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Sci Transl Med. 2019 Feb 27;11(481). pii: eaat9223. doi: 10.1126/scitranslmed.aat9223.

Patients with autism spectrum disorders display reproducible functional connectivity alterations.

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Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', 70121 Bari, Italy.
Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Centre for Cognitive Neuroimaging, Radboud University Nijmegen Medical center, Nijmegen 6525 EN, Netherlands.
Brain & Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences and School of Psychological Sciences, Monash University, Clayton, VIC 3800, Australia.
Pôle Universitaire de Psychiatrie de l'Enfant et de l'Adolescent, Hôpital Charles Perrens Bordeaux, 33076 Bordeaux, France.
INSERM, National Biobank Infrastructure, 75013 Paris, France.
INSERM, Clinical Research Department, 75014 Paris, France.
Institut Roche, 92100 Boulogne-Billancourt, France.
Hôpitaux Universitaires Mondor, DHU PePSY, Pôle de psychiatrie, Faculté de Médecine, Université Paris Est, INSERM U955, IMRB, Equipe 15, Psychiatrie Translationnelle, Fondation FondaMental, 94000 Créteil, France.
NeuroSpin, UNIACT Lab, Psychiatry Team, CEA Saclay, 91191 Gif-Sur-Yvette, France.
Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
Department of Applied Psychology: Health, Development, Enhancement, and Intervention, University of Vienna, 1010 Vienna, Austria.
APHP, Robert Debré Hospital, Child and Adolescent Psychiatry Department, Paris, France.
Pasteur Institute, 75019 Paris, France.
Therachon AG, Aeschenvorstadt 36, 4051 Basel, Switzerland.
Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research Centre Jülich, 52428 Jülich, Germany.
Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University Düsseldorf, 40223 Düsseldorf, Germany.


Despite the high clinical burden, little is known about pathophysiology underlying autism spectrum disorder (ASD). Recent resting-state functional magnetic resonance imaging (rs-fMRI) studies have found atypical synchronization of brain activity in ASD. However, no consensus has been reached on the nature and clinical relevance of these alterations. Here, we addressed these questions in four large ASD cohorts. Using rs-fMRI, we identified functional connectivity alterations associated with ASD. We tested for associations of these imaging phenotypes with clinical and demographic factors such as age, sex, medication status, and clinical symptom severity. Our results showed reproducible patterns of ASD-associated functional hyper- and hypoconnectivity. Hypoconnectivity was primarily restricted to sensory-motor regions, whereas hyperconnectivity hubs were predominately located in prefrontal and parietal cortices. Shifts in cortico-cortical between-network connectivity from outside to within the identified regions were shown to be a key driver of these abnormalities. This reproducible pathophysiological phenotype was partially associated with core ASD symptoms related to communication and daily living skills and was not affected by age, sex, or medication status. Although the large effect sizes in standardized cohorts are encouraging with respect to potential application as a treatment and for patient stratification, the moderate link to clinical symptoms and the large overlap with healthy controls currently limit the usability of identified alterations as diagnostic or efficacy readout.

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