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Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women

Stavros Trakoshis, Pablo Martínez-Cañada, Federico Rocchi, Carola Canella, View ORCID ProfileWonsang You, View ORCID ProfileBhismadev Chakrabarti, View ORCID ProfileAmber N. V. Ruigrok, Edward T. Bullmore, View ORCID ProfileJohn Suckling, View ORCID ProfileMarija Markicevic, View ORCID ProfileValerio Zerbi, MRC AIMS Consortium, View ORCID ProfileSimon Baron-Cohen, View ORCID ProfileStefano Panzeri, View ORCID ProfileAlessandro Gozzi, View ORCID ProfileMeng-Chuan Lai, View ORCID ProfileMichael V. Lombardo
doi: https://doi.org/10.1101/2020.01.16.909531
Stavros Trakoshis
Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Corso Bettini, 31, 38068 Rovereto, ItalyDepartment of Psychology, University of Cyprus, Nicosia, Cyprus
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Pablo Martínez-Cañada
Neural Computation Laboratory, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Corso Bettini, 31, 38068 Rovereto, ItalyOptical Approaches to Brain Function Laboratory, Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy
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Federico Rocchi
Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Corso Bettini 31, 38068 Rovereto, Italy
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Carola Canella
Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Corso Bettini 31, 38068 Rovereto, Italy
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Wonsang You
Children’s National Medical Center, Department of Diagnostic Imaging and Radiology, Washington, DC, USA
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  • ORCID record for Wonsang You
Bhismadev Chakrabarti
Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United KingdomCentre for Integrative Neuroscience and Neurodynamics, School of Psychology and Clinical Language Sciences, University of Reading, Reading, United Kingdom
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  • ORCID record for Bhismadev Chakrabarti
Amber N. V. Ruigrok
Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
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  • ORCID record for Amber N. V. Ruigrok
Edward T. Bullmore
Cambridgeshire and Peterborough National Health Service Foundation Trust, Cambridge, United KingdomBrain Mapping Unit, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
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John Suckling
Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
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  • ORCID record for John Suckling
Marija Markicevic
Neural Control of Movement Lab, D-HEST, ETH Zurich, Auguste-Piccard-Hof 1, 8093 Zurich, Switzerland
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  • ORCID record for Marija Markicevic
Valerio Zerbi
Neural Control of Movement Lab, D-HEST, ETH Zurich, Auguste-Piccard-Hof 1, 8093 Zurich, SwitzerlandNeuroscience Center Zurich, University and ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
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  • ORCID record for Valerio Zerbi
Simon Baron-Cohen
Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United KingdomCambridgeshire and Peterborough National Health Service Foundation Trust, Cambridge, United Kingdom
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  • ORCID record for Simon Baron-Cohen
Stefano Panzeri
Neural Computation Laboratory, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Corso Bettini, 31, 38068 Rovereto, Italy
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  • ORCID record for Stefano Panzeri
Alessandro Gozzi
Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Corso Bettini 31, 38068 Rovereto, Italy
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  • ORCID record for Alessandro Gozzi
Meng-Chuan Lai
Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United KingdomThe Margaret and Wallace McCain Centre for Child, Youth & Family Mental Health, Azrieli Adult Neurodevelopmental Centre, and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, CanadaCentre for Brain and Mental Health and Department of Psychiatry, The Hospital for Sick Children, Toronto, CanadaDepartment of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, CanadaDepartment of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
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Michael V. Lombardo
Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Corso Bettini, 31, 38068 Rovereto, ItalyAutism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
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  • ORCID record for Michael V. Lombardo
  • For correspondence: michael.lombardo@iit.it
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Abstract

Imbalance between neurophysiological excitation versus inhibition (E:I) has been theorized as a core pathophysiological mechanism of autism. However, a majority of the evidence behind the E:I theory comes from animal models of rare genetic mutations that account for only a small fraction of the autistic population. Scale-free metrics of neural time-series data could represent biomarkers for E:I imbalance and could enable a greater understanding of how E:I imbalance affects different types of autistic individuals and how such mechanisms relate to behavior. Here we show that a measure of scale-free dynamics, the Hurst exponent (H), measured in-vivo in resting state fMRI (rsfMRI) data, is a surrogate marker of E:I imbalance and differentially affects autistic males versus females. In-silico modeling of local field potentials (LFP) from recurrent networks of interacting excitatory and inhibitory neurons shows that increasing the E:I ratio by specifically enhancing excitation attenuates H and flattens the 1/f slope. These in-silico predictions are confirmed in-vivo with chemogenetic manipulations to enhance excitation of prefrontal cortex in mice. In humans, social brain areas such as ventromedial prefrontal cortex (vMPFC), show decreased H specifically in autistic males but not females. However, continuous variation in vMPFC H correlates with ability to behaviorally camouflage social-communicative difficulties in autistic females but not males. This work provides insight into how in-vivo neuroimaging readouts can be utilized to understand E:I imbalance in human clinical populations. E:I imbalance in social brain circuitry may differentially affect autistic males versus females and may help explain sex-related differences in compensatory phenomena.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 27, 2020.
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Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women
Stavros Trakoshis, Pablo Martínez-Cañada, Federico Rocchi, Carola Canella, Wonsang You, Bhismadev Chakrabarti, Amber N. V. Ruigrok, Edward T. Bullmore, John Suckling, Marija Markicevic, Valerio Zerbi, MRC AIMS Consortium, Simon Baron-Cohen, Stefano Panzeri, Alessandro Gozzi, Meng-Chuan Lai, Michael V. Lombardo
bioRxiv 2020.01.16.909531; doi: https://doi.org/10.1101/2020.01.16.909531
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Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women
Stavros Trakoshis, Pablo Martínez-Cañada, Federico Rocchi, Carola Canella, Wonsang You, Bhismadev Chakrabarti, Amber N. V. Ruigrok, Edward T. Bullmore, John Suckling, Marija Markicevic, Valerio Zerbi, MRC AIMS Consortium, Simon Baron-Cohen, Stefano Panzeri, Alessandro Gozzi, Meng-Chuan Lai, Michael V. Lombardo
bioRxiv 2020.01.16.909531; doi: https://doi.org/10.1101/2020.01.16.909531

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