rTMS of Limbic Circuitry in Stress Modulation in Healthy Volunteers

NCT04180969 | Withdrawn Phase 2 DMC

• 1 other identifier: TSM-1
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Stress; Healthy

Outcome Measures

Primary Outcomes (15)

• 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)

Study Arms (4)

placebo stressor, sham rTMS

PLACEBO COMPARATOR

placebo stressor is lactose, and sham rTMS is inactive figure of 8 coil

Drug: Placebo oral tablet; Device: sham rTMS

placebo stressor, active rTMS

EXPERIMENTAL

placebo stressor is lactose, and active rTMS is 1Hz stimulation over the medial prefrontal cortex

Device: medial prefrontal cortex rTMS; Drug: Placebo oral tablet

active stress, sham rTMS

EXPERIMENTAL

active stressor is the combination of yohimbine 54mg + hydrocortisone 20mg, and sham rTMS is inactive figure of 8 coil

Drug: yohimbine + hydrocortisone; Device: sham rTMS

active stress, active rTMS

EXPERIMENTAL

active stressor is the combination of yohimbine 54mg + hydrocortisone 20mg, and active rTMS is 1Hz stimulation over the medial prefrontal cortex

Drug: yohimbine + hydrocortisone; Device: medial prefrontal cortex rTMS

Interventions

yohimbine + hydrocortisone DRUG

yohimbine 54mg + hydrocortisone 20mg oral

active stress, active rTMS; active stress, sham rTMS

medial prefrontal cortex rTMS DEVICE

1 Hz mPFC rTMS

active stress, active rTMS; placebo stressor, active rTMS

Placebo oral tablet DRUG

placebo stressor

placebo stressor, active rTMS; placebo stressor, sham rTMS

sham rTMS DEVICE

sham mPFC rTMS

active stress, sham rTMS; placebo stressor, sham rTMS

Eligibility Criteria

• Age: 21 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Wayne State University: lead

MeSH Terms

Interventions

Yohimbine; Hydrocortisone

Intervention Hierarchy (Ancestors)

Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids

Study Officials

• Mark K Greenwald, PhD

  Wayne State University

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: sham (inactive) figure of 8 coil for rTMS, and placebo for pharmacological stressor
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Double-blind, 1Hz mPFC (vs. sham) rTMS X stressor (vs. placebo), 4-session, within-subjects, randomized crossover design

Study Record Dates

• First Submitted: November 24, 2019
• First Posted: November 29, 2019
• Study Start: April 10, 2023
• Primary Completion: April 10, 2023
• Study Completion: April 10, 2023
• Last Updated: April 13, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Materials will only become available after the study is completed and the first manuscript from this project is published.
• Access Criteria: Qualified investigators may apply in writing to Dr. Greenwald