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Immune HepatitisNCT03951870

Characterization of the Relationship Between the Human Mesolimbic Reward System and Immune Functioning

A study testing Neuromodulation via fMRI Neurofeedback task and Hepatitis B vaccination in people with Immune Hepatitis, run by Tel-Aviv Sourasky Medical Center at 1 site in Israel.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The purpose of this study is to characterize the link between neurobehavioral measures of the mesolimbic reward system and immune functioning in healthy individuals, via fMRI neurofeedback modulation of mesolimbic reward system, and the consecutive assesment of immune response to Hepatitis B vaccination. Read more about this study

Who is it for?
Ages 18 to 45 yearsHealthy volunteers can take part
Conditions the study is for
Immune Hepatitis
What is being tested?
Neuromodulation via fMRI Neurofeedback task and Hepatitis B vaccination
Could I receive a placebo?
No, everyone receives an active treatment
How many people
85 participants
Where
1 siteIsrael
Study dates
20 Jan 2019to 28 Aug 2022
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 45 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • Healthy participants
  • Normal or corrected to normal vision
  • Compatibility with general MRI requirements

Who cannot join

  • History of neurological or psychiatric diseases that lead to hospitalization
  • Have received Hepatitis B vaccination in the last 10 years
  • Memory/cognitive neurological impairments
  • Chronic heart disease, diabities, high blood pressure, or autoimmune disease.

Trial locations and contacts

1 site in 1 country.

Israel1 site

  • Functional Brain Center, Sourasky Medical Center

    Tel Aviv

Other trials in Israel

About this study

Official title: Characterization of the Relationship Between the Mesolimbic Reward System and Immune Functioning in Humans Via fMRI Neurofeedback

The purpose of this study is to characterize the link between neurobehavioral measures of the mesolimbic reward system and immune functioning in healthy individuals, via fMRI neurofeedback modulation of mesolimbic reward system, and the consecutive assesment of immune response to Hepatitis B vaccination.

Read the detailed description

For many years, the link between mental processes and physical health has remained obscure. Yet, over time, studies have begun to shed light on the intimate relationship between one's physical condition and mental state. One body of research aimed at elucidating the mind-body relationship is the study of the placebo effect. Placebo effects result mainly from conscious expectations to become healthy in therapeutic settings, and from unconscious conditioned responses to therapeutical settings that predict beneficial outcomes. Both processes are asociated with the neuronal reward system, which mediates reward processing, reward valuation and value based-learning. However, it remains unclear how do these processes mediated by the reward system promote therapeutic effects?

A recent study established a causal relationship between mesolimbic activation (VTA) and a measurable immunological response in mice. Stimulation of the VTA increased anti-bacterial immune functioning, an effect that was mediated by sympathetic nervous system, which is regulated by the brain and innervates all immune organs.

In light of these findings, the current study aims to assess the relationship between reward-related brain activation and immune functions in humans. fMRI Neurofeedback, a task that allows individuals to self modulate specified neural patterns in real-time, will be used to induce mesolimbic activation, following which healthy individuals will vaccinate against Hepatitis B. Immunological effects will be assessed by comparing immunological measures with respect to Hepatitis B prior and following mesolimbic activation and Hepatitis B vaccination.

The long-term goal of this study is to demonstrate a causal link between reward activation and an objective measurable physiological response of great significance, and to develop the means for individuals to exploit such mechanism for boosting immune functioning. i.e. to harness endogenous reward-related brain activation to strengthen the immune system, for clinical pathologies such as autoimmune diseases, maleble pathogens, cancer, etc.

Being tested
Neuromodulation via fMRI Neurofeedback task, Hepatitis B vaccination
Keywords
mesolimbic reward system, fMRI Neurofeedback

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Neuromodulation via fMRI Neurofeedback taskBehavioural

    Two active neurofeedback groups will practice to up regulate their designated neural targets via identical experimental protocol (varying only the origin of the feedback).

