A Pilot Study of Whole-Brain Low-Intensity Pulsed Ultrasound Therapy for Early Stage of Alzheimer’s Disease (LIPUS-AD): A Randomized, Double-Blind, Placebo-Controlled Trial

Shimokawa, Hiroaki; Shindo, Tomohiko; Ishiki, Aiko; Tomita, Naoki; Ichijyo, Sadamitsu; Watanabe, Tasuku; Nakata, Takashi; Eguchi, Kumiko; Kikuchi, Yoku; Shiroto, Takashi; Takahashi, Jun; Yasuda, Satoshi; Arai, Hiroyuki

doi:10.1620/tjem.2022.j078

Cited by 20 publications

(21 citation statements)

References 34 publications

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“…1. In the clinical trial, we designed to produce sound pressure of 0.15 to 0.19 MPa in the deepest part of the hippocampus (approximately 8 cm deep), and sound pressure just below the skull needed to be 1.0 to 1.5 MPa or less to ensure safety 10 . The cone angle of the diffusive probe was set according to the size of the average elderly Japanese skull.…”

Section: Discussionmentioning

confidence: 99%

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Optimal Treatment Conditions of the Low-intensity Pulsed Ultrasound Therapy for the Treatment of Alzheimer’s Disease -Applications from Mice to Humans-

Shindo

Eguchi

Monma

et al. 2023

Preprint

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Background and Purpose We have previously developed a novel therapy with low-intensity pulsed ultrasound (LIPUS) that ameliorates cognitive decline through upregulation of endothelial nitric oxide synthase in mouse models of Alzheimer's disease (AD) and vascular dementia. We then conducted a randomized, double-blind, placebo-controlled (RCT) pilot trial for efficacy and safety of the whole-brain LIPUS therapy in patients with early AD. We demonstrated that the LIPUS therapy is safe and tends to suppress the cognitive decline in AD patients. We here report the findings of our basic experiments that we performed for the pilot trial in order to apply the whole-brain LIPUS therapy from mice to humans. Methods We performed basic experiments of the LIPUS therapy to identify the optimal treatment condition. First, by using human temporal bone, we examined the relationship between bone density/thickness and ultrasound transmittance. Next, based on the results of ultrasound transmittance, we further examined mRNA expression of vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), and endothelial nitric oxide synthase (eNOS) in response to variable frequencies, duty cycles, and sound pressures. Results There was a significant correlation between bone thickness and transmittance (1.0 MHz, P < 0.001), while there was no significant correlation between bone density and transmittance (1.0 MHz, P = 0.421). At a frequency of 0.5 MHz, the optimum duty cycle was considered to be ~ 20%. When the tissue amplitude was in the range of 0.05–0.5 MPa, VEGF, FGF2 and eNOS were significantly upregulated by LIPUS. Thus, the conditions necessary for the LIPUS therapy for human brain were identified as sound pressure just below the probe 1.3 MPa (tissue amplitude 0.15 MPa), duty cycle 5%, and frequency 0.5 MHz. Conclusions We successfully found the optimal treatment conditions of the LIPUS therapy for the treatment of patients with AD.

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Section: Discussionmentioning

confidence: 99%

“…The LIPUS therapy was performed for a total of 6 sessions 10 . Among the 22 patients divided into 2 group in a 1:1 fashion, cognitive functions remained unchanged in the LIPUS group, while they progressively worsened at 24, 48, and 72 weeks in the placebo group 10 . Furthermore, no adverse effects were noted 10 .…”

Section: Introductionmentioning

confidence: 99%

Optimal Treatment Conditions of the Low-intensity Pulsed Ultrasound Therapy for the Treatment of Alzheimer’s Disease -Applications from Mice to Humans-

Shindo

Eguchi

Monma

et al. 2023

Preprint

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“…We also have demonstrated the effectiveness of "whole-brain" irradiation of the LIPUS therapy in mouse models of cerebrovascular dementia [22], cerebral infarction [23], and Alzheimer's disease [22], where eNOS plays a pivotal role. Moreover, we have recently conducted a randomized, double-blind, placebo-controlled pilot trial of the LIPUS therapy for early stage of Alzheimer's disease [24]. We found that the LIPUS therapy tended to suppress cognitive impairment at 24, 48, and 72 weeks as compared with the placebo group [24].…”

