Investigating Stress-Induced Dopamine Release: a fMRI-PET Study

Study Overview
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Brief Summary
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The stress response is mediated by the activation of the hypothalamo-pituitary-adrenal axis and the sympathetic nervous system, leading to glucocorticoid and catecholamines release respectively. This stress response is regulated by feedback loops, involving cortical and subcortical structures. Non-invasive brain stimulation applied over the dorsolateral prefrontal cortex modulates the subcortical dopaminergic transmission at rest and can reduce the hormonal and cognitive alterations induced by stress. This study aims to investigate the Non-invasive brain stimulation -induced modulation of dopamine transmission in an acute stress situation.

Detailed Description
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Objective: to investigate the influence of Dorsolateral Prefrontal Cortex stimulation during acute stress on the subcortical dopamine transmission in healthy subjects. Method: 30 healthy subjects will be enrolled and randomized into 2 parallel groups. 15 participants will receive active Transcranial direct current stimulation , the other 15 participants will receive sham Transcranial direct current stimulation. Transcranial direct current stimulation procedure: active Transcranial direct current stimulation corresponds to 30min of stimulation at 1mA intensity . The sham stimulation corresponds to 30s of real stimulation. Stress paradigm: In order to induce moderate stress in humans in laboratory condition, the investigators will use the Maastricht Acute Stress test . This test is a combination between physical, hand immersion in cold water and cognitive calculation stress. The test will start 5 minutes after the beginning of stimulation session. Stress measures: the stress response will be evaluated at the following levels: Neurochemical level: dopamine transmission measured with positron emission tomography Functional brain connectivity: resting-state networks measured with functional magnetic resonance imaging Hormonal level: adrenocorticotropic hormone and cortisol levels measured with blood samples Cognitive level: decision-making and memory assessed with delay-discounting task and reality-monitoring task, respectively Molecular level: expression of genes involved in the glucocorticoid receptor signaling pathway measured through blood samples Exploratory measure: Brain-Derived Neurotrophic Factor and cytoplasmic catechol-O-methyltransferase polymorphisms of participants involved in differential Transcranial direct current stimulation response will be assessed.

Official Title
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Investigating Stress-Induced Dopamine Release: a fMRI-PET Study

Conditions
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Stress Response

Intervention / Treatment
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* Device: tDCS actif
* Device: tDCS Sham


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Men and women aged between 18- and 30-year-old Non-smoker Non-psychotropic user Exclusion Criteria: - Have a psychiatric or somatic disorder Have a first-degree family history of a psychiatric disorder Pregnant or nursing women Be on medication, with the exception of oral contraceptives Contraindications to tDCS or MRI examination Participants with pacemaker or cardiac or cerebral implant

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In a randomized controlled double-blind study, 30 healthy subjects, will be randomly assigned to 2 groups. A group of 15 participants will receive 30 minutes of active tDCS (1mA, 30 minutes with the anode at the left DLPFC and the cathode at the right DLPFC); a group of 15 participants will receive 30 minutes of placebo stimulation. All participant will be in a PET-MRI scanner for 110min, during which they will undergo the stimulation (either active or sham). During this stimulation session, all participants will undergo a standardized stress test combining psychosocial stress and physical stress.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active tDCS<br>Active brain stimulation Direct current stimulation of DLPFC for 30min with an intensity of 1mA | Device: tDCS actif<br>* Active brain stimulation<br>|
| Sham Comparator: Sham tDCS<br>Sham brain stimulation Direct current stimulation of DLPFC for 30sec with an intensity of 1mA | Device: tDCS Sham<br>* Sham brain stimulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dopamine transmission measured with positron emission tomography | Subcortical dopaminergic transmission will be analyzed, using [11C]raclopride PET activity (D2 receptor antagonist) | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional brain connectivity | Resting-state functional connectivity | One year | 
| Hormonal stress reactivity | ACTH level will be measured | One year | 
| Cognitive stress reactivity | Decision-making capacities will be measured using a computerized version of the DDT in which participants have to choose between 2 rewards. Memory capacities will be measured using a computerized task evaluating reality-memory. | One year | 
| Expression of genes involved in the glucocorticoid receptor signaling pathway measured through blood samples | Expression rates of genes involved in the glucocorticoid receptor signaling pathway | One year | 
| Assessment of brain-derived neurotrophic factor before and after transcranial direct current stimulation. | Exploratory measure: brain-derived neurotrophic factor polymorphisms of participants, involved in differential Transcranial direct current stimulation response, will be assess. | One year | 
| Hormonal stress reactivity | Cortisol level will be measured | One year | 
| Assessment of Cytoplasmic catechol-O-methyltransferase polymorphisms before and after transcranial direct current stimulation. | Exploratory measure: Cytoplasmic catechol-O-methyltransferase polymorphisms of participants, involved in differential Transcranial direct current stimulation response, will be assess. | One year |