Feasibility and Efficacy of rTMS in Healthy Persons

Study Overview
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Brief Summary
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Transcranial magnetic stimulation (TMS) is a neuromodulation device that is FDA-approved for use in treating depression and obsessive compulsive disorder. TMS works by applying a safe, electromagnetic field on the scalp, which can either increase or decrease neuronal communication and activity (depending on the mode of stimulation). Although it is only approved for two disorders, there has been substantial research into the potential of TMS to treat a wide range of neuropsychiatric disorders, including substance use disorders (SUDs). This project aims to develop an initial TMS protocol in a sample of healthy controls and to establish the feasibility and efficacy of using repetitive TMS (rTMS) to impact several carefully-selected cognitive, behavioral, and physiologic measures. This pilot project will enable the research team to gather baseline data using this new method and to plan longer-term programmatic studies focusing on populations with SUDs. The overarching aim of this project is to develop an rTMS protocol for use in the human laboratory setting with both healthy controls and individuals with SUDs. The investigators also hope to learn about the impact of high frequency rTMS over the DLPFC on multiple aspects of functioning including: cognitive control, impulsivity, thermal pain sensitivity, motivation, and mood.

Detailed Description
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The short-term goal of this pilot project is to establish the feasibility and efficacy of repetitive transcranial magnetic stimulation (rTMS) on cognitive, behavioral, and physiological measures in a healthy community-recruited sample to plan longer-term programmatic studies focusing on substance use disorder (SUD) populations. Primary Aims are to examine the effect of one session of left dorsolateral prefrontal cortex (DLPFC) rTMS high-frequency (10 Hz) stimulation vs. placebo stimulation (no electromagnetic field but similar auditory and tactile sensations) on: (1) cognitive control, (2), impulsivity, and (3) thermal pain sensitivity. Secondary Aims are to test effects of rTMS on behavioral motivation (monetary incentive delay task, effort choice task), mood (PANAS), peripheral biomarkers (prolactin, BDNF) and collect biosamples for future genotyping. The investigators recognize the proposed sample size is relatively small to adequately power a full analysis across all outcomes, so will use this study to determine effect sizes for any differences to plan future studies with adequate power. Generally speaking, data will be analyzed using repeated measures ANCOVAs; covariates will include TMS resting motor threshold, sex, and age. Based on sample size calculations, the investigators intend to complete up to 30 subjects. For some outcomes, the results of previous studies indicate that a lower sample size may be appropriate, therefore the investigators will conduct interim analyses at n=18 to calculate effect sizes to determine how many more participants are needed.

Official Title
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Exploring the Feasibility and Efficacy of Repetitive Transcranial Magnetic Stimulation (rTMS) in a Healthy Population

Conditions
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Executive Dysfunction, Pain, Mood

Intervention / Treatment
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* Device: Repetitive Transcranial Magnetic Stimulation (rTMS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy Right handed 21-60 years of age IQ score greater than 80 Eligible if using tobacco, alcohol, or marijuana fewer than 3 times per week; each time must be less than 3 cigarettes or drinks, or less than 1 marijuana joint Exclusion Criteria: Under influence of any substances during any session Use of illicit substances in the past 30 days Pregnant Medical conditions that prohibit the use of rTMS (e.g. history of seizures or medications that lower seizure threshold) Current DSM-5 Axis I psychiatric disorders, or any history of substance use disorders.

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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Accepts Healthy Volunteers

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: This pilot study will use a single-blind, left dorsolateral prefrontal cortex (10-Hz) vs. sham, 2-session, within-subjects randomized crossover design.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Sham rTMS<br>Sham rTMS will be applied over the left dorsolateral prefrontal cortex using a sham figure of 8 coil (within-subject crossover). Sham rTMS will consist of the same auditory and tactile stimuli as the active condition, but does not induce an electromagnetic field and does not affect cortical excitability. | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* The investigators will use the Figure of 8 coil, which affects  10cm2 of cortical surface. The active condition will deliver stimulation at 110% of resting motor threshold (RMT). To determine RMT, the protocol will be: 10 trials of single-pulse TMS on the scalp position of the abductor pollicis brevis muscle (which controls thumb flexion); RMT is the lowest TMS power setting yielding visible motor contraction on >50% of trials.<br>|
| Active Comparator: Active rTMS<br>Active rTMS will be applied over the left dorsolateral prefrontal cortex using an active figure of 8 coil (within-subject crossover). In the active rTMS condition, the investigators will use high-frequency (10Hz) dorsolateral prefrontal cortex (dlPFC) stimulation with intensity of 110% of resting motor threshold. rTMS will consist of 120 trains with 50 stimuli per train (i.e. 5-sec long at 10 Hz) and 10-sec intertrain interval for a total of 6000 pulses. The entire protocol will last 30 min (120 trains with 5-sec on/10-sec off). | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* The investigators will use the Figure of 8 coil, which affects  10cm2 of cortical surface. The active condition will deliver stimulation at 110% of resting motor threshold (RMT). To determine RMT, the protocol will be: 10 trials of single-pulse TMS on the scalp position of the abductor pollicis brevis muscle (which controls thumb flexion); RMT is the lowest TMS power setting yielding visible motor contraction on >50% of trials.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stroop Task (cognitive control) | Examine the effect of rTMS stimulation on cognitive control as measured by the Stroop Color-Word task. | Change from pre- to 25-minutes post-rTMS stimulation in each session | 
| Stop Signal Task (impulsivity) | Examine the effect of rTMS stimulation on impulsivity as measured by the Stop Signal Task. | Change from pre- to 15-minutes post-rTMS stimulation in each session | 
| Pain Sensitivity | Examine the effect of rTMS stimulation on pain sensitivity as measured by thermal quantitative sensory threshold (QST) testing. | Change from pre- to 50-minutes post-rTMS stimulation in each session | 
| Delay Discounting Task (cognitive control) | Examine the effect of rTMS stimulation on cognitive control as measured by the brief (2-min) monetary delay discounting task | Change from pre- to 10-minutes post-rTMS stimulation in each session | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effort Choice Task (motivation) | Examine the effect of rTMS stimulation on behavioral responding as measured by the Effort Choice Task (number of responses on progressive ratio vs. fixed ratio schedules of reinforcement). | Change from pre- to 30-minutes post-rTMS stimulation in each session | 
| Mood | Examine the effect of rTMS stimulation on mood state as measured by the Positive and Negative Affect Schedule. | Change from pre- to 5-minutes post-rTMS stimulation in each session | 
| Peripheral Biomarkers | Examine the effect of rTMS stimulation on peripheral biomarkers as measured by the plasma concentrations (ng/ml) of brain derived neurotrophic factor (BDNF) and prolactin. | Change from pre- to 0-minutes post-rTMS stimulation in each session | 
| Monetary Incentive Delay Task (motivation) | Examine the effect of rTMS stimulation on behavioral responding as measured by the Monetary Incentive Delay Task | Change from pre- to 40-minutes post-rTMS stimulation in each session |