Self-referential and social cognition in a case of autism and agenesis of the corpus callosum.

BACKGROUND: While models of autism spectrum conditions (ASC) are emerging at the genetic level of analysis, clear models at higher levels of analysis, such as neuroanatomy, are lacking. Here we examine agenesis of the corpus callosum (AgCC) as a model at the level of neuroanatomy that may be relevant for understanding self-referential and social-cognitive difficulties in ASC. METHODS: We examined performance on a wide array of tests in self-referential and social-cognitive domains in a patient with both AgCC and a diagnosis of ASC. Tests included a depth-of-processing memory paradigm with self-referential and social-cognitive manipulations, self-report measures of self-consciousness, alexithymia, and empathy, as well as performance measures of first-person pronoun usage and mentalizing ability. The performance of the AgCC patient was compared to a group of individuals with ASC but without AgCC and with neurotypical controls. These comparison groups come from a prior study where group differences were apparent across many measures. We used bootstrapping to assess whether the AgCC patient exhibited scores that were within or outside the 95% bias-corrected and accelerated bootstrap confidence intervals observed in both comparison groups. RESULTS: Within the depth-of-processing memory paradigm, the AgCC patient showed decreased memory sensitivity that was more extreme than both comparison groups across all conditions. The patient's most pronounced difficulty on this task emerged in the social-cognitive domain related to information-processing about other people. The patient was similar to the ASC group in benefiting less from self-referential processing compared to the control group. Across a variety of other self-referential (i.e. alexithymia, private self-consciousness) and social-cognitive measures (i.e. self-reported imaginative and perspective-taking subscales of empathy, mentalizing), the AgCC patient also showed more extreme scores than those observed for both of the comparison groups. However, the AgCC patient scored within the range observed in the comparison groups on measures of first-person pronoun usage and self-reported affective empathy subscales. CONCLUSIONS: We conclude that AgCC co-occurring with a diagnosis of ASC may be a relevant model at the level of neuroanatomy for understanding mechanisms involved in self-referential and high-level social-cognitive difficulties in ASC.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Testing the 'Extreme Female Brain' Theory of Psychosis in Adults with Autism Spectrum Disorder with or without Co-Morbid Psychosis.

INTRODUCTION: Males and females in the general population differ, on average, in their drive for empathizing (higher in females) and systemizing (higher in males). People with autism spectrum disorder (ASD) show a drive for systemizing over empathizing, irrespective of sex, which led to the conceptualisation of ASD as an 'extreme of the typical male brain'. The opposite cognitive profile, an 'extreme of the typical female brain', has been proposed to be linked to conditions such as psychosis and mania/hypomania. METHODS: We compared an empathizing-over-systemizing bias (for short 'empathizing bias') in individuals with ASD, who had experienced psychotic illness (N = 64) and who had not (N = 71). RESULTS: There were overall differences in the distribution of cognitive style. Adults with ASD who had experienced psychosis were more likely to show an empathizing bias than adults with ASD who had no history of psychosis. This was modulated by IQ, and the group-difference was driven mainly by individuals with above-average IQ. In women with ASD and psychosis, the link between mania/hypomania and an empathizing bias was greater than in men with ASD. CONCLUSIONS: The bias for empathizing over systemizing may be linked to the presence of psychosis in people with ASD. Further research is needed in a variety of clinical populations, to understand the role an empathizing bias may play in the development and manifestation of mental illness.FVL was supported by the Medical Research Council (MRC) UK and the Baily Thomas Charitable Trust. M-CL was supported by the William Binks Autism Neuroscience Fellowship, the European Autism Interventions—A Multicentre Study for Developing New Medications (EU-AIMS), and Wolfson College, Cambridge. APW and AJH received support from the NIHR Collaboration for Leadership in Applied Health Research and Care East of England at the Cambridgeshire and Peterborough NHS Foundation Trust during the preparation of this manuscript. SB-C was supported by the MRC, EU-AIMS, and the Autism Research Trust.This is the final version. It was first published by PLOS at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128102#abstract0

Quantifying and exploring camouflaging in men and women with autism.

