First evidence of long-term effects of transcranial pulse stimulation (TPS) on the human brain.

BACKGROUND: With the high spatial resolution and the potential to reach deep brain structures, ultrasound-based brain stimulation techniques offer new opportunities to non-invasively treat neurological and psychiatric disorders. However, little is known about long-term effects of ultrasound-based brain stimulation. Applying a longitudinal design, we comprehensively investigated neuromodulation induced by ultrasound brain stimulation to provide first sham-controlled evidence of long-term effects on the human brain and behavior. METHODS: Twelve healthy participants received three sham and three verum sessions with transcranial pulse stimulation (TPS) focused on the cortical somatosensory representation of the right hand. One week before and after the sham and verum TPS applications, comprehensive structural and functional resting state MRI investigations and behavioral tests targeting tactile spatial discrimination and sensorimotor dexterity were performed. RESULTS: Compared to sham, global efficiency significantly increased within the cortical sensorimotor network after verum TPS, indicating an upregulation of the stimulated functional brain network. Axial diffusivity in left sensorimotor areas decreased after verum TPS, demonstrating an improved axonal status in the stimulated area. CONCLUSIONS: TPS increased the functional and structural coupling within the stimulated left primary somatosensory cortex and adjacent sensorimotor areas up to one week after the last stimulation. These findings suggest that TPS induces neuroplastic changes that go beyond the spatial and temporal stimulation settings encouraging further clinical applications.

Comparison of Transcranial Focused Ultrasound and Transcranial Pulse Stimulation for Neuromodulation: A Computational Study.

OBJECTIVE: The objective of the study was to investigate transcranial wave propagation through two low-intensity focused ultrasound (LIFU)-based brain stimulation techniques-transcranial focused ultrasound stimulation (tFUS) and transcranial pulse stimulation (TPS). Although tFUS involves delivering long trains of acoustic pulses, the newly introduced TPS delivers ultrashort (∼3 µs) pulses repeated at 4 Hz. Accordingly, only a single simulation study with limited geometry currently exists for TPS. We considered a high-resolution three-dimensional (3D) whole human head model in addition to water bath simulations. We anticipate that the results of this study will help researchers investigating LIFU have a better understanding of the effects of the two different techniques. APPROACH: With an objective to first reproduce previous computational results, we considered two spherical tFUS transducers that were previously modeled. We assumed identical parameters (geometry, position, and imaging data set) to demonstrate differences, purely because of the waveform considered. For simulations with a 3D head data set, we also considered a parabolic transducer that has been used for TPS delivery. RESULTS: Our initial results successfully verified previous modeling workflow. The tFUS distribution was characterized by the typical elliptical profile, with its major axis perpendicular to the face of the transducer. The TPS distribution resembled two mirrored meniscus profiles, with its widest diameter oriented parallel to the face of the transducer. The observed intensity value differences were theoretical because the two waveforms differ in both intensity and time. The consideration of a realistic 3D human head model resulted in only a minor distortion of the two waveforms. SIGNIFICANCE: This study simulated TPS administration using a 3D realistic image-derived data set. Although our comparison results are strictly limited to the model parameters and assumptions made, we were able to elucidate some clear differences between the two approaches. We hope this initial study will pave the way for systematic comparison between the two approaches in the future.

Transcranial pulse stimulation in Alzheimer's disease.

