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Enhanced detection of bubble emissions through the intact spine for monitoring ultrasound-mediated blood-spinal cord barrier opening

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Therapeutic delivery targeted to diseases and disorders of the central nervous system (CNS) poses a unique challenge due to the presence of the blood-brain and blood-spinal cord barriers (BBB and BSCB), which prevent the passage of foreign molecules from the vasculature into CNS parenchyma. Focused ultrasound (FUS) and microbubble (MB) mediated therapies have been shown to enhance the permeability of these barriers. Acoustic emissions from MBs during treatments can be used as predictors of treatment outcomes. We previously developed short burst, phase keying (SBPK) exposures to be used in a dual aperture configuration to address clinical scale targeting challenges of FUS delivery to the spinal canal. Here, we demonstrate that MB emissions can be detected through the human vertebral arch in ex vivo experiments, and that SBPK exposures can modify the BSCB in vivo in rats.

SBPK pulses were modified to include pulse inversion (PI), a technique used in ultrasound imaging to enhance detection of non-linear bubble signals and supress contribution from tissue. Circulating MBs were sonicated through ex vivo vertebrae using SBPK exposures at a frequency of 514kHz. Signals detected using 250kHz acoustic receiver were analyzed using short time Fourier analysis and a maximum intensity projection over the SBPK pulse train. At acoustic pressures between 0.2 and 0.4MPa, analysis using PI yielded a 2-fold enhancement at the second- and subharmonic frequencies.

A cohort of rats was treated with SBPK FUS + MBs at 3 locations per spinal cord at fixed pressures (0.20-0.47MPa). BSCB opening was confirmed by T1 MRI enhancement and extravasation of Evans blue dye at 40/42 targeted locations. MB emissions acquired during treatments were compared with bioeffects observed on histology. Detection of the subharmonic was linked to widespread bleeding throughout the focal region. At the lowest pressures, opening was achieved without damage observed at histology.

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