Characterization of the Relationship Between the Mesolimbic Reward System and Immune Functioning in Humans Via fMRI Neurofeedback
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Enrollment
- 85
- Locations
- 1
- Primary Endpoint
- Immunological: change in anti HBs immunoglobins in plasma
Study Overview
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.
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Basic Science
- 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.
Eligibility Criteria
- Ages
- 18 Years to 45 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Healthy participants
- •Normal or corrected to normal vision
- •Compatibility with general MRI requirements
Exclusion Criteria
- •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.
Arms & Interventions
Natural history
No brain manipulation (Assesment of natural history immune response).
Hepatitis B vaccination: subjects (n=17) will receive vaccination against Hepatitis B.
Intervention: Hepatitis B vaccination (Biological)
Mesolimbic Neurofeedback
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.
Intervention: Neuromodulation via fMRI Neurofeedback task (Behavioral)
Mesolimbic Neurofeedback
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.
Intervention: Hepatitis B vaccination (Biological)
Control Neurofeedback
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.
Intervention: Neuromodulation via fMRI Neurofeedback task (Behavioral)
Control Neurofeedback
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.
Intervention: Hepatitis B vaccination (Biological)
Outcomes
Primary Outcomes
Immunological: change in anti HBs immunoglobins in plasma
Time Frame: 6 weeks
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.
Immunological: change in cytokines blood concentrations following vaccination
Time Frame: 17 days
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.
Reward Mesolimbic network (or control networks) BOLD activity during fMRI-NF task
Time Frame: 1-3 weeks
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.
Secondary Outcomes
- Mental Strategies Questionnaire for NeuroFeedback (MSQ-NF)(6 weeks)
- Motivational tendencies based on K-means cluster analysis of questionnaires scores(6 week)
- Subjective reports of SHAPS (Snaith-Hamilton Pleasure Scale)(6 weeks)
- Subjective reports to Tridimensional Personality Questionnaire (TPQ)(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)
- long term immunological effects(3 months)
- Autonomic Nervous System (ANS) measure: Heart Rate Variability (HRV)(3 days - 4 weeks)
- Functional connectivity of mesolimbic network during rest fMRI scan(1-3 weeks)
- Subjective reports to Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ)(6 weeks)