslowsky J, Risi S, Lord C.
J Psychiatry Neurosci. 2010 Mar;35(2):105-14.

30. The nature of brain dysfunction in autism: functional brain imaging studies.

Minshew NJ, Keller TA.
Curr Opin Neurol. 2010 Apr;23(2):124-30.

This document prepared by
Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
April 2010