Subcortical volumetric alterations in four major psychiatric disorders: a mega-analysis study of 5604 subjects and a volumetric data-driven approach for classification

doi:10.1038/s41380-023-02141-9

. 2023 Dec;28(12):5206-5216.

doi: 10.1038/s41380-023-02141-9. Epub 2023 Aug 4.

Subcortical volumetric alterations in four major psychiatric disorders: a mega-analysis study of 5604 subjects and a volumetric data-driven approach for classification

Naohiro Okada^{1

2}, Masaki Fukunaga³, Kenichiro Miura⁴, Kiyotaka Nemoto⁵, Junya Matsumoto⁴, Naoki Hashimoto⁶, Masahiro Kiyota¹, Kentaro Morita⁷, Daisuke Koshiyama¹, Kazutaka Ohi^{8

9}, Tsutomu Takahashi^{10

11}, Michihiko Koeda¹², Hidenaga Yamamori^{4

13

14}, Michiko Fujimoto^{4

13}, Yuka Yasuda^{4

15}, Naomi Hasegawa⁴, Hisashi Narita⁶, Satoshi Yokoyama¹⁶, Ryo Mishima¹⁷, Takahiko Kawashima¹⁷, Yuko Kobayashi¹⁷, Daiki Sasabayashi^{10

11}, Kenichiro Harada¹⁸, Maeri Yamamoto¹⁹, Yoji Hirano^{20

21}, Takashi Itahashi²², Masahito Nakataki²³, Ryu-Ichiro Hashimoto^{22

24}, Khin K Tha^{25

26}, Shinsuke Koike^{2

27

28}, Toshio Matsubara¹⁸, Go Okada¹⁶, Theo G M van Erp^{29

30}, Neda Jahanshad³¹, Reiji Yoshimura³², Osamu Abe³³, Toshiaki Onitsuka³⁴, Yoshiyuki Watanabe³⁵, Koji Matsuo³⁶, Hidenori Yamasue³⁷, Yasumasa Okamoto¹⁶, Michio Suzuki^{10

11}, Jessica A Turner³⁸, Paul M Thompson³¹, Norio Ozaki^{19

39}, Kiyoto Kasai^{1

2

27}, Ryota Hashimoto^{40

41}

Affiliations

¹ Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² The International Research Center for Neurointelligence (WPI-IRCN), The University of Tokyo Institutes for Advanced Study (UTIAS), Tokyo, Japan.
³ Division of Cerebral Integration, National Institute for Physiological Sciences, Aichi, Japan.
⁴ Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
⁵ Department of Psychiatry, Institute of Medicine, University of Tsukuba, Ibaraki, Japan.
⁶ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
⁷ Department of Rehabilitation, University of Tokyo Hospital, Tokyo, Japan.
⁸ Department of Psychiatry, Gifu University Graduate School of Medicine, Gifu, Japan.
⁹ Department of General Internal Medicine, Kanazawa Medical University, Ishikawa, Japan.
¹⁰ Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan.
¹¹ Research Center for Idling Brain Science, University of Toyama, Toyama, Japan.
¹² Department of Neuropsychiatry, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
¹³ Department of Psychiatry, Graduate School of Medicine, Osaka University, Osaka, Japan.
¹⁴ Japan Community Health Care Organization Osaka Hospital, Osaka, Japan.
¹⁵ Life Grow Brilliant Mental Clinic, Medical Corporation Foster, Osaka, Japan.
¹⁶ Department of Psychiatry and Neuroscience, Hiroshima University, Hiroshima, Japan.
¹⁷ Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹⁸ Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
¹⁹ Department of Psychiatry, Graduate School of Medicine, Nagoya University, Aichi, Japan.
²⁰ Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
²¹ Department of Psychiatry, Division of Clinical Neuroscience, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
²² Medical Institute of Developmental Disabilities Research, Showa University, Tokyo, Japan.
²³ Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
²⁴ Department of Language Sciences, Graduate School of Humanities, Tokyo Metropolitan University, Tokyo, Japan.
²⁵ Department of Diagnostic Imaging, Hokkaido University Faculty of Medicine, Hokkaido, Japan.
²⁶ Global Center for Biomedical Science and Engineering, Hokkaido University Faculty of Medicine, Hokkaido, Japan.
²⁷ University of Tokyo Institute for Diversity & Adaptation of Human Mind (UTIDAHM), Tokyo, Japan.
²⁸ Center for Evolutionary Cognitive Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan.
²⁹ Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA.
³⁰ Center for the Neurobiology of Learning and Memory, University of California Irvine, Irvine, CA, USA.
³¹ Imaging Genetics Center, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, CA, USA.
³² Department of Psychiatry, University of Occupational and Environmental Health, Fukuoka, Japan.
³³ Department of Radiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
³⁴ National Hospital Organization Sakakibara Hospital, Mie, Japan.
³⁵ Department of Radiology, Shiga University of Medical Science, Shiga, Japan.
³⁶ Department of Psychiatry, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
³⁷ Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka, Japan.
³⁸ Department of Psychiatry and Behavioral Health, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
³⁹ Pathophysiology of Mental Disorders, Graduate School of Medicine, Nagoya University, Aichi, Japan.
⁴⁰ Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan. ryotahashimoto55@ncnp.go.jp.
⁴¹ Department of Psychiatry, Graduate School of Medicine, Osaka University, Osaka, Japan. ryotahashimoto55@ncnp.go.jp.

