Using rTMS to Explore Neural Mechanisms of Stress-Induced Opioid Use

Study Overview
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Brief Summary
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This study will use a stress (vs. placebo) exposure model, paired with single-session sham vs. active rTMS at two distinct cortical locations (dlPFC vs. mPFC in parallel groups) to assess whether rTMS neuromodulation at these alternative loci differentially influence stress-reactivity and opioid reinforcement in non-treatment seeking participants with OUD. Stress-reactivity will be measured using cognitive, affective, behavioral and biological phenotypes.

Detailed Description
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The Competing Neurobehavioral Decisions Systems (CNDS) model of addiction suggests that persons with SUDs have hyperactive limbic reward circuitry and hypoactive executive control circuitry. CNDS theory supports targeting the dorsolateral prefrontal cortex (dlPFC, part of executive control circuit) and other cortical targets with repetitive transcranial magnetic stimulation (rTMS). One candidate-the medial prefrontal cortex (mPFC)-is part of limbic reward circuitry and accessible using rTMS. We validated a rigorous pharmacological stress-induction method (yohimbine + hydrocortisone) that emulates endogenous stress-reactivity and have established linkages between stress-exposure, executive dysfunction, and drug seeking. Our lab is developing rTMS as a potential anti-stress neuromodulation approach in people with opioid use disorder (OUD). This study will use a stress (vs. placebo) exposure model, paired with single-session sham vs. active rTMS at two distinct cortical locations (dlPFC vs. mPFC in parallel groups) to assess whether rTMS neuromodulation at these alternative cortical loci differentially influence stress-reactivity and opioid reinforcement in non-treatment seeking participants with OUD. Stress-reactivity will be measured using cognitive, affective, behavioral and biological phenotypes.

Official Title
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Using Repetitive Transcranial Magnetic Stimulation (rTMS) to Explore Neural Mechanisms of Stress-Induced Opioid Use

Conditions
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Stress, Opioid-use Disorder

Intervention / Treatment
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* Drug: Placebo oral tablet
* Drug: Yohimbine + Hydrocortisone
* Device: sham rTMS
* Device: active rTMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meet DSM-5 criteria for OUD 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 within ranges for safe use of the pharmacological 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 other than opioids (except marijuana, which is legal in Michigan) Urinalysis positive for cocaine metabolites, benzodiazepines, barbiturates, amphetamines or pregnancy Medical conditions prohibiting use of rTMS (e.g. seizure history; based on rTMS screening questionnaire) Lifetime diagnosis of: psychotic disorder, bipolar disorder, generalized anxiety disorder, or obsessive compulsive disorder; major depression in the past 5 years; or potentially antisocial personality disorder (if the clinical psychologist judges such behaviors to be potentially disruptive or unsafe in our lab) Past-year SUD other than OUD Acute/unstable illness: 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 Past-month participation in a research study

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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No

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: mixed design, with 4 (2x2) within-subject conditions (placebo vs. stressor X sham vs. rTMS), each occurring in two parallel groups (10 Hz dorsolateral prefrontal cortex vs. sham rTMS in group 1, and 1 Hz medial prefrontal cortex vs. sham rTMS in group 2)
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo stressor, sham rTMS<br>placebo stressor (lactose), sham rTMS (inactive coil) | Drug: Placebo oral tablet<br>* placebo stressor<br>Device: sham rTMS<br>* sham rTMS (inactive coil)<br>|
| Active Comparator: placebo stressor, active rTMS<br>placebo stressor (lactose), active rTMS (10 Hz dlPFC in group 1; 1 Hz mPFC in group 2) | Drug: Placebo oral tablet<br>* placebo stressor<br>Device: active rTMS<br>* active rTMS (10 Hz dlPFC stimulation in group 1; 1 Hz mPFC stimulation in group 2)<br>|
| Active Comparator: stressor, sham rTMS<br>stressor (yohimbine 54mg + hydrocortisone 20mg), sham rTMS (inactive coil) | Drug: Yohimbine + Hydrocortisone<br>* Yohimbine 54mg + Hydrocortisone 20mg<br>Device: sham rTMS<br>* sham rTMS (inactive coil)<br>|
| Active Comparator: stressor, active rTMS<br>stressor (yohimbine 54mg + hydrocortisone 20mg), active rTMS (10 Hz dlPFC in group 1; 1 Hz mPFC in group 2) | Drug: Yohimbine + Hydrocortisone<br>* Yohimbine 54mg + Hydrocortisone 20mg<br>Device: active rTMS<br>* active rTMS (10 Hz dlPFC stimulation in group 1; 1 Hz mPFC stimulation in group 2)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Addiction Stroop task | reaction time (msec) measure of cognitive interference | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Digit Span Task | number of digits recalled, measure of verbal working memory | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Wisconsin Card Sorting Task | number of correct items, measures ability to shift set and assesses cognitive flexibility | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Monetary Incentive Delay task | number of rewards received, measure of motivation | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Delay Discounting task | rate of monetary discounting | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Drug/Money Choice Task | number of hypothetical choices between a constant amount of preferred opioid (relative to money) | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Blood pressure | Systolic/diastolic BP (mm Hg) | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Heart rate | Heart rate (beats/min) | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Saliva cortisol level | Saliva cortisol level (µg/dL) | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Saliva alpha-amylase level | Saliva alpha-amylase level (U/mL) | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Serum prolactin level | Serum prolactin level (pg/dL) | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Serum BDNF level | Serum brain derived neurotrophic factor level (pg/dL) | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Positive and Negative Affect Schedule (PANAS) positive affect | 10-item sub scale score of positive affect | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Positive and Negative Affect Schedule (PANAS) negative affect | 10-item sub scale score of negative affect | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| State Trait Anxiety Inventory | state anxiety scores | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Desire for Drug Questionnaire | opioid craving score | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Opiate-32 Questionnaire, Agonist score | total opioid agonist score (16 items) | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Opiate-32 Questionnaire, Withdrawal score | total opioid withdrawal symptom score (16 items) | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Resting-state EEG activation | relative (gamma band ÷ slow band) ratio in electroencephalogram (EEG) power during resting state | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) |