Autobiographical descriptions and clinician observations suggest that some individuals with autism, particularly females, 'camouflage' their social communication difficulties, which may require considerable cognitive effort and lead to increased stress, anxiety and depression. Using data from 60 age- and IQ-matched men and women with autism (without intellectual disability), we operationalized camouflaging in adults with autism for the first time as the quantitative discrepancy between the person's 'external' behavioural presentation in social-interpersonal contexts (measured by the Autism Diagnostic Observation Schedule) and the person's 'internal' status (dispositional traits measured by the Autism Spectrum Quotient and social cognitive capability measured by the 'Reading the Mind in the Eyes' Test). We found that the operationalized camouflaging measure was not significantly correlated with age or IQ. On average, women with autism had higher camouflaging scores than men with autism (Cohen's d = 0.98), with substantial variability in both groups. Greater camouflaging was associated with more depressive symptoms in men and better signal-detection sensitivity in women with autism. The neuroanatomical association with camouflaging score was largely sex/gender-dependent and significant only in women: from reverse inference, the most correlated cognitive terms were about emotion and memory. The underlying constructs, measurement, mechanisms, consequences and heterogeneity of camouflaging in autism warrant further investigation.The study was supported by the UK Medical Research Council (grant number GO 400061) and European Autism Interventions — a Multicentre Study for Developing New Medications (EU-AIMS); EU-AIMS has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115300, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007 - 2013) and EFPIA companies' in kind contribution. The study was conducted in association with the National Institute for Health Research Collaborations for Leadership in Applied Health Research and Care (NIHR CLAHRC) East of England (EoE). During the period of the study Dr Lai was supported by the William Binks Autism Neuroscience Fellowship and Wolfson College, Cambridge, UK, and the O’Brien Scholars Program within the Child and Youth Mental Health Collaborative at the Centre for Addiction and Mental Health and The Hospital for Sick Children, Toronto, Canada. Drs Baron-Cohen, Lombardo, Ruigrok, Chakrabarti, and Auyeung were supported by the Autism Research Trust during the period of this work

Impaired Communication Between the Motor and Somatosensory Homunculus Is Associated With Poor Manual Dexterity in Autism Spectrum Disorder

ABSTRACTBackgroundFine motor skill impairments are common in autism spectrum disorder (ASD), significantly affecting quality of life. Sensory inputs reaching the primary motor cortex (M1) from the somatosensory cortex (S1) are likely involved in fine motor skill and specifically motor learning. However, the role of these connections has not been directly investigated in humans. This study aimed to investigate, for the first time, the role of the S1-M1 connections in healthy subjects in vivo and whether microstructural alterations are associated with motor impairment in ASD.MethodsSixty right-handed neurotypical adult men aged 18 to 45 years, and 60 right-handed age- and sex-matched subjects diagnosed with ASD underwent fine motor skill assessment and scanning with diffusion tensor imaging (DTI). The streamlines of the hand region connecting S1-M1 of the motor-sensory homunculus were virtually dissected using TrackVis, and diffusion properties were extracted. The face/tongue region connections were used as control tracts.ResultsThe ASD group displayed lower motor performances and altered DTI measurements of the hand-region connection. Behavioral performance correlated with hand-region DTI measures in both groups, but not with the face/tongue connections, indicating anatomical specificity. There was a left-hemisphere association of motor ability in the control group and an atypical rightward shift in the ASD group.ConclusionsThese findings suggest that direct interaction between S1 and M1 may contribute to the human ability to precisely interact with and manipulate the environment. Because electrophysiological evidence indicates that these connections may underpin long-term potentiation in M1, our findings may lead to novel therapeutic treatments for motor skill disorders

Social anxiety in adult males with autism spectrum disorders

Background: Psychiatric conditions, notably anxiety, commonly co-occur with autism spectrum disorders (ASD). Method: This study investigated self-reported behavioural, cognitive and affective symptoms of social anxiety (SA) in 50 adult males with ASD. Associations between SA, core ASD symptoms and facets of neuropsychological functioning were also examined. Results: Twenty-six participants (52%) endorsed levels of SA that exceeded the suggested caseness threshold for social anxiety disorder. Categorical and dimensional data analyses indicated that there were no relationships between SA symptoms, present-state or childhood ASD symptom-severity, or measures of socio-emotional processing in this sample. Conclusions: Study findings suggest that severity of SA is not merely a reflection of ASD symptom-severity. Further research is needed to ascertain the prevalence of SA in adult ASD epidemiological samples, and identify causal and maintaining mechanisms for these co-morbid symptoms

Neuroanatomy of Individual Differences in Language in Adult Males with Autism.