PMID: 37537281
PMCID: PMC11041797
DOI: 10.1038/s41380-023-02141-9

Subcortical volumetric alterations in four major psychiatric disorders: a mega-analysis study of 5604 subjects and a volumetric data-driven approach for classification

Naohiro Okada et al. Mol Psychiatry. 2023 Dec.

. 2023 Dec;28(12):5206-5216.

doi: 10.1038/s41380-023-02141-9. Epub 2023 Aug 4.

Authors

Affiliations

¹ Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² The International Research Center for Neurointelligence (WPI-IRCN), The University of Tokyo Institutes for Advanced Study (UTIAS), Tokyo, Japan.
³ Division of Cerebral Integration, National Institute for Physiological Sciences, Aichi, Japan.
⁴ Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
⁵ Department of Psychiatry, Institute of Medicine, University of Tsukuba, Ibaraki, Japan.
⁶ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
⁷ Department of Rehabilitation, University of Tokyo Hospital, Tokyo, Japan.
⁸ Department of Psychiatry, Gifu University Graduate School of Medicine, Gifu, Japan.
⁹ Department of General Internal Medicine, Kanazawa Medical University, Ishikawa, Japan.
¹⁰ Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan.
¹¹ Research Center for Idling Brain Science, University of Toyama, Toyama, Japan.
¹² Department of Neuropsychiatry, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
¹³ Department of Psychiatry, Graduate School of Medicine, Osaka University, Osaka, Japan.
¹⁴ Japan Community Health Care Organization Osaka Hospital, Osaka, Japan.
¹⁵ Life Grow Brilliant Mental Clinic, Medical Corporation Foster, Osaka, Japan.
¹⁶ Department of Psychiatry and Neuroscience, Hiroshima University, Hiroshima, Japan.
¹⁷ Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹⁸ Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
¹⁹ Department of Psychiatry, Graduate School of Medicine, Nagoya University, Aichi, Japan.
²⁰ Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
²¹ Department of Psychiatry, Division of Clinical Neuroscience, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
²² Medical Institute of Developmental Disabilities Research, Showa University, Tokyo, Japan.
²³ Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
²⁴ Department of Language Sciences, Graduate School of Humanities, Tokyo Metropolitan University, Tokyo, Japan.
²⁵ Department of Diagnostic Imaging, Hokkaido University Faculty of Medicine, Hokkaido, Japan.
²⁶ Global Center for Biomedical Science and Engineering, Hokkaido University Faculty of Medicine, Hokkaido, Japan.
²⁷ University of Tokyo Institute for Diversity & Adaptation of Human Mind (UTIDAHM), Tokyo, Japan.
²⁸ Center for Evolutionary Cognitive Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan.
²⁹ Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA.
³⁰ Center for the Neurobiology of Learning and Memory, University of California Irvine, Irvine, CA, USA.
³¹ Imaging Genetics Center, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, CA, USA.
³² Department of Psychiatry, University of Occupational and Environmental Health, Fukuoka, Japan.
³³ Department of Radiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
³⁴ National Hospital Organization Sakakibara Hospital, Mie, Japan.
³⁵ Department of Radiology, Shiga University of Medical Science, Shiga, Japan.
³⁶ Department of Psychiatry, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
³⁷ Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka, Japan.
³⁸ Department of Psychiatry and Behavioral Health, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
³⁹ Pathophysiology of Mental Disorders, Graduate School of Medicine, Nagoya University, Aichi, Japan.
⁴⁰ Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan. ryotahashimoto55@ncnp.go.jp.
⁴¹ Department of Psychiatry, Graduate School of Medicine, Osaka University, Osaka, Japan. ryotahashimoto55@ncnp.go.jp.

