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Modulation of Hippocampal Circuitry and Memory Function With Focused Ultrasound in Amnestic MCI (LIFUP-MCI)

Primary Purpose

Mild Cognitive Impairment, Amnestic Mild Cognitive Disorder, Deep Brain Stimulation

Status

Recruiting

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Low-Intensity Focused Ultrasound Pulsation (LIFUP)

About this trial

This is an interventional treatment trial for Mild Cognitive Impairment focused on measuring deep brain stimulation (DBS), transcranial focused ultrasound stimulation (tFUS), memory, low-intensity focused ultrasound sonication (LIFUP), fMRI, mild cognitive impairment, mci, noninvasive brain stimulation (NIBS), ultrasound

Eligibility Criteria

50 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

Amnestic MCI diagnosis
Age 50-90
English-speaking
Right-handed
Ability to provide informed consent via UBACC (Jeste et.al., 2007) procedure
Normal or corrected-to-normal hearing or vision

Exclusion Criteria

GENERAL

Participation in another clinical trial

Active use of prescribed medications to improve cognition and/or memory, e.g., cholinesterase inhibitors, memantine, or Aduhelm

MRI Incompatibility

Weight exceeding 275 pounds

Pregnancy, suspicion of pregnancy, or attempting to become pregnant

Claustrophobia

Difficulties during previous MRIs

Top permanent retainer (bottom only is okay)

5 or more non-removable gold-teeth

Metal braces, top spacers, and/or palate expanders

Any of the following implants:

Aneurysm clips

Cochlear implants

Defibrillator

Electrodes or wires

Magnetically-activated device

Spinal cord stimulator

Infusion or insulin pumps

Implanted drug infusion device

Deep brain stimulation device

Cardiac pacemaker

Non-removable hairpieces, hairpiece extensions, and/or piercings

Facial tattoos or permanent makeup

Metal implants that are MR-incompatible, or where participant is unable to provide sufficient information to determine MR compatibility

Previous injury by metallic foreign body (e.g., bullet, BB, shrapnel) where the object entered the body and (one of the following conditions):

The metallic foreign body wasn't fully removed

Participant lacks a doctor's confirmation that the metallic foreign body was fully removed

Diagnosis of one or more of the following neurological disorders:

Alzheimer's disease

Parkinson's disease

Lou Gehrig's disease (ALS)

Multiple sclerosis

Cerebral Palsy

Diagnosis of one or more of the following genetic disorders

Cystic Fibrosis

Sickle Cell Disease

Diagnosis of one or more of the following psychiatric disorders

Psychosis

Dementia

Mental illness other than anxiety or depression

GAD and depression if they have not been controlled for at least one year (if controlled >1 year, with or without medication, they are not exclusionary)

Other Medical

Severe lung, liver, heart, and/or kidney disease/s (e.g., heart failure, liver failure, and etc...)

Diagnosis of thyroid disorder or change of thyroid medication dose within the last year

Cancer treatment/s with chemotherapy and/or radiation to head and neck

Stage 4 (metastatic) cancer

Treatment/s for:

Hepatitis

HIV

Rheumatoid arthritis

Lupus

Any autoimmune disorder

Treatment/s to prevent transplant rejection

History of substance abuse

Including alcohol, but not nicotine or caffeine

History of stroke

History of 2 or more seizures or diagnosis of epilepsy, unless the seizures occurred prior to age 5 alongside a fever.

History of brain tumor, brain aneurysm, brain hemorrhage, or subdural hematoma (transient ischemic attack not exclusionary)

History of concussion or similar head injury if any of the following were present:

Head injury requiring hospitalization

Head injury succeeded by loss of consciousness for more than 30 minutes

Head injury succeeded by amnesia, confusion, and/or loss of orientation lasting longer than 24 hours

CT scan that revealed brain abnormalities

2 or more of the following symptoms if they lasted for longer than 3 months after head injury

Headache

Dizziness

Hypersomnia or insomnia

Phono- or photophobia

Trouble with attention, memory, or staying on task

Decline in school performance

Depression and/or anxiety

Panic attacks

PTSD

Uncontrolled high blood pressure or diabetes

Heart attack within the last year

Daily use of prescribed migraine medication

Sites / Locations

UCLA Semel Institute for Neuroscience and BehaviorRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Sham Comparator

Arm Label

LIFUP Dose Group 1

LIFUP Dose Group 2

LIFUP Dose Group 3

Sham LIFUP

Arm Description

Administration of low intensity focused ultrasound (LIFUP) dose level 1 to the entorhinal cortex.