BACKGROUND: Transcranial pulse stimulation (TPS) is a novel noninvasive ultrasonic brain stimulation that can increase cortical and corticospinal excitability, induce neuroplasticity, and increase functional connectivity within the brain. Several trials have confirmed its potential in treating Alzheimer's disease (AD). OBJECTIVE: To investigate the effect and safety of TPS on AD. DESIGN: A systematic review. METHODS: PubMed, Embase via Ovid, Web of Science, Cochrane Library, CNKI (China National Knowledge Infrastructure), VIP (China Science and Technology Journal Database), and WanFang were searched from inception to April 1, 2023. Study selection, data extraction, and quality evaluation of the studies were conducted by two reviewers independently, with any controversy resolved by consensus. The Methodological Index for Nonrandomized Studies was used to assess the risk of bias. RESULTS: Five studies were included in this review, with a total of 99 patients with AD. For cognitive performance, TPS significantly improved the scores of the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) test battery, Alzheimer's Disease Assessment Scale (cognitive), Montreal Cognitive Assessment, and Mini-Mental Status Examination. For depressive symptoms, TPS significantly reduced the scores of the Alzheimer's Disease Assessment Scale (affective), Geriatric Depression Score, and Beck Depression Inventory. By functional magnetic resonance imaging, studies have shown that TPS improved cognitive performance in AD patients by increasing functional connectivity in the hippocampus, parahippocampal cortex, precuneus, and parietal cortex, and activating cortical activity in the bilateral hippocampus. TPS alleviated depressive symptoms in AD patients by decreasing functional connectivity between the ventromedial network (left frontal orbital cortex) and the salience network (right anterior insula). Adverse events in this review, including headache, worsening mood, jaw pain, nausea, and drowsiness, were reversible and lasted no longer than 1 day. No serious adverse events or complications were observed. CONCLUSIONS: TPS is promising in improving cognitive performance and reducing depressive symptoms in patients with AD. TPS may be a safe adjunct therapy in the treatment of AD. However, these findings lacked a sham control and were limited by the small sample size of the included studies. Further research may be needed to better explore the potential of TPS. PATIENT AND PUBLIC INVOLVEMENT: Patients and the public were not involved in this study.

Efficacy and safety of transcranial pulse stimulation in young adolescents with attention-deficit/hyperactivity disorder: a pilot, randomized, double-blind, sham-controlled trial.

Background: This is the first study to evaluate the efficacy and safety of transcranial pulse stimulation (TPS) for the treatment of attention-deficit/hyperactivity disorder (ADHD) among young adolescents in Hong Kong. Methods: This double-blind, randomized, sham-controlled trial included a TPS group and a sham TPS group, encompassing a total of 30 subjects aged 12-17 years who were diagnosed with ADHD. Baseline measurements SNAP-IV, ADHD RS-IV, CGI and executive functions (Stroop tests, Digit Span) and post-TPS evaluation were collected. Both groups were assessed at baseline, immediately after intervention, and at 1-month and 3-month follow-ups. Repeated-measures ANOVAs were used to analyze data. Results: The TPS group exhibited a 30% reduction in the mean SNAP-IV score at postintervention that was maintained at 1- and 3-month follow-ups. Conclusion: TPS is an effective and safe adjunct treatment for the clinical management of ADHD. Clinical trial registration: ClinicalTrials.Gov, identifier NCT05422274.

Novel ultrasound neuromodulation therapy with transcranial pulse stimulation (TPS) in Parkinson's disease: a first retrospective analysis.

BACKGROUND: Transcranial Pulse Stimulation (TPS) has been recently introduced as a novel ultrasound neuromodulation therapy with the potential to stimulate the human brain in a focal and targeted manner. Here, we present a first retrospective analysis of TPS as an add-on therapy for Parkinson's disease (PD), focusing on feasibility, safety, and clinical effects. We also discuss the placebo response in non-invasive brain stimulation studies as an important context. METHODS: This retrospective clinical data analysis included 20 PD patients who received ten sessions of TPS intervention focused on the individual motor network. Safety evaluations were conducted throughout the intervention period. We analyzed changes in motor symptoms before and after TPS treatment using Unified Parkinson's Disease Rating Scale part III (UPDRS-III). RESULTS: We found significant improvement in UPDRS-III scores after treatment compared to baseline (pre-TPS: 16.70 ± 8.85, post-TPS: 12.95 ± 8.55; p < 0.001; Cohen's d = 1.38). Adverse events monitoring revealed no major side effects. CONCLUSION: These preliminary findings suggest that TPS can further improve motor symptoms in PD patients already on optimized standard therapy. Findings have to be evaluated in context with the current literature on placebo effects.

The effectiveness and safety of low-intensity transcranial ultrasound stimulation: A systematic review of human and animal studies.

