Working Memory Training Combined With Transcranial Magnetic Stimulation in Smokers
Condition: Tobacco Use Disorder
MeSH terms: Tobacco Use Disorder
Study type: Interventional
Phase: Phase 2

Summary: 
      Smoking remains the leading cause of preventable death in the United States, and current
      first-line treatments leave the majority of tobacco dependent individuals unable to quit. The
      inability to quit despite motivation to do so, is thought to result in part, from
      self-control failure. Working memory (WM) deficits contribute to imbalanced self-control and
      allow automatic impulses to drive behavior. Thus, WM plays a critical role in addictive
      behavior, and is particularly relevant to smoking. Indeed, a strong link between WM and
      smoking has been established in the literature; most notably, degree of WM impairment and
      deficits in activation in associated brain regions predict time to relapse, and WM moderates
      the relationship between craving and relapse. Given these insights, researchers have been
      examining interventions that may target WM including WM training (WMT) and repetitive
      Transcranial Magnetic Stimulation (rTMS). WMT involves taxing this executive function
      repeatedly over time and has shown positive preliminary results in improving measures of
      self-control and reducing consumption of addictive substances. Similarly, rTMS, a
      non-invasive brain stimulation procedure that stimulates neuronal tissues and increases
      cortical excitability, has been shown to increase WM capacity and reduce craving and
      consumption of several addictive substances including nicotine. While these interventions
      have demonstrated initial promise in affecting addictive behaviors, the magnitude and
      durability of their effects may be limited. Recently, researchers have posited - but not yet
      empirically tested - that WMT administered in combination with rTMS may result in an additive
      or supra-additive effect in treating addictive processes. This is highly significant; the
      clinical utility of rTMS over current first line treatments may be limited if factors with
      potential to enhance its effectiveness are not examined. Given these recent advances in the
      literature, the primary objective of the proposed study is to evaluate the individual and
      combined effects of Working Memory (WM) training and repetitive Transcranial Magnetic
      Stimulation (rTMS) on WM performance and smoking behaviors as well as critical mediators of
      these effects. These aims will be examined in a sample of tobacco dependent adults (N=130)
      utilizing a 2x2 factorial experimental design including four groups (WMT+rTMS, sham WMT+rTMS,
      WMT+sham TMS, and sham WMT+sham rTMS) capable of isolating independent and combined effects
      of WMT and rTMS.
    

Detailed description: 
      SPECIFIC AIMS Smoking remains the leading cause of preventable death in the U.S. Current
      first line treatments leave approximately 70% of tobacco dependent individuals unsuccessful
      in their attempt to quit. Specifically, only 5-30% of those who initiate treatment, including
      intensive first-line interventions, are able to maintain abstinence for one or more years.
      The inability to quit despite motivation to do so is thought to result, in part, from
      self-control failure and can be understood within the framework of dual process models of
      addiction. Dual process models view vulnerability to tobacco dependence as the relative
      balance between automatic impulses and control processes orchestrated through the interplay
      of multiple executive function. Working memory (WM) is an executive function associated with
      updating information to solve immediate problems, and achieve current goals. WM is a key
      cognitive process underlying the regulatory control component of dual process models and is
      involved in the initiation, maintenance, and relapse stages of tobacco dependence. Most
      notably, deficits in WM performance and activation in associated brain regions predict time
      to relapse and strong WM has been shown to reduce the effect of craving on the ability to
      resist smoking. Given this relationship, individuals with tobacco dependence are likely to
      benefit from interventions that strengthen WM. Recently, several studies have demonstrated
      that increasing WM capacity through WM training (WMT) is associated with positive outcomes in
      several populations with substance use or impulse control disorders. Specifically, studies
      have demonstrated that WMT is associated with decreased: delay discounting in substance
      users, weight re-gain after a weight loss program, and alcohol use in heavy drinkers.

      A second emerging innovation in the treatment of addictions is repetitive Transcranial
      Magnetic Stimulation (rTMS), a procedure which sends magnetic pulses through the scalp to
      stimulate neuronal tissue resulting in observed changes in neuronal plasticity and striatal
      dopamine. rTMS has now demonstrated positive effects in several substance use disorders
      including nicotine, alcohol, and stimulant dependence. This procedure has been shown to be
      effective in reducing smoking urges in abstinent as well as satiated smokers and to reduce
      cigarette consumption. While promising results for this treatment have been demonstrated, the
      size and durability of the therapeutic effect may be limited. Additionally, the mechanism by
      which rTMS exerts positive effects on smoking outcomes is unknown. Recently it has been
      posited that changes in WM performance resulting from rTMS may be the key pathway to its
      observed effects on smoking related outcomes, and furthermore that WMT administered in close
      temporal precedence to rTMS may result in an additive or supra-additive effect in treating
      addictive processes. However, these hypotheses have not been tested to date despite their
      importance for understanding and improving the clinical impact of these emerging therapeutic
      modalities for treating addictive behaviors. Interventions with the ability to effectively
      target self-control processes fill in a critical gap in currently available treatment
      options.

