Stress, Opioid-use Disorder
Conditions
Brief summary
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
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.
Interventions
DRUGPlacebo oral tablet
placebo stressor
Yohimbine 54mg + Hydrocortisone 20mg
DEVICEsham rTMS
sham rTMS (inactive coil)
DEVICEactive rTMS
active rTMS (10 Hz dlPFC stimulation in group 1; 1 Hz mPFC stimulation in group 2)
Sponsors
Wayne State University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
placebo for stressor, and sham figure of 8 coil for rTMS
Intervention 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)
Eligibility
Sex/Gender
ALL
Age
21 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Addiction Stroop task | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | reaction time (msec) measure of cognitive interference |
| Digit Span Task | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | number of digits recalled, measure of verbal working memory |
| Wisconsin Card Sorting Task | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | number of correct items, measures ability to shift set and assesses cognitive flexibility |
| Monetary Incentive Delay task | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | number of rewards received, measure of motivation |
| Delay Discounting task | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | rate of monetary discounting |
| Drug/Money Choice Task | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | number of hypothetical choices between a constant amount of preferred opioid (relative to money) |
| Blood pressure | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | Systolic/diastolic BP (mm Hg) |
| Heart rate | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | Heart rate (beats/min) |
| Saliva cortisol level | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | Saliva cortisol level (µg/dL) |
| Saliva alpha-amylase level | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | Saliva alpha-amylase level (U/mL) |
| Serum prolactin level | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | Serum prolactin level (pg/dL) |
| Serum BDNF level | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | Serum brain derived neurotrophic factor level (pg/dL) |
| Positive and Negative Affect Schedule (PANAS) positive affect | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 10-item sub scale score of positive affect |
| Positive and Negative Affect Schedule (PANAS) negative affect | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | 10-item sub scale score of negative affect |
| State Trait Anxiety Inventory | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | state anxiety scores |
| Desire for Drug Questionnaire | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | opioid craving score |
| Opiate-32 Questionnaire, Agonist score | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | total opioid agonist score (16 items) |
| Opiate-32 Questionnaire, Withdrawal score | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | total opioid withdrawal symptom score (16 items) |
| Resting-state EEG activation | change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) | relative (gamma band ÷ slow band) ratio in electroencephalogram (EEG) power during resting state |
Outcome results
None listed