The goal of this clinical trial is to to inhibit the dorsal anterior insula (dAI) with low intensity focused ultrasound (LIFU) to determine the causal role for the dAI in smoking cue induced craving in individuals with tobacco use disorder (TUD); smoking cue induced craving is a clinically important behavior which has been associated with the severity of nicotine addiction. The main question[s] it aims to answer are:

• the safety and tolerability of dAI LIFU compared to sham stimulation in individuals with TUD
• the effects of LIFU vs sham to left dAI functional magnetic resonance imaging (fMRI) BOLD activity and craving in response to smoking cue exposure.

Participants will undergo anatomical MRI, neurological assessment, clinical assessment and patient query to assess the safety and tolerability of LIFU vs sham.

Participants will undergo functional magnetic resonance imaging where we will measure the effect of LIFU vs sham on 1) dAI blood-oxygen-level-dependent (BOLD) activation in response to smoking (compared to neutral) cue exposure and 2) cue-induced craving in individuals with TUD. Each participant will receive LIFU and sham stimulation.

Tobacco use disorder (TUD) remains the leading cause of preventable death in the world. Costs of smoking related illness in the United States totals more than $300 billion each year. The majority of adult cigarette smokers want to quit and more than half make an attempt but fewer than 1 in 10 smokers successfully quit at the end of 1 year. Rates of cigarette smoking are higher and cessation rates are lower in the veteran population in the United States compared to the nonveteran population. Noninvasive neuromodulation holds promise as a therapeutic approach to TUD as evidenced by the recent food and drug administration (FDA) clearance of deep transcranial magnetic stimulation (TMS) as such a treatment. One additional, emerging potential therapeutic is using low-intensity focused ultrasound (LIFU) to inhibit cortical and deep brain regions. The enormous potential of LIFU stems from the ability to focus ultrasound through the intact skull to a millimeter-sized focal spot size anywhere in the brain. This makes it a powerful alternative to both invasive neurosurgical procedures and other noninvasive brain stimulation techniques such as TMS that have limited spatial resolution and can only reach superficial areas of the brain. One promising target to treat TUD is the dorsal anterior insular cortex (dAI), a brain structure whose function is linked to the desire to smoke. The dAI is a part of the salience network (SN) that is involved in assigning significance and emotional value to stimuli and is consistently activated with exposure to smoking cues and craving. Remarkably, humans with damage to the insula were able to stop smoking easily and without experiencing cravings or relapse. As such, the insula is a promising target for reducing craving and use in individuals with TUD. Unfortunately, the dAI is small and lies deep within the lateral sulcus covered by the overlying opercula of the temporal lobe and is not accessible with conventional noninvasive neuromodulatory techniques. LIFU can selectively target the dAI and provides a potentially transformative method to reduce nicotine craving and addiction. The overall purpose of this proposal is to inhibit the dAI with LIFU to determine the causal role for the dAI in smoking cue induced craving which is a clinically important behavior which has been associated with the severity of nicotine addiction.

Inclusion Criteria:

1. Male and female veterans aged 18-75 years
2. Meet the Diagnostic and Statistical Manual, Fifth edition (DSM-5) criteria for current TUD (moderate to severe) as diagnosed by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.
3. Currently smoking > 10 cigarettes per day with no period of abstinence > 3 months in the last year
4. Current use of tobacco in last year is limited to cigarettes
5. Currently in Contemplation Stage of motivation for behavior change with respect to smoking as assessed by the University of Rhode Island Change Assessment Scale

Exclusion Criteria:

1. Not under current treatment for smoking cessation.
2. No history of head injury, seizures, neurologic disorders including cerebrovascular disease, multiple sclerosis, or neurodegenerative diseases or major medical illness
3. Current substance use disorder for a psychoactive substance (except nicotine)
4. DSM-5 psychiatric disorder requiring current treatment
5. Ferromagnetic implants or other contraindications for MRI
6. Taking any psychotropic medication such as antidepressants, anxiolytics and antipsychotics.
7. any medication other than psychotropic medications that is known to cross the blood brain barrier and achieve brain penetrance such that it will alter BOLD signal or lower seizure threshold, such as antibiotics, antihistamines or muscle relaxants.
8. currently pregnant or breast feeding

behavioral and imaging data

data will be available after analysis of primary and secondary outcomes are completed

The Sham condition will be conducted using an interface which does not allow ultrasound energy to pass from the transducer to the target. The administration of LIFU/sham will be conducted in a double-blind fashion.