Deep Brain Stimulation With LIFUP for Mild Cognitive Impairment and Mild Alzheimer's Disease (LIFUP)

July 12, 2023 updated by: Taylor Kuhn, University of California, Los Angeles

Study of Non-Invasive Deep Brain Stimulation With Low Intensity Focused Ultrasound Pulse (LIFUP) for Mild Cognitive Impairment (MCI) and Mild Alzheimer's Disease (AD)

The purpose of the proposed study is to determine the feasibility of brief brain stimulation, using a device called Low Intensity Focused Ultrasound Pulsation (LIFUP), for persons with mild cognitive impairment (MCI) or mild (early-stage) Alzheimer's disease (AD). As a secondary aim, the investigators will explore whether this brief intervention is associated with improvements in cognitive functioning immediately and one week following the intervention.

Subjects will be randomly assigned to one of two experimental groups: either the LIFUP administration will be designed to increase the activity of neurons in a certain part of the brain or decrease the activity of neurons.

The investigators will study up to 8 subjects with MCI or mild AD. Initially, subjects will undergo a screening assessment with a study physician to determine medical and psychiatric history, establish AD diagnosis, and undergo a blood draw, if standard recent labs for dementia and EKG are unavailable. Subjects that meet criteria and agree to participate in the study will undergo a follow-up visit. In the baseline measurement visit, participants will first undergo neuropsychological testing. Participants will be randomly assigned to one of two LIFUP pulsing paradigms. Participants will then be administered four successive LIFUP treatments while the participants are in a functional magnetic resonance imaging (MRI). Sixty minutes following the administration, participants will undergo a second neuropsychological test. A final follow-up assessment will be administered at one week.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Alzheimer disease (AD) is a neurodegenerative condition and the most common cause of dementia or a functional impairment in memory and other cognitive abilities. Prior to developing the functional impairment of dementia, patients develop mild cognitive impairment (MCI), which increases the risk for developing the functional impairment of dementia. Deep brain stimulation (DBS) is of interest as a potential therapeutic option for MCI and AD because it can directly target and modulate the activity of brain structures implicated in memory functioning.

Recently there have been multiple reports that DBS of different locations within the brain may be effective in improving symptoms characteristic of dementia (e.g., Heschman et al., 2013). For example, Laxton et al. (2010) performed DBS in the fornix/hypothalamus of six persons with AD in a phase I clinical trial. The investigators hypothesized that stimulation of the fornix would alter the activity of the medial temporal memory circuits, and thus delay and/or reverse memory loss. After 6-12 months, the investigators noted improvement or slowing in the progression of AD in some of the research participants, as measured by two commonly-used assessments of global cognitive function. In a recent literature review, Laxton et al. (2013) also described several additional studies demonstrating that DBS of the fornix or nucleus of Meynert or subthalamic nucleus influences the pathologic neurological circuits involved in AD.

Four separate groups recently have published reports concluding that ultrasound improves amyloid-β clearance in mouse models and restores memory (e.g., Leinenga & Götz, 2015). This finding raises the question of whether one method of DBS, Low Intensity Focused Ultrasound Pulse (LIFUP), could improve cognition in patients with AD, which is characterized by abnormal deposition of amyloid plaques in brain regions controlling memory and thinking. The use of LIFUP in animal models is well described (Bystritsky et al., 2014). LIFUP is able to penetrate the human skull and reach deep structures within the temporal therapeutic window. The structures that are reachable by LIFUP include the temporal cortices, hippocampus, thalamus, and subthalamic nuclei, all of which are implicated in the pathophysiology of AD. The Food and Drug Administration (FDA) recently approved an investigational device exemption (IDE) to begin a feasibility and safety trial of LIFUP for persons with refractory seizures.

Although symptomatic treatments are available for AD, their modest effects are temporary and there is a need for more effective interventions. In the current project, the investigators propose to use the FDA-approved protocol to:

  1. Determine the feasibility of a brief LIFUP intervention (four stimulations of 30 seconds each, with 2-minute intervals between each treatment) for persons with MCI or mild (early-stage) AD.
  2. As a secondary aim, the investigators will explore whether this brief LIFUP intervention is associated with improvements on neuropsychological measures of cognitive functioning immediately following the intervention.

To investigate these aims, subjects with MCI or mild AD will be enrolled. Subjects will be randomized using a single-blind design, to one of two LIFUP pulsing paradigms in which activity of neurons in a certain part of the brain are either increased. Subjects will then be administered four successive LIFUP treatments while the subjects are in a functional magnetic resonance imaging (MRI). Neuropsychological assessments will be performed at baseline, immediately after LIFUP is administered, and one week following the conclusion of the visit.