One potential source of heterogeneity within autism spectrum conditions (ASC) is language development and ability. In 80 high-functioning male adults with ASC, we tested if variations in developmental and current structural language are associated with current neuroanatomy. Groups with and without language delay differed behaviorally in early social reciprocity, current language, but not current autistic features. Language delay was associated with larger total gray matter (GM) volume, smaller relative volume at bilateral insula, ventral basal ganglia, and right superior, middle, and polar temporal structures, and larger relative volume at pons and medulla oblongata in adulthood. Despite this heterogeneity, those with and without language delay showed significant commonality in morphometric features when contrasted with matched neurotypical individuals (n = 57). In ASC, better current language was associated with increased GM volume in bilateral temporal pole, superior temporal regions, dorsolateral fronto-parietal and cerebellar structures, and increased white matter volume in distributed frontal and insular regions. Furthermore, current language-neuroanatomy correlation patterns were similar across subgroups with or without language delay. High-functioning adult males with ASC show neuroanatomical variations associated with both developmental and current language characteristics. This underscores the importance of including both developmental and current language as specifiers for ASC, to help clarify heterogeneity.This work was supported by the Waterloo Foundation [grant number 921/1247 to S.B-C. and M-C.L.], the UK Medical Research Council [grant number GO 400061 to D.G.M.M., S.B-C. and E.T.B.], and the European Autism Interventions - A Multicentre Study for Developing New Medications (EU-AIMS); EU-AIMS receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115300, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013), from the EFPIA companies in kind contribution and from Autism Speaks. During the period of this work M-C.L. was supported by the Waterloo Foundation, the Ministry of Education, Taiwan, Wolfson College, Cambridge, EU-AIMS, and the William Binks Autism Neuroscience Fellowship; M.V.L. by the Shirley Foundation, the Wellcome Trust, the British Academy, and Jesus College, Cambridge; B.C. by the UK Medical Research Council; S.B-C. by the Wellcome Trust, the UK Medical Research Council, the Waterloo Foundation, the Autism Research Trust, and EU-AIMS.This is the final published version. It was originally published by OUP at http://cercor.oxfordjournals.org/content/early/2014/09/18/cercor.bhu211

Disorder-specific and shared brain abnormalities during vigilance in autism and obsessive-compulsive disorder

Background Autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD) are often comorbid and share similarities across some cognitive phenotypes, including certain aspects of attention. However, no functional magnetic resonance imaging (fMRI) studies have compared the underlying neural mechanisms contributing to these shared phenotypes. Methods Age and IQ-matched boys between 11 and 17 years old with ASD (N=20), OCD (N=20) and healthy controls (N = 20) performed a parametrically modulated psychomotor vigilance fMRI task. Brain activation and performance were compared between adolescents with OCD, ASD and controls. Results While boys with ASD and OCD were not impaired on task performance, there was a significant group by attention load interaction in several brain regions. With increasing attention load, left inferior frontal cortex/insula as well as left inferior parietal lobe/pre/post-central gyrus were progressively less activated in OCD boys relative to the other two groups. In addition, OCD boys showed progressively increased activation with increasing attention load in rostromedial prefrontal/anterior cingulate cortex relative to ASD and control boys. Shared neurofunctional abnormalities between ASD and OCD boys included increased activation with increasing attention load in cerebellum and occipital regions, possibly reflecting increased default mode network activation. Conclusions This first fMRI study to compare boys with ASD and OCD showed shared abnormalities in posterior cerebellar-occipital brain regions. However, OCD boys showed a disorder-specific pattern of reduced activation in left inferior frontal and temporo-parietal regions but increased activation of medial frontal regions which may potentially be related to neurobiological mechanisms underlying cognitive and clinical phenotypes of OCD

A Machine Learning Approach to Reveal the NeuroPhenotypes of Autisms.

