Study terminated due to PI leaving the institution.

Cigarette smoking constitutes the greatest preventable cause of mortality and morbidity in the US. The most critical period for long term success of smoking cessation appears to be in the first 7 days after the quit date. A metaanalysis of 3 pharmacotherapy trials revealed that abstinence during the first 7 days was the strongest predictor of 6 month outcomes (n=1649; Odds ratio: 1.4, P <0.0001; Ashare et al. 2013). Prodigious relapse rates during this first week of smoking cessation are likely due to behavioral and neurobiological factors that contribute to high cue-associated craving and low executive control over smoking. The long term goal of the research is to develop evidence-based transcranial magnetic stimulation protocols to facilitate abstinence during this critical period.

The competing neurobehavioral decision systems (CNDS) theory posits that in addiction, choice results from a regulatory imbalance between two decision systems (impulsive and executive). These behavioral systems are functionally linked to two discrete frontal-striatal circuits which regulate limbic and executive control. Modulating these competing neural circuits (e.g. either dampening the limbic/impulsive system or amplifying the executive control system), may render smokers less vulnerable to factors associated with relapse. The scientific premise for the proposed research is that direct modulation of these neural circuits will induce changes in cigarette valuation and brain reactivity to smoking cues.

However, the relative efficacy of targeting one or the other systems is unknown. To address this gap the investigators will target the two components derived from the CNDS.

These two frontal-striatal neural circuits - the limbic loop (ventromedial prefrontal cortex (vmPFC)-ventral striatum), and executive control loop (dorsolateral PFC (dlPFC)-dorsal striatum) can be differentially stimulated by theta burst stimulation (TBS), a patterned form of transcranial magnetic stimulation (TMS). Continuous TBS (cTBS) results in long term depression (LTD) of cortical excitability and intermittent TBS (iTBS) results in potentiation (LTP). Recent studies by our group have demonstrated that LTD-like cTBS to the vmPFC (Aim 1) attenuates brain activity in the nucleus accumbens (Hanlon et al. 2015) and salience network (2017). In a collaborative MUSC/VTCRI study, 5 days of vmPFC cTBS reduced the value of cigarettes, preference for immediate gratification, and smoking cue-evoked brain activity. Alternatively, other investigators have demonstrated that LTP-like stimulation to the dlPFC (Aim 2) decreases cigarette craving and cigarette use. These studies support the targets specified by CNDS. The investigators will evaluate the relative efficacy of these 2 strategies as novel tools to change smoking-related behaviors and dampen brain reactivity to cues in two double-blind, sham-controlled neuroimaging studies. The investigators long-term vision is that TBS would be used as an acute intervention enabling individuals to get through the first week after a smoking quit attempt without relapsing, and transition to more sustainable mechanisms of behavioral change (e.g., medication, cognitive behavioral therapy).

Aim 1 (Strategy 1): Modulating the limbic system as an approach to treatment: vmPFC cTBS. Cigarette smokers will be randomized to receive 10 days of real cTBS or sham cTBS directed to the vmPFC. Intermittently the desire to smoke, cigarette value using behavioral economic demand, preference for immediate gratification (delay discounting), and cigarette self-administration will be assessed. Smoking cue-evoked brain activity will also be measured when individuals are asked to 'crave' (passive limbic engagement) versus 'resist' the craving (executive engagement). The investigators hypothesize that cTBS will: 1) decrease the behavioral smoking measures described above, which will be explained by a selective 2) decrease in the neural response to cues when individuals 'allow' themselves to crave, and 3) sustain these changes over a time period sufficient to overcome the initial quit attempt (~7-14 days).

Aim 2 (Strategy 2): Modulating the executive system as an approach to treatment: dlPFC iTBS. Aim 2 will follow the design of Aim 1. The procedures will be identical, except iTBS will be delivered to the left dlPFC. The investigators hypothesize that iTBS will: 1) decrease the behavioral smoking measures described above, which will be explained by a selective 2) increase in the neural response to cues when individuals attempt to 'resist' the cues, and again 3) sustain these changes over a similar period as specified in Aim 1.

Exploratory Aim: Evaluate baseline frontal striatal connectivity and discounting rate as factors to predict an individual's likelihood of responding to Strategy 1 versus Strategy 2. The investigators will test the hypotheses that individuals with a higher ratio of (vmPFC-striatal)/(dlPFC-striatal) connectivity will be more likely to have a behavioral change after Strategy 1. Various demographics (e.g. gender, smoking history, socioeconomic status, subclinical depressive symptoms, self-efficacy, & motivation to quit will be evaluated as explanatory variables.

The outcomes of the present aims will resolve a critical gap in the investigator's knowledge regarding the relative efficacy of 2 promising TMS treatment strategies. These outcomes will be directly translated to a larger longitudinal study evaluating a multipronged approach to improving outcomes in traditional pharmacotherapy or behavioral treatments.

Inclusion Criteria:

1. Age 18 70 (to maximize participation, and minimize effects of cortical atrophy on neuroimaging data)
2. Current cigarette smoker
3. Able to read and understand questionnaires and informed consent.
4. Has accommodations within 50 miles of the study site.
5. Is not at elevated risk of seizure (i.e., does not have a history of seizures, is not currently prescribed medications known to lower seizure threshold)
6. Does not have metal objects in the head/neck.
7. Does not have a history of traumatic brain injury, including a head injury that resulted in hospitalization, loss of consciousness for more than 10 minutes, or having ever been informed that they have an epidural, subdural, or subarachnoid hemorrhage.
8. Does not have a history of claustrophobia leading to significant clinical anxiety symptoms.

Exclusion Criteria:

1. Any psychoactive illicit substance use (except marijuana, alcohol, and nicotine) within the last 30 days by self-report and urine drug screen. For marijuana, no use within the last seven days by verbal report and negative (or decreasing) urine THC levels. Participation will be discontinued if participants use psychoactive illicit substances (except nicotine and alcohol) after study initiation.
2. Meets DSM IV criteria for current axis I disorders of major depression, panic disorder, obsessive-compulsive disorder, post traumatic stress syndrome, bipolar affective disorder, schizophrenia, dissociate disorders, eating disorders, and any other psychotic disorder or organic mental disorder.
3. Has current suicidal ideation or homicidal ideation.
4. Has the need for r acute treatment with any psychoactive medication including anti-seizure medications and medications for ADHD.
5. Females of childbearing potential who are pregnant (by urine HCG), nursing, or who are not using a reliable form of birth control.
6. Has current charges pending for a violent crime (not including DUI related offenses).
7. Does not have a stable living situation.
8. Suffers from chronic migraines.

No individual participant data will be shared. All data is de-identified.