Low-intensity transcranial ultrasound stimulation (LITUS) is a novel non-invasive neuromodulation technique. We conducted a systematic review to evaluate current evidence on the efficacy and safety of LITUS neuromodulation. Five databases were searched from inception to May 31, 2023. Randomized controlled human trials and controlled animal studies were included. The neuromodulation effects of LITUS on clinical or pre-clinical, neurophysiological, neuroimaging, histological and biochemical outcomes, and adverse events were summarized. In total, 11 human studies and 44 animal studies were identified. LITUS demonstrated therapeutic efficacy in neurological disorders, psychiatric disorders, pain, sleep disorders and hypertension. LITUS-related changes in neuronal structure and cortical activity were found. From histological and biochemical perspectives, prominent findings included suppressing the inflammatory response and facilitating neurogenesis. No adverse effects were reported in controlled animal studies included in our review, while reversible headache, nausea, and vomiting were reported in a few human subjects. Overall, LITUS alleviates various symptoms and modulates associated brain circuits without major side effects. Future research needs to establish a solid therapeutic framework for LITUS.

Clinical recommendations for non-invasive ultrasound neuromodulation.

Non-invasive ultrasound neuromodulation has experienced exponential growth in the neuroscientific literature, recently also including clinical studies and applications. However, clinical recommendations for the secure and effective application of ultrasound neuromodulation in pathological brains are currently lacking. Here, clinical experts with neuroscientific expertise in clinical brain stimulation and ultrasound neuromodulation present initial clinical recommendations for ultrasound neuromodulation with relevance for all ultrasound neuromodulation techniques. The recommendations start with methodological safety issues focusing on technical issues to avoid harm to the brain. This is followed by clinical safety issues focusing on important factors concerning pathological situations.

Non-invasive sound wave brain stimulation with Transcranial Pulse Stimulation (TPS) improves neuropsychiatric symptoms in Alzheimer's disease.

BACKGROUND: This study explores Transcranial Pulse Stimulation (TPS) as a potential non-invasive treatment for Alzheimer's disease (AD), focusing on its impact on cognitive functions and behavioral symptoms. METHODS: In a prospective, one-arm open-label trial, ten patients with mild to moderate dementia due to AD were assessed using the Alzheimer's Disease Assessment Scale (ADAS-Cog), Neuropsychiatric Inventory (NPI), Pfeffer Functional Activities Questionnaire, and Zarit Caregiver Burden Interview. Assessments occurred at 30- and 90-days post-treatment. The TPS protocol consisted of 10 sessions over five weeks, using the Neurolith® device to deliver 6000 focused shockwave pulses at 0.25 mJ/mm2 and a frequency of 4 Hz. RESULTS: TPS significantly reduced neuropsychiatric symptoms, with NPI scores decreasing by 23.9 points (95% CI: -39.19 to -8.61, p = 0.0042) after 30 days, and by 18.9 points (95% CI: -33.49 to -2.91, p = 0.022) after 90 days. These changes had large effect sizes (Cohen's dz = 1.43 and dz = 0.94, respectively). A decreasing trend was observed in the ADAS-Cog score (-3.6, 95% CI: -7.18 to 0.00, p = 0.05) after 90 days, indicating a potential reduction in cognitive impairment, though not statistically significant. CONCLUSION: The preliminary results indicate that TPS treatment leads to significant improvement in neuropsychiatric symptoms in AD patients, showing promise as a therapeutic approach for AD. Further research is needed to fully establish its effectiveness, especially concerning cognitive functions.

Current state of clinical ultrasound neuromodulation.

Unmatched by other non-invasive brain stimulation techniques, transcranial ultrasound (TUS) offers highly focal stimulation not only on the cortical surface but also in deep brain structures. These unique attributes are invaluable in both basic and clinical research and might open new avenues for treating neurological and psychiatric diseases. Here, we provide a concise overview of the expanding volume of clinical investigations in recent years and upcoming research initiatives concerning focused ultrasound neuromodulation. Currently, clinical TUS research addresses a variety of neuropsychiatric conditions, such as pain, dementia, movement disorders, psychiatric conditions, epilepsy, disorders of consciousness, and developmental disorders. As demonstrated in sham-controlled randomized studies, TUS neuromodulation improved cognitive functions and mood, and alleviated symptoms in schizophrenia and autism. Further, preliminary uncontrolled evidence suggests relieved anxiety, enhanced motor functions in movement disorders, reduced epileptic seizure frequency, improved responsiveness in patients with minimally conscious state, as well as pain reduction after neuromodulatory TUS. While constrained by the relatively modest number of investigations, primarily consisting of uncontrolled feasibility trials with small sample sizes, TUS holds encouraging prospects for treating neuropsychiatric disorders. Larger sham-controlled randomized trials, alongside further basic research into the mechanisms of action and optimal sonication parameters, are inevitably needed to unfold the full potential of TUS neuromodulation.