Study Type

Interventional

Enrollment (Estimated)

8

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

  • United States
    • California
      • Los Angeles, California, United States, 90095
        • UCLA Semel Institute

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

55 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Mild cognitive impairment or mild (early-stage) AD diagnosis through medical record review
  • Agreement to participate in a clinical and brain imaging study.
  • Age 55 years or older.
  • No significant cerebrovascular disease as determined by a modified Ischemic Score of ≤ 4.
  • Availability of a study partner (next of kin, family member) to attend all visits and to provide surrogate consent should it be determined that the participant does not have capacity.
  • Adequate visual and auditory acuity to allow neuropsychological testing.
  • Screening laboratory tests and ECG without significant abnormalities that might interfere with the study.
  • Use of cholinesterase inhibitors for AD (Aricept, Namenda, etc.) will be allowed as long as the participant has been on a stable dose for at least two months.
  • There must be a family member or caregiver available to make sure the participant gives informed consent, and in case the participant develops cognitive impairment that interferes with independent study participation.

Exclusion Criteria:

  • Evidence of any other major neurologic or other physical illness that could produce cognitive deterioration, except for mild cognitive impairment (MCI) and any history of stroke or diabetes.
  • History of myocardial infarction within the previous year or unstable cardiac disease.
  • Uncontrolled hypertension (systolic BP > 170 or diastolic BP > 100), history of significant liver disease, clinically significant pulmonary disease, diabetes, or cancer.
  • Major psychiatric disorders, such as bipolar disorder or schizophrenia, or persons with current untreated major depression
  • Current diagnosis or significant history of alcoholism or drug dependence.
  • Participants taking medications known to influence cognitive functioning will be excluded. Medications that will be excluded include: centrally active beta-blockers, narcotics, clonidine, anti-Parkinsonian medications, benzodiazepines, systemic corticosteroids, and medications with significant anticholinergic effects, anti-convulsants, or warfarin. During the screening visit, physicians will review all medications and determine whether the type, dose, and interaction of medications are likely to impact cognition and determine exclusion based on these factors.
  • Use of any investigational drugs within the previous month or longer, depending on the drug's half-life.
  • Contraindication for fMRI scan (e.g. metal in body, claustrophobia).

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: Device Feasibility
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Excitation
Excitation Paradigm: LIFUP excites the activity of hippocampal neurons.
Device: Excitation
Administration of LIFUP, a method of deep brain stimulation, according to excitation paradigms using the following parameters: Tone Burst Duration = 50ms; Pulse Repetition Frequency = 10Hz; ISPTA = 720 mW/cm2. Four treatments of thirty seconds each, with two-minute intervals between treatment (20 minutes, approximately)
Other Names:
  • Low Intensity Focused Ultrasound Pulse
Active Comparator: Inhibition
Inhibition Paradigm: LIFUP inhibits the activity of hippocampal neurons.
Device: Inhibition
Administration of LIFUP, a method of deep brain stimulation, according to inhibition paradigms using the following parameters: Tone Burst Duration = 50ms and Pulse Repetition Frequency = 10Hz. Four treatments of thirty seconds each, with two-minute intervals between treatment (20 minutes, approximately)
Other Names:
  • Low Intensity Focused Ultrasound Pulse

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from baseline in fMRI brain scan to 40 minutes.
Time Frame: 40 Minutes
Functional MRI of the brain will be obtained throughout the LIFUP session for the purposes of image acquisition.
40 Minutes

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from baseline in Hopkins Verbal Learning Test-Revised45 (HVLT-R)
Time Frame: 60 Minutes, 1 Week
The Hopkins Verbal Learning Test-Revised will provide a measure of verbal memory. It requires recall of a series of 12 words over three learning trials, free recall after a 25-minute delay, and a recognition trial. There are 6 equivalent alternate forms.
60 Minutes, 1 Week
Change from baseline in Brief Visual Memory Test-Revised
Time Frame: 60 Minutes, 1 Week
The Brief Visual Memory Test-Revised will provide a measure of visual memory. In three learning trials, the respondent views 6 geometric figures for 10 seconds and is asked to draw as many of the figures as possible from memory in their correct location on a page in the response booklet. A Delayed Recall Trial is administered after a 25-minute delay. Last, a Recognition Trial, in which the respondent is asked to identify which of 12 figures were included among the original geometric figures, is administered. There are 6 equivalent alternate forms.
60 Minutes, 1 Week
Change from baseline in Geriatric Anxiety Inventory (GAI)
Time Frame: 60 Minutes, 1 Week
Geriatric Anxiety Inventory (GAI) will be used as a measure to ensure that pre-LIFUP/pre-MRI anxiety is not significantly impacting performance on the first neuropsychological assessment.
60 Minutes, 1 Week

Collaborators and Investigators

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

Sponsor

University of California, Los Angeles

Investigators

  • Principal Investigator: Taylor P Kuhn, PhD, UCLA Longevity Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

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 (Actual)

November 10, 2018

Primary Completion (Actual)

March 31, 2023

Study Completion (Estimated)

October 1, 2023

Study Registration Dates

First Submitted

November 15, 2017

First Submitted That Met QC Criteria

November 15, 2017

First Posted (Actual)

November 20, 2017

Study Record Updates

Last Update Posted (Actual)

July 14, 2023

Last Update Submitted That Met QC Criteria

July 12, 2023

Last Verified

July 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 16-001314

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

Yes

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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