PMID: 37537281
PMCID: PMC11041797
DOI: 10.1038/s41380-023-02141-9

Abstract

Differential diagnosis is sometimes difficult in practical psychiatric settings, in terms of using the current diagnostic system based on presenting symptoms and signs. The creation of a novel diagnostic system using objective biomarkers is expected to take place. Neuroimaging studies and others reported that subcortical brain structures are the hubs for various psycho-behavioral functions, while there are so far no neuroimaging data-driven clinical criteria overcoming limitations of the current diagnostic system, which would reflect cognitive/social functioning. Prior to the main analysis, we conducted a large-scale multisite study of subcortical volumetric and lateralization alterations in schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorder using T1-weighted images of 5604 subjects (3078 controls and 2526 patients). We demonstrated larger lateral ventricles volume in schizophrenia, bipolar disorder, and major depressive disorder, smaller hippocampus volume in schizophrenia and bipolar disorder, and schizophrenia-specific smaller amygdala, thalamus, and accumbens volumes and larger caudate, putamen, and pallidum volumes. In addition, we observed a leftward alteration of lateralization for pallidum volume specifically in schizophrenia. Moreover, as our main objective, we clustered the 5,604 subjects based on subcortical volumes, and explored whether data-driven clustering results can explain cognitive/social functioning in the subcohorts. We showed a four-biotype classification, namely extremely (Brain Biotype [BB] 1) and moderately smaller limbic regions (BB2), larger basal ganglia (BB3), and normal volumes (BB4), being associated with cognitive/social functioning. Specifically, BB1 and BB2-3 were associated with severe and mild cognitive/social impairment, respectively, while BB4 was characterized by normal cognitive/social functioning. Our results may lead to the future creation of novel biological data-driven psychiatric diagnostic criteria, which may be expected to be useful for prediction or therapeutic selection.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1**
Meta-analytic overall effect sizes for subcortical regional volume differences between HCs and subjects with SZ, BP, MDD, and ASD. A positive effect size indicates that subjects with psychiatric disorders had larger volumes than HCs. *uncorrected p < 0.05 and **Bonferroni-corrected p < 0.05. ICV intracranial volume, L left, R right.

**Fig. 2. Merged results from the ENIGMA and COCORO consortiums for subcortical regional volume differences (effect sizes) between HCs and subjects with SZ, BP, MDD, and ASD.**
a Results for SZ. b Results for BP. c Results for MDD. d Results for ASD. * represents uncorrected p < 0.05, ** represents Bonferroni-corrected p < 0.05, and *** represents false positive rate corrected p < 0.05. L left, R right, ICV intracranial volume.

**Fig. 3**
Meta-analytic overall effect sizes for differences in laterality indices for subcortical regional volume between HCs and subjects with SZ, BP, MDD, and ASD. A positive effect size indicates that subjects with psychiatric disorders had a leftward alteration of lateralization compared to HCs. *uncorrected p < 0.05 and **Bonferroni-corrected p < 0.05.

**Fig. 4. MRI data-driven clustering results and their association with diagnosis and cognitive/social functioning.**
a Mean normalized volumes of each subcortical region in each cluster are shown. An italic underlined number and a bold underlined number represent the minimum and maximum averaged normalized volume of each subcortical region across clusters, respectively. Moreover, percentages of each cluster in each diagnostic group are demonstrated. An italic underlined number and a bold underlined number represent a significantly lower and higher rate than expected, respectively. b Mean functioning scale scores in each cluster are displayed.

**Fig. 5. Four-biotype classification driven by subcortical regional volumes and its association with cognitive/social functioning.**
a Mean normalized volumes are illustrated with a color scale. b The characteristics of each brain biotype are summarized.