Evaluating the efficacy and safety of transcranial pulse stimulation on adolescents with attention deficit hyperactivity disorder: Study protocol of a pilot randomized, double-blind, sham-controlled trial.

Background: Traditional treatment alone might not effectively control the severity of attention deficit hyperactivity disorder (ADHD) symptoms. Transcranial pulse stimulation (TPS) is a non-invasive brain stimulation (NIBS) technology used on older adults with mild neurocognitive disorders and adults with major depressive disorder. However, there has been no study conducted on young adolescents with ADHD. This will be the first nationwide study evaluating the efficacy and safety of TPS in the treatment of ADHD among young adolescents in Hong Kong. Methods: This study proposes a double-blinded, randomized, sham-controlled trial including TPS as an intervention group and a sham TPS group. Both groups will be measured at baseline (T1), immediately after the intervention (T2), and at the 1-month (T3) and 3-month follow-ups (T4). Recruitment: A total of 30 subjects aged between 12 and 17 years, diagnosed with attention deficit hyperactivity disorder (ADHD), will be recruited in this study. All subjects will be computer randomized into either the intervention group or the sham TPS group on a 1:1 ratio. Intervention: All subjects in each group will have to undertake functional MRI (fMRI) before and after six 30-min TPS sessions, which will be completed in 2 weeks' time. Outcomes: Baseline measurements and post-TPS evaluation of the ADHD symptoms and executive functions will also be conducted on all participants. The 1- and 3-month follow-up periods will be used to assess the long-term sustainability of the TPS intervention. For statistical analysis, ANOVA with repeated measures will be used to analyze data. Missing data were managed by multiple imputations. The level of significance will be set to p < 0.05. Significance of the study: Results emerging from this study will generate new knowledge to ascertain whether TPS can be used as a top-on treatment for ADHD. Clinical trial registration: clinicaltrails.gov, identifier: NCT05422274.

Ultrasound Neuromodulation as a New Brain Therapy.

Within the last decade, ultrasound has been "rediscovered" as a technique for brain therapies. Modern technologies allow focusing ultrasound through the human skull for highly focal tissue ablation, clinical neuromodulatory brain stimulation, and targeted focal blood-brain-barrier opening. This article gives an overview on the state-of-the-art of the most recent application: ultrasound neuromodulation as a new brain therapy. Although research centers have existed for decades, the first treatment centers were not established until 2020, and clinical applications are spreading rapidly.

Effects of transcranial pulse stimulation on autism spectrum disorder: a double-blind, randomized, sham-controlled trial.

