{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T22:38:38Z","timestamp":1792363118609,"version":"4.4.0"},"reference-count":30,"publisher":"American Medical Association (AMA)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>Given the increasing prevalence of dementia and the limited treatment options available, ultrasound neuromodulation could serve as a novel add-on therapy to standard treatments for Alzheimer disease (AD). As ultrasound neuromodulation is still in its early stages, further research is essential to fully explore its potential in treating brain disorders.<\/jats:p><\/jats:sec>Objective<\/jats:title>To evaluate clinical and functional imaging effects of transcranial pulse stimulation (TPS) in patients with AD.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>A randomized, double-blind, sham-controlled, crossover clinical trial was conducted at the Medical University of Vienna between January 1, 2017, and July 27, 2022. Sixty patients with clinically diagnosed AD receiving state-of-the-art treatment were randomly allocated to treatment sequence groups verum-sham (first cycle verum, second cycle sham, n\u2009=\u200930) and sham-verum (n\u2009=\u200930). Data analysis was performed from July 28, 2022, to September 5, 2024.<\/jats:p><\/jats:sec>Intervention<\/jats:title>Each participant received 6 verum and 6 sham TPS sessions (6000 pulses, 0.20 mJ\/mm2<\/jats:sup>, 5 Hz) to frontoparietal brain areas.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>Neuropsychological tests, including the primary outcome Consortium to Establish a Registry for Alzheimer\u2019s Disease (CERAD) corrected total score (CTS), were performed at baseline and 1 week, 1 month, and 3 months following the stimulations in each cycle. Primary and secondary outcomes, including functional magnetic resonance imaging and Beck Depression Inventory-II, were analyzed by intention-to-treat analysis and, for sensitivity, by per protocol analysis.<\/jats:p><\/jats:sec>Results<\/jats:title>For the intention-to-treat analysis, 60 patients between ages 51 and 82 years (mean [SD], 70.65 [8.16] years; 30 females; 30 males) were included. The CERAD CTS increased by a mean (SD) of 2.22 (6.87) points in the verum condition from 70.93 (14.27) points at baseline to 73.15 (14.90) 3 months after stimulation, while the mean (SD) score in the sham condition increased by 1.00 (6.82) point vs baseline from 71.68 (13.62] at baseline to 72.68 (14.48) 3 months after stimulation. Primary data analysis of the condition\u2009\u00d7\u2009session interaction was not significant (P<\/jats:italic>\u2009=\u2009.68; partial \u03b72<\/jats:sup> [\u03b7p2<\/jats:sup>]\u2009=\u20090.01), but its interaction with age was P<\/jats:italic>\u2009=\u2009.003; \u03b7p2<\/jats:sup>\u2009=\u20090.08, followed by post hoc analyses of age subsamples. Although several patients older than 70 years benefited from verum TPS, only the younger subgroup (\u226470 years) showed significantly higher CTS increases for verum in all poststimulation sessions (condition\u2009\u00d7\u2009session: P<\/jats:italic>\u2009=\u2009.005; \u03b7p2<\/jats:sup>\u2009=\u20090.16). At 3 months after stimulation, for example, a mean (SD) 3.91 (7.86)-point increase was found for verum TPS in the younger patients, but a mean (SD) CTS decrease of 1.83 (5.80) was observed for sham. Memory-associated brain activation was significantly higher after verum TPS in the precuneus, visual, and frontal areas, while resting state functional connectivity was significantly upregulated in the dorsal attention network. In the per protocol sample, a significant reduction of the Beck Depression Inventory-II scores 3 months following verum TPS was found (verum baseline: 7.27 [5.87]; verum 3 months after stimulation: 5.27 [5.27]; sham baseline: 6.70 [5.65]; sham 3 months after stimulation: 6.22 [4.40]; P<\/jats:italic>\u2009=\u2009.008; \u03b7p2<\/jats:sup>\u2009=\u20090.23). During both verum and sham conditions, the most common observed adverse symptom was depression; no major neuropathologic change was detected in the patients by detailed neuroradiologic assessments.