The purpose of this study is to determine if brain stimulation using repetitive transcranial magnetic stimulation (rTMS) directed at different parts of the brain can decrease feelings of cigarette craving and symptoms of cigarette withdrawal, and also if men and women have different responses to rTMS.

Participants will visit the University of California, Los Angeles (UCLA) five times: First, for in-person screening, then for four rTMS sessions, four three different brain regions. Everyone in the study will be assigned to all four treatment arms and they will take place in a random order. Before and after each rTMS session, a brief MRI will be performed, and participants will be asked to fill out questionnaires that describe how they are feeling.

After the initial telephone screening, potentially eligible candidates will meet with staff and receive a lay-language explanation of the study. Candidates will review, ask about, and sign the informed consent form for the study. Those who have difficulty understanding the information will be able to review and ask questions to a staff member, who will help clarify the requirements, potential risks and benefits of participation. Any participant who is unable to demonstrate understanding of the information presented despite assistance will be excluded. Participants may withdraw from the study at any time. They may also be withdrawn at the discretion of the investigators for inability to comply with procedures or if continuing participation is unsafe or not in their best interest. Any participant expressing a desire for smoking cessation treatment, at any point during screening or while engaged in the study, will be referred to appropriate counseling services.

Once the informed consent is obtained, participants will undergo a psychological evaluation (MINI) by trained study staff to rule out any exclusionary psychiatric diagnoses. Participants will provide a urine sample to be used for pregnancy and toxicology tests.

They will complete a series of questionnaires to provide demographic information, and complete the Fagerström Test for Nicotine Dependence, Smoking History Questionnaire, Timeline Follow Back (TLFB) to report smoking over the month before testing, Substance Use Inventory, as well as the Beck Depression Inventory, Beck Anxiety Inventory, and Positive and Negative Affect Scale (PANAS) to measure mood state and traits before beginning the study. Daily smoker status will be tested at screening.

Test Day Procedures:

1. Evaluation of wakefulness. Due to the possibility that sleep deprivation may reduce the seizure threshold, wakefulness will be self-reported via the Stanford Sleepiness Scale. Participants who score below a 5 will be asked to reschedule their appointment and return when they are better rested.
2. Abstinence from Drug and Alcohol Use. Each study will begin with a urine test to verify abstinence from drugs of abuse and a Breathalyzer test to verify abstinence from alcohol.
3. Smoking Abstinence. Expired air will be sampled for CO to verify overnight abstinence. Participants who are not abstinent will be allowed to return for testing on another day.
4. Pregnancy Testing. Female participants will each have a urine test to confirm absence of pregnancy.
5. Self-report of Spontaneous Craving. Data will be obtained on the 10-item Urge to Smoke Scale. Self-reports for each item are given on a scale from 1-7, with 1 = definitely not and 7 = definitely.
6. Self-report of Withdrawal. Participants will complete the Shiffman-Jarvik Withdrawal Scale, a 25-item questionnaire comprised of five scales: Craving; Psychological Withdrawal; Physiological Withdrawal; Stimulation/Sedation; and Appetite. Each question is rated on a 7-point scale (1 = definitely not to 7 = definitely) to indicate the respondent's feeling state. Scores are calculated as the mean response to each question on each particular subscale.
7. Self-report of Mood. Participants will complete the Positive and Negative Affect Schedule (PANAS), a 20-item questionnaire comprising two mood scales (positive and negative). Each item is rated on a 5-point scale ranging from 1 (very slightly or not at all) to 5 (extremely) to indicate their feeling state.
8. fMRI. Resting-state fMRI data will be collected while participants lie in the scanner with eyes open viewing a black screen. The scan duration is 8 minutes. Identical scanning procedures will be performed once before rTMS, and once after.
9. rTMS. Subjects will first undergo Motor Threshold (MT) determination using single pulses applied to the left motor cortex, with motor response determined using electromyography (EMG) electrodes applied to the right hand (standard clinical procedures). On active test days, rTMS will be performed using 10 Hz stimulation, a treatment paradigm that has previously reduced craving, with 3000 pulses administered over 15 min at 100% MT with 5 sec pulse trains and 10 sec inter-train interval. Participants will receive this stimulation to the left posterior parietal cortex, dorsolateral prefrontal cortex, and superior frontal gyrus on separate test days.
10. Repeated self-reports of craving, withdrawal, and mood (items 4-6).
11. Repeat fMRI.

Study timeline:

Each of the 4 TMS study visits will be scheduled at least 24 h apart to allow for washout.

Inclusion Criteria:

• 18-45 years old
• Self-identified as male or female
• English fluency;
• Generally good health without cardiovascular, hepatic, renal, or autoimmune diseases; diabetes; or cancer
• Must have smoked for 1 year; smoke 10 cigarettes per day
• Meeting DSM 5 criteria for Tobacco Use Disorder

Exclusion Criteria:

• Seeking treatment for nicotine dependence now or within 3 months before study entry
• A medical condition that may compromise safety
• A neurological disorder that would compromise compliance and/or informed consent
• A major psychiatric disorder
• Current drug use disorders other than Tobacco Use Disorder as defined by DSM 5
• Recent use of drugs of abuse as shown by urine test at the screening or testing sessions
• Smoke marijuana more than once a week
• Use of tobacco in forms other than cigarettes more than 10 days in last month
• Preference for menthol
• Pregnancy or nursing
• Seizure disorder
• Metal implants
• Any other circumstance that the investigators determine would compromise safety

Self-identified as male or female

This is a single-blind study and only the participant will not be aware of when they will be undergoing the sham stimulation arm.