rTMS of Limbic Circuitry in Stress Modulation in Healthy Volunteers (TSM-1)

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Healthy; Stress
• Intervention / Treatment: Drug: Placebo oral tablet; Device: sham rTMS; Device: medial prefrontal cortex rTMS; Drug: yohimbine + hydrocortisone

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Tabitha Moses; Phone Number: 313-577-8257; Email: druglabdetroit@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Wayne State University

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2023
• Primary Completion (Actual): April 10, 2023
• Study Completion (Actual): April 10, 2023

Study Registration Dates

• First Submitted: November 24, 2019
• First Submitted That Met QC Criteria: November 25, 2019
• First Posted (Actual): November 29, 2019

Study Record Updates

• Last Update Posted (Actual): April 13, 2023
• Last Update Submitted That Met QC Criteria: April 10, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Urological Agents; Anti-Inflammatory Agents; Adrenergic alpha-Antagonists; Mydriatics; Adrenergic alpha-2 Receptor Antagonists; Hydrocortisone; Yohimbine
• Other Study ID Numbers: TSM-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Full sharing plan is being developed.
• IPD Sharing Time Frame: Materials will only become available after the study is completed and the first manuscript from this project is published.
• IPD Sharing Access Criteria: Qualified investigators may apply in writing to Dr. Greenwald
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No