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[Preprint]. 2023 May 15:rs.3.rs-2853362.

doi: 10.21203/rs.3.rs-2853362/v1.

Generalizable neuromarker for autism spectrum disorder across imaging sites and developmental stages: A multi-site study

Takashi Itahashi¹, Ayumu Yamashita^{2

3}, Yuji Takahara^{2

4}, Noriaki Yahata^{2

5

6}, Yuta Y Aoki^{1

7}, Junya Fujino^{1

8}, Yujiro Yoshihara⁹, Motoaki Nakamura¹, Ryuta Aoki^{1

10}, Haruhisa Ohta¹, Yuki Sakai², Masahiro Takamura^{11

12}, Naho Ichikawa¹¹, Go Okada¹¹, Naohiro Okada^{6

13}, Kiyoto Kasai^{6

13

14}, Saori C Tanaka^{2

15}, Hiroshi Imamizu^{2

16}, Nobumasa Kato¹, Yasumasa Okamoto¹¹, Hidehiko Takahashi^{8

9

17}, Mitsuo Kawato^{2

18}, Okito Yamashita^{2

19}, Ryu-Ichiro Hashimoto^{1

9}

Affiliations

¹ Medical Institute of Developmental Disabilities Research, Showa University, Tokyo, Japan.
² Brain Information Communication Research Laboratory Group, Advanced Telecommunications Research Institute International, Kyoto, Japan.
³ Graduate School of Information Science and Technology, The University of Tokyo, Tokyo, Japan.
⁴ Laboratory for Drug Discovery and Disease Research, SHIONOGI & CO., LTD, Osaka, Japan.
⁵ Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, Chiba, Japan.
⁶ Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁷ Department of Psychiatry, Aoki Clinic, Tokyo, Japan.
⁸ Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
⁹ Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹⁰ Department of Language Sciences, Tokyo Metropolitan University, Tokyo, Japan.
¹¹ Department of Psychiatry and Neurosciences, Hiroshima University, Hiroshima, Japan.
¹² Department of Neurology, Shimane University, Shimane, Japan.
¹³ The International Research Center for Neurointelligence (WPI-IRCN) at The University of Tokyo Institutes for Advanced Study (UTIAS), The University of Tokyo, Tokyo, Japan.
¹⁴ UTokyo Institute for Diversity and Adaptation of Human Mind (UTIDAHM), The University of Tokyo, Tokyo, Japan.
¹⁵ Division of Information Science, Nara Institute of Science and Technology, Nara, Japan.
¹⁶ Department of Psychology, Graduate School of Humanities and Sociology, The University of Tokyo, Tokyo, Japan.
¹⁷ Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
¹⁸ XNef Incorporation, Kyoto, Japan.
¹⁹ RIKEN, Center for Advanced Intelligence Project, Tokyo, Japan.

PMID: 37292656
PMCID: PMC10246271
DOI: 10.21203/rs.3.rs-2853362/v1

Generalizable neuromarker for autism spectrum disorder across imaging sites and developmental stages: A multi-site study

Takashi Itahashi et al. Res Sq. 2023.

[Preprint]. 2023 May 15:rs.3.rs-2853362.

doi: 10.21203/rs.3.rs-2853362/v1.

Authors

Affiliations

¹ Medical Institute of Developmental Disabilities Research, Showa University, Tokyo, Japan.
² Brain Information Communication Research Laboratory Group, Advanced Telecommunications Research Institute International, Kyoto, Japan.
³ Graduate School of Information Science and Technology, The University of Tokyo, Tokyo, Japan.
⁴ Laboratory for Drug Discovery and Disease Research, SHIONOGI & CO., LTD, Osaka, Japan.
⁵ Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, Chiba, Japan.
⁶ Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁷ Department of Psychiatry, Aoki Clinic, Tokyo, Japan.
⁸ Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
⁹ Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹⁰ Department of Language Sciences, Tokyo Metropolitan University, Tokyo, Japan.
¹¹ Department of Psychiatry and Neurosciences, Hiroshima University, Hiroshima, Japan.
¹² Department of Neurology, Shimane University, Shimane, Japan.
¹³ The International Research Center for Neurointelligence (WPI-IRCN) at The University of Tokyo Institutes for Advanced Study (UTIAS), The University of Tokyo, Tokyo, Japan.
¹⁴ UTokyo Institute for Diversity and Adaptation of Human Mind (UTIDAHM), The University of Tokyo, Tokyo, Japan.
¹⁵ Division of Information Science, Nara Institute of Science and Technology, Nara, Japan.
¹⁶ Department of Psychology, Graduate School of Humanities and Sociology, The University of Tokyo, Tokyo, Japan.
¹⁷ Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
¹⁸ XNef Incorporation, Kyoto, Japan.
¹⁹ RIKEN, Center for Advanced Intelligence Project, Tokyo, Japan.

PMID: 37292656
PMCID: PMC10246271
DOI: 10.21203/rs.3.rs-2853362/v1

Update in

Generalizable and transportable resting-state neural signatures characterized by functional networks, neurotransmitters, and clinical symptoms in autism.
Itahashi T, Yamashita A, Takahara Y, Yahata N, Aoki YY, Fujino J, Yoshihara Y, Nakamura M, Aoki R, Okimura T, Ohta H, Sakai Y, Takamura M, Ichikawa N, Okada G, Okada N, Kasai K, Tanaka SC, Imamizu H, Kato N, Okamoto Y, Takahashi H, Kawato M, Yamashita O, Hashimoto RI. Itahashi T, et al. Mol Psychiatry. 2025 Apr;30(4):1466-1478. doi: 10.1038/s41380-024-02759-3. Epub 2024 Sep 28. Mol Psychiatry. 2025. PMID: 39342041 Free PMC article.

