TRANSCRANIAL PULSE STIMULATION FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER: A RANDOMIZED, DOUBLE-BLIND, SHAM- CONTROLLED, PILOT TRIALS

Abstract Background Major depressive disorder (MDD) is a global disease with a high disease burden. Transcranial pulse stimulation (TPS), a novel non-invasive brain stimulation technique utilizing ultrashort ultrasound to modulate brain function, has shown preliminary evidence of effectiveness in the treatment of MDD in an open-label clinical trial. However, no randomized controlled trial (RCT) has been conducted. Aims & Objectives To examine the feasibility and acceptability of conducting a future RCT of TPS for the treatment of MDD based on recruitment, retention, blinding, and adverse events, as well as to investigate the preliminary evidence of the efficacy of TPS on depressive symptoms. Method A total of 24 patients with MDD were randomized into an active group and a sham group (n = 12 active/n = 12 sham). TPS treatment consisted of three sessions per week for four weeks. In each session, 1000 ultrashort ultrasound pulses were delivered with a pulse frequency of 4 Hz and a flux energy of 0.2-0.25 mJ/mm2. The left dorsolateral prefrontal cortex (DLPFC) was located and marked by transforming the coordinates (x = -38, y = +44, z = +26 mm) in the MNI space to the individual T1- weighted space. During treatment, accurate positioning was achieved using MR-based real-time navigation. The primary outcome measure assessed the feasibility of the protocol. The secondary outcome evaluated the treatment effect on depressive symptoms as measured by the Hamilton Depression Rating Scale (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Patient Health Questionnaire (PHQ). Results Of eligible participants, 96% were enrolled and 83% of randomized participants completed the protocol. Of the four drop-out participants (n=2 active/n=2 sham), one in the sham group discontinued the study due to adverse events, and the other three due to factors unrelated to the study procedure. Mild adverse events occurred during the treatment period in 11/12 and 5/12 participants in the active and sham groups, respectively, including tingling, pain, numbness, headache, nausea, difficulty concentrating, redness in the skin, and sleep disturbances. In addition, 50% of participants guessed the grouping correctly. No significant difference was found between the active and sham groups regarding the change in depressive symptoms (Δ HDRS: -7.25±4.79 [mean± SD] in the active group vs. -7.08±6.84 [mean± SD] in the sham group). Discussion & Conclusion Our pilot RCT demonstrated the feasibility and acceptability of conducting randomized, double-blind, sham-controlled TPS trials for treating patients with MDD. At the current stage, there is insufficient power to determine the treatment effect. In the future, an RCT will be conducted to investigate the treatment effect as well as to explore the modulation of brain circuits using functional magnetic resonance imaging.