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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| placebo stressor, sham rTMS | Placebo Comparator | Placebo stressor (lactose) + sham (inactive) rTMS over the left dlPFC |
|
| placebo stressor, active rTMS | Experimental | Placebo stressor (lactose) + active 10Hz rTMS over the left dlPFC |
|
| active stressor, sham rTMS | Experimental | Stressor (yohimbine 54mg + hydrocortisone 20mg) + sham (inactive) rTMS over the left dlPFC |
|
| active stressor, active rTMS | Experimental | Stressor (yohimbine 54mg + hydrocortisone 20mg) + active 10Hz rTMS over the left dlPFC |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Yohimbine + Hydrocortisone | Drug | Yohimbine (54mg bulk powder inside capsule) administered in combination with Hydrocortisone (20mg tablet inside capsule) |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Tolan Park Medical Building | Detroit | Michigan | 48201 | United States |
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| ID | Term |
|---|---|
| D009293 | Opioid-Related Disorders |
| ID | Term |
|---|---|
| D000079524 | Narcotic-Related Disorders |
| D019966 | Substance-Related Disorders |
| D064419 | Chemically-Induced Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D015016 | Yohimbine |
| D006854 | Hydrocortisone |
| ID | Term |
|---|---|
| D046948 | Secologanin Tryptamine Alkaloids |
| D026121 | Indole Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
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Double-blind, 10Hz left dlPFC rTMS (vs. sham) X pharmacological stressor (vs. placebo) within-subject, randomized crossover design.
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Placebo (lactose) for pharmacological stressor, and sham for dlPFC rTMS
| Active rTMS | Device | 10Hz rTMS over the left dlPFC |
|
| Placebo | Drug | lactose (inside capsule) |
|
| Sham rTMS | Device | inactive stimulation over the left dlPFC |
|
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) |
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) |
| D007211 |
| Indoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D054836 | Indolizidines |
| D007212 | Indolizines |
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D015062 | 11-Hydroxycorticosteroids |
| D006889 | Hydroxycorticosteroids |
| D000305 | Adrenal Cortex Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D015065 | 17-Hydroxycorticosteroids |