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

11 min read Original article ↗
  • Wager, T. D. & Atlas, L. Y. The neuroscience of placebo effects: connecting context, learning and health. Nat. Rev. Neurosci. 16, 403–418 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gershman, S. J. & Uchida, N. Believing in dopamine. Nat. Rev. Neurosci. 20, 703–714 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ben-Shaanan, T. L. et al. Activation of the reward system boosts innate and adaptive immunity. Nat. Med 22, 940–944 (2016).

    Article  CAS  PubMed  Google Scholar 

  • Ben-Shaanan, T. L. et al. Modulation of anti-tumor immunity by the brain’s reward system. Nat. Commun. 9, 2723 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  • Kayama, T., Ikegaya, Y. & Sasaki, T. Phasic firing of dopaminergic neurons in the ventral tegmental area triggers peripheral immune responses. Sci. Rep. 12, 1447 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Costi, S. et al. Peripheral immune cell reactivity and neural response to reward in patients with depression and anhedonia. Transl. Psychiatry 11, 565 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chat, I. K.-Y. et al. Goal-striving tendencies moderate the relationship between reward-related brain function and peripheral inflammation. Brain Behav. Immun. 94, 60–70 (2021).

  • Treadway, M. T. et al. Association between interleukin-6 and striatal prediction-error signals following acute stress in healthy female participants. Biol. Psychiatry 82, 570–577 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sitaram, R. et al. Closed-loop brain training: the science of neurofeedback. Nat. Rev. Neurosci. 18, 86–100 (2017).

    Article  CAS  PubMed  Google Scholar 

  • Lubianiker, N. et al. Process-based framework for precise neuromodulation. Nat. Hum. Behav. 3, 436–445 (2019).

    Article  PubMed  Google Scholar 

  • Lubianiker, N., Paret, C., Dayan, P. & Hendler, T. Neurofeedback through the lens of reinforcement learning. Trends Neurosci. 45, 579–593 (2022).

    Article  CAS  PubMed  Google Scholar 

  • Klöbl, M. et al. Reinforcement and punishment shape the learning dynamics in fMRI neurofeedback. Front. Hum. Neurosci. 14, 304 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  • Oblak, E. F., Lewis-Peacock, J. A. & Sulzer, J. S. Self-regulation strategy, feedback timing and hemodynamic properties modulate learning in a simulated fMRI neurofeedback environment. PLoS Comput. Biol. 13, e1005681 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  • Zoefel, B., Huster, R. J. & Herrmann, C. S. Neurofeedback training of the upper alpha frequency band in EEG improves cognitive performance. NeuroImage 54, 1427–1431 (2011).

    Article  PubMed  Google Scholar 

  • Autenrieth, M., Kober, S. E., Neuper, C. & Wood, G. How much do strategy reports tell about the outcomes of neurofeedback training? A study on the voluntary up-regulation of the sensorimotor rhythm. Front. Hum. Neurosci. 14, 218 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  • Qiu, S. et al. Significant transcriptome and cytokine changes in hepatitis B vaccine non-responders revealed by genome-wide comparative analysis. Hum. Vaccin. Immunother. 14, 1763–1772 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  • Kirschner, M. et al. Ventral striatal hypoactivation is associated with apathy but not diminished expression in patients with schizophrenia. J. Psychiatry Neurosci. 41, 152–161 (2016).

    Article  PubMed  Google Scholar 

  • Ohmann, H. A., Kuper, N. & Wacker, J. Examining the reliability and validity of two versions of the Effort-Expenditure for Rewards Task (EEfRT). PLOS ONE 17, e0262902 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gonen, T. et al. Human mesostriatal response tracks motivational tendencies under naturalistic goal conflict. Soc. Cogn. Affect. Neurosci. 11, 961–972 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  • Munshi, S. & Rosenkranz, J. A. Effects of peripheral immune challenge on in vivo firing of basolateral amygdala neurons in adult male rats. Neuroscience 390, 174–186 (2018).