Section: Plos Onementioning

confidence: 94%

A randomized, double-blind, placebo-controlled pilot trial of low-intensity pulsed ultrasound therapy for refractory angina pectoris

et al. 2023

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Background Despite the advances in the treatment of cardiovascular diseases, effective treatment remains to be established to improve the quality of life and prognosis of patients with chronic coronary syndromes. This study was aimed to evaluate the effectiveness and safety of the low-intensity pulsed ultrasound (LIPUS) therapy, which we have developed as a novel non-invasive angiogenic therapy through upregulation of endothelial nitric oxide synthase (eNOS). Methods and findings We conducted a randomized, double-blind, placebo-controlled (RCT) pilot trial of the LIPUS therapy for patients with refractory angina pectoris. The patients who received optimal medical therapy without indication of PCI or CABG due to the lack of graftability or complexity of coronary lesions were enrolled. They were randomly divided into the LIPUS treatment group (N = 31) and the placebo group (N = 25) in a 1:1 fashion. The LIPUS therapy was performed in a transthoracic manner for 20 min for 3 sections each (mitral, papillary muscle, and apex levels) under the conditions that we identified; frequency 1.875 MHz, intensity 0.25 MPa, and 32 cycles. The primary endpoint was weekly use of nitroglycerin. Secondary endpoints included stress myocardial perfusion imaging and others. The average weekly nitroglycerin use (times/week) was decreased from 5.50 to 2.44 in the LIPUS group and from 5.94 to 2.83 in the placebo group. The changes in the average weekly nitroglycerin use were comparable; -3.06 (95% CI: -4.481 to -1.648) in the LIPUS group (P<0.01) and -3.10 (95% CI: -4.848 to -1.356) in the placebo group (P<0.01). No adverse effects were noted. Conclusions In the present study, the LIPUS therapy did not further ameliorate chest pain as compared with optimal medications alone in patients with refractory angina pectoris. The present findings need to be confirmed in another trial with a large number of patients. (Registration ID: UMIN000012369).

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“…The major problem with the current clinical data concerns a lack of sham-controlled trials. Only 3 studies included a sham control, [33,37,41] with 2 of them reporting a significant clinical benefit for verum over sham. [33,37] Although there is clear independent evidence from neurophysiological techniques that ultrasound generates local neuromodulation in patients (see above) and healthy individuals (compare Sarica et al [46] ) and recently the first study showing true more than sham fMRI effects in humans appeared, [48] it is yet unknown to what extent changed neuronal activity translates into clinical effects.…”

Section: Safety Of Clinical Ultrasound Neuromodulationmentioning

confidence: 99%

“…The major problem with the current clinical data concerns a lack of sham‐controlled trials. Only 3 studies included a sham control, [ 33 , 37 , 41 ] with 2 of them reporting a significant clinical benefit for verum over sham. [ 33 , 37 ] Although there is clear independent evidence from neurophysiological techniques that ultrasound generates local neuromodulation in patients (see above) and healthy individuals (compare Sarica et al.…”

Section: Perspectives For Ultrasound Neuromodulation As a New Brain T...mentioning

confidence: 99%

Ultrasound Neuromodulation as a New Brain Therapy

2023

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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.

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A Pilot Study of Whole-Brain Low-Intensity Pulsed Ultrasound Therapy for Early Stage of Alzheimer’s Disease (LIPUS-AD): A Randomized, Double-Blind, Placebo-Controlled Trial

Abstract: A pilot study of whole-brain low-intensity pulsed ultrasound therapy for early stage of Alzheimer's disease (LIPUS-AD): A randomized, doubleblind, placebo-controlled trial

Cited by 20 publications

References 34 publications

Optimal Treatment Conditions of the Low-intensity Pulsed Ultrasound Therapy for the Treatment of Alzheimer’s Disease -Applications from Mice to Humans-

Optimal Treatment Conditions of the Low-intensity Pulsed Ultrasound Therapy for the Treatment of Alzheimer’s Disease -Applications from Mice to Humans-

A randomized, double-blind, placebo-controlled pilot trial of low-intensity pulsed ultrasound therapy for refractory angina pectoris

Ultrasound Neuromodulation as a New Brain Therapy

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