Pulse inversion therapy for improved monitoring of blood-brain barrier opening

Abstract

Microbubble-based ultrasound therapy has enabled non-invasive and reversible opening of the blood-brain barrier (BBB). However, the skull limits our ability to monitor microbubble activity due to high attenuation and beam aberrations. In ultrasound imaging, pulse inversion is used to cancel echoes from linear scatterers by summing the signal obtained from consecutive positive (phase: 0o degrees) and negative (phase: 180o degrees) pulses, thus facilitating imaging of non-linear scatterers such as microbubbles. Here, we adapt the pulse inversion technique to improve monitoring of BBB opening, by transmitting consecutive therapeutic pulses of inverse polarity. Pulse inversion therapy (PIT) was achieved by synchronizing the emission of inverted short pulses (pulse length: 2–3 cycles, PRF: 2 kHz, and pressure: 400 kPa) through a focused 0.5 MHz therapeutic transducer driven by two function generators. A concentric P12-5 linear array was used to passively capture the microbubble emissions. Absolute time-of-flight information was introduced in the beamforming since emission and reception were synchronous. PIT suppressed the signals from linear scatterers within the focal region by up to 6 dB in a gelatine phantom containing microbubbles and in mice in vivo, compared to positive-only pulses. Ongoing in vivo work aims at correlating the BBB opening with the microbubble signal identified by PIT.