    Article  CAS  PubMed  Google Scholar 

  • Zhu, X. et al. Somatosensory cortex and central amygdala regulate neuropathic pain-mediated peripheral immune response via vagal projections to the spleen. Nat. Neurosci. 27, 471–483 (2024).

    Article  CAS  PubMed  Google Scholar 

  • Boukezzi, S. et al. Exaggerated amygdala response to threat and association with immune hyperactivity in depression. Brain, Behav., Immun. 104, 205–212 (2022).

    Article  CAS  PubMed  Google Scholar 

  • Yin, L. et al. Inflammation and decreased functional connectivity in a widely-distributed network in depression: Centralized effects in the ventral medial prefrontal cortex. Brain Behav. Immun. 80, 657–666 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  • Hui, M. & Beier, K. T. Defining the interconnectivity of the medial prefrontal cortex and ventral midbrain. Front. Mol. 15, 971349 (2022).

  • Jennings, J. H. et al. Distinct extended amygdala circuits for divergent motivational states. Nature 496, 224–228 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glimcher, P. W. Understanding dopamine and reinforcement learning: the dopamine reward prediction error hypothesis. Proc. Natl Acad. Sci. 108, 15647–15654 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lerner, T. N., Holloway, A. L. & Seiler, J. L. Dopamine, updated: reward prediction error and beyond. Curr. Opin. Neurobiol. 67, 123–130 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Niv, Y. Cost, benefit, tonic, phasic. Ann. N. Y. Acad. Sci. 1104, 357–376 (2007).

    Article  PubMed  Google Scholar 

  • Beeler, J. A. Tonic dopamine modulates exploitation of reward learning. Front. Behav. Neurosci. 4, 170 (2010).

  • Niv, Y., Daw, N. D., Joel, D. & Dayan, P. Tonic dopamine: opportunity costs and the control of response vigor. Psychopharmacology 191, 507–520 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Hahn, A. et al. Functional dynamics of dopamine synthesis during monetary reward and punishment processing. J. Cereb. Blood Flow. Metab. 41, 2973–2985 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmidt, *Clemens et al. Multimodal assessment of dopamine synthesis and bold- signaling in reward and punishment processing - a hybrid fpet/fmri study. Int. J. Neuropsychopharmacol. 28, i39–i40 (2025).

    Article  PubMed Central  Google Scholar 

  • Fields, H. L. & Margolis, E. B. Understanding opioid reward. Trends Neurosci. 38, 217–225 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laurent, V., Morse, A. K. & Balleine, B. W. The role of opioid processes in reward and decision-making. Br. J. Pharmacol. 172, 449–459 (2015).

    Article  CAS  PubMed  Google Scholar 

  • Bossong, M. G., Wilson, R., Appiah-Kusi, E., McGuire, P. & Bhattacharyya, S. Human striatal response to reward anticipation linked to hippocampal glutamate levels. Int. J. Neuropsychopharmacol. 21, 623–630 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benedetti, F. & Amanzio, M. Mechanisms of the placebo response. Pulm. Pharmacol. Therapeutics 26, 520–523 (2013).

    Article  CAS  Google Scholar 

  • Zubieta, J.-K. & Stohler, C. S. Neurobiological mechanisms of placebo responses. Ann. N. Y. Acad. Sci. 1156, 198–210 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacInnes, J. J., Dickerson, K. C., Chen, N. & Adcock, R. A. Cognitive neurostimulation: learning to volitionally sustain ventral tegmental area activation. Neuron 89, 1331–1342 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Totah, N. K. B., Kim, Y. & Moghaddam, B. Distinct prestimulus and poststimulus activation of VTA neurons correlates with stimulus detection. J. Neurophysiol. 110, 75–85 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Howe, M. W., Tierney, P. L., Sandberg, S. G., Phillips, P. E. M. & Graybiel, A. M. Prolonged dopamine signalling in striatum signals proximity and value of distant rewards. Nature 500, 575–579 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kahn, I. & Shohamy, D. Intrinsic connectivity between the hippocampus, nucleus accumbens, and ventral tegmental area in humans. Hippocampus 23, 187–192 (2013).

