Computational mechanisms of neuroimaging biomarkers uncovered by multicenter resting-state fMRI connectivity variation profile.

Journal: Molecular psychiatry
Published Date: Aug 7, 2025

Abstract

Resting-state functional connectivity (rsFC) is increasingly used to develop biomarkers for psychiatric disorders. Despite progress, development of the reliable and practical FC biomarker remains an unmet goal, particularly one that is clinically predictive at the individual level with generalizability, robustness, and accuracy. In this study, we propose a new approach to profile each connectivity from diverse perspective, encompassing not only disorder-related differences but also disorder-unrelated variations attributed to individual difference, within-subject across-runs, imaging protocol, and scanner factors. By leveraging over 1500 runs of 10-min resting-state data from 84 traveling-subjects across 29 sites and 900 participants of the case-control study with three psychiatric disorders, the disorder-related and disorder-unrelated FC variations were estimated for each individual FC. Using the FC profile information, we evaluated the effects of the disorder-related and disorder-unrelated variations on the output of the multi-connectivity biomarker trained with ensemble sparse classifiers generalizable to the multicenter data. Our analysis revealed hierarchical variations in individual functional connectivity, ranging from within-subject across-run variations, individual differences, disease effects, inter-scanner discrepancies, and protocol differences, which were drastically inverted by the sparse machine-learning algorithm. We found this inversion mainly attributed to suppression of both individual difference and within-subject across-runs variations relative to the disorder-related difference by weighted-summation of the selected FCs and ensemble averaging. This comprehensive approach will provide an analytical tool to develop reliable individual-level biomarkers.

Authors

  • Okito Yamashita
    From the Institute for Advanced Co-Creation Studies (T.Y.), Osaka University; Departments of Neurosurgery (T.Y., R.F., M.T., K.H., H.K., Y.S.) and Neuromodulation and Neurosurgery (K.H., Y.S.), Osaka University Graduate School of Medicine; Department of Neuroinformatics (T.Y., R.F., Y.K.), ATR Computational Neuroscience Laboratories, Kyoto, Japan; Computational and Biological Learning Laboratory, Department of Engineering (B.S.), University of Cambridge, UK; Center for Information and Neural Networks (B.S.), National Institute for Information and Communications Technology, Osaka; RIKEN Center for Advanced Intelligence Project (O.Y.), Tokyo; Department of Computational Brain Imaging (O.Y.), ATR Neural Information Analysis Laboratories, Kyoto; and Graduate School of Informatics (Y.K.), Kyoto University, Japan.
  • Ayumu Yamashita
    Brain Information Communication Research Laboratory Group, Advanced Telecommunications Research Institute International, Kyoto, Japan; Graduate School of Information Science and Technology, The University of Tokyo, Tokyo, Japan.
  • Yuji Takahara
    Brain Information Communication Research Laboratory Group, Advanced Telecommunications Research Institute International, Kyoto, Japan; Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan. Electronic address: yuji.takahara@shionogi.co.jp.
  • Yuki Sakai
    Division of Radiology, Department of Medical Technology, Kyushu University Hospital, Fukuoka, Japan.
  • Yasumasa Okamoto
    Department of Psychiatry and Neurosciences. Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
  • Go Okada
    Department of Psychiatry and Neurosciences. Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
  • Masahiro Takamura
    Department of Psychiatry and Neurosciences, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.
  • Motoaki Nakamura
    Medical Institute of Developmental Disabilities Research, Showa University, 6-11-11 Kitakarasuyama, Tokyo, 157-8577, Japan.
  • Takashi Itahashi
    Medical Institute of Developmental Disabilities Research, Showa University, 6-11-11 Kitakarasuyama, Tokyo, 157-8577, Japan.
  • Takashi Hanakawa
    Department of Integrated Neuroanatomy and Neuroimaging, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Hiroki Togo
    Department of Integrated Neuroanatomy and Neuroimaging, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Yujiro Yoshihara
    Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Toshiya Murai
    Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.
  • Tomohisa Okada
    Human Brain Research Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Jin Narumoto
    Department of Psychiatry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
  • Hidehiko Takahashi
    Department of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
  • Haruto Takagishi
    Brain Science Institute, Tamagawa University, Tokyo, Japan.
  • Koichi Hosomi
    Department of Neurosurgery, Osaka University Graduate School of Medicine.
  • Kiyoto Kasai
    Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • Naohiro Okada
    Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; The International Research Center for Neurointelligence (WPI-IRCN) at The University of Tokyo Institutes for Advanced Study (UTIAS), The University of Tokyo, Tokyo, Japan.
  • Osamu Abe
    From the Department of Radiology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 113-8655.
  • Hiroshi Imamizu
    Brain Information Communication Research Laboratory Group, Advanced Telecommunications Research Institute International, Kyoto, Japan; Department of Psychology, Graduate School of Humanities and Sociology, The University of Tokyo, Tokyo, Japan.
  • Takuya Hayashi
    Laboratory for Brain Connectomics Imaging, RIKEN Center for Biosystems Dynamics Research, Hyogo, Japan.
  • Shinsuke Koike
    Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan.
  • Saori C Tanaka
    Computational Neuroscience Labs, ATR Institute International, 619-0288, Kyoto, Japan.
  • Mitsuo Kawato
    ATR Brain Information Communication Research Laboratory Group, Advanced Telecommunications Research Institute International, Hikaridai, Kyoto, Japan. Electronic address: kawato@atr.jp.

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