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, in a small sample of patients has been shown to improve memory, but 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 to 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; increased 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, 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 effect 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.

Grant Number: 5R01AG073480-05
NIH Institute/Center: NIH
Principal Investigator: SUSAN BOOKHEIMER