    Article  CAS  PubMed  Google Scholar 

  • Cauda, F. et al. Functional connectivity and coactivation of the nucleus accumbens: a combined functional connectivity and structure-based meta-analysis. J. Cogn. Neurosci. 23, 2864–2877 (2011).

    Article  PubMed  Google Scholar 

  • Hammes, J. et al. Dopamine metabolism of the nucleus accumbens and fronto-striatal connectivity modulate impulse control. Brain 142, 733–743 (2019).

    Article  PubMed  Google Scholar 

  • Zunhammer, M., Gerardi, M. & Bingel, U. The effect of dopamine on conditioned placebo analgesia in healthy individuals: a double-blind randomized trial. Psychopharmacology 235, 2587–2595 (2018).

    Article  CAS  PubMed  Google Scholar 

  • Kunkel, A. et al. Dopamine has no direct causal role in the formation of treatment expectations and placebo analgesia in humans. PLOS Biol. 22, e3002772 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lange, T., Dimitrov, S., Bollinger, T., Diekelmann, S. & Born, J. Sleep after vaccination boosts immunological memory. J. Immunol. 187, 283–290 (2011).

    Article  CAS  PubMed  Google Scholar 

  • Yu, X. et al. GABA and glutamate neurons in the VTA regulate sleep and wakefulness. Nat. Neurosci. 22, 106–119 (2019).

    Article  CAS  PubMed  Google Scholar 

  • Schiller, M., Ben-Shaanan, T. L. & Rolls, A. Neuronal regulation of immunity: why, how and where? Nat. Rev. Immunol. 21, 20–36 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Castro, D. C. & Bruchas, M. R. A motivational and neuropeptidergic hub: anatomical and functional diversity within the nucleus accumbens shell. Neuron 102, 529–552 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Dongen, Y. C. et al. Anatomical evidence for direct connections between the shell and core subregions of the rat nucleus accumbens. Neuroscience 136, 1049–1071 (2005).

    Article  PubMed  Google Scholar 

  • Cloninger, C. R., Przybeck, T. R. & Svrakic, D. M. The tridimensional personality questionnaire: U.S. normative data. Psychol. Rep. 69, 1047–1057 (1991).

    Article  CAS  PubMed  Google Scholar 

  • Costa, P. T. & McCrae, R. R. Normal personality assessment in clinical practice: the NEO Personality Inventory. Psychol. Assess. 4, 5 (1992).

    Article  Google Scholar 

  • Torrubia, R., Avila, C., Moltó, J. & Caseras, X. The sensitivity to punishment and sensitivity to reward questionnaire (SPSRQ) as a measure of Gray’s anxiety and impulsivity dimensions. Personal. Individ. differences 31, 837–862 (2001).

    Article  Google Scholar 

  • Treadway, M. T., Buckholtz, J. W., Schwartzman, A. N., Lambert, W. E. & Zald, D. H. Worth the ‘EEfRT’? The effort expenditure for rewards task as an objective measure of motivation and anhedonia. PloS one 4, e6598 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  • Knutson, B., Westdorp, A., Kaiser, E. & Hommer, D. FMRI visualization of brain activity during a monetary incentive delay task. Neuroimage 12, 20–27 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Kirschner, M. et al. Deficits in context-dependent adaptive coding of reward in schizophrenia. npj Schizophr. 2, 16020 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  • Murty, V. P. et al. Resting state networks distinguish human ventral tegmental area from substantia nigra. Neuroimage 100, 580–589 (2014).

    Article  PubMed  Google Scholar 

  • Koush, Y. et al. OpenNFT: an open-source Python/Matlab framework for real-time fMRI neurofeedback training based on activity, connectivity and multivariate pattern analysis. NeuroImage 156, 489–503 (2017).

    Article  PubMed  Google Scholar 

  • Lindquist, M. A. The statistical analysis of fMRI data. Statist. Sci. 23, (2008).

  • Hinds, O. et al. Computing moment-to-moment BOLD activation for real-time neurofeedback. NeuroImage 54, 361–368 (2011).

