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Altered basal forebrain regulation of intrinsic brain networks in depressive and anxiety disorders

Nature Mental Health volume 3, pages 1202–1213 (2025)Cite this article

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Abstract

Depressive and anxiety disorders are characterized by altered connectivity within and between the default mode network (DMN) and salience network. Basal forebrain subdivisions, critical for regulating network activity, remain understudied across these conditions. To address this gap, we analyzed 7-Tesla resting-state functional magnetic resonance imaging data from a transdiagnostic sample (n = 70), primarily with depressive and anxiety disorders, and healthy controls (n = 77). We used spectral dynamic causal modeling to assess effective connectivity between the medial septum/diagonal band (Ch1–3), nucleus basalis of Meynert (Ch4), ventral pallidum, and DMN and salience network. Healthy participants showed excitatory connectivity from Ch1–3 to the DMN and from Ch4 to the anterior insula. By contrast, clinical participants exhibited greater inhibitory Ch4 to DMN connectivity and increased excitatory connectivity from Ch4 to the anterior insula. Widespread Ch4 connectivity dysfunction may implicate the cholinergic system as a mechanistic and therapeutic target for depressive and anxiety disorders.

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Fig. 1: Visualization of the brain regions used in the spectral dynamic causal modeling analysis.
Fig. 2: Effective connectivity of the basal forebrain across healthy controls and clinical participants.
Fig. 3: LOOCV predicting group category for each participant.
Fig. 4: Association between effective connectivity and depressive and anxiety symptom severity in clinical participants.

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Data availability

Individual participant and group-level effective connectivity data for this study are available at https://github.com/alecJamieson/basal_forebrain_EC/tree/main/Data.

Code availability

MATLAB and R scripts used to generate the second-level results and associated figures of this study are also available at https://github.com/alecJamieson/basal_forebrain_EC.

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Acknowledgements

The authors thank B. Thai, H. Carey and A. Nielson for their contributions to data collection. The authors also acknowledge the facilities and scientific and technical assistance of the National Imaging Facility, a National Collaborative Research Infrastructure Strategy (NCRIS) capability, at the Melbourne Brain Centre Imaging Unit, University of Melbourne. In addition, the authors are grateful to Siemens for providing the MP2RAGE sequence as a ‘works in progress package’ and CMRR (University of Minnesota) for sharing the multiband EPI sequence. This study was supported by National Health and Medical Research Council of Australia (NHMRC) Project Grants (1161897) to B.J.H. and (1073041) to K.L.F. T.S. is supported by a NHMRC/MRFF Investigator Grant (MRF1193736), a BBRF Young Investigator Grant, and a University of Melbourne McKenzie Fellowship. J.A.A. and S.I. are supported by Australian Government Research Training Program Scholarships.

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Authors and Affiliations

  1. Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia

    Alec J. Jamieson, Trevor Steward, Christopher G. Davey, Sevil Ince, James A. Agathos & Ben J. Harrison

  2. Melbourne School of Psychological Sciences, The University of Melbourne, Parkville, Victoria, Australia

    Trevor Steward, Sevil Ince & Kim L. Felmingham

  3. The Melbourne Brain Centre Imaging Unit, Department of Radiology, The University of Melbourne, Parkville, Victoria, Australia

    Bradford A. Moffat & Rebecca K. Glarin

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  1. Alec J. Jamieson
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Contributions

A.J.J. conceived the study, performed the formal analyses, drafted the manuscript and prepared the visualizations. T.S. and B.J.H. contributed to conceptualization, secured funding and assisted in reviewing and editing the manuscript. C.G.D. contributed through critical review and editing. B.A.M. and K.L.F. supported the work through funding acquisition and provision of resources, respectively. S.I., J.A.A. and R.K.G. were involved in data collection and assisted in reviewing and editing the manuscript.

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Correspondence to Alec J. Jamieson.

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Jamieson, A.J., Steward, T., Davey, C.G. et al. Altered basal forebrain regulation of intrinsic brain networks in depressive and anxiety disorders. Nat. Mental Health 3, 1202–1213 (2025). https://doi.org/10.1038/s44220-025-00496-2

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  • DOI: https://doi.org/10.1038/s44220-025-00496-2

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