Patients with autism spectrum disorders display reproducible functional connectivity alterations

Štefan Holiga; Joerg F. Hipp; Christopher H. Chatham; Pilar Garces; Will Spooren; Xavier Liogier D’Ardhuy; Alessandro Bertolino; Céline Bouquet; Jan K. Buitelaar; Carsten Bours; Annika Rausch; Marianne Oldehinkel; Manuel Bouvard; Anouck Amestoy; Mireille Caralp; Sonia Gueguen; Myriam Ly Le Moal; Josselin Houenou; Christian F. Beckmann; Eva Loth; Declan Murphy; Tony Charman; Julian Tillmann; Charles Laidi; Richard Delorme; Anita Beggiato; Alexandru Gaman; Isabelle Scheid; Marion Leboyer; Marc Antoine d’Albis; Jeff Sevigny; Christian Czech; Federico Bolognani; Garry D. Honey; Juergen Dukart

doi:10.1126/scitranslmed.aat9223

Patients with autism spectrum disorders display reproducible functional connectivity alterations

Štefan Holiga^*, Joerg F. Hipp, Christopher H. Chatham, Pilar Garces, Will Spooren, Xavier Liogier D’Ardhuy, Alessandro Bertolino, Céline Bouquet, Jan K. Buitelaar, Carsten Bours, Annika Rausch, Marianne Oldehinkel, Manuel Bouvard, Anouck Amestoy, Mireille Caralp, Sonia Gueguen, Myriam Ly Le Moal, Josselin Houenou, Christian F. Beckmann, Eva LothDeclan Murphy, Tony Charman, Julian Tillmann, Charles Laidi, Richard Delorme, Anita Beggiato, Alexandru Gaman, Isabelle Scheid, Marion Leboyer, Marc Antoine d’Albis, Jeff Sevigny, Christian Czech, Federico Bolognani, Garry D. Honey, Juergen Dukart

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Article number	eaat9223
Number of pages	12
Journal	Science Translational Medicine
Volume	11
Issue number	481
Early online date	27 Feb 2019
DOIs	https://doi.org/10.1126/scitranslmed.aat9223
Publication status	Published - 27 Feb 2019

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Patients with autism spectrum disorder_MURPJHY_Publishedonline27February2019_GREEN AAMAccepted author manuscript, 1.31 MBLicence: Other

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Holiga, Š., Hipp, J. F., Chatham, C. H., Garces, P., Spooren, W., D’Ardhuy, X. L., Bertolino, A., Bouquet, C., Buitelaar, J. K., Bours, C., Rausch, A., Oldehinkel, M., Bouvard, M., Amestoy, A., Caralp, M., Gueguen, S., Moal, M. L. L., Houenou, J., Beckmann, C. F., ... Dukart, J. (2019). Patients with autism spectrum disorders display reproducible functional connectivity alterations. Science Translational Medicine, 11(481), Article eaat9223. https://doi.org/10.1126/scitranslmed.aat9223

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title = "Patients with autism spectrum disorders display reproducible functional connectivity alterations",

abstract = "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.",

author = "{\v S}tefan Holiga and Hipp, {Joerg F.} and Chatham, {Christopher H.} and Pilar Garces and Will Spooren and D{\textquoteright}Ardhuy, {Xavier Liogier} and Alessandro Bertolino and C{\'e}line Bouquet and Buitelaar, {Jan K.} and Carsten Bours and Annika Rausch and Marianne Oldehinkel and Manuel Bouvard and Anouck Amestoy and Mireille Caralp and Sonia Gueguen and Moal, {Myriam Ly Le} and Josselin Houenou and Beckmann, {Christian F.} and Eva Loth and Declan Murphy and Tony Charman and Julian Tillmann and Charles Laidi and Richard Delorme and Anita Beggiato and Alexandru Gaman and Isabelle Scheid and Marion Leboyer and d{\textquoteright}Albis, {Marc Antoine} and Jeff Sevigny and Christian Czech and Federico Bolognani and Honey, {Garry D.} and Juergen Dukart",

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Holiga, Š, Hipp, JF, Chatham, CH, Garces, P, Spooren, W, D’Ardhuy, XL, Bertolino, A, Bouquet, C, Buitelaar, JK, Bours, C, Rausch, A, Oldehinkel, M, Bouvard, M, Amestoy, A, Caralp, M, Gueguen, S, Moal, MLL, Houenou, J, Beckmann, CF, Loth, E , Murphy, D , Charman, T , Tillmann, J, Laidi, C, Delorme, R, Beggiato, A, Gaman, A, Scheid, I, Leboyer, M, d’Albis, MA, Sevigny, J, Czech, C, Bolognani, F, Honey, GD & Dukart, J 2019, 'Patients with autism spectrum disorders display reproducible functional connectivity alterations', Science Translational Medicine, vol. 11, no. 481, eaat9223. https://doi.org/10.1126/scitranslmed.aat9223

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T1 - Patients with autism spectrum disorders display reproducible functional connectivity alterations

AU - Holiga, Štefan

AU - Hipp, Joerg F.

AU - Chatham, Christopher H.

AU - Garces, Pilar

AU - Spooren, Will

AU - D’Ardhuy, Xavier Liogier

AU - Bertolino, Alessandro

AU - Bouquet, Céline

AU - Buitelaar, Jan K.

AU - Bours, Carsten

AU - Rausch, Annika

AU - Oldehinkel, Marianne

AU - Bouvard, Manuel

AU - Amestoy, Anouck

AU - Caralp, Mireille

AU - Gueguen, Sonia

AU - Moal, Myriam Ly Le

AU - Houenou, Josselin

AU - Beckmann, Christian F.

AU - Loth, Eva

AU - Murphy, Declan

AU - Charman, Tony

AU - Tillmann, Julian

AU - Laidi, Charles

AU - Delorme, Richard

AU - Beggiato, Anita

AU - Gaman, Alexandru

AU - Scheid, Isabelle

AU - Leboyer, Marion

AU - d’Albis, Marc Antoine

AU - Sevigny, Jeff

AU - Czech, Christian

AU - Bolognani, Federico

AU - Honey, Garry D.

AU - Dukart, Juergen

PY - 2019/2/27

Y1 - 2019/2/27

N2 - 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.

AB - 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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U2 - 10.1126/scitranslmed.aat9223

DO - 10.1126/scitranslmed.aat9223

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SN - 1946-6234

VL - 11

JO - Science Translational Medicine

JF - Science Translational Medicine

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ER -

Patients with autism spectrum disorders display reproducible functional connectivity alterations

Abstract

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