This study will develop novel low intensity focused ultrasound (LIFU) therapy to help people to quit cigarette smoking. Smoking is associated with cancers of the lung. Available smoking cessation methods help many to quit. However, for the many who continue to smoke despite the strong desire to quit and after exhausting existing therapeutic approaches, new treatment methods are needed. Without more effective treatment, many will continue to smoke, and our progress on cancer prevention through smoking cessation may decelerate as these associated cancer risks will remain. Brain imaging research has identified specific areas of the brain linked to severe nicotine addiction, but up to now there are no effective ways to directly target most of these deeper brain regions. LIFU is a new and safe method to modulate brain functions that can either inhibit overactive activity or restore normal activity levels. The purpose of this study is to provide a novel ultrasound-based neuromodulation strategy for smoking cessation in people who have difficulty to quit smoking despite numerous serious attempts in their lives. LIFU works by sending acoustic pressure modulating neural activity in the human brain.

Inclusion Criteria:

1. Must be a smoker for 5 or more years and within 20 to 60 years of age
2. Must not meet exclusion criteria for MRI scanning (e.g., non-fixed magnetizable objects)
3. Must not have ongoing unstable medical, neurological or psychiatric illness as determined by a combination of history, medical record, and/or examination.
4. Must be a current smoker with average of 5 cigarettes or more a day for the last month or longer.
5. Report 3 or more trials of smoking cessation attempts using nicotine replacement, e-cig, TMS, varenicline or other smoking cessation drugs, psychotherapy or other means.

Exclusion Criteria:

1. Failed TMS screening questionnaire.
2. Significant alcohol or other drug use (substance dependence within the recent months) or positive urine toxicology screen for substance not prescribed other than nicotine or marijuana dependence.
3. Cannot refrain from using alcohol and/or marijuana 24 hours or more prior to experiments.
4. Taking > 400 mg clozapine/day and not on anti-seizure medication(s) with sufficient dose.
5. Woman who is pregnant (child-bearing potential but not on contraceptive and missing menstrual period; or by self-report; or by positive pregnancy test) or has had unprotected sexual intercourse without birth control in the last 4 weeks.
6. In ongoing smoking cessation treatment, clinical trial, or nicotine replacements (except for the current study)