Upregulation of reward mesolimbic activity and immune response to vaccination: a randomized controlled trial

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Requests for de-identified data can be directed at the corresponding author (T.H., talma@tlvmc.gov.il). All requests for data sharing will be reviewed by the Tel Aviv Sourasky Medical Center IRB committee to verify whether the request is subject to any intellectual property or confidentiality obligations. Requests will be reviewed on the basis of scientific merit, ethical review, available resources and regulatory requirements and will be responded within 90 days. After approval of a proposal, anonymized individual-level data will be made available for reuse in accordance with the signed consent IRB form. A signed data access agreement with the collaborator is required before accessing shared data.

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Acknowledgements

This study was funded by Joy Ventures foundation and by KAMIN program in the Israeli ministry of innovation (grant 2029678; A.R. and T.H.) and Teva Bio-Innovation Forum (N.L.). A.R. would like to thank the AMRF Adelson Family Foundation support. We thank Y. Benjamini for his statistical advice, N. Noy for her assistance in creating the graphical illustrations depicted in Fig. 1, A. Kuzli and M. Szwarcwort for their assistance in measuring plasma antibody titers, S. Schwartzbaum for her help with editing, and R. Cohen for his inspiration and encouragement for pursuing this animal-to-human translation effort.

Author information

Author notes

  1. These authors contributed equally: Nitzan Lubianiker, Tamar Koren, Asya Rolls, Talma Hendler.

Authors and Affiliations

  1. School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel

    Nitzan Lubianiker, Itamar Jalon & Talma Hendler

  2. Department of Psychology, Yale University, New Haven, CT, USA

    Nitzan Lubianiker

  3. Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA

    Nitzan Lubianiker & Itamar Jalon

  4. Department of Pathology, Tel Aviv Sourasky Medical Center, in affiliation with the Gray Faculty of Medical and Health Sciences at Tel Aviv University, Tel Aviv, Israel

    Tamar Koren, Margarita Sirotkin, Hilla Azulay-Debby & Asya Rolls

  5. School of Neuroscience, Biochemistry and Biophysics, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

    Tamar Koren, Margarita Sirotkin, Hilla Azulay-Debby & Asya Rolls

  6. Sagol Brain Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Meshi Djerasi, Neomi Singer, Avigail Lerner, Haggai Sharon & Talma Hendler

  7. Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

    Meshi Djerasi, Neomi Singer, Avigail Lerner & Talma Hendler

  8. Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel

    Roi Sar-el, Haggai Sharon & Talma Hendler

  9. The Tel-Aviv University Center for AI and Data Science, Tel Aviv, Israel

    Moni Shahar

  10. Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel

    Asya Rolls

Authors

  1. Nitzan Lubianiker
  2. Tamar Koren
  3. Meshi Djerasi
  4. Margarita Sirotkin
  5. Neomi Singer
  6. Itamar Jalon
  7. Avigail Lerner
  8. Roi Sar-el
  9. Haggai Sharon
  10. Moni Shahar
  11. Hilla Azulay-Debby
  12. Asya Rolls
  13. Talma Hendler

Contributions

N.L., T.K., A.R. and T.H. conceptualized the study and designed the experiments. N.L. and T.H conceptualized the MSQ questionnaire. N.L. developed the randomized-network control condition and the mental strategies characterization protocol. I.J. and N.S. developed online fMRI-NF analysis pipelines. N.L. and M.D. collected the behavioral, neural, and mental data. A.L., R.S. and H.S. collected blood samples and vaccinated participants. N.L. and M.D. analyzed the behavioral and neuroimaging data. T.K., R.S. and H.A.D. collected and analyzed the immunological data. M.S. provided statistical advice. A.R. and T.H. secured funding and supervised the study. N.L., T.K., A.R. and T.H. wrote the paper. All authors edited the paper.

Corresponding authors

Correspondence to Nitzan Lubianiker, Asya Rolls or Talma Hendler.