Administration of low intensity focused ultrasound (LIFUP) dose level 2 to the entorhinal cortex.

Administration of low intensity focused ultrasound (LIFUP) dose level 3 to the entorhinal cortex.

No administration of LIFUP. The device will be affixed to the user's head but not turned on. Additionally, if at the end of the study, the treatment has been shown to be effective, placebo subjects will be offered a free session using the optimally effective dose, if they consented to being contacted for this purpose.

Outcomes

Primary Outcome Measures

Change in Perfusion Arterial Spin Labeling (ASL) fMRI Signal throughout Brain

Perfusion ASL fMRI data will be collected before and after sonication. Analyses will assess the statistical relationship between ASL signal throughout the brain pre and post sonication.

Changes in BOLD-related functional connectivity from baseline in fMRI brain scan to 40 minutes.

Primary outcomes for proof of mechanism that may be depicted in the fMRI scans may include changes in BOLD-related functional connectivity increases within the DMN including regions functionally connected to the target. BOLD data will be collected before, during, and following LIFUP sonication. Analyses will assess any changes in BOLD signal in the brain following sonication.

Secondary Outcome Measures

Change in Brief Visual Memory Test Scores

Potential LIFUP-related changes in memory will be assessed via neuropsychological assessments including the Brief Visual Memory Tests (BVMT). Scores range from 0 to 12 and reflect recent, long-term learning, with higher scores indicating better learning.

Change in Verbal Learning Test Scores

Potential LIFUP-related changes in memory will be assessed via the Rey Verbal Learning Test (RAVLT) neuropsychological assessment. The RAVLT involves providing participants with 15 unrelated words and asking them to recall the word list. There are 5 trials designed to determine short-term memory and then a 30 minute delay to assess long-term memory. The total words correct in both the short- and long-term trials are used as outcome measures.

Post-hoc biomarker analysis of APOE-4 status as a predictor of tFUS efficacy

Post-hoc biomarker analysis of plasma AB42/40 ratio as a predictor of tFUS efficacy

Biomarker post hoc analysis will determine the degree to which blood based biomarkers predict the level of effectiveness of tFUS. Analyses conducted post-data collection phase of the entire study, up to four years after study visit. An Aβ42/40 ratio <0.160 suggests a higher-than-normal risk of having of AD and is warranted to support a diagnosis of AD (West et al 2021).

Post-hoc biomarker analysis of plasma ptau as a predictor of tFUS efficacy

Full Information

NCT ID

NCT05417555

First Posted

June 1, 2022

Last Updated

February 8, 2023

Sponsor

University of California, Los Angeles

Collaborators

National Institute on Aging (NIA)

1. Study Identification

Unique Protocol Identification Number

NCT05417555

Brief Title

Modulation of Hippocampal Circuitry and Memory Function With Focused Ultrasound in Amnestic MCI

Acronym

LIFUP-MCI

Official Title

Modulation of Hippocampal Circuitry and Memory Function With Focused Ultrasound in Amnestic MCI

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Recruiting

Study Start Date

September 1, 2022 (Actual)

Primary Completion Date

July 31, 2026 (Anticipated)

Study Completion Date

July 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of California, Los Angeles

Collaborators

National Institute on Aging (NIA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Device Product Not Approved or Cleared by U.S. FDA

Yes

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This study is a proof of concept/proof of mechanism study addressing the hypothesis that Low Intensity Focused Ultrasound Pulsation (LIFUP) targeting the entorhinal cortex can (A) successfully target and increase activity in the entorhinal cortex and functionally connected brain regions (B) improve connectivity of memory networks (C) improve memory for information (D) have a dose-dependent effect on memory and brain activity. A secondary objective is to determine the relationship between blood-based AD biomarkers and LIFUP treatment outcomes, and the relationship between magnitude of HC volume decline and LIFUP treatment outcomes.