  • Hepatitis B vaccinationBiological

    Subjects will be vaccinated against Hepatitis B

Study groups in NCT03951870
Study groupRoleWhat they receive
Mesolimbic NeurofeedbackExperimentalNeuromodulation via fMRI Neurofeedback task: subjects (n=34) will participate in four fMRI-NF sessions, up-regulating activation of three mesolimbic reward nodes: ventral tegmental area, and bilateral ventral striatum. ROIs are 5 mm spheres around peak activations in funcitonal localizer task (Monetary Incentive delay, reward anticipation contrast), within a predifned meta-analytic anatomical masks of the three regions. anatomical masks: VTA (Midbrain): -4 -24 -10 *see below Right Nac: 12 10 -4 Left Nac: -10 10 -6 Oldham, Stuart, et al. Human brain mapping (2018). * 23/08/22: Due to VTA complex contours, it was not restricted according to Oldham et al as mentioned above, but via more accurate VTA mask (Murty et al. 2014, NeuroImage). This was mistakenly left out of the original preregistration. It is noteworthy that, to date (23/8/22), ROI analyses haven't been performed. Hepatitis B vaccination: subjects will receive vaccination against Hepatitis B.
Receives: Behavioral: Neuromodulation via fMRI Neurofeedback task; Biological: Hepatitis B vaccination
Control NeurofeedbackActive comparatorNeuromodulation via fMRI Neurofeedback task: subjects (n=34) will participate in four fMRI-NF sessions, up-regulating activation of regions comprising one of 4 control networks (5mm spheres around MNI coordinates): Motor Imagery (Hétu, Sébastien, et al. Neurosci. \& Biobehav Rev (2013)) R. Cerebellum: 32 -62 -28 L. Cerebellum: -32 -56 -30 L. Precentral Gyrus: -26 -2 58; Auditory imagery (McNorgan, Chris.Front in Human Neurosci 6 (2012)) R STG:64 -30 9 L IFG:-48 24 -5 L precentral Gyrus: -52 1 47; Arithmetic processing (Arsalidou, Marie, and Margot J. Taylor. Nuroimage (2011)) R. SPL: 29 -66 49 L. MFG (dlpfc): -45 32 29 L. precuneus: -28 -71 33; Spatial Navigation (Kühn, Simone, and Jürgen Gallinat. Human Brain Map. (2014)) R. hippocampus 26 -35 -11 L. hippocampus -26 -47 -9 L. Post. cingulate -15 -59 19 Hepatitis B vaccination: subjects will receive vaccination against Hepatitis B.
Receives: Behavioral: Neuromodulation via fMRI Neurofeedback task; Biological: Hepatitis B vaccination
Natural historyOtherNo brain manipulation (Assesment of natural history immune response). Hepatitis B vaccination: subjects (n=17) will receive vaccination against Hepatitis B.
Receives: Biological: Hepatitis B vaccination

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Immunological: change in anti HBs immunoglobins in plasma

    To measure antibody titers in plasma, blood samples will be taken at four time points: before neurofeedback training (-14d); before Hepatitis B vaccination (day 0), 14 days and 28 days after vaccination. Anti-HBs change will be defined as average levels post-vaccination (14 and 28 days) minus average levels pre-vaccination (-14 and 0 days).

    *19.09.22: due to extensive variability in baseline levels, anti-HB change will be defined as fold change between pre-and post-vaccination TPs, instead of absolute differences (blinding unharmed).

    The investigators predict that:

    i.Simple group effect: experimental arm subjects (mesolimbic fMRI NF) will exhibit higher levels of anti-HBs change than both the active comparator group (control fMRI-NF) and the no-treatment group.

    ii.Mesolimbic activation-Immunologic response correlation: mesolimbic activity during the neurofeedback task (across all NF participants) during the last session will predict anti-HBs levels following vaccination.

    Measured: 6 weeks

  2. Immunological: change in cytokines blood concentrations following vaccination

    To assess cytokine levels (e.g. IL-4, IL-6, TNFalpha, IFNgamma), the investigators will isolate peripheral blood mononuclear cells from the blood, and using flow cytometry analysis, characterize cytokine expression profile (initial intentions of using ELISA will be replaced due to quality tests (blinding unharmed) that showed poor signal, 28/12/21). As mere NF practice may affect cytokines levels, cytokines will be assessed in three time points - before NF training (-14d), before vaccination (day 0) and 3 days following vaccination. groupXtime (3X3) main effect and interactions will be inspected.