    Article  PubMed  Google Scholar 

  • Koush, Y., Zvyagintsev, M., Dyck, M., Mathiak, K. A. & Mathiak, K. Signal quality and Bayesian signal processing in neurofeedback based on real-time fMRI. NeuroImage 59, 478–489 (2012).

    Article  PubMed  Google Scholar 

  • Bagarinao, E., Matsuo, K., Nakai, T. & Sato, S. Estimation of general linear model coefficients for real-time application. NeuroImage 19, 422–429 (2003).

    Article  CAS  PubMed  Google Scholar 

  • McCrae, R. R. & Costa, P. T. Empirical and theoretical status of the five-factor model of personality traits. SAGE Handb. Personal. Theory Assess. 1, 273–294 (2008).

    Google Scholar 

  • Esteban, O. et al. fMRIPrep: a robust preprocessing pipeline for functional MRI. Nat. Methods 16, 111–116 (2019).

    Article  CAS  PubMed  Google Scholar 

  • Jenkinson, M., Beckmann, C. F., Behrens, T. E., Woolrich, M. W. & Smith, S. M. Fsl. Neuroimage 62, 782–790 (2012).

    Article  PubMed  Google Scholar 

  • Oldham, S. et al. The anticipation and outcome phases of reward and loss processing: a neuroimaging meta-analysis of the monetary incentive delay task. Hum. Brain Mapp. 39, 3398–3418 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  • Woolrich, M. Robust group analysis using outlier inference. NeuroImage 41, 286–301 (2008).

    Article  PubMed  Google Scholar 

  • Beckmann, C. F., Jenkinson, M. & Smith, S. M. General multilevel linear modeling for group analysis in fMRI. NeuroImage 20, 1052–1063 (2003).

    Article  PubMed  Google Scholar 

  • Woolrich, M. W., Behrens, T. E. J., Beckmann, C. F., Jenkinson, M. & Smith, S. M. Multilevel linear modelling for FMRI group analysis using Bayesian inference. NeuroImage 21, 1732–1747 (2004).

    Article  PubMed  Google Scholar 

  • R Core Team, R. R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2020).

  • Chikhi, S., Matton, N., Sanna, M. & Blanchet, S. Mental strategies and resting state EEG: effect on high alpha amplitude modulation by neurofeedback in healthy young adults. Biol. Psychol. 178, 108521 (2023).

    Article  PubMed  Google Scholar 

  • Kober, S., Witte, M., Ninaus, M., Neuper, C. & Wood, G. Learning to modulate one’s own brain activity: the effect of spontaneous mental strategies. Front. Hum. Neurosci. 7, 695 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  • McLaren, D. G., Ries, M. L., Xu, G. & Johnson, S. C. A generalized form of context-dependent psychophysiological interactions (gPPI): a comparison to standard approaches. NeuroImage 61, 1277–1286 (2012).

    Article  PubMed  Google Scholar 

  • Sescousse, G., Caldú, X., Segura, B. & Dreher, J.-C. Processing of primary and secondary rewards: a quantitative meta-analysis and review of human functional neuroimaging studies. Neurosci. Biobehav. Rev. 37, 681–696 (2013).

    Article  PubMed  Google Scholar 

  • Virtanen, P. et al. SciPy 1.0: fundamental algorithms for scientific computing in Python. Nat. Methods 17, 261–272 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kühn, S. & Gallinat, J. Segregating cognitive functions within hippocampal formation: a quantitative meta-analysis on spatial navigation and episodic memory. Hum. Brain Mapp. 35, 1129–1142 (2014).

    Article  PubMed  Google Scholar 

  • Arsalidou, M. & Taylor, M. J. Is 2 + 2 = 4? Meta-analyses of brain areas needed for numbers and calculations. NeuroImage 54, 2382–2393 (2011).

    Article  PubMed  Google Scholar 

  • Hétu, S. et al. The neural network of motor imagery: an ALE meta-analysis. Neurosci. Biobehav. Rev. 37, 930–949 (2013).

    Article  PubMed  Google Scholar 

  • McNorgan, C. A meta-analytic review of multisensory imagery identifies the neural correlates of modality-specific and modality-general imagery. Front. Hum. Neurosci. 6, 285 (2012).