Detailed Description

PRÉCIS --- This is a proof of concept/proof of mechanism trial of Low Intensity Focused Ultrasound Pulsation (LIFUP) targeting the entorhinal cortex in patients with amnestic MCI. The study will integrate behavioral and multimodal neuroimaging to assess the utility, dose and duration of LIFUP to a) increase neural activity in deep neural structures and 2) to enhance memory function in patients with amnestic MCI. The intervention will randomly assign subjects to one of four dose conditions (0, 1, 2, or 3 doses). Each dose consists of six 30-second sonications, alternating with 30-second OFF blocks for a total of 6 minutes. Each participant will have two LIFUP sessions with the same condition, spaced 2 weeks apart. Sessions occur within the MRI scanner with pre-sonication ASL and rsfMRI, simultaneous rsfMRI, and post-sonication ASL. Verbal and visuospatial memory will be assessed at baseline, 48 hours after each session via Zoom, and two weeks after the last in-person session. Objectives --- Imaging markers of target modulation: Use fMRI collected simultaneously with LIFUP to assess modulation of neural activity in the hippocampal region and DMN, and ASL pre- and post- LIFUP to assess direct up-regulation of ErC perfusion Measure LIFUP changes in functional connectivity (change from grant based on reviews: the investigators initially also included cortical thickness changes; current research methods now use CT as a predictor) Determine whether LIFUP-induced changes in ErC perfusion and ErC/DMN FC will be associated with improved learning and memory Determine the relationship between AD risk and LIFUP-induced changes: LIFUP-induced functional changes will be associated with blood-based biomarker status (AB42/40 and Ptau217) ---Design and Outcomes --- This is an intervention assessing the effects of focused ultrasound on memory, cerebral blood flow, and functional connectivity in memory circuits in patients with MCI. Patients will be assigned to one of 4 dose groups: 0, 1, 2, or 3 doses at each LIFUP session. At an initial baseline in-person session, subjects will receive structural MRI, a premorbid intelligence test and memory pre-testing. At the second in-person visit, the subjects will undergo a blood draw, pre- and simultaneous resting-state functional MRI and LIFUP sonication, as well as pre- and post-LIFUP ASL to measure blood flow changes. Memory will be assessed remotely 48 hours after the treatment. An identical in-person MRI-LIFUP session and follow-up session will occur 2 weeks later, and a final memory evaluation will occur remotely 2 weeks after the last in-person session. Those administrating memory assessments and analyzing data will be blind to dosage group. The study design section presents a diagram and more detailed description of procedures. --- Interventions and Duration --- At each of the two MRI-LIFUP sessions, subjects will receive 0, 1, 2, or 3 doses of LIFUP, with each dose consisting of six 30-second sonication blocks.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Mild Cognitive Impairment, Amnestic Mild Cognitive Disorder, Deep Brain Stimulation

Keywords

deep brain stimulation (DBS), transcranial focused ultrasound stimulation (tFUS), memory, low-intensity focused ultrasound sonication (LIFUP), fMRI, mild cognitive impairment, mci, noninvasive brain stimulation (NIBS), ultrasound

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Model Description

Subjects are randomly assigned to one of four treatment dosage conditions: 0, 1, 2 or 3 treatments at each MRI-LIFUP session. After 2 weeks, a second dose is administered with the same dosage level for each subject. Memory assessment occurs once at baseline and remotely after each treatment at the onset of the optimal time window (48 hours) for LIFUP-induced change based on prior data. Finally, after 2 weeks, memory is again assessed. Alternate forms are used for the primary outcome measures to avoid practice effects.

Masking

Participant

Masking Description

Participants and the participants' caregivers will be blinded to arm assignment.