Ethics declarations

Competing interests

T.H. is the Chief Medical Scientist and Chair of the advisory board in GrayMatters Health. T.H., A.R., N.L. and T.K. have a filed patent related to the topic of this paper in the United States Patent and Trademark Office (application number: 17/435.906; Title of Invention: Neurofeedback and Induction of an Immune Response). The other authors declare no competing interests.

Peer review

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Nature Medicine thanks Ulrike Bingel, Marta Peciña and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Jerome Staal, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Offline functional localization of the reward mesolimbic network. a. Reward anticipation contrast map.

Whole-brain results for the high vs neutral reward anticipation contrast during the Monetary Incentive Delay (MID) task. The overlaid predefined meta-analytic masks of the mesolimbic system, taken from refs. 57,66, are shown in white. Abbreviations: Nucleus Accumbens (Nac); Ventral Tegmental Area (VTA). Statistical threshold was set at a cluster-level p(FWE) < .05. b. ROIs of the reward mesolimbic network. The offline functional localization of the reward mesolimbic regions. For the VTA, the predefined anatomical mask57 was intersected with the high>neutral reward anticipation maps presented in A. For the bilateral Nac, a 5 mm sphere was created around the peak activation voxel within the 8 mm predefined Nac masks (defined based on reward anticipation meta-analysis66).

Extended Data Fig. 2 Randomized Network control condition.

a. Conceptual scheme. In randomized ROI-NF, each participant is randomly assigned to one of K subgroups of different functionally defined neural targets (colored in pink, orange, and yellow). While in each sub-group, a specific neural target is modulated along with the general task processes (colored in green – control, learning and reward processes), group-level modulations (right panel) include only the averaged (non-specific) general processes common to all subgroups (that is the target process specific to each subgroup is averaged over the whole group). Conversely, in a typical experimental NF group, all participants modulate both the general and target processes (colored in green and blue, respectively). Therefore, group-level modulations include both the general processes and the reoccurring target process modulations. Consequently, differences in outcome effects (such as immune function) between groups can be attributed solely to the target-specific effects (Figure adapted from ref. 10). b. Neural networks of subgroups. Targets of the randomized ROI-NF control condition. All target networks were selected from meta-analyses of fMRI studies on specific functional processes. MNI coordinates: T1. Spatial navigation network76: right medial temporal lobe: 26, -35, -11; left medial temporal lobe: -26, -47, -9; left posterior cingulate: -15, -59, 19; T2. Arithmetic processing network77: right SPL: 29, -66, 49; left dlpfc: -45, 32, 29; left precuneus: -28, -71, 33; T3; Motor imagery network78: right cerebellum: 32, -62, -28; left cerebellum: -32, -56, -30; left precentral gyrus: -26, -2, 58; T4. Auditory imagery network79: right STG:64, -30, 9; left IFG: -48, 24, −5; left precentral gyrus: -52 1 47.

Extended Data Fig. 3 Mental Strategies Questionnaire for Neurofeedback (MSQ-NF).

Following practice, participants fill out the MSQ-NF for each strategy applied during the session, based on their logged choices during training. “Other” strategies, as well as those with predefined names, are verbally described, and then each strategy is labeled across the MSQ space.

Extended Data Fig. 4 BOLD activity during the last NF session across conditions and groups.

a. Upregulate>Rest contrast, showing differing regulation effects per group (reward ml NF – light blue, randomized ROI NF – pink). b. Feedback contrast. c. Choice contrast. Abbreviations: right Insula (r Ins); subgenual ACC (sgACC); Thalamus (Thal), ventromedial prefrontal cortex (vmpfc). The VTA and bilateral Nac ROIs are overlaid in white.

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Lubianiker, N., Koren, T., Djerasi, M. et al. Upregulation of reward mesolimbic activity and immune response to vaccination: a randomized controlled trial. Nat Med 32, 572–581 (2026). https://doi.org/10.1038/s41591-025-04140-5

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