Effects of Transcranial Pulse Stimulation (TPS) on Adults with Symptoms of Depression-A Pilot Randomized Controlled Trial

The study addresses the urgent mental health impact of the COVID-19 pandemic in Hong Kong, where depression prevalence rose markedly. Conventional treatments for major depressive disorder (MDD) include pharmacotherapy, electroconvulsive therapy, and psychotherapy, but not all patients respond adequately. Non-invasive brain stimulation (NIBS) modalities such as tDCS and TMS have shown efficacy in depression, and a newer ultrasound-based NIBS method—transcranial pulse stimulation (TPS)—has demonstrated cognitive and mood benefits in Alzheimer’s disease. Given a lack of trials testing TPS in adults with MDD in Hong Kong or nationwide, this pilot RCT aimed to assess whether TPS targeting the left dorsolateral prefrontal cortex (DLPFC) reduces depression severity, with secondary aims to examine effects on anhedonia, instrumental activities of daily living (IADL), cognition, and working memory/executive function. The central hypothesis was that TPS would significantly reduce HDRS-17 scores compared to a waitlist control and that benefits would sustain to 3 months.

The authors review: (1) wide-ranging mental health consequences of COVID-19, including high depression prevalence in Hong Kong; (2) conventional depression treatments and their limitations; (3) prior NIBS evidence for tDCS/rTMS/TMS in depression; (4) TPS fundamentals—ultrashort, low-intensity focused ultrasound pulses with high spatial precision that can reach subcortical/deep regions, potentially overcoming conductivity limitations of electrical stimulation; (5) biological mechanisms via mechanotransduction, promoting VEGF/BDNF expression, cerebral blood flow, angiogenesis, neuroplasticity, NO release, and neural stem cell proliferation; (6) clinical neuromodulation effects of focused ultrasound; (7) prior TPS clinical studies: a small series in unresponsive wakefulness syndrome suggesting vigilance and swallowing improvements, and an uncontrolled study in AD showing improved CERAD scores and increased memory network connectivity, with concomitant reductions in depressive symptoms (GDS and BDI). The gap identified is the absence of controlled trials of TPS for adults with MDD, motivating the present pilot RCT.

Design: Single-blind, randomized controlled, two-arm repeated-measures trial (TPS intervention vs waitlist control), adhering to CONSORT and Good Clinical Practice. Assessments at baseline (T1), post-intervention (T2), and 3-month follow-up (T3). Trial registration: NCT05006365. Sample size: Pilot target of n=30 based on prior TPS literature in AD. Recruitment: Mass email and campus flyers with QR code at The Hong Kong Polytechnic University (HKPU) and University of Hong Kong (HKU), 1 Aug–31 Oct 2021. Participants: Inclusion—age ≥18, Chinese reading ability, HAM-D-17 ≥8, informed consent. Exclusion—psychiatric diagnoses other than MDD (e.g., bipolar, schizophrenia), alcohol/substance dependence, unstable major medical/neurological conditions (e.g., brain tumor/aneurysm), bleeding/clotting disorders or thrombosis, significant communication impairments, metal implants in brain/head treatment area, corticosteroid use within 6 weeks pre-TPS, pregnancy or breastfeeding. SCID-5 used to confirm MDD diagnosis; medication regimens verified from clinician prescriptions. Randomization and masking: Off-site statistician generated allocation (random.org; stochastic minimization) to balance age, gender, and HAM-D-17. 1:1 allocation to TPS or waitlist control. Participants were blinded to group assignment. Intervention (TPS): Conducted at HKPU Integrative Health Clinic by licensed medical professionals using the NEUROLITH (Storz Medical) TPS system with neuro-navigation and real-time MRI guidance. Device parameters: single ultrashort pulses (~3 µs), energy 0.2–0.25 mJ/mm^2, pulse frequency 3–5 Hz. Target: left dorsolateral prefrontal cortex (DLPFC) based on depression-related hypoactivity and prior NIBS literature. Dosing: 6 sessions over 2 weeks (3/week on alternate days), each ~30 min, delivering 300 pulses per session to left DLPFC (total 1800 pulses). Pre-treatment MRI (T1) ensured absence of structural brain abnormalities and enabled neuronavigation. Fidelity and monitoring: Experienced PI delivered protocolized stimulation; research associate coordinated scheduling and adherence via reminders; adverse events monitored each session with a predefined checklist. Ethics: Approved by HKPU Human Subjects Ethics Subcommittee (HSEARS20210608002). Written informed consent obtained; participants received minor compensation and travel reimbursement for follow-up. Outcomes: - Primary: Depression severity via 17-item Hamilton Depression Rating Scale (HDRS-17). Clinical response: ≥50% reduction; remission: HDRS-17 ≤7. - Secondary: Anhedonia (Chinese Snaith-Hamilton Pleasure Scale, SHAPS); Instrumental Activities of Daily Living (HK Chinese Lawton IADL); Global cognition (HK Chinese Montreal Cognitive Assessment, MoCA); Working memory/executive function (Digit Span forward/backward; Trail Making Test-A and -B). Safety: Prior literature indicates low risk; adverse events tracked each session. In this study, a few headaches (4%) and one transient nausea/vomiting episode (resolved within 2 h) were reported; no serious adverse events. Statistical analysis: R 4.1.0. Descriptive statistics for demographics; between-group baseline differences tested via t-tests/chi-square. Normality by Shapiro–Wilk. Repeated-measures ANOVA examined group, time, and group×time interaction for primary outcome; Bonferroni-corrected post hocs. Secondary outcomes: repeated-measures ANOVA for normal variables; Friedman test otherwise. Effect sizes as Cohen’s d (0.2 small, 0.5 medium, 0.8 large). Attrition and follow-up completion reported (n=28 at 3 months; 6.7% attrition).

