R01AG073480

Modulation of Hippocampal Circuitry and Memory Function with Focused Ultrasound in Amnestic MCI - Abstract

For patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD), there are few effective treatments for memory enhancement. Strategies that directly manipulate neural activity are promising but currently have serious limitations.

Deep brain stimulation (DBS) of the entorhinal cortex (ERC), a part of the brain important for memory, has been shown to improve memory in a small sample of patients. However, DBS is highly invasive and requires neurosurgery. Other neuromodulation techniques that do not require surgery are limited in that they target only surface brain structures. In MCI and AD, it is the deep brain structures, including the ERC and the hippocampus (HC), that are most affected.

Low intensity focused ultrasound pulsation (LIFUP) uses acoustic energy waves with frequencies higher than humans can hear to penetrate the skull and effect specifically targeted deep brain regions. Therefore, LIFUP could be targeted at the deep brain structures critical for episodic memory formation, the same regions that are affected in MCI and AD.

We are the first to do just this, and our preliminary data shows that LIFUP increases perfusion of the ERC, increases functional connectivity of the ERC/HC memory network, and may improve behavioral memory performance. Our LIFUP set-up is safe to use inside a magnetic resonance imaging (MRI) machine, which allows for simultaneous brain modulation and real-time measurement of the modulation using MRI.

We will use each participant's structural brain MRI to aim LIFUP at the ERC. This will allow us to directly test the effects of LIFUP on activity in the ERC, in other brain regions connected to the ERC (e.g. HC), as well as on blood flow in the HC and other brain areas important for memory.

Applying this to patients with MCI, we will try to determine the dose, booster effect, and duration of LIFUP effects on brain and blood flow, structure and function. We will also determine whether these LIFUP-related changes improve memory in this population and evaluate the effect of LIFUP on blood-based biomarkers of AD-related neurodegeneration.

Understanding how the parameters of LIFUP dose and booster session affect the impact and duration of LIFUP on brain, biomarker, and memory performance will be a significant step towards constructing a comprehensive clinical trial. The ability to change the activity and blood flow of brain regions by targeting them with LIFUP would be an important step towards developing a non-invasive memory prosthetic that would make a very significant contribution to AD treatment.

Los Angeles University Of California

NOT APPLICABLE

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Los Angeles, California 900958348 United States

Single Zip Code

Early Stage Clinical Trials for the Spectrum of Alzheimers Disease and Age-related Cognitive Decline (R01 Clinical Trial Optional) (PAR-18-877)

Amendment Since initial award the End Date has been extended from 07/31/26 to 07/31/27 and the total obligations have increased 399% from $621,961 to $3,100,642.