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Abnormal Functional Activation and Maturation of Fronto-Striato-Temporal and Cerebellar Regions During Sustained Attention in Autism Spectrum Disorder
Clodagh M. Murphy, M.R.C.Psych.; Anastasia Christakou, Ph.D.; Eileen M. Daly, Ph.D.; Christine Ecker, Ph.D.; Vincent Giampietro, Ph.D.; Michael Brammer, Ph.D.; Anna B. Smith, Ph.D.; Patrick Johnston, Ph.D.; Dene M. Robertson, M.R.C.Psych.; MRC AIMS Consortium; Declan G. Murphy, M.D., F.R.C.Psych.; Katya Rubia, Ph.D.
Am J Psychiatry 2014;171:1107-1116. doi:10.1176/appi.ajp.2014.12030352
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Dr. C.M. Murphy has received funding from Lilly and speaking honoraria from Shire and Flynn Pharma. Professor Brammer has served as a consultant for P1Vital. Professor Rubia has received funding from Lilly and speaking honoraria from Lilly, Shire, and Medice. The other authors report no financial relationships with commercial interests.

Supported by grant MRC GO300155 (to Professor Rubia) from the U.K. MRC; by a grant (to Prof. D.G. Murphy) from the MRC Autism Imaging Multicentre Study (MRC AIMS); by a grant (to Prof. D.G. Murphy) from the EU Innovative Medicines Initiative (IMI) AIMS network (receiving support from the Innovative Medicines Initiative Joint Undertaking under grant agreement 115300, which includes financial contributions from the EU Seventh Framework Programme [FP7/2007–2013] and from the European Federation of Pharmaceutical Industries and Associations); and a grant (to Prof. D.G. Murphy) from the Sackler Institute for Translational Neurodevelopment.

The MRC AIMS Consortium is a collaboration of autism research centers in the United Kingdom including the Institute of Psychiatry, London; the Autism Research Centre, University of Cambridge; and the Autism Research Group, University of Oxford. It is funded by the MRC and headed by the Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry. The Consortium members are in, alphabetical order, A.J. Bailey, S. Baron-Cohen, P.F. Bolton, E.T. Bullmore, S. Carrington, B. Chakrabarti, E.M. Daly, S.C. Deoni, C. Ecker, F. Happe, J. Henty, P. Jezzard, P. Johnston, D.K. Jones, M. Lombardo, A. Madden, D. Mullins, C.M. Murphy, D.G. Murphy, G. Pasco, S. Sadek, D. Spain, R. Steward, J. Suckling, S. Wheelwright, and S.C. Williams.

Prof. D.G. Murphy and Dr. Rubia contributed equally to this work.

From the Sackler Institute for Translational Neurodevelopment, the Department of Forensic and Neurodevelopmental Sciences, the Department of Child and Adolescent Psychiatry, and the Centre for Neuroimaging, Institute of Psychiatry, King’s College London; the Behavioural Genetics Clinic, Adult Autism Service, Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley Foundation NHS Trust; the School of Psychology and Clinical Language Sciences, University of Reading, Reading, U.K.

Address correspondence to Dr. Clodagh M. Murphy (clodagh.m.murphy@kcl.ac.uk).

Copyright © 2014 by the American Psychiatric Association

Received March 15, 2012; Revised October 31, 2013; March 03, 2014; Accepted March 28, 2014.

Abstract

Objective  Sustained attention problems are common in people with autism spectrum disorder (ASD) and may have significant implications for the diagnosis and management of ASD and associated comorbidities. Furthermore, ASD has been associated with atypical structural brain development. The authors used functional MRI to investigate the functional brain maturation of attention between childhood and adulthood in people with ASD.

Method  Using a parametrically modulated sustained attention/vigilance task, the authors examined brain activation and its linear correlation with age between childhood and adulthood in 46 healthy male adolescents and adults (ages 11–35 years) with ASD and 44 age- and IQ-matched typically developing comparison subjects.

