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

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ClinicalTrials.gov Identifier: NCT03951870
Recruitment Status : Recruiting
First Posted : May 15, 2019
Last Update Posted : May 15, 2019
Sponsor:
Collaborator:
Technion, Israel Institute of Technology
Information provided by (Responsible Party):
Tel-Aviv Sourasky Medical Center

Brief 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.

Condition or disease Intervention/treatment Phase
Immune Hepatitis Behavioral: Neuromodulation via fMRI Neurofeedback task Biological: Hepatitis B vaccination Not Applicable

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 87 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Investigator, Outcomes Assessor)
Masking Description: Both participants and study personnel (Investigators and outcomes assessor) in the two active experimental arms (Mesolimbic NF and Control NF) will be blinded to group allocation.
Primary Purpose: Basic Science
Official Title: Characterization of the Relationship Between the Mesolimbic Reward System and Immune Functioning in Humans Via fMRI Neurofeedback
Actual Study Start Date : January 20, 2019
Estimated Primary Completion Date : February 28, 2020
Estimated Study Completion Date : February 28, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Mesolimbic Neurofeedback

Neuromodulation via fMRI Neurofeedback task: subjects will participate in four fMRI-NF sessions, up-regulating co-activation of three mesolimbic reward nodes: ventral tegmental area, and bilateral ventral striatum.

Hepatitis B vaccination: subjects will receive vaccination against Hepatitis B.

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

Biological: Hepatitis B vaccination
Subjects will be vaccinated against Hepatitis B

Active Comparator: Control Neurofeedback

Neuromodulation via fMRI Neurofeedback task: subjects will participate in four fMRI-NF sessions, up-regulating co-activation of regions comprising with one of K control networks.

Hepatitis B vaccination: subjects will receive vaccination against Hepatitis B.

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

Biological: Hepatitis B vaccination
Subjects will be vaccinated against Hepatitis B

Natural history

No brain manipulation (Assesment of natural history immune response).

Hepatitis B vaccination: subjects will receive vaccination against Hepatitis B.

Biological: Hepatitis B vaccination
Subjects will be vaccinated against Hepatitis B




Primary Outcome Measures :
  1. Immunological: anti HBs immunoglobins in plasma [ Time Frame: 6 weeks ]

    To measure antibody titers in plasma, blood samples will be drawn from participants at three time points: Immediately before Hepatitis B vaccination (day 0), 14 days and 28 days after vaccination.

    We predict that:

    i.Simple group effect: experimental arm subjects (mesolimbic fMRI NF) will exhibit higher levels of anti-HBs* 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*.

    * Since all of the participants were vaccinated to Hepatitis B during childhood, we expect variation in baseline levels of plasma antibodies. Therefore, we will take into account both fold change (between day 0 and 14, and between day 0 and 28) and titers in international units (IU/mL).


  2. fMRI Neurofeedback task modulation success [ Time Frame: 4 weeks ]
    fMRI-NF neural targets BOLD activations in the 4th (last) NF session (vaccination day), as measured by differential contrasts of experimental vs active control group: Mesolimbic reward network ROI: Experimental > Active control


Secondary Outcome Measures :
  1. Immunological: secretion of pro-inflammatory cytokines following vaccination [ Time Frame: 3 days ]

    To assess cytokine levels in plasma, we will use the enzyme-linked immunosorbent assay (ELISA) in plasma taken on the day of vaccination (day 0) and three days after.

    b. we expect that there will be elevated secretion of pro-inflammatory cytokines following vaccination, in the mesolimbic-activated group compared to both control groups.


  2. Immunological responses (anti HBs / cytokines) correlation with neurobehavioral mesolimbic functioning during Monetary Incentive Delay task. [ Time Frame: 6 weeks ]

    Exploratory analysis: neurobehavioral measures of the mesolimbic reward system will be assessed via application of Monetary Incentive Delay (MID) task at the beginning of the first fMRI session (for all three groups).

    We intend to inspect whether neural and behavioral indices extracted from the MID task could account for differences in immunological responses, as measured throughout the experiment.


  3. Subjective reports of SHAPS (Snaith-Hamilton Pleasure Scale) [ Time Frame: 6 weeks ]

    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 analysis: we 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. Moreover, we will track changes in this score along the experiment in order to inspect the relationship between subjective hedonic experience and NF success/immune functioning.


  4. Subjective reports to Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ) [ Time Frame: 6 weeks ]

    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: we 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. Moreover, we will track changes in this measure along the experiment in order to inspect the relationship between responsivity to rewards and punishments, and NF success/immune functioning.


  5. Subjective reports to Tridimensional Personality Questionnaire (TPQ) [ Time Frame: 6 weeks ]

    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: we 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. Moreover, we will track changes in these measure along the experiment in order to inspect the relationship between personality traits and NF success/immune functioning.


  6. Functional connectivity of mesolimbic network during rest fMRI scan [ Time Frame: 2-3 weeks ]

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

    We expect to find changes in functional connectivity of the reward circuit specifically in the mesolimbic fMRI-NF group (when compared with control fMRI NF group).




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

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

Exclusion Criteria:

  • History of neurological or psychiatric diseases
  • Have received Hepatitis B vaccination in the last 10 years

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03951870


Contacts
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Contact: Nitzan Lubianiker 972-5033334538 nitzanlubi@gmail.com
Contact: Talma Hendler, MD, PhD 972-36973953 talma@tlvmc.gov.il

Locations
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Israel
Functional Brain Center, Sourasky Medical Center Recruiting
Tel Aviv, Israel
Contact: Talma Hendler, MD, PhD    972-36973953    talma@tlvmc.gov.il   
Sponsors and Collaborators
Tel-Aviv Sourasky Medical Center
Technion, Israel Institute of Technology
Investigators
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Principal Investigator: Talma Hendler, MD, PhD Tel-Aviv Sourasky Medical Center

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Responsible Party: Tel-Aviv Sourasky Medical Center
ClinicalTrials.gov Identifier: NCT03951870     History of Changes
Other Study ID Numbers: 0664-17-TLV
First Posted: May 15, 2019    Key Record Dates
Last Update Posted: May 15, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Tel-Aviv Sourasky Medical Center:
mesolimbic reward system
fMRI Neurofeedback

Additional relevant MeSH terms:
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Vaccines
Immunologic Factors
Physiological Effects of Drugs