A Pilot Study of Transcranial Magnetic Stimulation for Treatment of Methamphetamine Use Disorders

简要总结

详细描述

Overview: This is a two-arm randomized controlled trial. Participants with MAUD will receive 16 sessions of dual-target theta burst stimulation to the DLPFC and MPFC over 4 weeks. Participants will be randomized to whether they receive stimulation to the DLPFC or MPFC first, but both sites will be stimulated at each treatment. 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, depending on randomization group. We will use Kaplan-Meier curves to describe retention in the study and in psychosocial treatment, and log-rank tests to compare them. 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. Randomization group by time interactions will be the primary variables of interest to assess the differences between slopes of change between groups 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 Wilcoxon rank-sum tests to compare changes in connectivity at baseline vs. after TMS treatment between groups. 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 between the two randomization groups. 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.

主要结局

次要结局

• Flanker Inhibitor Control and Attention Test, Age 12+(Baseline, 4 weeks)
• Functional Connectivity of the Dorsolateral Prefrontal Cortex and Anterior Insula(Baseline, 4 weeks)
• Functional Connectivity Dorsolateral Prefrontal Cortex and Anterior Cingulate Cortex(Baseline, 4 weeks)
• Functional Connectivity of the Medial Prefrontal Cortex and Ventral Striatum (Nucleus Accumbens)(Baseline, 4 weeks)
• Kirby Delay Discounting Questionnaire, 27 Item(Baseline, 4 weeks)
• Number of Days of Stimulant Use in the Past Week (Estimated Change Per Day)(Baseline, 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks)
• Urine Drug Screen Positive for Stimulant(Baseline, 1 week, 2 weeks, 3 weeks, 4 weeks)
• Brief Substance Craving Scale (Estimated Change in Score Per Day)(12 weeks)
• Brief Addiction Monitor Use Subscale (Estimated Change in Score Per Day)(Baseline, 4 weeks, 8 weeks, 12 weeks)
• Brief Addiction Monitor Risk Factors Subscale (Estimated Change in Score Per Day)(Baseline, 4 weeks, 8 weeks, 12 weeks)
• Brief Addiction Monitor Protective Factors Subscale (Estimated Change in Score Per Day)(Baseline, 4 weeks, 8 weeks, 12 weeks)
• Brief Addiction Monitor Satisfaction With Progress Toward Achieving Recovery Goals (Estimated Change Per Day)(Baseline, 4 weeks, 8 weeks, 12 weeks)
• Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Estimated Change in Score Per Day)(Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks)
• Patient Health Questionnaire--8 Item Scale (Estimated Change in Score Per Day)(Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks)
• Generalized Anxiety Disorder 7-item Scale (Estimated Change Per Day)(Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks)
• Assessment of Recovery Capital (Estimated Change Per Day)(Baseline, 4 weeks, 8 weeks, 12 weeks)
• Positive and Negative Affect Scale Positive Affect Score (Estimated Change Per Day)(Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks)
• Positive and Negative Affect Scale Negative Affect Score (Estimated Change Per Day)(Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks)
• Pittsburgh Sleep Quality Index (Estimated Change Per Day)(Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks)
• Difficulties in Emotion Regulation Scale--Short Form (Estimated Change Per Day)(Baseline, 4 weeks)
• UPPS-P Impulsive Behavior Scale, 59-item Revised Version (Estimated Change Per Day)(Baseline, 4 weeks)