Abstract

Autism spectrum disorder (ASD) is a lifelong condition, and its underlying biological mechanisms remain elusive. The complexity of various factors, including inter-site and development-related differences, makes it challenging to develop generalizable neuroimaging-based biomarkers for ASD. This study used a large-scale, multi-site dataset of 730 Japanese adults to develop a generalizable neuromarker for ASD across independent sites and different developmental stages. Our adult ASD neuromarker achieved successful generalization for the US and Belgium adults and Japanese adults. The neuromarker demonstrated significant generalization for children and adolescents. We identified 141 functional connections (FCs) important for discriminating individuals with ASD from TDCs. Finally, we mapped schizophrenia (SCZ) and major depressive disorder (MDD) onto the biological axis defined by the neuromarker and explored the biological continuity of ASD with SCZ and MDD. We observed that SCZ, but not MDD, was located proximate to ASD on the biological dimension defined by the ASD neuromarker. The successful generalization in multifarious datasets and the observed relations of ASD with SCZ on the biological dimensions provide new insights for a deeper understanding of ASD.

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Conflict of interest statement

Competing interests: MK is an inventor of patents owned by the Advanced Telecommunications Research Institute International related to the present work (PCT/JP2014/061544 [WO2014178323] and JP2015-228970/6195329). AY and MK are inventors of a patent application submitted by the Advanced Telecommunications Research Institute International related to the present work (JP2018-192842). YT is an employee of SHIONOGI & CO., LTD.

Figures

**Fig. 1.. The classification performance of the ASD classifier in the discovery and adult validation datasets.**
(A) The probability of the ASD diagnosis in the discovery dataset. (B) The probability of the ASD diagnosis in the ABIDE adult validation dataset. (C) The probability of the ASD diagnosis in the Japanese adult validation dataset. **Abbreviations:** AUC: area under the curve, ASD: autism spectrum disorder, MCC: Matthews correlation coefficient, and TDC: typically developing control.

**Fig. 2.. The classification performance of the ASD classifier in the child and adolescent validation datasets.**
(A) The probability of ASD diagnosis in children. (B) The probability of ASD diagnosis in adolescents. **Abbreviations:** AUC: area under the curve, ASD: autism spectrum disorder, MCC: Matthews correlation coefficient, and TDC: typically developing control.

**Fig. 3.. The spatial distribution and network-based characterization of discriminative functional connections for the ASD diagnosis.**
(A) The spatial distribution of discriminative hyper-connections and affected brain regions for the ASD diagnosis. (B) The spatial distribution of discriminative hypo-connections and affected brain regions for the ASD diagnosis. The node color represents the corresponding resting-state network. (C) Network-based characterization of hyper-connections. (D) Network-based characterization of hypo-connections. **Abbreviations:** ASD: autism spectrum disorder, DAN: dorsal attention network, DMN: default mode network, FPN: frontoparietal network, TDC: typically developing control, and VAN: ventral attention network.

**Fig. 4.. The distribution of atypical functional connections that are consistent across the datasets.**
(A) The spatial distribution of discriminative hyper-connections consistent across cohorts. (B) The spatial distribution of discriminative hypo-connections consistent across cohorts. (C) Pie-donut chart showing the details of reproducible hypo-and hyperconnections. **Abbreviations:** ABIDE: autism brain imaging data exchange, DAN: dorsal attention network, DMN: default mode network, FPN: frontoparietal network, L: left, N: Negative, P: positive, R: right, and VAN: ventral attention network.

**Fig. 5.. Sensitivity of each neuromarker to other psychiatric disorders and dimensional relationships between ASD and other psychiatric disorders.**
(A) Sensitivity of the neuromarker for autism spectrum disorder (ASD) to schizophrenia (SCZ) and major depressive disorder (MDD). (B) Sensitivity of the SCZ neuromarker to ASD and MDD. (C) Sensitivity of the MDD neuromarker to ASD and SCZ. (D) Dimensional relationship between the ASD-ness and SCZ-ness defined by the diagnostic probability in ASD and SCZ classifiers, respectively. (E) Dimensional relationship between the ASD-ness and MDD-ness defined by the diagnostic probability in ASD and MDD neuromarkers, respectively.

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References

1. Parellada M. et al. In Search of Biomarkers to Guide Interventions in Autism Spectrum Disorder: A Systematic Review. Am. J. Psychiatry 180, 23–40 (2023). - PMC - PubMed
1. Cortese S. et al. Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: a systematic review. World Psychiatry 22, 129–149 (2023). - PMC - PubMed
1. Hallmayer J. et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch. Gen. Psychiatry 68, 1095–1102 (2011). - PMC - PubMed
1. Colvert E. et al. Heritability of Autism Spectrum Disorder in a UK Population-Based Twin Sample. JAMA Psychiatry 72, 415–423 (2015). - PMC - PubMed
1. Floris D. L. et al. The Link Between Autism and Sex-Related Neuroanatomy, and Associated Cognition and Gene Expression. Am. J. Psychiatry appiajp20220194 (2022). - PubMed

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This is a preprint.

Generalizable neuromarker for autism spectrum disorder across imaging sites and developmental stages: A multi-site study

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Generalizable neuromarker for autism spectrum disorder across imaging sites and developmental stages: A multi-site study

Authors

Affiliations

Update in

Abstract

Conflict of interest statement

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