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

NCT03951870 | Completed

• 1 other identifier: 0664-17-TLV
• Study Type: interventional
• Target: 85
• Locations: 1 country
• Sites: 1

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.

Conditions

Immune Hepatitis

Keywords

mesolimbic reward system; fMRI Neurofeedback

Outcome Measures

Primary Outcomes (3)

• 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.

  6 weeks

• 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.

  17 days

• 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: i. 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.

  1-3 weeks

Secondary Outcomes (10)

• Mental Strategies Questionnaire for NeuroFeedback (MSQ-NF)

  6 weeks

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

  6 weeks

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

  6 weeks

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

  6 week

• Functional connectivity of mesolimbic network during rest fMRI scan

  1-3 weeks

Study Arms (3)

Mesolimbic Neurofeedback

EXPERIMENTAL

Neuromodulation 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.

Behavioral: Neuromodulation via fMRI Neurofeedback task; Biological: Hepatitis B vaccination

Control Neurofeedback

ACTIVE COMPARATOR

Neuromodulation 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.

Behavioral: Neuromodulation via fMRI Neurofeedback task; Biological: Hepatitis B vaccination

Natural history

OTHER

No brain manipulation (Assesment of natural history immune response). Hepatitis B vaccination: subjects (n=17) will receive vaccination against Hepatitis B.

Biological: Hepatitis B vaccination

Interventions

Neuromodulation via fMRI Neurofeedback task BEHAVIORAL

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

Control Neurofeedback; Mesolimbic Neurofeedback

Hepatitis B vaccination BIOLOGICAL

Subjects will be vaccinated against Hepatitis B

Control Neurofeedback; Mesolimbic Neurofeedback; Natural history

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Tel-Aviv Sourasky Medical Center: lead
• Technion, Israel Institute of Technology: collaborator

Study Sites (1)

Functional Brain Center, Sourasky Medical Center

Tel Aviv, Israel

Location

Related Publications (1)

• 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 Jan 19. doi: 10.1038/s41591-025-04140-5. Online ahead of print.

  PMID: 41555034 DERIVED

Study Officials

• Talma Hendler, MD, PhD

  Tel-Aviv Sourasky Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: April 17, 2019
• First Posted: May 15, 2019
• Study Start: January 20, 2019
• Primary Completion: August 28, 2022
• Study Completion: August 28, 2022
• Last Updated: September 22, 2022

Record last verified: 2022-07

Locations

IL (1)