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

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

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

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 TBS. Cigarette smokers will be randomized to receive 10 days of real TBS or sham TBS 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 TBS 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 TBS will be delivered to the left dlPFC. The investigators hypothesize that TBS 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, sub clinical 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 multi-pronged approach to improving outcomes in traditional pharmacotherapy or behavioral treatments.

Smoking, Smoking Cessation, Craving, Addiction, Addiction Nicotine, Nicotine Dependence, Cigarette Smoking

Ten sessions of real Theta Burst Stimulation (TBS) will be delivered to the left medial prefrontal cortex (mPFC)

Ten sessions of sham Theta Burst Stimulation (TBS) will be delivered to the left medial prefrontal cortex (mPFC)

Ten sessions of real intermittent Theta Burst Stimulation (TBS) will be delivered to the left dorsolateral prefrontal cortex (dlPFC)

Ten sessions of sham Theta Burst Stimulation (iTBS) will be delivered to the left dorsolateral prefrontal cortex (dlPFC)

The MagVenture MagPro system has an integrated active sham that uses two surface electrodes placed on the skin beneath the coil.

The MagVenture MagPro system has an integrated active sham that uses two surface electrodes placed on the skin beneath the coil.

This 10-item questionnaire assesses cigarette craving. Participants will be asked to rate from 1 (strongly disagree) to 100 (strongly agree) their agreement with several statements (e.g., "I have a desire for a cigarette right now," and "Nothing would be better than smoking a cigarette right now."). Factor analyses support two factors: one that reflects a strong desire and intention to smoke and one that reflects relief from negative affect associated with an urgent desire to smoke.

This self-reported tobacco product use interview asks participants to retrospectively estimate the number of tobacco products they've used each day for the past 30 days or since the previous assessment, whichever is fewer.

Changes in cigarette use as detected by quantitative cotinine urine screens collected at visits 1, 6, 10, and all follow-ups

Breath CO provides an accurate measure of recent exposure to CO, including from smoking combustible tobacco products (95). The CO measurement will be used to determine recency of smoking.

The effect of real vs. sham iTBS to the left DLPFC vs. real vs. sham cTBS to the left MPFC as a tool to modulate the brain response to cigarette cravings will be assessed by comparing the brain activity in the executive circuit and limbic circuit before and after TMS. Participants will receive an MRI brain scan before their first TMS treatment, and at the end of their 10th days of TMS. At each MRI scan, participants will be subjected to a cigarette craving "cue" task within the scanner where elevated brain activity (BOLD signal) will be measured using an fMRI sequence. During each scan, they will see pictures of cigarette cues, neutral cues, and blurred images. The task is meant to induce craving and see how the brain responds to these craving cues.

Participants will be asked to choose between two conditions in which varying amounts and delays to behavioral outcomes (e.g., $50 now or $100 later) are presented. We will use magnitudes of $100 and $1000 which are the most thoroughly documented among the literature. Across consecutive choices, the delay to the larger outcome will be titrated until reaching the participant's indifference delay (i.e., the delay at which s/he equally values both options). This indifference delay indexes individual participants' rates of delay discounting. Monetary delay discounting has been documented to be predictive to treatment success for smokers.

The hypothetical purchase task (HPT), a validated measure for cigarette demand, will assess cigarette purchases at various price conditions. Participants will hypothetically purchase quantities of cigarettes to use over a 24-hour period across ascending prices (e.g., $0, 0.12, $0.25, $0.50, $1.00, and $2.00 per cigarette). The HPT has been shown to be predictive of treatment outcomes. It will measure how participants value cigarettes throughout the course of the study visits.

Inclusion Criteria: Age 18-75 (to maximize participation, and minimize effects of cortical atrophy on neuroimaging data) Current cigarette smoker (at least 10 cigarettes per day). Able to read and understand questionnaires and informed consent. Has accommodations within 50 miles of the study site. 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) Does not have metal objects in the head/neck. 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. Does not have a history of claustrophobia leading to significant clinical anxiety symptoms. Exclusion Criteria: 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. Meets Diagnostic and Statistical Manual of Mental Disorders (DSM)-V 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. Has current suicidal ideation or homicidal ideation. Has the need for acute treatment with any psychoactive medication including anti-seizure medications and medications for attention-deficit/ hyperactivity disorder. Females of childbearing potential who are pregnant (by urine HCG), nursing, or who are not using a reliable form of birth control. Has current charges pending for a violent crime (not including DUI related offenses). Does not have a stable living situation. Suffers from chronic migraines. Does not have a stable phone number for contact through calling and/or texting. Does not have a stable means of using WebEx (e.g. personal computer, Internet) for interaction with study personnel during COVID-19.