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>In this randomized clinical trial of TPS in patients with AD, a 2-week verum treatment improved cognitive scores in the younger subgroup, ameliorated depressive symptoms, and induced upregulation of functional brain activation and connectivity. These findings suggest TPS may be a safe and promising add-on therapy for patients with AD receiving state-of-the-art treatment.<\/jats:p><\/jats:sec>Trial Registration<\/jats:title>ClinicalTrials.gov Identifier: NCT03770182<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2024.59170","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T16:32:45Z","timestamp":1740587565000},"page":"e2459170","source":"Crossref","is-referenced-by-count":43,"title":["Ultrasound Neuromodulation With Transcranial Pulse Stimulation in Alzheimer Disease"],"prefix":"10.1001","volume":"8","author":[{"given":"Eva","family":"Matt","sequence":"first","affiliation":[{"name":"Functional Brain Diagnostics and Therapy, Department of Neurology, Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Mitterwallner","sequence":"additional","affiliation":[{"name":"Functional Brain Diagnostics and Therapy, Department of Neurology, Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Radjenovic","sequence":"additional","affiliation":[{"name":"Functional Brain Diagnostics and Therapy, Department of Neurology, Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Grigoryeva","sequence":"additional","affiliation":[{"name":"Functional Brain Diagnostics and Therapy, Department of Neurology, Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Weber","sequence":"additional","affiliation":[{"name":"Functional Brain Diagnostics and Therapy, Department of Neurology, Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"St\u00f6gmann","sequence":"additional","affiliation":[{"name":"Memory Outpatient Clinic, Department of Neurology, Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Domitner","sequence":"additional","affiliation":[{"name":"Functional Brain Diagnostics and Therapy, Department of Neurology, Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Zettl","sequence":"additional","affiliation":[{"name":"Functional Brain Diagnostics and Therapy, Department of Neurology, Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Osou","sequence":"additional","affiliation":[{"name":"Functional Brain Diagnostics and Therapy, Department of Neurology, Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Beisteiner","sequence":"additional","affiliation":[{"name":"Functional Brain Diagnostics and Therapy, Department of Neurology, Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2025,2,26]]},"reference":[{"issue":"8","key":"zoi241649r1","doi-asserted-by":"publisher","first-page":"5143","DOI":"10.1002\/alz.13859","article-title":"Revised criteria for diagnosis and staging of Alzheimer\u2019s disease: Alzheimer\u2019s Association Workgroup.","volume":"20","author":"Jack","year":"2024","journal-title":"Alzheimers Dement"},{"issue":"11","key":"zoi241649r2","doi-asserted-by":"publisher","first-page":"e645","DOI":"10.1016\/S2666-7568(23)00193-9","article-title":"Evaluation of clinical benefits of treatments for Alzheimer\u2019s disease.","volume":"4","author":"Liu","year":"2023","journal-title":"Lancet Healthy Longev"},{"issue":"4","key":"zoi241649r3","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.1002\/alz.13016","article-title":"2023 Alzheimer\u2019s disease facts and figures.","volume":"19","author":"Alzheimer\u2019s Association","year":"2023","journal-title":"Alzheimers Dement"},{"key":"zoi241649r4","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2023.102012","article-title":"Efficacy and safety of anti-amyloid-\u00df monoclonal antibodies in current Alzheimer\u2019s disease phase III clinical trials: a systematic review and interactive web app-based meta-analysis.","volume":"90","author":"Jeremic","year":"2023","journal-title":"Ageing Res Rev"},{"issue":"February","key":"zoi241649r5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1017\/S1041610224000085","article-title":"Efficacy and safety of transcranial magnetic stimulation on cognition in mild cognitive impairment, Alzheimer\u2019s disease, Alzheimer\u2019s disease\u2013related dementias, and other cognitive disorders: a systematic review and