Low Intensity Focused Ultrasound for Learning and Memory

Hippocampus and medial temporal lobe (MTL)-dependent memory is impacted by a wide range of psychiatric and neurologic conditions. These cognitive limitations often result in limited functional abilities for patients. Currently available pharmacologic and behavioral treatments are somewhat controversial and have minimal evidence-based effectiveness. Recently, deep brain stimulation was used to modulate MTL activity and subsequently improve memory performance. However, such implantable devices require neurosurgery with major associated health risk. At present, there are no publications reporting non-invasive neurostimulation targeting MTL regions to improve memory. The central hypothesis of this project is that non-invasive, low intensity focused ultrasound pulsation (LIFUP) can selectively increase regional MTL activity and thus be used as a cognitive neural prosthetic capable of improving memory performance. The aims of this study focus on whether LIFUP can increased blood oxygen level dependent (BOLD) activation in the entorhinal cortex and functionally associated regions, whether this increased activation is greater using short train or long train LIFUP parameters, and whether this LIFUP-induced activation, when applied during learning, results in improved memory.

This proposal proposes the use of personalized neuronavigation, based on each participant's structural brain MRI, to aim LIFUP at the white matter underlying the entorhinal cortex in the pursuit of enhancement of learning and memory in humans. A comprehensive approach will integrate behavioral and multimodal neuroimaging to assess the utility of LIFUP to increase activity in deep neural structures and in the enhancement of memory. Further, this is the first study to use LIFUP in (A) ventral cortical and hippocampal regions and (B) for pro-cognitive effects. Findings from this study will provide important insight into the utility of LIFUP modulation of subcortical regions and their associated networks and functions, which have wide ranging implications for clinical LIFUP as a therapeutic device for numerous patient populations. Participants will complete a brief T1-weighted structural brain scan. Then, they will be removed from the scanner and, using the T1 image in Neurocare Brainsight software60, the LIFUP transducer will be aimed at the white matter underlying the entorhinal cortex and gently strapped in place to their head. Participants will then return to the scanner where a second T1 image will verify the position of the LIFUP transducer and allow for estimation of the spatial location of the sonification beam focus (approximately .5cm long x 7mm diameter). BOLD fMRI will be collected during three conditions, randomized and counterbalanced across participants (with sham always separating the two LIFUP conditions: short train sonification LIFUP, sham LIFUP long train LIFUP: total time = 30min. Short train LIFUP (previously used in primary sensory cortices47 will be administered in 75 sonifications at 210 KHz frequency with pulse repetition frequency of 500Hz, 35mW/cm2, sonification duration 0.5s with 7s inter-stimulation interval. Sham LIFUP will involve the same procedures (e.g. participant provided the same instructions) except the sonification will not occur. Before and after completing the scan and a short break, these participants will receive short train LIFUP47 while they are administered a series of three computerized, hippocampally-dependent episodic memory tasks. Given that routine clinical neuropsychological measures are designed to provide diagnostic information and are not sensitive or specific enough to precisely measure longitudinal cognitive change related to an intervention, we will use validated experimental neurocognitive measures.