Although much research has been undertaken, the spatial patterns, developmental course, and sexual dimorphism of brain structure associated with autism remains enigmatic. One of the difficulties in investigating differences between the sexes in autism is the small sample sizes of available imaging datasets with mixed sex. Thus, the majority of the investigations have involved male samples, with females somewhat overlooked. This paper deploys machine learning on partial least squares feature extraction to reveal differences in regional brain structure between individuals with autism and typically developing participants. A four-class classification problem (sex and condition) is specified, with theoretical restrictions based on the evaluation of a novel upper bound in the resubstitution estimate. These conditions were imposed on the classifier complexity and feature space dimension to assure generalizable results from the training set to test samples. Accuracies above 80% on gray and white matter tissues estimated from voxel-based morphometry (VBM) features are obtained in a sample of equal-sized high-functioning male and female adults with and without autism (N = 120, n = 30/group). The proposed learning machine revealed how autism is modulated by biological sex using a low-dimensional feature space extracted from VBM. In addition, a spatial overlap analysis on reference maps partially corroborated predictions of the "extreme male brain" theory of autism, in sexual dimorphic areas.This work was partly supported by the MINECO under the TEC2015-64718-R project, the Salvador de Madariaga Mobility Grants 2017 and the Consejer´ıa de Econom´ıa, Innovaci´on, Ciencia y Empleo (Junta de Andaluc´ıa, Spain) under the Excellence Project P11-TIC-7103. The study was conducted in association with the National Institute for Health Research Collaborations for Leadership in Applied Health Research and Care (NIHR CLAHRC) East of England (EoE). The project was supported by the UK Medical Research Council (grant number GO 400061) and European Autism Interventions—a Multicentre Study for Developing New Medications (EU-AIMS); EU-AIMS has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n◦ 115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007 - 2013) and EFPIA companies’ in-kind contribution. During the period of this work M-CL was supported by the O’Brien Scholars Program in the Child and Youth Mental Health Collaborative at the Centre for Addiction and Mental Health (CAMH) and The Hospital for Sick Children, Toronto, the Academic Scholar Award from the Department of Psychiatry, University of Toronto, the Slaight Family Child and Youth Mental Health Innovation Fund, CAMH Foundation, and the Ontario Brain Institute via the Province of Ontario Neurodevelopmental Disorders (POND) Network; MVL was supported by the British Academy, Jesus College Cambridge,Wellcome Trust, and an ERC Starting Grant (ERC-2017- STG; 755816); SB-C was supported by the Autism Research Trust. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health, U

Examining volumetric gradients based on the frustum surface ratio in the brain in autism spectrum disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is accompanied by neurodevelopmental differences in regional cortical volume (CV), and a potential layer-specific pathology. Conventional measures of CV, however, do not indicate how volume is distributed across cortical layers. In a sample of 92 typically developing (TD) controls and 92 adult individuals with ASD (aged 18-52 years), we examined volumetric gradients by quantifying the degree to which CV is weighted from the pial to the white surface of the brain. Overall, the spatial distribution of Frustum Surface Ratio (FSR) followed the gyral and sulcal pattern of the cortex and approximated a bimodal Gaussian distribution caused by a linear mixture of vertices on gyri and sulci. Measures of FSR were highly correlated with vertex-wise estimates of mean curvature, sulcal depth, and pial surface area, although none of these features explained more than 76% variability in FSR on their own. Moreover, in ASD, we observed a pattern of predominant increases in the degree of FSR relative to TD controls, with an atypical neurodevelopmental trajectory. Our findings suggest a more outward-weighted gradient of CV in ASD, which may indicate a larger contribution of supragranular layers to regional differences in CV

On the brain structure heterogeneity of autism: Parsing out acquisition site effects with significance-weighted principal component analysis.

Neuroimaging studies have reported structural and physiological differences that could help understand the causes and development of Autism Spectrum Disorder (ASD). Many of them rely on multisite designs, with the recruitment of larger samples increasing statistical power. However, recent large-scale studies have put some findings into question, considering the results to be strongly dependent on the database used, and demonstrating the substantial heterogeneity within this clinically defined category. One major source of variance may be the acquisition of the data in multiple centres. In this work we analysed the differences found in the multisite, multi-modal neuroimaging database from the UK Medical Research Council Autism Imaging Multicentre Study (MRC AIMS) in terms of both diagnosis and acquisition sites. Since the dissimilarities between sites were higher than between diagnostic groups, we developed a technique called Significance Weighted Principal Component Analysis (SWPCA) to reduce the undesired intensity variance due to acquisition site and to increase the statistical power in detecting group differences. After eliminating site-related variance, statistically significant group differences were found, including Broca's area and the temporo-parietal junction. However, discriminative power was not sufficient to classify diagnostic groups, yielding accuracies results close to random. Our work supports recent claims that ASD is a highly heterogeneous condition that is difficult to globally characterize by neuroimaging, and therefore different (and more homogenous) subgroups should be defined to obtain a deeper understanding of ASD. Hum Brain Mapp 38:1208-1223, 2017. © 2016 Wiley Periodicals, Inc.Contract grant sponsor: UK Medical Research Council AIMS network; Contract grant number: G0400061; Contract grant sponsors: “Vicerrectorado de Relaciones Internacionales de la Universidad de Granada” and CEI BioTic Granada; Contract grant: “Convocatoria de Movilidad Internacional de Estudiantes de Doctorado Curso 2013/2014”; Contract grant sponsor: MINECO/ FEDER; Contract grant numbers: TEC2012-34306 and TEC2015- 64718-R; Contract grant sponsor: Consejeria de Economia, Innovacion, Ciencia y Empleo (Junta de Andalucia, Spain); Contract grant numbers: P09-TIC-4530 and P11-TIC-710