Transcranial Magnetic Stimulation and Tobacco Use Disorder

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 They may also be withdrawn at the discretion of the investigators for inability to comply with procedures or if continuing participation is unsafe or not in their best interest.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 (SCID) by a trained diagnostician to rule out any 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, the Shipley Hartford Vocabulary Test to document English language fluency, 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 13 min, which was found to produce optimally reliable RSFC results. We plan for a single, long-duration run because single-session resting state scans produce more reliable results than combining two shorter sessions and the short TR (800 ms) used offers flexibility in eliminating motion-related images. 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 37.5 min at 120% MT with 4 sec pulse trains and 26 sec inter-train interval. Participants will receive this stimulation to the left PPC, dlPFC, and SMA on separate test days. All participants will undergo sham stimulation (10% of MT) on the first test day due to evidence that sham stimulation may have low participant blinding success; therefore, sham stimulation will occur first to minimize the impact of this problem (i.e., participants will be unaware that they received sham stimulation until after the sham test day is complete). The order of the active stimulation targets will be randomized.

10. Repeated self-reports of craving, withdrawal, and mood (items 4-6).

11. Repeat fMRI.

12. Smoking. Participants will be permitted to smoke a cigarette.

13. Blood sampling. Approximately 4mL of blood will be collected by venipuncture for assay of nicotine metabolite ratio (ratio of 3'hydroxycotinine to cotinine) to determine participants' rate of nicotine metabolism, and, in female participants, ovarian hormone levels.

Study timeline:

Each of the 4 TMS study visits will be scheduled approximately 1 week apart to minimize carryover effects.