Allocation

Randomized

Enrollment

144 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

LIFUP Dose Group 1

Arm Type

Active Comparator

Arm Description

Administration of low intensity focused ultrasound (LIFUP) dose level 1 to the entorhinal cortex.

Arm Title

LIFUP Dose Group 2

Arm Type

Active Comparator

Arm Description

Administration of low intensity focused ultrasound (LIFUP) dose level 2 to the entorhinal cortex.

Arm Title

LIFUP Dose Group 3

Arm Type

Active Comparator

Arm Description

Administration of low intensity focused ultrasound (LIFUP) dose level 3 to the entorhinal cortex.

Arm Title

Sham LIFUP

Arm Type

Sham Comparator

Arm Description

Intervention Type

Device

Intervention Name(s)

Low-Intensity Focused Ultrasound Pulsation (LIFUP)

Other Intervention Name(s)

transcranial focused ultrasound, tFUS, LIFUP, low intensity focused ultrasound

Intervention Description

Focused ultrasound is a re-emerging neuromodulation technology. Ultrasound uses high-frequency longitudinal pressure waves to generate clinical images via refraction. At high intensities, ultrasound can be used to cause ablations (e.g. for neurosurgical pallidotomy). Low intensity tFUS can penetrate the skull and dura, thereby affecting neuron populations in the brain, likely through cellular modulation. By changing the parameters of the ultrasound such as pulse repetition frequency and duty cycle, it is possible to create potentiating or disruptive effects at the network level, without also causing tissue damage via the heating effects seen at higher intensities.

Primary Outcome Measure Information:

Title

Change in Perfusion Arterial Spin Labeling (ASL) fMRI Signal throughout Brain

Description

Perfusion ASL fMRI data will be collected before and after sonication. Analyses will assess the statistical relationship between ASL signal throughout the brain pre and post sonication.

Time Frame

40 minutes

Title

Changes in BOLD-related functional connectivity from baseline in fMRI brain scan to 40 minutes.

Description

Time Frame

40 minutes

Secondary Outcome Measure Information:

Title

Change in Brief Visual Memory Test Scores

Description

Time Frame

48 hours

Title

Change in Verbal Learning Test Scores

Description

Time Frame

48 hours

Title

Post-hoc biomarker analysis of APOE-4 status as a predictor of tFUS efficacy

Description

Time Frame

4 years

Title

Post-hoc biomarker analysis of plasma AB42/40 ratio as a predictor of tFUS efficacy

