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Multimodal brain imaging of insomnia, depression and anxiety symptoms indicates transdiagnostic commonalities and differences

Nature Mental Health volume 3, pages 517–529 (2025)Cite this article

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Abstract

Insomnia disorder, major depressive disorder and anxiety disorders are the most common mental health conditions, often co-occurring and sharing genetic risk factors, suggesting possible common brain mechanisms. Here we analyzed multimodal magnetic resonance imaging data from over 25,604 UK Biobank participants to identify shared versus symptom-specific brain features associated with symptom severity of these disorders. Smaller total cortical surface area, smaller thalamic volumes and weaker functional connectivity were linked to more severe symptoms of all three disorders. Disorder-specific symptom severity associations were also observed: smaller reward-related subcortical regions were associated with more severe insomnia symptoms; thinner cortices in language, reward and limbic regions with more severe depressive symptoms; and weaker amygdala reactivity and functional connectivity of dopamine-, glutamate- and histamine-enriched regions with more severe anxiety symptoms. These symptom-specific associations were often in parts of the amygdala–hippocampal–medial prefrontal circuit, highlighting the interconnectedness of these disorders and suggesting new pathways for research and treatment.

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Fig. 1: Associations of brain morphology and severity of insomnia, depression and anxiety symptoms.
Fig. 2: Functional annotation of regional brain associations.
Fig. 3: Associations of structural and functional connectivity with symptom severity of insomnia, depression and anxiety.
Fig. 4: Summary of cross-modal findings.

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Data availability

The phenotype and MRI data from the UK Biobank that were used in this study are available upon application via UK Biobank at https://www.ukbiobank.ac.uk/register-apply. Cognitive–emotional annotations were obtained using data available via GitHub at https://github.com/ehbeam/neuro-knowledge-engine. Neurotransmission systems were derived from data available via GitHub at https://github.com/netneurolab/hansen_receptors.

Code availability

Structural and functional connectivity was reconstructed using CATO, whose source code is available via GitHub at https://github.com/dutchconnectomelab/CATO. Brain plots were visualized using the Simple Brain Plot toolbox65 available via GitHub at https://github.com/dutchconnectomelab/Simple-Brain-Plot. MATLAB code used in the statistical analyses is available via GitHub at https://github.com/Sleep-and-Cognition/multimodal-insomnia-depression-anxiety.

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Acknowledgements

This work has received funding from ZonMw, the Hague, the Netherlands, project no. 09120011910032 REMOVE, the European Research Council (ERC), Brussels, Belgium, Advanced Grant 101055383 OVERNIGHT, and the Dutch Research Council (NWO), the Hague, the Netherlands, VENI 201G.064 (to J.E.S.); from the Dutch Research Council (NWO), the Hague, the Netherlands, VIDI 452-16-015 (to M.P.v.d.H.); and from the ERC under the European Union’s Horizon 2020 research and innovation program (grant agreement no. ERC CONNECT 101001062) (to M.P.v.d.H.). This work is co-funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council Executive Agency. Neither the European Union nor the granting authority can be held responsible for them.

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Authors and Affiliations

  1. Department of Sleep and Cognition, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands

    Siemon C. de Lange, Elleke Tissink, Tom Bresser & Eus J. W. van Someren

  2. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands

    Siemon C. de Lange, Tom Bresser, Jeanne E. Savage, Danielle Posthuma & Martijn P. van den Heuvel

  3. Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands

    Danielle Posthuma & Martijn P. van den Heuvel

  4. Department of Integrative Neurophysiology, Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands

    Eus J. W. van Someren

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  1. Siemon C. de Lange
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Contributions

S.C.d.L.: conceptualization; data curation; writing—original draft; formal analysis; methodology; writing—reviewing and editing. E.T.: data curation; methodology; writing—review and editing. T.B.: methodology; writing—review and editing. J.E.S.: data curation; methodology; writing—review and editing. D.P.: resources; methodology; writing—review and editing. M.P.v.d.H.: resources; methodology; writing—review and editing. E.J.W.v.S.: conceptualization; funding acquisition; methodology; writing—original draft; writing—reviewing and editing.

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Correspondence to Eus J. W. van Someren.

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Nature Mental Health thanks Julian Mutz, Edward Pace-Schott and Siyi Yu for their contribution to the peer review of this work.

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Supplementary methods, results, discussion, references, Figs. 1–14 and Tables 1–7.

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de Lange, S.C., Tissink, E., Bresser, T. et al. Multimodal brain imaging of insomnia, depression and anxiety symptoms indicates transdiagnostic commonalities and differences. Nat. Mental Health 3, 517–529 (2025). https://doi.org/10.1038/s44220-025-00412-8

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