      The primary objective of the proposed study is to evaluate the potential for improved effects
      and examine mediating pathways of WMT in combination with rTMS on a laboratory based smoking
      task and neuropsychological measures of WM performance. These aims will be examined in a
      sample of tobacco dependent adults (N=130) utilizing a 2x2 factorial design including four
      groups (WMT+rTMS, sham WMT+rTMS, WMT+sham TMS, and sham WMT+sham rTMS) capable of isolating
      independent and combined effects of WMT and rTMS. The study will include a baseline
      laboratory assessment, 10 WMT sessions over two weeks, followed by 10 days of WMT immediately
      preceding and following brain stimulation sessions (10 Hz rTMS, 2000 pulses per session,
      applied to left DLPFC). Neurocognitive and psychological mediators will be assessed between
      baseline and final laboratory assessment. Lastly, a follow-up assessment will occur one-month
      after the final laboratory visit. The proposed study will test the following Specific Aims:

      Aim 1: To test the potential for improved effects of combining WMT with rTMS on smoking
      behaviors as compared to the independent effects of either condition alone. Hypothesis:
      Single active conditions (WMT+sham rTMS and sham WMT+rTMS) will result in significant
      increases in time to lapse on an analogue task as compared to the double sham condition (sham
      WMT+sham rTMS), and the WMT+rTMS condition will result in significant increases in time to
      lapse as compared to the single active conditions.

      Aim 2: To test the potential for improved effects of combining WMT with rTMS on WM
      performance.

      Hypothesis: WMT + rTMS will result in significant increases in WM performance as compared to
      all other conditions, including the additive increases in conditions outlined in Aim 1.

      Aim 3: To test mediating pathways of the effects rTMS on smoking behaviors including changes
      in craving, mood, and WM performance. Hypothesis: The direct effect of rTMS on smoking
      outcomes will be mediated by gains in WM performance, and this effect will be largest in the
      WMT+rTMS condition.
    

Intervention name(s): Working Memory Training; Sham Working Memory Training; repetitive Transcranial Magnetic Stimulation; Sham repetitive Transcranial Magnetic Stimulation
Intervention type(s): Other; Other; Device; Device
Intervention description(s): The Working Memory Training condition: This condition will include 30 sessions across 4 weeks (10 remote sessions prior to initiation of the rTMS stimulation, and 20 lab sessions on rTMS stimulation days). Participants will complete three distinct WM tasks in each session: a visuospatial WM task, a backward digit span task, and a letter span task. In the training condition, the difficulty level of all three WM tasks will be automatically adjusted on a trial-by-trial basis. An identical protocol and software have demonstrated efficacy in increasing WM capacity, and this improvement in WM predicts reduction in addictive behavior.; In the Sham WMT condition, the difficulty level of the WM tasks will not be adjusted; instead it will remain at the initial easy level throughout each task (i.e., three items in each sequence). All other aspects of the condition are identical to the active WMT condition.; The rTMS Condition: rTMS will be delivered with a Magstim Rapid2 system using Magstim Air Film Coils. rTMS pulses will be delivered at 10 Hz (100% resting motor threshold, RMT) in 40, 5 second trains, with 15 second inter-train interval, for a total of 2000 pulses per session. Active or sham rTMS will be applied over the left DLPFC; corresponding with the standard "F3" location on scalp (F3=left frontal lobe, location #3 for electrode placement using international 10-20 system for scalp measurements). Five consecutive daily sessions will occur on two consecutive weeks, for a total of 10 sessions. RMT, defined as the amount of energy required to induce movement in the contralateral abducer pollicis brevis in at least 50% of stimulations, will be assessed on first day of application.; Sham rTMS will be identical to active treatment, with the exception that mu-metal plates attached to the sham coil block the magnetic field while providing a sensation of stimulation.
Other intervention name(s): Executive Function Training; Sham Executive Function Training; Neuromodulation; Sham Neuromodulation
Allocation: Randomized
Intervention model: Factorial Assignment
Intervention model description: A 2x2 factorial model will include four groups (Working Memory Training [WMT] + repetitive Transcranial Magnetic Stimulation ]rTMS], sham WMT+rTMS, WMT+sham TMS, and sham WMT+sham rTMS) capable of isolating independent and combined effects of WMT and rTMS on the primary outcome variables.
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment