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.
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.