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Network homeostasis: functional brain network alterations and relapse in remitted late-life depression

Neuropsychopharmacology (2025)Cite this article

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Abstract

Late-life depression (LLD) is highly recurrent and associated with disability and increased mortality. In this study, we aim to identify neurobiological factors that are prospectively associated with relapse risk in late-life depression. We recruited 145 older adults (age ≥ 60): 102 recently remitted LLD participants and 43 healthy comparisons. Participants underwent baseline MRI and evaluation of depression symptoms/status for up to 2 years. We evaluated intrinsic network connectivity for 111 participants (39 healthy comparisons, 47 stable remitted, 25 relapsed). Compared to healthy comparisons, LLD participants had lower connectivity within the somatomotor network and greater connectivity between the executive control and default mode networks (DMN). Lower connectivity of DMN to somatomotor and salience networks was associated with relapse. Overall, connectivity of relapse participants was more similar to healthy comparisons than connectivity of stable remitted participants was. We found robust differences in network functional connectivity between stable remitted and relapsed participants. We also found evidence of neural “scarring,” or persistent functional network differences at baseline in all participants with a history of depression. Alterations in DMN connectivity were observed most prominently. Notably, the network structure of relapsed participants was more similar to healthy comparisons than stable remitted participants. These findings indicate that remission is associated with persistent functional network alterations while vulnerability to relapse is associated with a failure to establish a new stable homeostatic functional network structure.

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Fig. 1: Conceptualization of recurrence and relapse in late-life depression.
Fig. 2: Network connectivity differences for all remitted late-life depression (LLD) vs. healthy comparisons (Health.).
Fig. 3: Pairwise network connectivity differences between stable remitted (Rem.), relapse (Rel.), and healthy comparisons (Health.).
Fig. 4: Network connectivity differences associated with time to relapse.

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Data availability

Deidentified data is available upon reasonable request after all planned primary analyses have been completed.

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Acknowledgements

We’d like to thank the numerous staff at VUMC, Pitt, and UIC who helped administer the study protocol and process the data. This work was supported by National of Institute of Health grants R01 MH121619, R01 MH121620, R01 MH121384, K01 MH133913, R01 MH108509, K01 MH122741, T32 MH019986, and the National Center for Advancing Translational Sciences grants UL1 TR000445 and UL1 TR002243.

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Authors and Affiliations

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

    Andrew R. Gerlach, Helmet T. Karim, Antonija Kolobaric & Carmen Andreescu

  2. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA

    Andrew R. Gerlach & Helmet T. Karim

  3. Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, The Vanderbilt Center for Cognitive Medicine, Nashville, TN, USA

    Brian D. Boyd & Warren D. Taylor

  4. School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Kevin Kahru

  5. Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA, USA

    Robert T. Krafty

  6. Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA

    Olusola Ajilore

  7. Geriatric Research, Education, and Clinical Center, Veterans Affairs Tennessee Valley Health System, Nashville, TN, USA

    Warren D. Taylor

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  1. Andrew R. Gerlach
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Contributions

ARG—methodology, formal analysis, writing original draft, visualization; HTK—conceptualization, writing review and editing; AK—writing original draft, visualization; BDB—software, formal analysis, data curation; KK—writing original draft; RTK—conceptualization, supervision, writing review and editing; OA—conceptualization, funding acquisition, supervision, writing review and editing; WDT—conceptualization, funding acquisition, supervision, writing review and editing; CA—conceptualization, funding acquisition, supervision, writing review and editing.

Corresponding author

Correspondence to Carmen Andreescu.

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Competing interests

OA is a co-founder of Keywise AI, has served as a consultant for Sage Therapeutics and Otsuka, has received honoraria from Boehringer Ingelheim, and is on the advisory board for Blueprint Health and Embodied Labs. AK serves as a consultant for Radicle Science. No other authors have disclosures to report.

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Gerlach, A.R., Karim, H.T., Kolobaric, A. et al. Network homeostasis: functional brain network alterations and relapse in remitted late-life depression. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02138-8

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