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Older and wiser? The neural correlates of worry induction and reappraisal in older adults

Neuropsychopharmacology volume 50, pages 1949–1958 (2025)Cite this article

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Abstract

Severe worry is a transdiagnostic, highly prevalent symptom, difficult to treat and associated with significant morbidity in late life. Understanding the neural correlates of worry induction and reappraisal in older adults is key to developing novel treatments. We recruited 124 older adults ( ≥ 50 years old) with varying worry severity and clinical comorbidity (27% generalized anxiety disorder, 23% depressive disorders). Participants completed a naturalistic worry induction and reappraisal task during functional magnetic resonance imaging (fMRI), and they rated worry severity after each condition. We compared conditions using voxel-wise paired t-tests and conducted k-means clustering on regional activation to identify groups. We predicted the clinical features of cluster groupings using elastic net regression. Worry induction activated regions in default mode network, executive control network, anterior salience network, visual cortex, and subcortical regions (including basal ganglia and thalamus). Reappraisal was characterized by a broader activation of the cingulate and prefrontal cortex. Activity during worry induction clustered into a largely hyperactive compared to a largely hypoactive group. We accurately predicted clusters using elastic net regression and found the hypoactive group exhibited higher reflection, lower in-scanner worry, and greater cumulative illness compared to hyperactive group. We expand our previous work on neural correlates of worry induction and reappraisal, and we identify two novel neuro-endophenotypes: one with neural hyperactivation and high acute worry and another with relatively lower worry, higher reflection and neural hypoactivation. These results identify potential target networks in chronic severe worriers that may be amenable to neuromodulation. “By three methods we may learn wisdom: First, by reflection, which is noblest; Second, by imitation, which is easiest; and third by experience, which is the bitterest.” -Confucius

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Fig. 1: The design of the worry induction task.
Fig. 2: Main effect of the worry induction task.
Fig. 3: Clinical differences between the hypoactive (Hypo) and hyperactive (Hyper) clusters as identified by the elastic net regression.

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Acknowledgements

We would like to acknowledge the staff of the ARGO Neuroscience of Aging Research Group for their work and support.

Funding

This work was funded by NIMH R01MH108509, NIMH R01 MH 076079, NIMH R01 MH121619, R01GM113243, and NIA T32AG055381. HTK was funded on NIMH K01MH122741.

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Authors and Affiliations

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

    Helmet T. Karim, Andrew Gerlach, Dana L. Tudorascu, Meryl A. Butters, Cecile Ladouceur & Carmen Andreescu

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

    Helmet T. Karim

  3. Department of Psychology, Stanford University, Stanford, CA, USA

    James J. Gross

  4. Department of Clinical Psychology, Columbia University, New York, NY, USA

    Douglas Mennin

  5. Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA

    Dana L. Tudorascu

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  1. Helmet T. Karim
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  8. Carmen Andreescu
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Contributions

Study Conception and Design – HTK, JG, DM, DLT, MB, CA; Data Acquisition – HTK, CA; Analysis and Interpretation of Data – HTK, CA; Drafting – HTK, CA; and Critical Revision – HTK, JG, DM, AG, DLT, MB, CDL, CA.

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Correspondence to Carmen Andreescu.

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Karim, H.T., Gross, J.J., Mennin, D. et al. Older and wiser? The neural correlates of worry induction and reappraisal in older adults. Neuropsychopharmacol. 50, 1949–1958 (2025). https://doi.org/10.1038/s41386-025-02193-1

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