Transcranial pulse stimulation has been proven effective to improve cognition, memory and depressive symptoms of Alzheimer's disease, but supporting evidence on other neurological diseases or neuropsychiatric disorders remains limited. This study aimed to investigate the effects of transcranial pulse stimulation on the right temporoparietal junction, which is a key node for social cognition for autism spectrum disorder, and to examine the association between transcranial pulse stimulation and executive and social functions. This double-blinded, randomized, sham-controlled trial included 32 participants (27 males), aged 12-17 years with autism spectrum disorder. All eligible participants were randomized into either the verum or sham transcranial pulse stimulation group, on a 1:1 ratio, based on the Childhood Autism Rating Scale screening score. Sixteen participants received six verum transcranial pulse stimulation sessions (energy level: 0.2-0.25 mJ/mm2; pulse frequency: 2.5-4.0 Hz, 800 pulse/session) in 2 weeks on alternate days. The remaining 16 participants received sham transcranial pulse stimulation. The primary outcome measure included Childhood Autism Rating Scale score changes, evaluated by parents, from baseline to 3-month follow-ups. Secondary outcomes included a self-reported questionnaire responded to by parents and cognitive tests responded to by participants. A licensed mental health professional evaluated clinical global impression severity, improvement, efficacy and total score. Results revealed significant interactions in Childhood Autism Rating Scale and other secondary outcomes. Significant group and time effects were found in most secondary outcomes. Additionally, significant differences were found between the transcranial pulse stimulation and sham transcranial pulse stimulation groups in Childhood Autism Rating Scale and clinical global impression improvement and total score immediately after 2 weeks of transcranial pulse stimulation intervention (all P < 0.05), and effects were sustainable at 1- and 3-month follow-up, compared with baseline. The effect size of Childhood Autism Rating Scale (d = 0.83-0.95) and clinical global impression improvement (d = 4.12-4.37) were large to medium immediately after intervention and sustained at 1-month post-stimulation; however, the effects were reduced to small at 3-month post-stimulation (d = 2.31). These findings indicated that transcranial pulse stimulation over right temporoparietal junction was effective to reduce the core symptoms of autism spectrum disorder, as evidenced by a 24% reduction in the total Childhood Autism Rating Scale score in the verum transcranial pulse stimulation group. Additionally, the clinical global impression total score was reduced by 53.7% in the verum transcranial pulse stimulation group at a 3-month follow-up, compared with the baseline. Participants in the verum transcranial pulse stimulation group had shown substantial improvement at 1- and 3-month follow-ups, compared with baseline, although some of the neuropsychological test results were deemed statistically insignificant. Future replication of this study should include a larger sample derived from multi-nations to determine transcranial pulse stimulation as an alternative top-on treatment option in neuropsychiatry.

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

Transcranial pulse stimulation (TPS) is a recent development in non-invasive brain stimulations (NIBS) that has been proven to be effective in terms of significantly improving Alzheimer patients' cognition, memory, and execution functions. Nonetheless, there is, currently, no trial evaluating the efficacy of TPS on adults with major depression disorder (MDD) nationwide. In this single-blinded, randomized controlled trial, a 2-week TPS treatment comprising six 30 min TPS sessions were administered to participants. Participants were randomized into either the TPS group or the Waitlist Control (WC) group, stratified by gender and age according to a 1:1 ratio. Our primary outcome was evaluated by the Hamilton depression rating scale-17 (HDRS-17). We recruited 30 participants that were aged between 18 and 54 years, predominantly female (73%), and ethnic Chinese from 1 August to 31 October 2021. Moreover, there was a significant group x time interaction (F(1, 28) = 18.8, p < 0.001). Further, when compared with the WC group, there was a significant reduction in the depressive symptom severity in the TPS group (mean difference = -6.60, p = 0.02, and Cohen's d = -0.93). The results showed a significant intervention effect; in addition, the effect was large and sustainable at the 3-month follow-up. In this trial, it was found that TPS is effective in reducing depressive symptoms among adults with MDD.

Effect of Transcranial Pulse Stimulation for the Treatment of Alzheimer´s Disease and its Related Symptoms.

Alzheimer's disease (AD) is the most common cause of neurodegenerative cognitive impairment. Brain stimulation techniques based on the delivery of transcranial shockwaves are currently being studied for their increasing popularity as an approach to modulate the human brain in a focal and targeted manner making this therapy a promising line of action against AD. In the present manuscript, we review for further understanding whether transcranial pulse stimulation (TPS) is a beneficial treatment for AD patients. PubMed, Google Scholar, and Cochrane databases were accessed with the search criteria set from year 2001 to 2022 and the following keywords were used: "transcranial pulse stimulation", "focused ultrasound", "noninvasive treatment and Alzheimer" and "TPS". The search was focused on papers that provide evidence on the biological bases of the method, as well as its safety and tolerability. Even though more studies are needed with greater scientific rigor, such as a doubleblind and randomized study versus a placebo, TPS is an excellent and safe therapeutic option for AD. This novel approach accompanies currently available treatments and complements them, helping to maintain greater stability of the disease and slowing its progression. The biological effects and potential mechanisms of action of TPS for the improvement of cognitive function are further discussed.

Retrospective real-world pilot data on transcranial pulse stimulation in mild to severe Alzheimer's patients.

