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Imbalanced social-communicative and restricted repetitive behavior subtypes of autism spectrum disorder exhibit different neural circuitry

Natasha Bertelsen 1, 2 Isotta Landi 1 Richard Bethlehem 3 Jakob Seidlitz 4, 5 Elena Maria Busuoli 1, 2 Veronica Mandelli 1, 2 Eleonora Satta 1 Stavros Trakoshis 1, 6 Bonnie Auyeung 7, 3 Prantik Kundu 3 Eva Loth 8 Guillaume Dumas 9 Sarah Baumeister 10 Christian Beckmann 11 Sven Bölte 12, 13, 14 Thomas Bourgeron 9 Tony Charman 8 Sarah Durston 15 Christine Ecker 16 Rosemary Holt 3 Mark Johnson 3 Emily Jones 17 Luke Mason 17 Andreas Meyer-Lindenberg 10 Carolin Moessnang 10 Marianne Oldehinkel 11, 18 Antonio Persico 19, 20 Julian Tillmann 8, 21 Steve Williams 8 Will Spooren 22 Declan Murphy 8 Jan Buitelaar 11 Eu-Aims Leap Group Simon Baron-Cohen 3 Meng-Chuan Lai 3, 23, 24, 25, 26 Michael Lombardo 1, 3, *
Abstract : Social-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here, we developed a phenotypic stratification model that makes highly accurate (97–99%) out-of-sample SC = RRB, SC > RRB, and RRB > SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset ( n = 509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show replicable differences within some networks compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC > RRB and visual association circuitry in SC = RRB. The SC = RRB subtype show hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these networks show a differential enrichment pattern with known autism-associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share many commonalities, but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry.
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Natasha Bertelsen, Isotta Landi, Richard Bethlehem, Jakob Seidlitz, Elena Maria Busuoli, et al.. Imbalanced social-communicative and restricted repetitive behavior subtypes of autism spectrum disorder exhibit different neural circuitry. Communications Biology, Nature Publishing Group, 2021, 4 (1), pp.574. ⟨10.1038/s42003-021-02015-2⟩. ⟨pasteur-03325356⟩

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