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Neural variability in three major psychiatric disorders

Molecular Psychiatry volume 28, pages 5217–5227 (2023)Cite this article

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Abstract

Across the major psychiatric disorders (MPDs), a shared disruption in brain physiology is suspected. Here we investigate the neural variability at rest, a well-established behavior-relevant marker of brain function, and probe its basis in gene expression and neurotransmitter receptor profiles across the MPDs. We recruited 219 healthy controls and 279 patients with schizophrenia, major depressive disorder, or bipolar disorders (manic or depressive state). The standard deviation of blood oxygenation level-dependent signal (SDBOLD) obtained from resting-state fMRI was used to characterize neural variability. Transdiagnostic disruptions in SDBOLD patterns and their relationships with clinical symptoms and cognitive functions were tested by partial least-squares correlation. Moving beyond the clinical sample, spatial correlations between the observed patterns of SDBOLD disruption and postmortem gene expressions, Neurosynth meta-analytic cognitive functions, and neurotransmitter receptor profiles were estimated. Two transdiagnostic patterns of disrupted SDBOLD were discovered. Pattern 1 is exhibited in all diagnostic groups and is most pronounced in schizophrenia, characterized by higher SDBOLD in the language/auditory networks but lower SDBOLD in the default mode/sensorimotor networks. In comparison, pattern 2 is only exhibited in unipolar and bipolar depression, characterized by higher SDBOLD in the default mode/salience networks but lower SDBOLD in the sensorimotor network. The expression of pattern 1 related to the severity of clinical symptoms and cognitive deficits across MPDs. The two disrupted patterns had distinct spatial correlations with gene expressions (e.g., neuronal projections/cellular processes), meta-analytic cognitive functions (e.g., language/memory), and neurotransmitter receptor expression profiles (e.g., D2/serotonin/opioid receptors). In conclusion, neural variability is a potential transdiagnostic biomarker of MPDs with a substantial amount of its spatial distribution explained by gene expressions and neurotransmitter receptor profiles. The pathophysiology of MPDs can be traced through the measures of neural variability at rest, with varying clinical-cognitive profiles arising from differential spatial patterns of aberrant variability.

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Fig. 1: A general overview of the main preprocessing pipeline and analyzing framework.
Fig. 2: Results of Group-PLSC.
Fig. 3: Results of Symptom-PLSC and spatial associations between SDBOLD aberrant patterns and Neurosynth meta-analytic cognitive terms.
Fig. 4: Associations between spatial patterns of bootstrap ratios of SDBOLD aberrant patterns and densities of neurotransmitter receptors.
Fig. 5: Results of Gene-PLSC and enrichments analyses.

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Data availability

Microarray data can be downloaded and preprocessed with abagen toolbox (https://github.com/rmarkello/abagen). Pre-calculated meta-analytic cognition-relevant activation map of Neurosynth can be downloaded from BrainStat toolbox (https://github.com/MICA-MNI/BrainStat). Neurotransmitter receptor density maps were downloaded with neuromap toolbox (https://netneurolab.github.io/neuromaps/index.html).

Code availability

All codes for analysis can be used or downloaded online from following website: for PLSC (https://github.com/danizoeller/myPLS/), for spatial correlation tests (https://netneurolab.github.io/neuromaps/index.html) and for gene enrichment analysis with GOrilla (http://cbl-gorilla.cs.technion.ac.il/). We also provide the fully documented codes in GitHub (https://github.com/weiwei-wch/SDBOLD_MP) of all the analyzes for replication.

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Acknowledgements

We thank all of patients and health individuals and others who participated in this study. This work was partly supported by National Natural Science Foundation of China (grant number 81920108018 to TL. and PS, 82001410 to WW, and 82230046 to TL.), the Key R & D Program of Zhejiang (2022C03096 to TL), Project for Hangzhou Medical Disciplines of Excellence & Key Project for Hangzhou Medical Disciplines (grant number 202004A11 to TL), and special Foundation for Brain Research from Science and Technology Program of Guangdong (2018B030334001 to TL). LP acknowledges research support from the Monique H. Bourgeois Chair in Developmental Disorders and Graham Boeckh Foundation (Douglas Research Centre, McGill University) and salary award from the Fonds de recherche du Quebec-Sante ́ (FRQS).

Author information

Authors and Affiliations

  1. Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310013, China

    Wei Wei, Yamin Zhang, Xiaojing Li, Hua Yu, Wanjun Guo, Wei Deng & Tao Li

  2. Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China

    Wei Wei, Yamin Zhang, Xiaojing Li, Hua Yu, Wanjun Guo, Wei Deng & Tao Li

  3. NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou, 310058, China

    Wei Wei, Yamin Zhang, Xiaojing Li, Hua Yu, Wanjun Guo, Wei Deng & Tao Li

  4. Psychiatric Laboratory and Mental Health Center, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China

    Lihong Deng, Chunxia Qiao, Yubing Yin, Lingqi Jian, Mingli Li, Qiang Wang, Xiaohong Ma & Liansheng Zhao

  5. Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Pak C. Sham

  6. Centre for PanorOmic Sciences, The University of Hong Kong, Hong Kong SAR, China

    Pak C. Sham

  7. State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong SAR, China

    Pak C. Sham

  8. Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada

    Lena Palaniyappan

  9. Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada

    Lena Palaniyappan

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  1. Wei Wei
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Contributions

WW, XM, LZ, PS, and TL concepted and designed this research. WW, LD, CQ, YY, YZ, XL, HY, LJ, ML, WG, QW, WD, XM, and LZ collected data. WW, LD, CQ, QW, WD, XM, and LZ performed data quality control. WW, LD, WD, and LP analyzed data. WW, PS, LP, and TL drafted and revised the paper.

Corresponding authors

Correspondence to Lena Palaniyappan or Tao Li.

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Competing interests

LP reports personal fees from Janssen Canada, Otsuka Canada, SPMM Course Limited, UK, Canadian Psychiatric Association; book royalties from Oxford University Press; investigator-initiated educational grants from Janssen Canada, Sunovion and Otsuka Canada outside the submitted work. The other authors declare no competing interests.

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Wei, W., Deng, L., Qiao, C. et al. Neural variability in three major psychiatric disorders. Mol Psychiatry 28, 5217–5227 (2023). https://doi.org/10.1038/s41380-023-02164-2

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  • DOI: https://doi.org/10.1038/s41380-023-02164-2

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