Introduction: Transcranial pulse stimulation (TPS) is a non-invasive neuromodulation therapy that uses short, repetitive shockwaves through a neuro-navigated device. Current research suggests that these pulses lead to a wide range of vascular, metabolic, and neurotrophic changes. This relatively new CE-marked treatment provided first promising results in a clinical pilot study for improving cognition in mild-to-moderate Alzheimer's. Data from other centers is lacking, so here we analyzed safety and pilot real-world short-term results of TPS from the first center in Germany. To gain information about effects in different stages, patients with not only mild but also moderate-to-severe Alzheimer's were analyzed. Methods: A total of 11 patients were retrospectively examined for cognitive and emotional function before and after the first stimulation series. The effect was assessed using several neuropsychological tests [Alzheimer's Disease Assessment Scale (ADAS), including the ADAS cognitive score (ADAS Cog) and ADAS affective scores, Mini-Mental Status Examination (MMSE), and Montreal Cognitive Assessment (MoCA)] including in comparison between the groups of mild-to-severe patients. Moreover, subjective improvement of symptom severity, potential effects on depressive symptoms, and side effects were analyzed using Numeric Rating Scales (NRS). Results: Side effects were rare (in 4% of sessions) with moderate subjective severity and only transient. Patients significantly improved in the ADAS and ADAS Cog, while there was no significant effect in MMSE and MoCA. Patients' self-reported symptom severity improved significantly. The depressive symptoms measured in an ADAS subscale also improved significantly. Statistical data analyses revealed no significant correlation of clinical improvement with baseline symptom severity. Conclusion: TPS might be a safe and promising add-on therapy for Alzheimer's, even for moderate-to-severe patients. More research on long-term effects in patients as well as studies with sham control groups is needed. Moreover, translational research on the mechanisms of action and effects on cerebral network physiology will be needed to understand this new neuromodulation technique.

Evaluating the Safety and Efficacy of Transcranial Pulse Stimulation on Autism Spectrum Disorder: A Double-Blinded, Randomized, Sham-Controlled Trial Protocol.

Autistic spectrum disorder (ASD) is a common developmental disorder in children. The latest non-intrusive brain stimulation (NIBS) technology-transcranial pulse stimulation (TPS)-has been proven effective in older adults with mild neurocognitive disorders and adults with major depressive disorder. Nonetheless, there is so far no robust randomized controlled trial (RCT) conducted on adolescents with ASD nationwide. This study proposes a two-armed (verum TPS group vs. sham TPS group), double-blinded, randomized, sham-controlled trial. Both groups will be measured at four timepoints, namely, baseline (T1), 2 weeks immediately after post-TPS intervention (T2), and at the 1-month (T3) and 3-month (T4) follow-ups. Thirty-four subjects, aged between 12 and 17, diagnosed with ASD will be recruited in this study. All subjects will be computerized randomised into the verum TPS group or the sham TPS group on a 1:1 ratio. All subjects will undertake functional MRI (fMRI) before and after the 2-weeks TPS interventions, which will be completed in 2 weeks' time. This will be the first RCT evaluating the efficacy of TPS adolescents with ASD in Hong Kong. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT05408793.

Functional Specificity of TPS Brain Stimulation Effects in Patients with Alzheimer's Disease: A Follow-up fMRI Analysis.

INTRODUCTION: Transcranial pulse stimulation (TPS) has been recently introduced as a novel clinical brain stimulation technique based on highly focused ultrasound pressure pulses. In a first pilot study on clinical effects of navigated and focused ultrasound neuromodulation, a dichotomy of functional effects was found: patients with Alzheimer's disease improved cognition and language but deteriorated with visuo-constructive functions. METHODS: We analyzed changes in functional connectivity measured with functional magnetic resonance imaging (fMRI) using graph analysis of a visuo-constructive network in 18 patients with Alzheimer's disease. We calculated the network's global efficiency and tested for correlation with visuo-constructive test scores to explain this dichotomy. RESULTS: Important visuo-constructive network nodes were not stimulated in the pilot setting and correspondingly global efficiency of a visuo-constructive network was decreased after TPS therapy, compatible with a natural progress of the disease. A correlation between visuo-constructive scores and changes in global efficiency was found. CONCLUSION: Results argue for a high functional specificity of ultrasound-based neuromodulation with TPS.