    The investigators predict that:

    i.Experimental arm group will exhibit higher levels of cytokines concentration that the active control group and natural history group.

    ii.Mesolimbic activation-Immunologic response correlation: mesolimbic activity during the neurofeedback task (across all NF participants) during the last session will predict changes in cytokines blood concentrations.

    Measured: 17 days

  3. Reward Mesolimbic network (or control networks) BOLD activity during fMRI-NF task

    ROIs of Mesolimbic reward network (or control networks) will be defined as mentioned in arms description *see below. CSF voxels will be excluded from all ROIs. Outcome will be measured for each experimental group/control sub-group, as the contrast between regulation and watch conditions, for each NF run, each session (3*4=12 runs).

    To assess differences in meoslimbic reward network activation between experimental and active control groups, a 12 by 2 (runXgroup) model will be constructed.

    *23/8/22 to exploit superior offline processing, ROIs will be deifned via group instead of online individual subs analysis.

    The investigators predict that:

    1. Simple group effects during last (fourth) NF session: experimental arm subjects (mesolimbic fMRI NF) will exhibit higher meoslimbic reward network activity than the active comparator group. ii. Simple experimental arm group learning effects: a significant effect of run (time) for the experimental arm mesolimbic reward network acitivity.

    Measured: 1-3 weeks

Secondary outcomes (10)

  1. Mental Strategies Questionnaire for NeuroFeedback (MSQ-NF)

    For each NF cycle in their training, subjects will fill out the MSQ-NF, a quesitonnaire that characterize mental strategies according to a hierarchical mental categorization.

    Exploratory analysis: The investigators suspect that mental features that relate to motivation and reward processing will be associated with reward mesolimbic activity during NF training, and that such mental features will be associated post-practice immunological effects.

    Measured: 6 weeks

  2. Neurobehavioral measures of reward anticipation and responsivity during Monetary Incentive Delay (MID) task.

    Neurobehavioral measures of reward responsitivity and reward anticipation will be assessed via application of MID task during fMRI scanning at the beginning of the first fMRI session (for all three study groups).

    The investigators intend to explore whether neural and behavioral indices of reward anticipation and consumption could account for differences in immunological outcome measures, as defined above (see primary outcome measures).

    Specifically, the investigators predict that:

    1. BOLD responses to reward anticipation will be positively correlated with immunological outcome measures - Cytokines levels change and HBV antibodeis change (as defined above).

    Measured: 6 weeks

  3. Behavioral measures of incentive motivation extracted from Effort Expenditure for Rewards Task (EEfRT).

    Behavioral measures of incentive saliance and incentive motivation will be assessed via application of EEfRT at the beginning of the first experimental session (for all three study groups).

    The investigators intend to explore whether EEfRT scores could account for differences in immunological and NF success outcome measures, as defined above (see primary outcome measures).

    Measured: 6 weeks

  4. Motivational tendencies based on K-means cluster analysis of questionnaires scores

    Subjects' classification as having approach/avoidance tendencies based on K-means cluster analysis of scores in three questionnaires: SPSRQ, TPQ and NEO-ffi.

    The investigators predict that:

    1. subjects with approach tendencies will exhibit stronger mesolimbic reward network activations during the MID task and NF task, compared to avoiders. ii. Approachers will exhibit higher immunological changes as reflected by the main immunological outcome measures, compared to avoiders.

    Measured: 6 week

  5. Functional connectivity of mesolimbic network during rest fMRI scan

    Rest scans will be applied at the beginning of the first and at the end of the fourth (last) NF practice session, in order to assess functional changes in the mesolimbic reward circuit following NF training.

    The investigators intend to explore whether changes in functional connectivity of the mesolimbic reward network will occur specifically in the mesolimbic fMRI-NF group (compared with control fMRI NF group).

