Neurodegeneration Associated with Repeated High-Frequency Transcranial Focused Ultrasound

Abstract

Transcranial Focused Ultrasound (tFUS) is a popular tool for non-invasive neuromodulation which prior testing paradigms have suggested is benign. However, emerging use cases such as clinical therapies and brain-machine interfaces will likely require repeated or long-duration exposures with novel combinations of stimulus parameters (e.g., frequency, focal volume), and the safety of these conditions has not yet been rigorously validated. Therefore, as an initial study we delivered 1.8 MHz tFUS stimulation to the cortex of 4 non-human primates in 4 sessions each of approximately 90 min over 2 weeks. Motor skills were measured daily with a food pellet picking task. Animals were euthanized and the brain sections were processed for histological markers of neurodegeneration (Fluoro-Jade C). While the animals did not show disruption on the behavioral task, there was clear evidence of neurodegeneration in regions associated with short, intermediate, and extended-duration stimulation, but not with unstimulated control tissues in deeper brain areas. Additional neurodegeneration was observed at locations distant from but functionally connected to stimulated regions, consistent with retrograde damage propagated from neuron processes. We discuss alternative causes for the neurodegeneration, and we recommend the use of additional animal studies to understand this phenomenon, especially for novel stimulation paradigms or parameters and applications where extended or repeated exposures are planned.