The COVID-19 pandemic significantly increased the prevalence of depression globally, with Hong Kong exhibiting a particularly high rate (45.7%). Traditional treatments for depression, including antidepressants, electroconvulsive therapy, and psychotherapy, are not always sufficient. Non-invasive brain stimulation (NIBS) techniques like transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) have emerged as alternative treatments, however their limitations include conductivity issues and difficulty reaching deep brain regions. Transcranial pulse stimulation (TPS), a newer NIBS technology using focused ultrasound, has shown promise in improving cognition in Alzheimer's disease patients. However, its efficacy in treating MDD remains unexplored. This study aimed to fill this research gap by investigating the effectiveness of TPS in reducing depression severity among adults in Hong Kong, addressing the urgent need for effective interventions to combat the rising prevalence of depression during and after the pandemic. The study also sought to evaluate TPS's impact on anhedonia, instrumental activities of daily living (IADL), and cognition, although detailed examination of brain functional connectivity will be reported separately.

Existing literature highlights the significant increase in depression prevalence globally, particularly in Hong Kong, during the COVID-19 pandemic. Traditional treatments, including pharmacological interventions and psychotherapy, are often effective but not always sufficient for all patients. Non-invasive brain stimulation (NIBS) techniques, such as tDCS and TMS, have shown some promise in treating depression but suffer from limitations like conductivity issues and difficulty accessing deep brain structures. TPS, using low-intensity focused ultrasound, addresses these issues with good spatial precision. Prior studies have demonstrated TPS's efficacy in improving cognition in Alzheimer's patients; however, this study is the first to investigate its potential in treating MDD.

This study employed a single-blind, randomized controlled trial (RCT) design with two arms: a TPS intervention group and a waitlist control (WC) group. Thirty participants (aged 18-54 years, predominantly female and ethnic Chinese) were recruited from August 1 to October 31, 2021. Inclusion criteria included an HDRS-17 score ≥8 and the ability to provide informed consent. Exclusion criteria involved other DSM-5 diagnoses, substance dependence, unstable medical conditions, blood clotting disorders, metal implants in the head, corticosteroid treatment within six weeks, and pregnancy/breastfeeding. Participants were randomized 1:1 to TPS or WC groups, stratified by gender and age. The TPS intervention involved six 30-minute sessions over two weeks, targeting the left dorsolateral prefrontal cortex (DLPFC). Each session delivered 300 pulses (total 1800 pulses) at 0.2-0.25 mJ/mm² energy levels and 3-4 Hz frequency, guided by real-time MRI brain imaging. The primary outcome measure was the HDRS-17, with secondary measures including the Chinese version of the Snaith-Hamilton Pleasure Scale (SHAPS), the Hong Kong Chinese version of the Lawton IADL scale, the Hong Kong Chinese version of the Montreal Cognitive Assessment (MoCA), forward and backward digit span tests, and the Trail Making Test-A and B. Statistical analyses included ANOVA with repeated measures for normally distributed outcomes and the Friedman test for non-normally distributed outcomes. Effect sizes were calculated using Cohen's d.

No significant baseline differences existed between the TPS and WC groups. A significant group x time interaction was observed for the HDRS-17 (F(1, 28) = 18.8, p < 0.001), indicating that the effect of TPS on depression depended on time. The TPS group showed a significant reduction in depression scores at post-test (p = 0.02, Cohen's d = −0.93) compared to the WC group. This large effect size was sustained at the 3-month follow-up (Cohen's d = 1.35). Secondary outcomes also showed significant improvements in the TPS group, including cognition (large effect sizes at post-test and 3-month follow-up), anhedonia (medium effect sizes), and IADL, working memory, and executive functions (small to medium effects at post-test and larger effect sizes at the 3 month follow-up). A few subjects reported minor side effects (headaches, nausea/vomiting), but none were serious and all resolved quickly. The attrition rate was low (6.7%).

This study provides the first evidence of TPS's effectiveness in treating MDD in a nationwide, randomized controlled trial. The significant reduction in depression scores and sustained effects at 3-month follow-up support TPS as a promising treatment option. The observed improvements in cognition, anhedonia, and IADL align with previous research on the impact of depression on these areas. The large effect sizes, especially for depression and cognition, suggest that TPS may be a more potent intervention compared to existing NIBS techniques like TMS and tDCS, possibly because of TPS's ability to reach deeper brain regions. The observed side effects were minor and transient.

This pilot RCT provides strong preliminary evidence for the efficacy and safety of TPS in reducing depressive symptom severity in adults with MDD. The significant and sustained improvements observed across multiple outcome measures suggest that TPS could be a valuable addition to existing treatment approaches for depression. Future larger-scale, double-blinded, sham-controlled trials are warranted to confirm these findings and further investigate the underlying mechanisms of TPS's effects. This includes investigating the efficacy of TPS on more severely depressed individuals and examining brain functional connectivity changes.

This study's limitations include its small sample size, single-blinded design, and reliance on self-reported data for some outcome measures. The potential for placebo effects and contamination in the waitlist control group due to the use of other treatments cannot be fully excluded. Furthermore, individuals with severe depression were excluded, limiting the generalizability of the findings to this specific population. Future studies should address these limitations by employing a larger sample size, double-blinding, and objective measures alongside self-report assessments.