Pilot TMS for Methamphetamine Use Disorder
Condition: Stimulant Dependence; Methamphetamine-dependence; Addiction, Drug
MeSH terms: Substance-Related Disorders; Behavior, Addictive
Study type: Interventional

Summary: 
      This is a pilot study to test the feasibility of a recruitment strategy and study protocol to
      examine the effects of a dual target transcranial magnetic stimulation treatment in
      methamphetamine use disorder. The study will test intermittent theta burst stimulation (TBS)
      targeting the dorsolateral prefrontal cortex (DLPFC) combined with continuous TBS targeting
      the medial prefrontal cortex (MPFC) in people with methamphetamine use disorder (MAUD) who
      are engaged in psychosocial treatment. Intermittent TBS targeting the DLPFC is approved by
      the Food and Drug Administration for major depressive disorder, and continuous TBS targeting
      the MPFC has been studied in cocaine use disorder. We will administer this dual target TBS
      daily for 2 weeks, followed by three times weekly for 2 weeks, and monitor depressive
      symptoms, anxiety, sleep, craving, quality of life, and methamphetamine use for three months.
      Changes in functional connectivity of brain circuits will be evaluated with functional
      magnetic resonance imaging (fMRI) before and after treatment. We expect to observe changes in
      connectivity between the DLPFC, MPFC, and other regions implicated in addiction and
      impulsivity. Furthermore, we will evaluate if baseline differences in functional connectivity
      can be used to predict response. Psychological tests focusing on state impulsivity and risk
      taking will be administered, and we expect to observe reductions in these characteristics
      after treatment. We will test this protocol in 20 patients recruited from clinical care
      settings at University of Iowa Hospitals and Clinics, University of New Mexico Health System,
      and University of Utah Health to illustrate the feasibility of recruitment and completing the
      protocol, to support an external funding proposal.
    

Detailed description: 
      Overview: This is a single-arm clinical trial, with historical controls as a comparison group
      for select outcomes. Subjects with MAUD will receive 16 sessions of dual-target theta burst
      stimulation to the DLPFC and MPFC over 4 weeks. We will follow outcomes for 12 weeks.
      Outcomes include treatment retention, craving, self-reported MA or stimulant use, urine drug
      screen results, depressive symptoms, anxiety symptoms, sleep quality, quality of life,
      response inhibition, and functional connectivity. Magnetic resonance imaging (MRI) to measure
      functional connectivity and a flanker task to measure response inhibition will be completed
      at baseline and four weeks. More detail is provided in the outcome measures section. Subjects
      will also complete the Big Five Inventory at baseline, a measure of personality
      characteristics, to explore how these relate to outcomes including retention in treatment and
      the study.

      MR Image Acquisition: MRI will be completed at baseline and after the last TMS session. The
      MRI sessions will be conducted using research dedicated MRI scanners at each site. Anatomical
      images will include volumetric T1 and T2 weighted images with a 1.0 mm isotropic spatial
      resolution. Resting state fMRI will be performed to collect 20 minutes worth of data.

      Statistical Analysis:

      Retention in the Study and Psychosocial Treatment: We will describe the proportion of
      subjects who complete the 4-week TMS treatment period and complete each subsequent monthly
      follow-up visit. We will use Kaplan-Meier curves to describe retention in the study and in
      psychosocial treatment. If non-retention is common enough, we will use Cox regression to
      explore baseline measures as predictors of retention. We anticipate that multivariate
      analysis will not be feasible with the sample size.

      Symptoms and Impulse Control Measures: Primary analyses for other measures will focus on
      changes over the 4-week TMS treatment period. Changes in symptoms evaluated weekly or
      biweekly (e.g. craving, depression, affect, anxiety, sleep) will be assessed using
      generalized linear mixed models with appropriate distributions. We anticipate a Poisson
      distribution for days of MA or other stimulant use and will use a binomial distribution with
      a logit link to evaluate changes in positive urine drug screens. Time will be the primary
      variable of interest to assess the slopes of change during treatment. Paired t-tests or
      Wilcoxon signed-rank tests will be used to evaluate changes in measures completed at baseline
      and after 4 weeks of treatment. We will compare measures at baseline and 4 weeks to those at
      8 weeks and 12 weeks similarly, but in separate analyses since decay in effects may occur
      after TMS ends.

      Functional Connectivity Analysis: fMRI functional connectivity analysis will be performed
      using a standard analysis pipeline. Functional images will undergo pre-processing including
      brain extraction, motion correction, spatial smoothing (6 mm FWHM), and temporal filtering
      (.008 Hz < f < 0.08 Hz). Following preprocessing, the fMRI signal will be corrected for
      potential sources of noise using image-based estimates and motion correction parameters. The
      resulting corrected time-series will be used for all functional connectivity analyses.
      Functional connectivity will be measured by extracting time-series data from the
      pre-processed imaging data for the regions of interest (ROIs). Multiple ROIs will be examined
      and will be defined as spheres (6mm radius) based on coordinate locations previously
      published by Yeo and colleagues. Specifically, we will focus on connectivity in the
      cingulo-opercular network involved in cognitive control and salience (DLPFC - anterior
      insula; DLPFC - anterior cingulate) and reward processing/motivation circuit (MPFC - ventral
      striatum). Analyses will be averaged across right and left hemispheres but we will also
      explore differences between right and left hemispheres. The time series from the ROIs will be
      cross-correlated with the time-series from the other ROIs to determine the strength of
      functional connectivity between regions. The resulting Pearson's r will be converted to
      Fisher's z scores to improve normality for the statistical analysis. We will treat each ROI
      pair connection (DLPFC - anterior insula, DLPFC - anterior cingulate, MPFC - ventral
      striatum) as a dependent variable. Primary analyses will use paired t-tests or Wilcoxon
      signed-rank tests to compare connectivity at baseline vs. after TMS treatment. We will
      explore correlates of connectivity and changes using Pearson or Spearman correlations and
      linear regression or mixed models.

      Exploratory Analysis: Follow-up exploratory voxel-wise analyses will be conducted for
      functional connectivity, which will provide thousands of individual predictors. This will
      help confirm findings in large parcel ROI based analysis. We will use the same statistical
      models as used for the ROI based analysis described above but at the voxel level. Voxel-wise
      data creates a high-dimensional problem in which the number of predictors far exceeds the
      number of participants. Machine learning methods, such as random forest will be used to
      handle the high-dimensional sub-analyses. Random forest requires a minimum of data
      assumptions, automatically accounts for non-linear and interaction effects, and it has proven
      useful in identifying useful predictors in high-dimensional contexts.

      Comparison with Historical Controls: We will compare retention in psychosocial treatment
      programs and positive urine drug screens from chart review with a historical control group of
      patients with MA use disorder matched on age, sex, site, and psychosocial treatment modality.
      Treatment retention will be compared using a log-rank test. Positive urine drug screens in
      each week of follow-up will be compared using generalized estimating equation models with a
      logit link, clustered on subject, with participation in the TMS study as the variable of
      interest.
    

Intervention name(s): Transcranial Magnetic Stimulation
Intervention type(s): Device
Intervention description(s): Participants will undergo 16 treatments consisting of intermittent theta burst stimulation targeting the dorsolateral prefrontal cortex and continuous theta burst stimulation targeting the medial prefrontal cortex, over a 4-week period that coincides with psychosocial treatment for methamphetamine use disorder.
Other intervention name(s): Theta burst stimulation
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized order of TMS site stimulated first
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: methamphetamine; addiction treatment; transcranial magnetic stimulation