Leveraging the parametric array effect for transcranial focused ultrasound interventions

Slightly different high-frequency beams can interact nonlinearly to generate a low-frequency "difference frequency," a phenomenon known as the parametric array effect. While this physical effect can offer sub-wavelength targeting in the brain, creating it through the skull during trans skull focused ultrasound (FUS) procedures has remained unexplored. Here, we show focused ultrasonic fields can produce different frequencies in brain tissue by exploiting the skull's inherent nonlinearity. We find that the drop in difference-frequency amplitude —particularly around 100 kHz— can be reliably detected through the skull and serve as an active acoustic feedback to perform precise acoustic hologram-to-skull registration. Furthermore, by examining changes in the difference-frequency signal, we propose a noninvasive strategy to identify ventricular enlargement in hydrocephalus, where excess cerebrospinal fluid can be distinguished from surrounding brain tissue. This approach has the potential to guide early diagnostic assessments and realtime monitoring of draining excess cerebrospinal fluid from the brain. More broadly, our findings underscore the potential of the parametric array effect in guiding transcranial FUS interventions. [This work is funded by the National Science Foundation CMMI Award 1933158.]