Imaging the brain by traversing the skull with light and sound

Optical and ultrasonic techniques for imaging the living brain have traditionally been limited to low-resolution interrogations or highly invasive craniotomy procedures. Localization-based techniques for super-resolution ultrasound and optical imaging, as well as hybrid optoacoustic techniques, are now enabling multiscale interrogations of the brain to exploit anatomical, functional and molecular contrasts non-invasively or minimally invasively. However, the skull bone remains a substantial obstacle to the transcranial application of light- and sound-based imaging techniques. Our knowledge of the skull's acoustic properties inherited from transcranial ultrasound has been primarily limited to a narrowband and normal-incidence-angle detection regimen, which is inapplicable to more advanced ultrasound and optoacoustic brain imaging technology. In this Perspective, we examine the transcranial wave-propagation problem, as well as recent efforts to characterize and model skull-induced distortions and develop compensatory strategies. We then summarize recent preclinical and human applications of brain imaging and delve into the most pressing challenges facing this dynamic field at the crossroads of physics, engineering and medicine.