QuitFast: Evaluating Transcranial Magnetic Stimulation as a Tool to Reduce Smoking Directly Following a Quit Attempt

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.