Theta-Burst Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder

Abstract

Objective: Posttraumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder associated with disruption in social and occupational function. Transcranial magnetic stimulation (TMS) represents a novel approach to PTSD, and intermittent theta-burst stimulation (iTBS) is a new, more rapid administration protocol with data supporting efficacy in depression. The authors conducted a sham-controlled study of iTBS for PTSD.

Methods: Fifty veterans with PTSD received 10 days of sham-controlled iTBS (1,800 pulses/day), followed by 10 unblinded sessions. Primary outcome measures included acceptability (retention rates), changes in PTSD symptoms (clinician- and self-rated), quality of life, social and occupational function, and depression, obtained at the end of 2 weeks; analysis of variance was used to compare active with sham stimulation. Secondary outcomes were evaluated 1 month after treatment, using mixed-model analyses. Resting-state functional MRI was acquired at pretreatment baseline on an eligible subset of participants (N=26) to identify response predictors.

Results: Retention was high, side effects were consistent with standard TMS, and blinding was successful. At 2 weeks, active iTBS was significantly associated with improved social and occupational function (Cohen's d=0.39); depression was improved with iTBS compared with the sham treatment (d=-0.45), but the difference fell short of significance, and moderate nonsignificant effect sizes were observed on self-reported PTSD symptoms (d=-0.34). One-month outcomes, which incorporated data from the unblinded phase of the study, indicated superiority of active iTBS on clinician- and self-rated PTSD symptoms (d=-0.74 and -0.63, respectively), depression (d=-0.47), and social and occupational function (d=0.93) (all significant). Neuroimaging indicated that clinical improvement was significantly predicted by stronger (greater positive) connectivity within the default mode network and by anticorrelated (greater negative) cross-network connectivity.

Conclusions: iTBS appears to be a promising new treatment for PTSD. Most clinical improvements from stimulation occurred early, which suggests a need for further investigation of optimal iTBS time course and duration. Consistent with previous neuroimaging studies of TMS, default mode network connectivity played an important role in response prediction.

Trial registration: ClinicalTrials.gov NCT02769312.

Keywords: Brain Imaging Techniques; Posttraumatic Stress Disorder; Theta Burst Stimulation; Transcranial Magnetic Stimulation.

Figure 1.. CONSORT Diagram

Definitions: PTSD, posttraumatic stress disorder; SAE, serious adverse event; TBS, theta burst stimulation

Figure 2:. Neuroimaging Predictors of PTSD Improvement

Baseline resting state functional connectivity predicted clinical changes with active stimulation; superior improvement was associated with stronger within-default mode network functional connectivity (Figure 2A), and stronger anticorrelated (greater negative) connectivity between the default mode and externally oriented networks (Figure 2B). Images are shown in brain location (top left), followed by connectome-style representation (right). Box plots show examples of the direction of effects, e.g., greater pretreatment connectivity between the left anterior temporal cortex to medial prefrontal cortex predicted superior improvement, compared less connectivity between these two regions (top pane). Conversely, greater anticorrelated connectivity between the temporoparietal junction and dorsolateral prefrontal cortex observed at baseline predicted superior improvement (bottom pane). Abbreviations: L, left; R, Right; DMPFC, dorsomedial prefrontal cortex; MPFC, medial prefrontal cortex; LTC, lateral temporal cortex; TPJ, temporoparietal junction; RS, retrosplenial; DLPFC, dorsolateral prefrontal cortex; Ant DLPFC, Anterior DLFPC.