Low-intensity Hippocampal Transcranial Ultrasound Stimulation for Managing Cognitive and Sleep Dysfunction in Preclinical Alzheimer's Disease

December 20, 2025 updated by: LU Hanna, Chinese University of Hong Kong

Low-intensity Hippocampal Transcranial Ultrasound Stimulation for Managing Cognitive and Sleep Dysfunction in Preclinical Alzheimer's Disease Patients: A Randomized Clinical Trial

Background: Sleep disturbances, as a common symptom, can jeopardize the brain health and cognitive function and even lead to cognitive impairments in older adults. The co-occurring sleep disturbances cognitive complaints can significantly affect brain functions, and even be implicated as a key contributing factor in the development of prodromal Alzheimer's disease (AD). At present, very few non-pharmacological therapies are developed for managing these comorbidities in older adults. Focused low-intensity transcranial ultrasound stimulation (TUS) enables to stimulation the deep brain structures, such as hippocampus, with optimized focality and specific frequency.

Objectives: 1) To investigate the safety, feasibility and efficacy of a 2-week focused low-intensity hippocampal TUS on the severity of sleep disturbances and cognitive impairments in elderly patients; 2) to determine the sample size of a full-scale randomized clinical trial of low-intensity TUS in patients with preclinical AD; 3) to evaluate the effects of low-intensity TUS on the severity of sleep quality and cognitive functions at 2, 6 and 10 weeks after the treatments.

Design: A 2-week randomized, double-blind, controlled clinical trial. Methods: Chinese right-handed preclinical AD patients with sleep disturbances (aged from 60 to 90 years) will be randomly assigned to a 2-week intervention of either low intensity TUS or sham TUS, with 10 participants per arm. Before intervention, T1-weighted magnetic resonance imaging (MRI) data is used to construct individual realistic head model. Comprehensive assessments, including sleep quality, cognitive performance and plasma p-tau217, Aß42 and Aß40 will be conducted at baseline, 2nd week, 6th week and 10th week. Program adherence and adverse effects will be monitored throughout intervention.

Study Overview

Status

Enrolling by invitation

Conditions

Intervention / Treatment

Detailed Description

Significance: This study aims to investigate the feasibility, safety and efficacy of low intensity hippocampal TUS for sleep disturbances and cognitive impairments in patients with preclinical Alzheimer's disease. It wills also test the program adherence, tolerability and adverse effects of this innovative neuromodulation. Information will be helpful for in-depth understanding the relationship of "sleep, glymphatic function and cognition" and guiding the further studies of neurodegenerative diseases and sleep medicine.

Data analysis: The primary outcomes will be the changes in sleep quality and cognition, and the comparisons of group differences across different time points. Secondary outcomes will be the changes of glymphatic function and neuropathological factors. Intention-to-treat analysis will be carried out. Changes of efficacy indicators from baseline to each follow up point will be tested with mixed effect model.

Study Type

Interventional

Enrollment (Estimated)

20

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Hong Kong
    • Tai Po District
      • Hong Kong, Tai Po District, Hong Kong, 100000
        • Tai Po Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Chinese, right-handed, aged from 60 to 85 years.
  • Mild neurocognitive disorder due to Alzheimer's disease (NCD-AD) is identified with the Montreal Cognitive Assessment (MoCA) score range from 22 to 26.
  • Sleep disturbances or poor sleep quality is assessed and defined with a total score of the Pittsburgh Sleep Quality Index (PSQI) greater than 5.
  • No impairments in the activities of daily living.

Exclusion Criteria:

  • Previous diagnosis of age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson disease.
  • History of neurological diseases including brain tumor, and stroke.
  • History of psychiatric disorders including schizophrenia and depression.
  • Presence of positive neurological diseases, such as stroke, brain tumor, dementia.
  • Physically unable to attend the sessions of intervention.
  • Currently enrolled in another intervention study.
  • Currently taking a psychiatric or other medication that may affect sleep quality and cognition.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Active TUS
In active TUS group, participants will receive 500 kHz low-intensity TUS.
Device: Low-intensity transcranial ultrasound stimulation
Low-intensity TUS, as an advanced modality of transcranial brain stimulation, enables to stimulate the deep brain structures with optimized focality and specific frequency.
Sham Comparator: Sham TUS
In sham TUS group, participants will receive sham TUS.
Device: Sham low-intensity transcranial ultrasound stimulation
Sham TUS uses the same settings as the active low-intensity TUS. During the sham treatment, the power will be off.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pittsburg Sleep Quality Index (PSQI)
Time Frame: 10 weeks
Description: The PSQI is a 19-item questionnaire that includes seven areas of subjective sleep quality and patterns in adults over the last month including the following components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, SDs, use of sleeping medications, and daytime dysfunction. Each item in the scale is scored from 0 to 3 scale (0 = no difficulty; 3 = severe difficulty). The scores are added to yield a global score ranging from 0 to 21 (0 = no difficulty; 21 = severe difficulties in all areas). This scale has good reliability and validity psychometrics and is widely used in research: Cronbach's alpha (0.77 to 0.83), sensitivity (89.6%), specificity (86.5%). Greater score of PSQI indicates worse sleep quality.
10 weeks
Delayed recall of the words
Time Frame: 10 weeks
Word-list learning test (WLLT), consisting of sixteen semantically non-associated words that is presented consecutively over three free trials of immediate recall, a 20-min delayed recall (to prevent recency effects). Delayed recall of the words derived from WLLT is used as a proxy for measuring working memory function.
10 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective sleep quality
Time Frame: 2 weeks
Actigraphy records will be used to quantify sleep-wake cycle during treatment.
2 weeks
The levels of plasma Aß
Time Frame: 10 weeks
The levels of plasma Aß, including Aß42, Aß40 and Aß42/40 ratio, are assessed at the baseline and post-intervention time points.
10 weeks
The levels of plasma tau
Time Frame: 10 weeks
The levels of plasma tau, are assessed at the baseline and post-intervention time points.
10 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Chinese University of Hong Kong

Collaborators

The Hong Kong Polytechnic University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

April 1, 2026

Primary Completion (Estimated)

March 31, 2027

Study Completion (Estimated)

May 16, 2027

Study Registration Dates

First Submitted

September 1, 2025

First Submitted That Met QC Criteria

December 20, 2025

First Posted (Actual)

December 23, 2025

Study Record Updates

Last Update Posted (Actual)

December 23, 2025

Last Update Submitted That Met QC Criteria

December 20, 2025

Last Verified

September 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2024.652

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

This clinical trial will have patients' information.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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