Acoustic Transparency Enabling Functional Ultrasound Imaging Through Mouse and Human Skulls

Ultrasound is one of the most widely used non-invasive imaging modalities for internal organs, yet its application to the brain has been hindered for decades by the skull’s acoustic barrier. This same barrier has kept functional ultrasound imaging (fUSI)—an emerging technology capable of capturing brain-wide neural activity in real time at sub-100 μm resolution—from reaching its transformative potential in neuroscience and clinical medicine. Here, we present an acoustic transparency strategy by modulating skull acoustic properties, to render the brain visible to ultrasound. A brief topical application of an FDA-approved chelating agent matches the skull’s acoustic impedance and sound speed to those of soft tissue, enabling nearly complete ultrasound transmission (94.0 ± 4.4%) with minimal energy loss or distortion. Leveraging this discovery, we developed an acoustic-transparent fUSI platform that maps brain activation across the full brain depth at ∼20 μm spatial resolution without skull removal. This method enables safe, longitudinal brain imaging, is fully reversible, and is demonstrated to be applicable to the ex vivo human skull. This conceptually distinct paradigm—controlling acoustic wave propagation via acoustic property modulation—offers a practical and generalizable solution to one of the most persistent obstacles in transcranial ultrasound imaging, opening the door to broader clinical and research application of ultrasound neuroimaging.