Effects of Pharmacological Stress and rTMS on Executive Function in Opioid Use Disorder

Study Overview
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Brief Summary
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This preliminary study is designed to evaluate mechanisms by which excitatory dorsolateral prefrontal cortex (dlPFC) repetitive transcranial magnetic stimulation (rTMS) (vs. sham) and pharmacological stress (vs. placebo) alter behavior in non-treatment seeking individuals with opioid use disorder (OUD). Specific Aims are to (1) Evaluate how stress impacts domains of behavior including (1a) executive function and (1b) opioid-seeking behavior; and (2) Determine whether rTMS stimulation attenuates (2a) executive dysfunction, (2b) stress-reactivity, and (2c) opioid-seeking in individuals with OUD not receiving treatment.

Detailed Description
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This study will use a double-blind, 10Hz left dlPFC rTMS (vs. sham) and pharmacological stressor ([yohimbine + hydrocortisone] vs. placebo) within-subject, randomized crossover design. Each participant will complete 4 sessions (stressor vs. placebo, crossed with rTMS vs. sham), each separated by at least 1 week. Participants will complete these 4 (2x2 within subject) test conditions in randomized order: sham rTMS/placebo stress, sham rTMS/active stress, active rTMS/ placebo stress, and active rTMS/active stress. The PI will perform randomization using a Latin Square and will assign participants to conditions and prepare medication (stressor or placebo) for each participant's sessions. The PI will keep others blinded and will not be involved in study assessments.

Official Title
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Effects of Pharmacological Stress and Repetitive Transcranial Magnetic Stimulation Interventions on Executive Function in Opioid Use Disorder

Conditions
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Opioid Use Disorder

Intervention / Treatment
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* Drug: Yohimbine + Hydrocortisone
* Device: Active rTMS
* Drug: Placebo
* Device: Sham 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; and 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: Double-blind, 10Hz left dlPFC rTMS (vs. sham) X pharmacological stressor (vs. placebo) within-subject, randomized crossover design.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo stressor, sham rTMS<br>Placebo stressor (lactose) + sham (inactive) rTMS over the left dlPFC | Drug: Placebo<br>* lactose (inside capsule)<br>Device: Sham rTMS<br>* inactive stimulation over the left dlPFC<br>|
| Experimental: placebo stressor, active rTMS<br>Placebo stressor (lactose) + active 10Hz rTMS over the left dlPFC | Device: Active rTMS<br>* 10Hz rTMS over the left dlPFC<br>Drug: Placebo<br>* lactose (inside capsule)<br>|
| Experimental: active stressor, sham rTMS<br>Stressor (yohimbine 54mg + hydrocortisone 20mg) + sham (inactive) rTMS over the left dlPFC | Drug: Yohimbine + Hydrocortisone<br>* Yohimbine (54mg bulk powder inside capsule) administered in combination with Hydrocortisone (20mg tablet inside capsule)<br>Device: Sham rTMS<br>* inactive stimulation over the left dlPFC<br>|
| Experimental: active stressor, active rTMS<br>Stressor (yohimbine 54mg + hydrocortisone 20mg) + active 10Hz rTMS over the left dlPFC | Drug: Yohimbine + Hydrocortisone<br>* Yohimbine (54mg bulk powder inside capsule) administered in combination with Hydrocortisone (20mg tablet inside capsule)<br>Device: Active rTMS<br>* 10Hz rTMS over the left dlPFC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Color-Word Stroop Task | measures cognitive control in response to opioid-related words. | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Digit Span Task | measures verbal working memory. Participants are asked to repeat strings of numbers of increasing length, both forward and backward. | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Wisconsin Card Sorting Task | measures ability to shift set and assesses cognitive flexibility. | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Emotion Regulation Task | subjects rate the unpleasantness and arousal of different emotional pictures | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Positive and Negative Affect Schedule | subjects rate their positive and negative affect | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| State-Trait Anxiety Inventory | subjects rate their level state anxiety | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Monetary Incentive Delay Task | Participants respond to a visual target that follows 2 different cues: incentive or non-incentive. No reward or punishment occurs on non-incentive trials. On incentive trials, participants must respond within a fixed amount of time. In the reward condition, responses within that time result in receiving the incentive , else nothing. In the punishment condition, the participant will lose money if they do not respond within the time limit | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Delay Discounting Task | Participants perform a brief (<1min) hypothetical version of the traditional monetary task with a 5-trial adjusting delay previously validated to rapidly assess discount rate | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Drug/Money Choice Task | participants choose hypothetically between a constant amount of their preferred opioid ($10 unit dose) or money ($2) | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Systolic blood pressure | millimeters mercury (mmHg) | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Diastolic blood pressure | millimeters mercury (mmHg) | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Heart rate | beats per minute | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Saliva cortisol level | measure of the activity of the HPA axis | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Saliva alpha-amylase level | indirect measure of adrenergic stimulation | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Serum prolactin level | indirect measure of dopamine stimulation | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Serum brain derived neurotrophic factor (BDNF) level | indirect measure of brain derived neurotrophic factor activation | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Relative electroencephalogram (EEG) gamma power | Prefrontal gamma (25-100 Hz) EEG power, relative to slow-wave EEG power, is a stress biomarker | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Opioid craving | Desire for Drug Questionnaire total score; higher scores indicate greater craving | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Opioid agonist symptoms | Opiate-32 questionnaire agonist symptom total score; higher scores indicate greater opioid symptom severity | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) | 
| Opioid withdrawal symptoms | Opiate-32 questionnaire withdrawal symptom total score; higher scores indicate greater withdrawal severity | change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total) |