    Measured: 1-3 weeks

  6. long term immunological effects

    A sub-group of 30 subjects will arrive for an aditional blood sample session three months following vaccination, in order to assess long term differences in anti-HBs levels.

    Exploratory analysis: differences between groups and brain-immune correlations will be examined.

    Measured: 3 months

  7. Subjective reports of SHAPS (Snaith-Hamilton Pleasure Scale)

    A 14 items (answered on a four points scale ranging from 'strongly disagree' to 'strongly agree') questionnaire for estimation of the degree of which a person is able to experience pleasure or the anticipation of a pleasurable experience. The questionnaire is scored as the sum of of the items (totals scores ranged from 0 to 14). A higher total score indicates higher levels of anhedonia.

    Exploratory Analyses: The investigators will examine whether the questionnaire scores prior to NF practice and vaccination, will account for differences in NF learning and in immunological outcome measures. Moreover, the investigators will track changes in this score along the experiment in order to inspect the relationship between subjective hedonic experience and NF success/immune functioning.

    Measured: 6 weeks

  8. Subjective reports to Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ)

    A questionnaire for assessing responsiveness to reward and punishment. The questionnaire includes 48 yes/no questions divided into two scales - sensitivity to punishment (SP) and sensitivity to reward (SR). Each sub-scale score is derived by summation of the reports.

    Exploratory analysis: the investigators will examine whether the questionnaire score during the first session (prior to NF practice and vaccination), will account for differences in NF learning and in immunological outcome measures.

    Measured: 6 weeks

  9. Subjective reports to Tridimensional Personality Questionnaire (TPQ)

    A questionnaire with 100 true/false items to characterize individual's three traits of personality - reward dependence, harm avoidance and novelty seeking. Each trait has 4 sub-scales that sums to the trait's score.

    Exploratory analysis: the investigators will examine whether the questionnaire score during the first session (prior to NF practice and vaccination), will account for differences in NF learning and in immunological outcome measures.

    Measured: 6 weeks

  10. Autonomic Nervous System (ANS) measure: Heart Rate Variability (HRV)

    Measurements of HRV are taken during fMRI scans in all NF practices, in order to monitor the activity of the sympathetic system. For each fMRI scan, HRV measures such as average variability and frequency ratios will be calculated.

    Exploratory analyses: the investigators suspect the sympathetic system will mediate the correlation between the mesolimbic reward activations and immunological outcome meaures (see primary outcome measures 1 and 2). Therefore, the investigators will explore the link between sympathetic measures taken at TP4 (prior to vaccination) and the correlation between reward mesolimbic activations during TP4 NF practice and the immunological outcome measures described above.

    Measured: 3 days - 4 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 May 2019
  2. Study start20 Jan 2019
  3. Primary completion28 Aug 2022
  4. Study completion28 Aug 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Parallel groups
Model description
1. Experimental arm: fMRI neurofeedback to mesolimbic system (the ventral tegmental area, and bilateral ventral striatum). 2. Active control arm: fMRI neurofeedback to a control network. 3. Natural history arm: assessment of immunological response to Hepatitis B without neurofeedback manipulation.
Masking
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
85 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03951870
Sponsor's protocol ID
0664-17-TLV
Status last verified
Jul 2022
First submitted
17 Apr 2019
Last updated
22 Sep 2022
Results posted
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Publications

  • Lubianiker N, Koren T, Djerasi M, Sirotkin M, Singer N, Jalon I, Lerner A, Sar-El R, Sharon H, Shahar M, Azulay-Debby H, Rolls A, Hendler T. Upregulation of reward mesolimbic activity and immune response to vaccination: a randomized controlled trial. Nat Med. 2026 Feb;32(2):572-581. doi: 10.1038/s41591-025-04140-5. Epub 2026 Jan 19.

    PubMed 41555034

Questions about this trial

What is this clinical trial studying?

A study testing Neuromodulation via fMRI Neurofeedback task and Hepatitis B vaccination in people with Immune Hepatitis, run by Tel-Aviv Sourasky Medical Center at 1 site in Israel.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Sep 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Immunological: change in anti HBs immunoglobins in plasma (time frame: 6 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03951870, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Sep 2022.

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