Brain-on-Chip Platform for Studying the Optimum Parameter of Ultrasound Neuromodulation

Brain stimulation techniques are essential tools to address various neurological conditions. Approved neuromodulation techniques are either invasive in which patients have to undergo risky surgery or non-invasive but suffer from low spatial resolution. Focused ultrasound stimulation (FUS) is a promising new modality for non-invasive and minimally invasive brain stimulation which has been shown to elicit and suppress neural activity. In comparison to other non-invasive modalities, FUS offers comparable spatial resolution to invasive modalities. Stimulation is delivered deep into the brain using acoustic waves with sub-millimeter spatial resolution. However, the role of the FUS parameters is still heavily debated due to the limited performance of commercial FUS transducers and its inadequate pairing with typical <i>in vivo </i>neuronal recording technologies. To tackle the latter issue, Organ-on-chip (OoC), specifically brain-on-chip (BoC) is a promising new technology that can recapitulate human physiology using cerebral organoids <i>in vitro</i>. Mounting scientific literature evidences the superior physiological relevance of tissue response in OoCs compared to standard 2D static cell cultures. Multielectrode arrays are implemented on the BoC platform to record the neural activity of the organoids directly. We envision a tailored brain-on-chip platform could provide a suitable match for FUS to unravel its working principles, with the long-term goal of providing an electrical, thermal and mechanical sensing map of brain tissue response when locally stimulated by focused ultrasound. In this regard, one of the major technological drawbacks of ultrasound stimulation is the big form factor of the ultrasound transducers. Available ultrasound transducers are limited in terms of spatial resolution to study the effect of ultrasound in neuronal level and also bulky in terms of volume to be integrated into the context of BoC. We used microfabrication techniques to miniaturize the ultrasound transducer with the goal of having an ultrasound transducer with a small form factor with flexibility in the stimulation parameter. Lead zirconate titanate(PZT) piezoelectric film of various resonance frequencies is incorporated into an array on a silicon wafer. Unlike ultrasound transducer for imaging application, the acoustic pressure generated by the transducer is a crucial parameter of the transducer to induce neural activity, which can go up to 2 MPa for the central nervous system. In order to improve the spatial resolution of our transducer, a collimation technique based on slit diffraction is investigated to reach a single-neuron resolution. The resulting platform can be a step forward in understanding the mechanism of ultrasound neuromodulation by understanding the role of each ultrasound parameter and enabling the comparison of different neurons in an identical environment.