Controlled delivery of ultrasound through the head for effective and safe therapies of the brain

Transcranial focused ultrasound provides noninvasive and reversible approaches for precise and personalized manipulations of brain circuits, with the potential to transform our understanding of brain function and treatments of brain dysfunction. However, the effectiveness and safety of these approaches have been limited by the human head, which attenuates and distorts ultrasound strongly and unpredictably. To address this lingering barrier, we have developed a "Relative Through-Transmit" (RTT) approach that directly measures and compensates for the attenuation and distortion of a given skull and scalp. We have implemented RTT in hardware and demonstrated that it accurately restores the operators intended intensities inside ex-vivo human skulls. Moreover, this functionality enabled effective and intensity-dependent transcranial modulation of nerves and effective release of defined doses of propofol inside the skull. RTT was essential for these new applications of transcranial ultrasound; when not applied, there were no significant differences from sham conditions. Moreover, RTT was safely applied in humans and accounted for all intervening obstacles including hair and ultrasound coupling. This method and hardware unlock the potential of ultrasound-based approaches to provide effective, safe, and reproducible precision therapies of the brain.