See this image and copyright information in PMC

Cited by

Highly demarcated structural alterations in the brain and impaired social incentive learning in Tbx1 heterozygous mice.
Hiramoto T, Sumiyoshi A, Kato R, Yamauchi T, Takano T, Kang G, Esparza M, Matsumura B, Stevens LJ, Hiroi YJ, Tanifuji T, Ryoke R, Nonaka H, Machida A, Nomoto K, Mogi K, Kikusui T, Kawashima R, Hiroi N. Hiramoto T, et al. Mol Psychiatry. 2024 Oct 27. doi: 10.1038/s41380-024-02797-x. Online ahead of print. Mol Psychiatry. 2024. PMID: 39463450
Cortical similarities in psychiatric and mood disorders identified in federated VBM analysis via COINSTAC.
Rootes-Murdy K, Panta S, Kelly R, Romero J, Quidé Y, Cairns MJ, Loughland C, Carr VJ, Catts SV, Jablensky A, Green MJ, Henskens F, Kiltschewskij D, Michie PT, Mowry B, Pantelis C, Rasser PE, Reay WR, Schall U, Scott RJ, Watkeys OJ, Roberts G, Mitchell PB, Fullerton JM, Overs BJ, Kikuchi M, Hashimoto R, Matsumoto J, Fukunaga M, Sachdev PS, Brodaty H, Wen W, Jiang J, Fani N, Ely TD, Lorio A, Stevens JS, Ressler K, Jovanovic T, van Rooij SJH, Federmann LM, Jockwitz C, Teumer A, Forstner AJ, Caspers S, Cichon S, Plis SM, Sarwate AD, Calhoun VD. Rootes-Murdy K, et al. Patterns (N Y). 2024 May 2;5(7):100987. doi: 10.1016/j.patter.2024.100987. eCollection 2024 Jul 12. Patterns (N Y). 2024. PMID: 39081570 Free PMC article.
Tablet-Based Cognitive and Eye Movement Measures as Accessible Tools for Schizophrenia Assessment: Multisite Usability Study.
Morita K, Miura K, Toyomaki A, Makinodan M, Ohi K, Hashimoto N, Yasuda Y, Mitsudo T, Higuchi F, Numata S, Yamada A, Aoki Y, Honda H, Mizui R, Honda M, Fujikane D, Matsumoto J, Hasegawa N, Ito S, Akiyama H, Onitsuka T, Satomura Y, Kasai K, Hashimoto R. Morita K, et al. JMIR Ment Health. 2024 May 30;11:e56668. doi: 10.2196/56668. JMIR Ment Health. 2024. PMID: 38815257 Free PMC article.
Longitudinal reduction in brain volume in patients with schizophrenia and its association with cognitive function.
Yamazaki R, Matsumoto J, Ito S, Nemoto K, Fukunaga M, Hashimoto N, Kodaka F, Takano H, Hasegawa N, Yasuda Y, Fujimoto M, Yamamori H, Watanabe Y, Miura K, Hashimoto R. Yamazaki R, et al. Neuropsychopharmacol Rep. 2024 Mar;44(1):206-215. doi: 10.1002/npr2.12423. Epub 2024 Feb 13. Neuropsychopharmacol Rep. 2024. PMID: 38348613 Free PMC article.
Aberrant brain dynamics of large-scale functional networks across schizophrenia and mood disorder.
Ishida T, Yamada S, Yasuda K, Uenishi S, Tamaki A, Tabata M, Ikeda N, Takahashi S, Kimoto S. Ishida T, et al. Neuroimage Clin. 2024;41:103574. doi: 10.1016/j.nicl.2024.103574. Epub 2024 Feb 10. Neuroimage Clin. 2024. PMID: 38346380 Free PMC article.

See all "Cited by" articles

References

1. Strauss GP, Cohen AS. A transdiagnostic review of negative symptom phenomenology and etiology. Schizophr Bull. 2017;43:712–719. - PMC - PubMed
1. Fellowes S. Symptom modelling can be influenced by psychiatric categories: choices for research domain criteria (RDoC) Theor Med Bioeth. 2017;38:279–94. - PMC - PubMed
1. Bora E, Yücel M, Pantelis C. Cognitive impairment in schizophrenia and affective psychoses: implications for DSM-V criteria and beyond. Schizophr Bull. 2010;36:36–42. - PMC - PubMed
1. Jain R, Maletic V, McIntyre RS. Diagnosing and treating patients with mixed features. J Clin Psychiatry. 2017;78:1091–102. - PubMed
1. Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010;167:748–51. - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Consumer Health Information
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

[1] Strauss GP, Cohen AS. A transdiagnostic review of negative symptom phenomenology and etiology. Schizophr Bull. 2017;43:712–719. - PMC - PubMed

[2] Strauss GP, Cohen AS. A transdiagnostic review of negative symptom phenomenology and etiology. Schizophr Bull. 2017;43:712–719. - PMC - PubMed

[3] Fellowes S. Symptom modelling can be influenced by psychiatric categories: choices for research domain criteria (RDoC) Theor Med Bioeth. 2017;38:279–94. - PMC - PubMed

[4] Fellowes S. Symptom modelling can be influenced by psychiatric categories: choices for research domain criteria (RDoC) Theor Med Bioeth. 2017;38:279–94. - PMC - PubMed

[5] Bora E, Yücel M, Pantelis C. Cognitive impairment in schizophrenia and affective psychoses: implications for DSM-V criteria and beyond. Schizophr Bull. 2010;36:36–42. - PMC - PubMed

[6] Bora E, Yücel M, Pantelis C. Cognitive impairment in schizophrenia and affective psychoses: implications for DSM-V criteria and beyond. Schizophr Bull. 2010;36:36–42. - PMC - PubMed

[7] Jain R, Maletic V, McIntyre RS. Diagnosing and treating patients with mixed features. J Clin Psychiatry. 2017;78:1091–102. - PubMed

[8] Jain R, Maletic V, McIntyre RS. Diagnosing and treating patients with mixed features. J Clin Psychiatry. 2017;78:1091–102. - PubMed

[9] Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010;167:748–51. - PubMed

[10] Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010;167:748–51. - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Subcortical volumetric alterations in four major psychiatric disorders: a mega-analysis study of 5604 subjects and a volumetric data-driven approach for classification

Affiliations

Subcortical volumetric alterations in four major psychiatric disorders: a mega-analysis study of 5604 subjects and a volumetric data-driven approach for classification

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous