rTMS of Limbic Circuitry in Stress Modulation in Healthy Volunteers

Study Overview
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Brief Summary
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This study will be conducted with healthy male and female participants. Aim 1 will determine during sham repetitive transcranial magnetic stimulation (rTMS) how a drug stressor combination (yohimbine + hydrocortisone) relative to placebo alters : (1a) impulsivity; (1b) mood; and (1c) physiology. Aim 2 will determine whether active rTMS over the medial prefrontal cortex alters the effects of stress-exposure on (2a) decision-making, (2b) mood, and (2c) biomarkers of stress.

Detailed Description
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This study will use a double-blind, within-subjects randomized crossover design. Each participant will complete 4 sessions in this two-factor (2x2) combinatorial design: 1Hz medial prefrontal cortex (mPFC) vs. sham repetitive transcranial magnetic stimulation (rTMS) X pharmacological stressor (yohimbine 54mg + hydrocortisone 20mg) vs. placebo, with each session separated by at least 1 week. Participants will be asked not to use alcohol or drugs for 24-hr before arriving at the lab. We expect to complete screen at least 20 individuals to complete 12 individuals in this study. Candidates will first undergo psychiatric and medical screening to rule out contraindications to participation. Once enrolled, each participant will complete, in randomized order, the 4 conditions above. Periodic measures will be collected before and after the rTMS/sham and stress/placebo interventions. These measures will include subjective, behavioral and physiological assessments, as well as saliva and blood samples.

Official Title
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Impact of Repetitive Transcranial Magnetic Stimulation (rTMS) of Limbic Brain Circuitry in Stress Modulation in a Healthy Population

Conditions
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Stress, Healthy

Intervention / Treatment
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* Drug: yohimbine + hydrocortisone
* Device: medial prefrontal cortex rTMS
* Drug: Placebo oral tablet
* Device: sham rTMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 21-60 yr Right-handed Males and non-pregnant/non-lactating females Cognitively intact (total IQ score >80 on Shipley Institute of Living Scale) Screening cardiovascular indices must be within ranges that allow for safe use of stressor: resting HR 50-90 bpm, systolic BP 90-140 mmHg, and diastolic BP 50-90 mmHg Use alcohol and/or marijuana <3 times/week; each time should consist of <1 marijuana joint equivalent and <3 alcoholic drinks Exclusion Criteria: Under influence of any substance during session Past 7-day use of illicit drugs (excluding marijuana) based on Timeline Followback interview Urine positive for opioids, cocaine metabolites, benzodiazepines, barbiturates, amphetamines or pregnancy Medical conditions prohibiting use of rTMS (e.g. seizure history; using validated rTMS screening instrument) Lifetime diagnosis of: psychotic disorder, bipolar disorder, generalized anxiety disorder, obsessive compulsive disorder, or major depression that is not substance-induced Past-year substance use disorder Medical conditions making it unsafe for participation (e.g. neurological, cardiovascular, pulmonary, or systemic diseases) Lactose intolerance (placebo dose) Any prohibited medications: medications that lower seizure threshold, psychiatric medications, prescription pain medications, or blood pressure medications Chronic head or neck pain Taken part in any research studies in the past month

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 60 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: Crossover Assignment
Interventional Model Description: Double-blind, 1Hz mPFC (vs. sham) rTMS X stressor (vs. placebo), 4-session, within-subjects, randomized crossover design
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo stressor, sham rTMS<br>placebo stressor is lactose, and sham rTMS is inactive figure of 8 coil | Drug: Placebo oral tablet<br>* placebo stressor<br>Device: sham rTMS<br>* sham mPFC rTMS<br>|
| Experimental: placebo stressor, active rTMS<br>placebo stressor is lactose, and active rTMS is 1Hz stimulation over the medial prefrontal cortex | Device: medial prefrontal cortex rTMS<br>* 1 Hz mPFC rTMS<br>Drug: Placebo oral tablet<br>* placebo stressor<br>|
| Experimental: active stress, sham rTMS<br>active stressor is the combination of yohimbine 54mg + hydrocortisone 20mg, and sham rTMS is inactive figure of 8 coil | Drug: yohimbine + hydrocortisone<br>* yohimbine 54mg + hydrocortisone 20mg oral<br>Device: sham rTMS<br>* sham mPFC rTMS<br>|
| Experimental: active stress, active rTMS<br>active stressor is the combination of yohimbine 54mg + hydrocortisone 20mg, and active rTMS is 1Hz stimulation over the medial prefrontal cortex | Drug: yohimbine + hydrocortisone<br>* yohimbine 54mg + hydrocortisone 20mg oral<br>Device: medial prefrontal cortex rTMS<br>* 1 Hz mPFC rTMS<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Color-Word Stroop Task | reaction time (msec) measure of cognitive interference | change from pre- to post-intervention in each of the 4 sessions (through study completion, about 1 month total) | 
| Digit Span Task | number of digits recalled, measure of verbal working memory | change from pre- to post-intervention in each of the 4 sessions (through study completion, about 1 month total) | 
| Wisconsin Card Sorting Task | number of correct items, measure of ability to shift set and assesses cognitive flexibility | change from pre- to post-intervention in each of the 4 sessions (through study completion, about 1 month total) | 
| Monetary Incentive Delay Task | number of rewards received, measure of motivation | change from pre- to post-intervention in each of the 4 sessions (through study completion, about 1 month total) | 
| Delay Discounting Task | rate of monetary discounting | change from pre- to post-intervention in each of the 4 sessions (through study completion, about 1 month total) | 
| Effort Choice Task | number of progressive ratio (PR) choices vs. fixed ratio (FR) choices | change from pre- to post-intervention in each of the 4 sessions (through study completion, about 1 month total) | 
| Positive and Negative Affect Schedule (PANAS) positive affect | 10-item questionnaire sub scale that measures positive affect | change from pre- to post-intervention in each of the 4 sessions (through study completion, about 1 month total) | 
| Positive and Negative Affect Schedule (PANAS) negative affect | 10-item questionnaire sub scale that measures negative affect | change from pre- to post-intervention in each of the 4 sessions (through study completion, about 1 month total) | 
| State-Trait Anxiety Inventory | questionnaire subscale that measures state anxiety | change from pre- to post-intervention in each of the 4 sessions (through study completion, about 1 month total) | 
| Blood pressure | Blood pressure (mm Hg) | change from pre- to post-intervention in each of the 4 sessions (through study completion, about 1 month total) | 
| Heart rate | Heart rate (beats/min) | change from pre- to post-intervention in each of the 4 sessions (through study completion, about 1 month total) | 
| Saliva cortisol level | Saliva cortisol level (µg/mL) | change from pre- to post-intervention in each of the 4 sessions (through study completion, about 1 month total) | 
| Saliva alpha-amylase level | Saliva alpha-amylase level (U/mL) | change from pre- to post-intervention in each of the 4 sessions (through study completion, about 1 month total) | 
| Plasma prolactin level | Plasma prolactin level (pg/mL) | change from pre- to post-intervention in each of the 4 sessions (through study completion, about 1 month total) | 
| Plasma BDNF level | Plasma brain derived neurotrophic factor level (pg/mL) | change from pre- to post-intervention in each of the 4 sessions (through study completion, about 1 month total) |