Results  Relative to the comparison group, the ASD group had significantly poorer task performance and significantly lower activation in inferior prefrontal cortical, medial prefrontal cortical, striato-thalamic, and lateral cerebellar regions. A conjunction analysis of this analysis with group differences in brain-age correlations showed that the comparison group, but not the ASD group, had significantly progressively increased activation with age in these regions between childhood and adulthood, suggesting abnormal functional brain maturation in ASD. Several regions that showed both abnormal activation and functional maturation were associated with poorer task performance and clinical measures of ASD and inattention.

Conclusions  The results provide first evidence that abnormalities in sustained attention networks in individuals with ASD are associated with underlying abnormalities in the functional brain maturation of these networks between late childhood and adulthood.

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FIGURE 1. Horizontal fMRI Sections Showing Group Differences in Brain Activation Between Individuals With Autism Spectrum Disorder (ASD) (N=46) and Typically Developing Comparison Subjects (N=44)a

a In panel A, the sections show analysis-of-variance (ANOVA) group differences in the sustained attention task for all long delays combined (2, 5, or 8 seconds), each contrasted with the 0.5-second delay. Activation clusters in orange indicate regions where the ASD group had significantly lower activation relative to the comparison group. No areas showed higher activation in the ASD group relative to the comparison group. In panel B, the sections show group differences in whole-brain correlations between brain activation and age for the 8-second delay contrasted with the 0.5-second delay. Activation clusters shown in orange are those where the comparison group showed progressively greater activation with increasing age relative to the ASD group, which showed no significant age correlations in these regions. In panel C, the sections show results of the conjunction analysis between the ANOVA of between-group differences for all long delays versus the 0.5-second delay (panel A) and the group differences in whole-brain age correlations for the 8-second versus the 0.5-second delay (panel B). The resulting activation clusters (in orange) show areas where the comparison group had higher activation relative to the ASD group for long versus short delays and where, at the same time, activation was progressively correlated with increasing age in the comparison group but not in the ASD group during the 8-second delay versus the 0.5 delay. Talairach z coordinates are indicated for slice distance (in mm) from the intercommissural line. The right hemisphere corresponds to the right side of the image.

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TABLE 1.Characteristics of Individuals With Autism Spectrum Disorder (ASD) (N=46) and Typically Developing Comparison Subjects (N=44)
Table Footer Note

a For verbal and performance IQ, data were available for all participants in the ASD group and 24 in the comparison group (24 comparison subjects completed the Wechsler Abbreviated Scale of Intelligence and 20 completed the Raven’s Performance Matrices). For the Strengths and Difficulties Questionnaire, data were available for 23 children in the comparison group and 29 children in the ASD group. Conners’ Parent Rating Scale–Revised, Long Version was completed by 17 parents of comparison children and by all 29 parents of children in the ASD group. The Barkley Self-Report Behavior Questionnaire was completed by all 17 adults with ASD, and the Barkley Parent Report Behavior Questionnaire was completed by all 17 parents of adults with ASD.

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TABLE 2.Analysis of Variance Group Differences in Brain Activation Between Individuals With Autism Spectrum Disorder (ASD) (N=46) and Typically Developing Comparison Subjects (N=44) in a Sustained Attention Task
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TABLE 3.Group Differences Between Individuals With Autism Spectrum Disorder (ASD) (N=46) and Typically Developing Comparison Subjects (N=44) in Whole-Brain Correlations Between Brain Activation and Age for the 8-Second Delay and Age Correlations
Table Footer Note

a Age correlation between group differences in whole-brain correlations between brain activation and age (for the 8-second delay) and age in months. The maps are thresholded to give less than one type I error cluster per map.

Table Footer Note

*p<0.05. **p<0.01.

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TABLE 4.Conjunction Analysis of Group Differences in Brain Activation and Group Differences in Whole-Brain Age Correlations in Individuals With Autism Spectrum Disorder (N=46) and Typically Developing Comparison Subjects (N=44)
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