Cortical rTMS as a Tool to Change Brain Reactivity to Alcohol Cues
Condition: Alcohol Dependance
MeSH terms: Alcoholism
Study type: Interventional
Phase: Early Phase 1

Summary: 
      The goal of this investigation is to determine if, in heavy alcohol users, a single session
      of transcranial magnetic brain stimulation (TMS) over a brain region involved in craving
      (medial prefrontal cortex) and a brain region involved in cogntive control (dorsolateral
      prefrontal cortex) can lower an individual's craving and brain response to alcohol cues. This
      study involves a screening visit, followed by three visits which involve brain imaging (using
      functional MRI) and brain stimulation (using TMS). There is also an additional Magnetic
      resonance spectroscopy (MRS) exploratory Aim in which we will measure the concentration of
      glutamate in the prefrontal cortex before and after a session of TMS.
    

Detailed description: 
      Alcohol Use Disorders (AUDs) are prevalent, devastating, and difficult to treat. High relapse
      rates are likely due to factors that affect limbic and executive circuits in the brain,
      including vulnerability to salient cues and loss of cognitive control. Limbic drive and
      executive control are regulated by two cortical-subcortical neural circuits -the limbic loop
      that includes projections from the medial prefrontal cortex (mPFC) to the ventral striatum,
      and the executive control loop that includes projections from the dorsolateral prefrontal
      cortex (dlPFC) to the dorsal striatum. Optogenetic manipulation in animals has demonstrated a
      causal relationship between activity in these frontal-striatal circuits and drinking
      behavior. Consequently, an innovative and potentially fruitful new strategy in the treatment
      of AUDs in humans would be to selectively attenuate limbic circuitry (to reduce reward
      salience), and/or amplify executive circuitry, through targeted brain stimulation. Previous
      studies have demonstrated that a single session of 10 Hz transcranial magnetic stimulation
      (TMS) over the dlPFC can lead to a decrease in craving for alcohol, nicotine, and cocaine.
      Our laboratory has demonstrated that a single session of continuous theta burst (cTBS) TMS
      over the mPFC can also decrease craving, as well as the brain response to drug cues in
      cocaine users (Hanlon et al, in review) and alcohol users (see Significance). The overarching
      goal of this proposal is to determine which of these two TMS strategies - amplifying dlPFC
      activity or inhibiting mPFC activity - is more efficacious in decreasing alcohol craving and
      the brain response to cues. This will provide an evidence-based foundation for cortical
      target selection in future TMS clinical trials - an innovative treatment strategy for AUD
      patients.

      As a recent FDA-approved treatment for depression, there is a growing interest in
      investigating TMS as a treatment for drug and alcohol use disorders. By changing the
      frequency and pattern of stimulation, it is possible to induce a long-term potentiation (LTP)
      or long-term depression (LTD) of activity in the cortical area stimulated as well in its
      monosynaptic targets. To date, nearly all published reports of brain stimulation as a tool
      for decreasing craving have focused on applying LTP-like stimulation (typically 10 Hz) to the
      dlPFC, thereby strengthening executive control circuitry. An alternative approach is to apply
      LTD-like TMS (such as cTBS) to the mPFC, thereby weakening limbic drive circuitry (which is
      engaged during craving). A sham TMS-controlled crossover study of 12 heavy alcohol users in
      our lab indicated that a single dose of mPFC cTBS decreases self-reported craving and the
      BOLD response to alcohol cues in the mPFC and striatum (limbic regions involved in craving).
      Using MR spectroscopy, we further demonstrated that cTBS-reduced the glutamine concentration
      in the mPFC, which may be related to the decrease in BOLD signal and functional connectivity
      with this region. Before moving forward with large and expensive multisite clinical trials,
      it is important to determine which cortical target (mPFC vs dlPFC) is likely to have a
      greater effect on the brain response to alcohol cues (Aim 1), and which will have a greater
      effect on self-reported craving (Aim 2) -a major factor contributing to relapse and sustained
      heavy drinking among individuals with AUDs. In this three-visit crossover design, a cohort of
      non-treatment seeking AUD individuals will receive sham, mPFC, or dlPFC TMS at each visit
      followed by alcohol-cue induced BOLD imaging and MR Spectroscopy. We will determine whether
      LTD-like mPFC TMS is more effective than LTP-like dlPFC TMS in:

      Aim 1: Reducing alcohol cue-elicited brain activity in limbic circuitry. Participants will be
      exposed to our well-established fMRI alcohol cue paradigm. We will measure the percent BOLD
      signal change within a network of limbic regions typically activated by alcohol cues (e.g.
      mPFC, ACC, striatum) (Schacht et al., 2014), as well as functional connectivity between these
      regions (using psychophysiologic interactions). We will test the hypotheses that 1) both
      LTD-like stimulation to the mPFC (via cTBS) and LTP-like stimulation to the dlPFC (via 10Hz
      TMS) will significantly decrease alcohol cue-induced activation of limbic circuitry compared
      to sham stimulation and 2) this attenuating effect will be more robust when stimulation is
      targeted at the mPFC directly with cTBS stimulation (rather than indirectly via 10 Hz dlPFC
      stimulation).

      Aim 2: Reducing self-reported alcohol craving. Using intermittent self-reported assessments
      of the desire to drink alcohol throughout the experimental sessions (before, during, and at
      several time points after the TMS treatment), we will test the hypothesis that LTD-like
      stimulation to the mPFC (via cTBS) will decrease self-reported alcohol craving more than will
      LTP-like stimulation to the dlPFC (via 10Hz TMS).

      Finally, to develop a comprehensive and evidence-based foundation for future clinical trials,
      we will also explore the effects of these innovative brain stimulation treatment strategies
      on neurochemistry:

      Exploratory Aim 3: Regional neurochemistry. Through MR Spectroscopy, we will test the
      hypothesis that the effects of TMS on the outcomes of Aim 1 & 2 are mediated by changes in
      mPFC excitatory/inhibitory neurochemical balance (i.e., changes in glutamate, glutamine, GABA
      concentrations).
    

Intervention name(s): medial prefrontal cortex; dorsolateral prefrontal cortex; sham
Intervention type(s): Device; Device; Device
Intervention description(s): a form of theta burst stimulation that noninvasively induces a depression in brain reactivity; a form of transcranial magnetic stimulation that noninvasively induces an increase in brain reactivity; sham stimulation
Other intervention name(s): medial prefrontal; dorsolateral prefrontal
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: alcohol; addiction; cTBS