RTMS Targets Neural Circuits for Smoking Cessation

Study Overview
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Brief Summary
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Cigarette smoking is a significant public health concern. Transcranial magnetic stimulation (TMS) is a non-invasive form of brain stimulation that has already displayed remarkable potential for producing novel, non-pharmacological interventions for depression and cigarette smokers. In this study, we will use brain MRI to guide TMS therapy for smoking cessation.

Detailed Description
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Smoking cessation is difficult, despite the demonstrated efficacy of several pharmacotherapeutic agents and cognitive behavioral therapies. This may be due to imbalanced neuronal circuits, including elevated functional connectivity in the drive-reward circuit (medial orbital frontal cortex [mOFC] to nucleus accumbens [NAc]) and decreased functional connectivity in the executive control circuit (dorsolateral prefrontal cortex[ DLPFC] to NAc). Repetitive transcranial magnetic stimulation (rTMS) is a new class of therapeutics that has already displayed remarkable potential for producing novel, non-pharmacological interventions for neuropsychiatric disorders. Previous studies have reported that rTMS decreased cue craving, reduced cigarette consumption, and increased smoking quit rate in tobacco use disorders(TUDs). However, the treatment parameters and exact mechanism for rTMS increasing smoking quit rate need further refinement. The goal of this study is to develop a circuit-based precision rTMS therapy for smoking cessation further. In the 2-year UG3 phase, investigators will recruit 45 TUDs. Participants will undergo a baseline cue-exposure fMRI and a resisting-to smoke fMRI session. Participants will be randomized into three groups: 1) Sham rTMS over the left mOFC or the left DLPFC. 2) Active, inhibitory low-frequency rTMS (LF-rTMS) over the left mOFC (1 Hz, 900 pulses, E-field modeling, 15 minutes, smoking cue exposure fMRI-guided target). Or 3) Active, high-frequency rTMS (HF-rTMS) over the left DLPFC (10 Hz, 3000 pulses, E-field modeling,15 minutes, resisting-to-smoke fMRI guided target). Fifteen sessions of rTMS will be completed over three weeks, after which the investigators will acquire fMRI scans. The investigators will also test the imbalanced function of drive-reward and executive control before and after 3 weeks of treatments to compare the imbalanced function between groups.

Official Title
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RTMS Manipulates Imbalanced Drive-reward and Executive Control Circuitry for Smoking Cessation

Conditions
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Tobacco Use, Cigarette Smoking

Intervention / Treatment
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* Device: Sham rTMS
* Device: Active rTMS 10 Hz DLPFC
* Device: Active rTMS 1 Hz mOFC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be between the ages of 18 and 60 years old. Smoke 10 or more cigarettes per day and have a carbon monoxide (CO) level > 10 ppm indicative of recent smoking. Have not received substance abuse treatment within the previous 30 days. Meet the criteria for tobacco use disorder as determined by DSM-5. Be in stable mental and physical health. If female, test non-pregnant and use adequate birth control. Show no evidence of focal or diffuse brain lesions on MRI. Be willing to provide informed consent. Be able to comply with protocol requirements and likely to complete all study procedures. Be motivated to quit smoking (based on responses of very likely, or somewhat likely in the motivation questionnaire). Exclusion Criteria: Current moderate to severe substance use of any psychoactive substances other than nicotine or caffeine, as defined by DSM-V criteria. Contraindications to MRI (e.g., presence of metal in the skull, orbital or intracranial cavity, or having claustrophobia). Contraindication to rTMS. History of autoimmune, endocrine, viral, or vascular disorders affecting the brain. History or MRI evidence of neurological disorder that would lead to local or diffuse brain lesions or significant physical impairment. Unstable cardiac disease, uncontrolled hypertension, severe renal or liver insufficiency, or sleep apnea. Lifetime history of major Axis I disorders such as: bipolar affective disorder (BPAD), schizophrenia, post-traumatic stress disorder (PTSD), dementia, suicidal ideation or major depression. Self-report of >21 standard alcohol drinks per week in any week in the 30 days prior to screening. Use of other forms of nicotine delivery, such as nicotine patches, electronic cigarettes, gum, nasal spray, inhalers, and nicotine lozenges. Use of other tobacco products, including cigars, cigarillos, chew, snuff, and pouches/snus. Previous treatment with TMS.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Forty-five treatment-seeking TUDs between the ages of 18 and 60 will be randomly divided into three groups on a 1:1:1 basis (15 participants/condition). The first condition will receive E-sham rTMS (half will get 1Hz sham; half will get 10Hz sham), the second condition will receive active 1Hz personalized-fMRI and E-field-modeling guided rTMS (900 pulses/session) over the left mOFC, and the third condition will receive active 10 Hz personalized-fMRI and E-field modeling guided rTMS (3000 pulses/session) over the left DLPFC.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Sham rTMS<br>Participants will be fitted with two electrodes on the scalp just below the hairline. Electrodes will be connected to an Epix VT® Transcutaneous Electrical Nerve Stimulation Device with adjustable output amplitude and powered by a 9-V battery. We will use electrode stimulation with 10 Hz over DLPFC, total 3000 pulses or 1 Hz over mOFC total 900 pulses. The sham-TMS scalp discomfort was matched to that of active TMS. During real TMS there was no current flowing through the scalp electrodes. | Device: Sham rTMS<br>* Two electrodes on the scalp will be connected to transcutaneous electrical nerve stimulation.<br>|
| Active Comparator: Active rTMS 10 Hz DLPFC<br>A stimulation frequency of 10 Hz, pulse train duration (on time) of 5 seconds, inter-train interval (off time) of 10 seconds (15 second cycle time), E-field-modeling to determine TMS intensity and coil orientation, total of 60 trains, session time of 15 minutes, and 3000-total pulses per day, will be delivered over the left DLPFC. | Device: Active rTMS 10 Hz DLPFC<br>* 10 Hz repetitive transcranial magnetic stimulation (rTMS) will be delivered over left dorsolateral prefrontal cortex (DLPFC).<br>|
| Active Comparator: Active rTMS 1 Hz mOFC<br>A stimulation frequency of 1Hz, E-field-modeling to determine TMS intensity and coil orientation, session time of 15 minutes, and 900-total pulses per day, will be the same for all subjects (both active and sham). TMS will be delivered over the left mOFC. | Device: Active rTMS 1 Hz mOFC<br>* 1 Hz repetitive transcranial magnetic stimulation (rTMS) will be delivered over left medial orbitofrontal cortex (mOFC).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean number of cigarettes smoked per day | The primary objective is to compare 1 Hz-mOFC rTMS to 10 Hz-DLPFC rTMS. Cigarettes smoked per day will be the primary outcome measure. | 3-week rTMS treatment | 
| Changes of brain connectivity | Compared to sham rTMS, either active rTMS significantly increase the negative correlation between DLPFC and NAc, DLPFC and mOFC, while decrease the correlation coefficient between NAc and mOFC. | Pre and post 3-week treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of participants who have quit by their target quit date | Quit smoke rate on the target quit the date will be measured during the phase. | 4-week follow-up |