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

Study Overview
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Brief Summary
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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
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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.

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

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

Intervention / Treatment
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* Device: Low-Intensity Focused Ultrasound Pulsation (LIFUP)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: LIFUP Dose Group 1<br>Administration of low intensity focused ultrasound (LIFUP) dose level 1 to the entorhinal cortex. | Device: Low-Intensity Focused Ultrasound Pulsation (LIFUP)<br>* 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.<br>* Other names: low intensity focused ultrasound;|
| Active Comparator: LIFUP Dose Group 2<br>Administration of low intensity focused ultrasound (LIFUP) dose level 2 to the entorhinal cortex. | Device: Low-Intensity Focused Ultrasound Pulsation (LIFUP)<br>* 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.<br>* Other names: low intensity focused ultrasound;|
| Active Comparator: LIFUP Dose Group 3<br>Administration of low intensity focused ultrasound (LIFUP) dose level 3 to the entorhinal cortex. | Device: Low-Intensity Focused Ultrasound Pulsation (LIFUP)<br>* 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.<br>* Other names: low intensity focused ultrasound;|
| Sham Comparator: Sham LIFUP<br>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. | Device: Low-Intensity Focused Ultrasound Pulsation (LIFUP)<br>* 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.<br>* Other names: low intensity focused ultrasound;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 40 minutes | 
| 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. | 40 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 48 hours | 
| 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. | 48 hours | 
| Post-hoc biomarker analysis of APOE-4 status 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. | 4 years | 
| 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). | 4 years | 
| Post-hoc biomarker analysis of plasma ptau 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. | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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