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Multimodal evidence of mediodorsal thalamus-prefrontal circuit dysfunctions in clinical high-risk for psychosis: findings from a combined 7T fMRI, MRSI and sleep Hd-EEG study

Molecular Psychiatry volume 30, pages 3384–3392 (2025)Cite this article

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Abstract

Deficits in mediodorsal thalamus-dorsolateral prefrontal cortex (MDT-DLPFC) resting-state functional magnetic resonance imaging (rs-fMRI) connectivity and prefrontal sleep spindles have been reported in chronic and early course schizophrenia. However, the presence of these alterations in clinical high-risk for psychosis (CHR), alongside their relationships with underlying neurotransmission and cognitive function, remains to be established. Thirty-one CHR and thirty-two HC underwent: 1) 7 T rs-fMRI; 2) 7 T magnetic resonance spectroscopy imaging (MRSI); and 3) sleep electroencephalography (EEG). Rs-fMRI connectivity was analyzed by seeding the whole thalamus (WT) and seven thalamic subsections. Spindle duration was computed across all EEG channels. GABA/creatine (Cr) and glutamate/Cr were calculated in DLPFC and MDT. Relative to HC, CHR showed WT-DLPFC hypoconnectivity (p-FDR = 0.001), especially involving MDT-DLPFC (p-FDR < 0.001) and reduced prefrontal spindle duration (t-stat = −2.64, p = 0.010), while no differences were found for MRSI neuro-metabolites. We then performed clustering analysis using rs-fMRI connectivity and spindle duration to identify CHR and HC subgroups and predict their working memory (WM) performance. A cluster with intact rs-fMRI and spindle duration included mostly HC (83.33% purity), while a cluster with both measures altered involved almost entirely CHR (91.66% purity) and showed worse WM performances. We also examined MRSI metabolites’ contribution to spindles and rs-fMRI connectivity with a within-group multivariable regression analysis. In HC, but not in CHR, MDT glutamate/Cr negatively predicted spindle duration and positively predicted MDT-DLPFC connectivity. Combined, these findings indicate that a multimodal neuroimaging approach can identify distinct thalamocortical dysfunctions in CHR individuals, thus informing future research aimed at developing personalized interventions in these individuals.

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Fig. 1: In CHR, resting-state functional connectivity and sleep spindle duration were decreased compared to HC subjects.
Fig. 2: Clustering analyses showed that combined MDT-DLPFC connectivity and spindle deficits best differentiated CHR from HC and identified individuals with worst WM performance.
Fig. 3: In HC, but not in CHR individuals, MRSI metabolites significantly added to predicting rs-fMRI connectivity and spindle duration while considering age and medication status as covariates.

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The data supporting the findings of this study are included in the main article and its supplementary materials. Additional details will be provided upon request by contacting the corresponding author.

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Acknowledgements

This work was supported by the NIMH R01MH113827 BRAINS award. We would also like to thank all the individuals who participated in the study.

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Author notes

  1. These authors contributed equally: Ahmadreza Keihani, Francesco L. Donati.

  2. These authors jointly supervised this work: Ahmad Mayeli, Fabio Ferrarelli.

Authors and Affiliations

  1. Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Ahmadreza Keihani, Francesco L. Donati, Sabine A. Janssen, Chloe A. Huston, Ahmad Mayeli & Fabio Ferrarelli

  2. Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Chan-Hong Moon

  3. Department Radiology, University of Missouri Columbia, Columbia, MO, USA

    Hoby P. Hetherington

  4. Department of Mathematics and Statistics, University of San Francisco, San Francisco, CA, USA

    James D. Wilson

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Contributions

AK, FD, AM, and FF helped with conceptualization, data curation, visualization, methodology and data analysis, investigation, validation, project administration, writing – review and editing. SJ and CH helped with running experiments, data curation and writing – review and editing. CM, HH helped with conceptualization, methodology and writing – review and editing. JW helped with methodology, conceptualization and writing – review and editing.

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Correspondence to Fabio Ferrarelli.

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Keihani, A., Donati, F.L., Janssen, S.A. et al. Multimodal evidence of mediodorsal thalamus-prefrontal circuit dysfunctions in clinical high-risk for psychosis: findings from a combined 7T fMRI, MRSI and sleep Hd-EEG study. Mol Psychiatry 30, 3384–3392 (2025). https://doi.org/10.1038/s41380-025-02924-2

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