Description

Time Frame

4 years

Title

Post-hoc biomarker analysis of plasma ptau as a predictor of tFUS efficacy

Description

Time Frame

4 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

50 Years

Maximum Age & Unit of Time

90 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria Amnestic MCI diagnosis Age 50-90 English-speaking Right-handed Ability to provide informed consent via UBACC (Jeste et.al., 2007) procedure Normal or corrected-to-normal hearing or vision Exclusion Criteria GENERAL Participation in another clinical trial Active use of prescribed medications to improve cognition and/or memory, e.g., cholinesterase inhibitors, memantine, or Aduhelm MRI Incompatibility Weight exceeding 275 pounds Pregnancy, suspicion of pregnancy, or attempting to become pregnant Claustrophobia Difficulties during previous MRIs Top permanent retainer (bottom only is okay) 5 or more non-removable gold-teeth Metal braces, top spacers, and/or palate expanders Any of the following implants: Aneurysm clips Cochlear implants Defibrillator Electrodes or wires Magnetically-activated device Spinal cord stimulator Infusion or insulin pumps Implanted drug infusion device Deep brain stimulation device Cardiac pacemaker Non-removable hairpieces, hairpiece extensions, and/or piercings Facial tattoos or permanent makeup Metal implants that are MR-incompatible, or where participant is unable to provide sufficient information to determine MR compatibility Previous injury by metallic foreign body (e.g., bullet, BB, shrapnel) where the object entered the body and (one of the following conditions): The metallic foreign body wasn't fully removed Participant lacks a doctor's confirmation that the metallic foreign body was fully removed Diagnosis of one or more of the following neurological disorders: Alzheimer's disease Parkinson's disease Lou Gehrig's disease (ALS) Multiple sclerosis Cerebral Palsy Diagnosis of one or more of the following genetic disorders Cystic Fibrosis Sickle Cell Disease Diagnosis of one or more of the following psychiatric disorders Psychosis Dementia Mental illness other than anxiety or depression GAD and depression if they have not been controlled for at least one year (if controlled >1 year, with or without medication, they are not exclusionary) Other Medical Severe lung, liver, heart, and/or kidney disease/s (e.g., heart failure, liver failure, and etc...) Diagnosis of thyroid disorder or change of thyroid medication dose within the last year Cancer treatment/s with chemotherapy and/or radiation to head and neck Stage 4 (metastatic) cancer Treatment/s for: Hepatitis HIV Rheumatoid arthritis Lupus Any autoimmune disorder Treatment/s to prevent transplant rejection History of substance abuse Including alcohol, but not nicotine or caffeine History of stroke History of 2 or more seizures or diagnosis of epilepsy, unless the seizures occurred prior to age 5 alongside a fever. History of brain tumor, brain aneurysm, brain hemorrhage, or subdural hematoma (transient ischemic attack not exclusionary) History of concussion or similar head injury if any of the following were present: Head injury requiring hospitalization Head injury succeeded by loss of consciousness for more than 30 minutes Head injury succeeded by amnesia, confusion, and/or loss of orientation lasting longer than 24 hours CT scan that revealed brain abnormalities 2 or more of the following symptoms if they lasted for longer than 3 months after head injury Headache Dizziness Hypersomnia or insomnia Phono- or photophobia Trouble with attention, memory, or staying on task Decline in school performance Depression and/or anxiety Panic attacks PTSD Uncontrolled high blood pressure or diabetes Heart attack within the last year Daily use of prescribed migraine medication

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Bianca H Dang

Phone

‭(310) 794-0077‬

tfus@mednet.ucla.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Natalie M Rotstein

Phone

‭(310) 794-0077‬

tfus@mednet.ucla.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Susan Y Bookheimer, PhD

Organizational Affiliation

UCLA Psychiatry & Biobehavioral Sciences

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Taylor P Kuhn, PhD

Organizational Affiliation

UCLA Psychiatry & Biobehavioral Sciences

Official's Role

Principal Investigator

Facility Information:

Facility Name

UCLA Semel Institute for Neuroscience and Behavior

City

Los Angeles

State/Province

California

ZIP/Postal Code

90024

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Bianca H Dang

Phone

310-794-0077

tfus@mednet.ucla.edu

First Name & Middle Initial & Last Name & Degree

Natalie M Rotstein

Phone

3107940077

tfus@mednet.ucla.edu

First Name & Middle Initial & Last Name & Degree

Taylor P Kuhn, PhD

First Name & Middle Initial & Last Name & Degree

Susan Y Bookheimer, PhD

12. IPD Sharing Statement

Plan to Share IPD

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Citation

Benedict RHB. Brief Visuospatial Memory Test - Revised: Professional Manual. Lutz, FL: Psychological Assessment Resources, Inc; 1997

Results Reference

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PubMed Identifier

16805925

Citation

Pachana NA, Byrne GJ, Siddle H, Koloski N, Harley E, Arnold E. Development and validation of the Geriatric Anxiety Inventory. Int Psychogeriatr. 2007 Feb;19(1):103-14. doi: 10.1017/S1041610206003504.

Results Reference

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Links:

URL

http://kuhnlab.io/studies/mci

Description

Related Info

URL

https://www.alzint.org/u/WorldAlzheimerReport2011.pdf

Description

Related Info

Available IPD and Supporting Information:

Available IPD/Information Type

Neuroimaging Analysis Software

Available IPD/Information URL

http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/

Available IPD/Information Type

Neuroimaging Analysis Software

Available IPD/Information URL

http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FEAT

Available IPD/Information Comments

Analysis Group, Oxford, UK. FSL FEAT

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Modulation of Hippocampal Circuitry and Memory Function With Focused Ultrasound in Amnestic MCI

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