meta-analysis.","author":"Pagali","year":"2024","journal-title":"Int Psychogeriatr"},{"issue":"1","key":"zoi241649r6","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s40035-024-00423-y","article-title":"Transcranial alternating current stimulation (tACS) at gamma frequency: an up-and-coming tool to modify the progression of Alzheimer\u2019s Disease.","volume":"13","author":"De Paolis","year":"2024","journal-title":"Transl Neurodegener"},{"issue":"4","key":"zoi241649r7","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1016\/j.brs.2024.07.013","article-title":"Clinical recommendations for non-invasive ultrasound neuromodulation.","volume":"17","author":"Beisteiner","year":"2024","journal-title":"Brain Stimul"},{"key":"zoi241649r8","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2024.1420255","article-title":"Current state of clinical ultrasound neuromodulation.","volume":"18","author":"Matt","year":"2024","journal-title":"Front Neurosci"},{"issue":"14","key":"zoi241649r9","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202205634","article-title":"Ultrasound neuromodulation as a new brain therapy.","volume":"10","author":"Beisteiner","year":"2023","journal-title":"Adv Sci (Weinh)"},{"issue":"4","key":"zoi241649r10","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1016\/j.brs.2024.06.005","article-title":"A systematic review of preclinical and clinical transcranial ultrasound neuromodulation and opportunities for functional connectomics.","volume":"17","author":"Pellow","year":"2024","journal-title":"Brain Stimul"},{"key":"zoi241649r11","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2021.102563","article-title":"Evaluating transcranial magnetic stimulation (TMS) induced electric fields in pediatric stroke.","volume":"29","author":"Mantell","year":"2021","journal-title":"Neuroimage Clin"},{"issue":"5","key":"zoi241649r12","doi-asserted-by":"publisher","first-page":"1995","DOI":"10.1002\/hbm.23981","article-title":"Neuromodulation with single-element transcranial focused ultrasound in human thalamus.","volume":"39","author":"Legon","year":"2018","journal-title":"Hum Brain Mapp"},{"issue":"4","key":"zoi241649r13","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1016\/j.neurom.2021.12.012","article-title":"Comparison of transcranial focused ultrasound and transcranial pulse stimulation for neuromodulation: a computational study.","volume":"25","author":"Truong","year":"2022","journal-title":"Neuromodulation"},{"issue":"3","key":"zoi241649r14","doi-asserted-by":"publisher","DOI":"10.1002\/advs.201902583","article-title":"Transcranial pulse stimulation with ultrasound in Alzheimer\u2019s disease\u2014a new navigated focal brain therapy.","volume":"7","author":"Beisteiner","year":"2019","journal-title":"Adv Sci (Weinh)"},{"issue":"1","key":"zoi241649r15","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12245","article-title":"Transcranial pulse stimulation (TPS) improves depression in AD patients on state-of-the-art treatment.","volume":"8","author":"Matt","year":"2022","journal-title":"Alzheimers Dement (N Y)"},{"issue":"3","key":"zoi241649r16","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1007\/s40120-022-00362-8","article-title":"Functional specificity of TPS brain stimulation effects in patients with Alzheimer\u2019s disease: a follow-up fMRI analysis.","volume":"11","author":"D\u00f6rl","year":"2022","journal-title":"Neurol Ther"},{"issue":"1","key":"zoi241649r17","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12121","article-title":"Transcranial ultrasound pulse stimulation reduces cortical atrophy in Alzheimer\u2019s patients: a follow-up study.","volume":"7","author":"Popescu","year":"2021","journal-title":"Alzheimers Dement (N Y)"},{"issue":"3","key":"zoi241649r18","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.jalz.2011.03.005","article-title":"The diagnosis of dementia due to Alzheimer\u2019s disease: recommendations from the National Institute on Aging\u2013Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease.","volume":"7","author":"McKhann","year":"2011","journal-title":"Alzheimers Dement"},{"issue":"1","key":"zoi241649r19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3233\/JAD-230026","article-title":"CERAD (Consortium to Establish