Over the last decade, there has been growing interest in ultrasound-based non-invasive brain stimulation techniques in neuroscience and as a potential therapy for disorders of the brain. Transcranial pulse stimulation (TPS) has been introduced as an innovative neuromodulation technique, applying ultrashort pressure pulses through the skull into neural tissue with 3D navigation in real time. In the first clinical pilot study, patients suffering from Alzheimer's disease showed an increase in memory and language functions for up to 3 months after TPS therapy. However, visuo-constructive capacities (e.g., copying a geometrical figure) worsened. Notably, brain areas relevant for such processes had been left out during stimulation. This begged the question whether the brain areas that were targeted for brain stimulation as well as functional changes could explain this diverse response pattern. We therefore analyzed functional magnetic resonance data from patients. Specifically, we compared graph theoretical functional connectivity measures in a visuo-constructive network before and after TPS therapy. We found a decrease in connectivity in a central network node, which also correlated with visuo-constructive test scores. This deterioration is likely associated with normal disease progression. Together with the already reported improvement in global cognitive functions, these results argue for a functional specific effect of TPS.

Effects of Transcranial Pulse Stimulation (TPS) on Young Adults With Symptom of Depression: A Pilot Randomised Controlled Trial Protocol.

Background: Since the emergence of the COVID-19 pandemic, there have been lots of published work examining the association between COVID-19 and mental health, particularly, anxiety and depression in the general populations and disease subpopulations globally. Depression is a debilitating disorder affecting individuals' level of bio-psychological-social functioning across different age groups. Since almost all studies were cross-sectional studies, there seems to be a lack of robust, large-scale, and technological-based interventional studies to restore the general public's optimal psychosocial wellbeing amidst the COVID-19 pandemic. Transcranial pulse stimulation (TPS) is a relatively new non-intrusive brain stimulation (NIBS) technology, and only a paucity of studies was conducted related to the TPS treatment on older adults with mild neurocognitive disorders. However, there is by far no study conducted on young adults with major depressive disorder nationwide. This gives us the impetus to execute the first nationwide study evaluating the efficacy of TPS on the treatment of depression among young adults in Hong Kong. Methods: This study proposes a two-armed single-blinded randomised controlled trial including TPS as an intervention group and a waitlist control group. Both groups will be measured at baseline (T1), immediately after the intervention (T2), and at the 3- month follow-up (T3). Recruitment: A total of 30 community-dwelling subjects who are aged 18 and above and diagnosed with major depressive disorder (MDD) will be recruited in this study. All subjects will be computer randomised into either the intervention group or the waitlist control group, balanced by gender and age on a 1:1 ratio. Intervention: All subjects in each group will have to undertake functional MRI (fMRI) before and after six 30-min TPS sessions, which will be completed in 2 weeks' time. Outcomes: Baseline measurements and post-TPS evaluation of the psychological outcomes (i.e., depression, cognition, anhedonia, and instrumental activities of daily living) will also be conducted on all participants. A 3-month follow-up period will be usedto assess the long-term sustainability of the TPS intervention. For statistical analysis, ANOVA with repeated measures will be used to analyse data. Missing data were managed by multiple mutations. The level of significance will be set to p < 0.05. Significance of the Study: Results of this study will be used to inform health policy to determine whether TPS could be considered as a top treatment option for MDD. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT05006365.

Transcranial pulse stimulation (TPS) improves depression in AD patients on state-of-the-art treatment.

INTRODUCTION: Ultrasound-based brain stimulation is a novel, non-invasive therapeutic approach to precisely target regions of interest. Data from a first clinical trial of patients with Alzheimer's disease (AD) receiving 2-4 weeks transcranial pulse stimulation (TPS) have shown memory and cognitive improvements for up to 3 months, despite ongoing state-of-the-art treatment. Importantly, depressive symptoms also improved. METHODS: We analyzed changes in Beck Depression Inventory (BDI-II) and functional connectivity (FC) changes with functional magnetic resonance imaging in 18 AD patients. RESULTS: We found significant improvement in BDI-II after TPS therapy. FC analysis showed a normalization of the FC between the salience network (right anterior insula) and the ventromedial network (left frontal orbital cortex). DISCUSSION: Stimulation of areas related to depression (including extended dorsolateral prefrontal cortex) appears to alleviate depressive symptoms and induces FC changes in AD patients. TPS may be a novel add-on therapy for depression in AD and as a neuropsychiatric diagnosis.