Participants: N=30 randomized (TPS n=15; waitlist n=15), ages 18–54, 73% female, 80% tertiary educated; all with clinician-confirmed MDD. Attrition: 6.7% (n=2) by 3-month follow-up (n=28 analyzed for long-term effects). Baseline differences were not statistically significant across sociodemographic variables. Primary outcome (HDRS-17): - Normally distributed across groups/time. - Significant group×time interaction: F(1,28)=18.8, p<0.001. - No baseline difference (p=0.15). - Post-test between-group difference favored TPS: mean difference −6.60 (TPS lower), p=0.02; Cohen’s d=−0.93 (large). - Sustained and further improved at 3 months with a very large effect (Cohen’s d=1.35). Secondary outcomes (pre–post within-subjects): - Cognition (MoCA): +2.64 points; p=0.003; d=0.88 (large). - Trail Making Test-A: −2.91 (faster); p<0.001; d=−0.40 (small-to-medium). - Trail Making Test-B: −2.15; p=0.07; d=−0.09 (ns). - IADL: +1.83; p<0.001; d=0.40 (small-to-medium). - Anhedonia (SHAPS): −6.0; p<0.001; d=−0.79 (medium-to-large). - Digit Span Forward: +0.93; p=0.003; d=0.43 (small-to-medium). - Digit Span Backward: +2.14; p<0.001; d=0.69 (medium). Secondary outcomes (baseline to 3 months, Table 4 summary): - Very large sustained effects for global cognition (d=1.2), TMT-B (d=1.1), and Digit Span Backward (d=1.09). - Medium-to-large sustained effects for TMT-A, IADL, SHAPS, and Digit Span Forward (d≈0.5–0.8), with all highly significant (p<0.001) except Digit Span Forward (p=0.2). Safety/tolerability: No serious adverse events; minor transient headaches (~4%) and one transient nausea/vomiting episode after first session; no analgesics required.

Targeted TPS of the left DLPFC produced a rapid and substantial reduction in depressive symptoms compared with a waitlist control after only two weeks, with effects not only sustained but further enhanced at 3 months. The findings support the hypothesis that TPS is effective for MDD symptom reduction. Improvements extended beyond mood to cognitive domains (global cognition, working memory, executive function) and daily functioning (IADL), and anhedonia decreased, aligning with the interrelationship between mood, reward processing, and functional outcomes in depression. Compared to meta-analytic effects of TMS/tDCS on cognition (typically small), TPS yielded larger and more durable cognitive benefits, potentially owing to focused ultrasound’s capacity to modulate deeper brain regions with high spatial precision and fewer conductivity limitations. Overall, TPS appears to be a promising, well-tolerated neuromodulation approach that could serve as an adjunct to standard psychiatric treatments, with meaningful impacts on core depressive symptoms and associated cognitive/functional impairments.

This first nationwide pilot RCT in Hong Kong indicates that TPS is a safe, effective, and durable intervention for reducing depressive symptom severity in adults with MDD, with additional benefits on cognition, working memory/executive function, anhedonia, and IADL after a brief 2-week course. TPS may be considered as an add-on NIBS option, particularly for patients seeking rapid improvements or with treatment resistance. Future studies should implement larger, multicenter, double-blind, sham-controlled RCTs with longer follow-up, incorporate neuroimaging biomarkers to elucidate mechanisms and target engagement, and include broader clinical populations (e.g., severe MDD) to enhance generalizability.

Pilot sample with modest size (n=30) limits power and generalizability; two participants were lost by 3 months (6.7% attrition). The control condition was waitlist rather than sham TPS, raising potential placebo effects and expectancy biases. Outcomes were predominantly psychometric rather than objective neuroimaging metrics in this RCT (prior TPS imaging evidence is from AD cohorts). Possible contamination in the waitlist group via concurrent treatments (e.g., self-prescribed remedies). Exclusion of individuals with severe depression and suicidal ideation limits applicability to higher-risk populations. Budget/time constraints precluded a larger sample and double-blinding in this pilot.