a Registry for Alzheimer\u2019s Disease) Neuropsychology Assessment Battery: 35 Years and Counting.","volume":"93","author":"Fillenbaum","year":"2023","journal-title":"J Alzheimers Dis"},{"issue":"1","key":"zoi241649r20","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1212\/01.wnl.0000167607.63000.38","article-title":"A total score for the CERAD neuropsychological battery.","volume":"65","author":"Chandler","year":"2005","journal-title":"Neurology"},{"issue":"3","key":"zoi241649r21","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1089\/brain.2012.0073","article-title":"CONN: a functional connectivity toolbox for correlated and anticorrelated brain networks.","volume":"2","author":"Whitfield-Gabrieli","year":"2012","journal-title":"Brain Connect"},{"key":"zoi241649r22","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/j.neuropsychologia.2015.06.034","article-title":"Specifying the core network supporting episodic simulation and episodic memory by activation likelihood estimation.","volume":"75","author":"Benoit","year":"2015","journal-title":"Neuropsychologia"},{"issue":"2","key":"zoi241649r23","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1038\/s41380-018-0098-1","article-title":"Brain age and other bodily \u201cages\u201d: implications for neuropsychiatry.","volume":"24","author":"Cole","year":"2019","journal-title":"Mol Psychiatry"},{"issue":"1","key":"zoi241649r24","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s12967-021-03222-5","article-title":"First evidence of long-term effects of transcranial pulse stimulation (TPS) on the human brain.","volume":"20","author":"Matt","year":"2022","journal-title":"J Transl Med"},{"key":"zoi241649r25","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2022.948204","article-title":"Retrospective real-world pilot data on transcranial pulse stimulation in mild to severe Alzheimer\u2019s patients.","volume":"13","author":"Cont","year":"2022","journal-title":"Front Neurol"},{"issue":"2","key":"zoi241649r26","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.brs.2024.03.007","article-title":"Non-invasive sound wave brain stimulation with transcranial pulse stimulation (TPS) improves neuropsychiatric symptoms in Alzheimer\u2019s disease.","volume":"17","author":"Shinzato","year":"2024","journal-title":"Brain Stimul"},{"issue":"3","key":"zoi241649r27","doi-asserted-by":"publisher","first-page":"2333","DOI":"10.3390\/ijerph20032333","article-title":"Effects of transcranial pulse stimulation (TPS) on adults with symptoms of depression\u2014a pilot randomized controlled trial.","volume":"20","author":"Cheung","year":"2023","journal-title":"Int J Environ Res Public Health"},{"issue":"3","key":"zoi241649r28","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1620\/tjem.2022.J078","article-title":"A pilot study of whole-brain low-intensity pulsed ultrasound therapy for early stage of Alzheimer\u2019s Disease (LIPUS-AD): a randomized, double-blind, placebo-controlled trial.","volume":"258","author":"Shimokawa","year":"2022","journal-title":"Tohoku J Exp Med"},{"key":"zoi241649r29","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1016\/j.trci.2019.06.007","article-title":"Focused transcranial ultrasound for treatment of neurodegenerative dementia.","volume":"5","author":"Nicodemus","year":"2019","journal-title":"Alzheimers Dement (N Y)"},{"issue":"4","key":"zoi241649r30","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1080\/13854046.2012.680913","article-title":"Scoring higher the second time around: meta-analyses of practice effects in neuropsychological assessment.","volume":"26","author":"Calamia","year":"2012","journal-title":"Clin Neuropsychol"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2830764\/matt_2025_oi_241649_1744127676.03235.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T15:01:03Z","timestamp":1744297263000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2830764"}},"subtitle":["A Randomized Clinical Trial"],"short-title":[],"issued":{"date-parts":[[2025,2,26]]},"references-count":30,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2,3]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2024.59170","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,26]]}}}