Multidimensional Safety Assessment of a Low-Intensity Scanning Ultrasound (SUS) Protocol in Sheep.

Area of Science:

• Neuromodulation
• Neuroscience
• Medical Devices

Background:

• Preclinical studies in mouse models suggest low-intensity ultrasound in a scanning mode (SUS) is a promising neuromodulatory technique for Alzheimer's disease.
• Significant differences in brain scale and complexity between mice and humans necessitate large animal models for safety assessment before human trials.

Purpose of the Study:

• To assess the safety and tolerability of a novel investigational device delivering SUS in a large animal model (sheep).
• To evaluate both acute and long-term effects of SUS on brain tissue and function prior to human clinical trials.

Main Methods:

• Image-guided neuro-navigation was used to deliver SUS (peak negative pressure 2.6 MPa) to four sheep.
• Three sheep underwent non-recovery procedures with histological assessment; one sheep received five repeated treatments over 12 weeks, monitored by MRI and behavioral observations.

Main Results:

• A total of 631 sonications were performed without evidence of tissue damage or blood-brain barrier (BBB) opening.
• Histological and MRI assessments revealed no SUS-induced anatomical abnormalities, microhemorrhages, or edema.
• Repeated treatments in one sheep showed no adverse behavioral changes, pain, or distress, despite mild localized heating at the inner skull surface.

Conclusions:

• The acute and long-term safety assessment in the sheep model supports the translation of SUS to human studies for Alzheimer's disease.
• SUS is a safe neuromodulatory approach for potential therapeutic applications in neurodegenerative diseases.