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Reward circuit function and treatment outcome following vALIC deep brain stimulation in treatment-resistant depression

Molecular Psychiatry volume 31, pages 209–216 (2026)Cite this article

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Abstract

Depression is associated with abnormal functioning of the reward circuit. Several deep brain stimulation (DBS) targets for treatment-resistant depression (TRD) directly modulate white matter bundles of the reward circuit. Here we investigated whether baseline reward processing in the brain is associated with ventral anterior limb of the internal capsule (vALIC) DBS outcome and whether vALIC DBS changes neural activity in the reward circuit. We studied fifteen patients with TRD who performed a monetary reward task during functional magnetic resonance imaging (fMRI) before vALIC DBS surgery, after DBS parameter optimization, and during a sham-controlled crossover phase. DBS devices were switched off during scanning for MRI safety reasons. Additionally, fifteen matched healthy controls were investigated twice to account for test-retest effects. We investigated brain responses to reward anticipation, loss anticipation, reward feedback and loss feedback. Results showed that lower baseline nucleus accumbens activation during loss anticipation and higher baseline caudate nucleus and midcingulate cortex activation during reward feedback processing were associated with worse DBS outcome. No significant changes in reward processing were observed following vALIC DBS in comparison to healthy controls or after active compared to sham stimulation. Instead, increased middle frontal gyrus responses following DBS to loss feedback was associated with better DBS outcome. These results suggest that DBS efficacy in TRD is related to individual differences in reward circuit functioning at baseline and to changes in middle frontal gyrus responses following DBS.

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Fig. 1: Negative association between nucleus accumbens response during loss anticipation at baseline and DBS outcome.
Fig. 2: Positive association between right midcingulate response to reward feedback at baseline and DBS outcome.
Fig. 3: Positive association between right caudate nucleus response to reward feedback at baseline and DBS outcome.
Fig. 4: Association between longitudinal changes in the left middle frontal gyrus response to loss feedback and DBS outcome.

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Data availability

De-identified participant data are available from the corresponding authors upon reasonable request and following completion of a signed data access agreement.

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Acknowledgements

This investigator-initiated study was funded by Medtronic Inc (25 DBS systems, in kind) and a research grant from ZonMw (nr. 171201008).

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Author notes

  1. These authors contributed equally: N. Runia, L. A. van de Mortel.

Authors and Affiliations

  1. Amsterdam UMC location University of Amsterdam, Department of Psychiatry, Meibergdreef 9, Amsterdam, The Netherlands

    N. Runia, L. A. van de Mortel, I. O. Bergfeld, J. Luigjes, D. A. J. P. Denys & G. A. van Wingen

  2. Amsterdam Neuroscience, Amsterdam, The Netherlands

    N. Runia, L. A. van de Mortel, I. O. Bergfeld, J. Luigjes, D. A. J. P. Denys & G. A. van Wingen

  3. Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Radiology and Nuclear Medicine, Boelelaan 1117, Amsterdam, The Netherlands

    C. L. C. Smith

  4. Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands

    C. L. C. Smith

  5. Martini Hospital, Department of Radiology and Nuclear Medicine, Groningen, the Netherlands

    B. P. de Kwaasteniet

  6. Department of Psychiatry, ETZ, location Elisabeth, Tilburg, The Netherlands

    J. van Laarhoven & P. Notten

  7. Department of Neurosurgery, ETZ, location Elisabeth, Tilburg, The Netherlands

    G. Beute

  8. Amsterdam UMC location University of Amsterdam, Department of Neurosurgery, Amsterdam, the Netherlands

    P. van den Munckhof & P. R. Schuurman

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Contributions

NR and LM contributed equally to this work. NR and LM conceptualized the study together with GW. Methodology was developed by NR, LM, and GW. Formal analyses were conducted by NR and LM. Investigation was carried out by all authors (NR, LM, CS, IB, BK, JL, JvL, PN, GB, PM, RS, DD, and GW). NR and LM prepared the original draft and visualizations. Supervision was provided by DD, IB, and GW. All authors (NR, LM, CS, IB, BK, JL, JvL, PN, GB, PM, RS, DD, and GW) reviewed and edited the manuscript and approved the final version.

Corresponding authors

Correspondence to N. Runia, L. A. van de Mortel or G. A. van Wingen.

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Competing interests

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This investigator-initiated study was funded by Medtronic Inc (25 DBS systems, in kind) and a grant from ZonMw (nr. 171201008). The funders had no role in the design, execution, and analysis of the study, nor in writing of the manuscript or the decision to publish. Nora Runia, Isidoor Bergfeld, Pepijn van den Munckhof, P. Richard Schuurman, Damiaan Denys, and Guido van Wingen currently execute an investigator-initiated clinical trial on deep brain stimulation for depression, which is funded by Boston Scientific (24 DBS systems in kind) and a grant of ZonMw (nr. 636310016). P. Richard Schuurman acts as consultant for Boston Scientific and Medtronic on educational events. All other authors do not declare any conflicts of interest.

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Runia, N., van de Mortel, L.A., Smith, C.L.C. et al. Reward circuit function and treatment outcome following vALIC deep brain stimulation in treatment-resistant depression. Mol Psychiatry 31, 209–216 (2026). https://doi.org/10.1038/s41380-025-03284-7

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