In a new paper published in Light: Science and Applications, a team of scientists and engineers led by Ji-Xin Cheng and Chen Yang (Boston University, Boston, USA) has developed an optically generated focused ultrasound (OFUS) method for non-invasive brain stimulation with ultrahigh precision.
As a press release announcing this publication notes, a neuromodulation tool with ultrahigh precision is needed for mapping subregions of the brain by modulating a small population of the neurons—as less precise brain stimulation modalities usually activate multiple functional regions and cause unintended responses.
Electrical stimulation tools are a ‘gold standard’ for neuromodulation studies and disease treatments, but the current leakage over several millimetres limits how precisely targeting can be controlled. Optogenetics provides an “unrivalled sub-cellular spatial resolution and specificity in targeted cell types”, yet viral transfection has limited applications of these technologies in the human brain to date, the release continues, while transcranial focused ultrasound (tFUS) is stunted by a spatial resolution of 1–5mm despite offering a potentially viable non-invasive neuromodulation technique.
Thus, to date, non-invasive brain stimulation by focused ultrasound with the optimal spatial resolution of 0.1mm has not been demonstrated; and non-invasive, non-genetic neuromodulation with ultrahigh precision remains a “critical unmet need”.
In their paper, the Boston University researchers outline the fact that OFUS is generated by a soft optoacoustic pad (SOAP) fabricated through embedding candle-soot nanoparticles in a curved polydimethylsiloxane film. Through the ‘optoacoustic effect’, candle-soot nanoparticles absorb the incident laser pulse and convert the energy to thermal expansion and compression—resulting in the generation of an ultrasound pulse.
A transcranial focus with ultrahigh precision of 83µm was achieved by SOAP, which is beyond the reach of the piezo-based low-frequency associated with tFUS. Such a breakthrough benefitted by the high acoustic frequency generated from the mixed layer of candle-soot nanoparticles and polydimethylsiloxane (PDMS), and was pushed towards the limit through the geometric design with a high numerical aperture.
The team further detail how OFUS enabled direct and transcranial single-cycle stimulation to be performed reliably and safely, verified by calcium imaging in cultured neurons in vitro. The unique single-cycle modulation of OFUS was found to evoke action potentials with much lower total ultrasound energy input than that of tFUS. The researchers also validated non-invasive transcranial neurostimulation with OFUS in mice by immunofluorescence imaging and electrophysiological recording.
Therefore, they assert that OFUS offers ultrahigh precision non-invasively towards neurological research in subregions of a brain. Notably, according to the release, it shows the “exciting potential” for disease treatment, such as modulating complex brain function and histotripsy. To evoke complex functions of the brain, OFUS devices can potentially be scaled up into a massive ultrasound array for multisite neuromodulation as well.
While conventional lead zirconate titanate (PZT)-based ultrasound arrays with massive cables connected to each element are heavy to wear for patients, the lightweight OFUS device disclosed by the researchers provides the added benefit of improved accessibility and wearability for long-term treatments. In addition, OFUS devices with no metal components further offer improved compatibility with real-time magnetic resonance imaging (MRI) guidance and functional MRI monitoring, enabling real-time functional MRI evaluation of stimulation treatment and providing opportunities for closed-loop treatments in clinical applications.
Furthermore, OFUS offers an opportunity to improve spatiotemporal control in histotripsy. Conventional transducers for histotripsy are driven under thousands of volts, suffering from the risk of dielectric breakdown. OFUS can improve the spatial control with a higher frequency, deliver a better temporal precision with a single cycle, and provide ultrasound with high intensity by simply improving the energy of input light without the risk of dielectric breakdown, the release states.
The researchers summarise their paper by writing: “OFUS offers ultrahigh precision non-invasively towards neurological research in subregions of a brain. Its flexibility in fabrication, high spatiotemporal resolution, and improved electromagnetic compatibility, further enable clinical applications—such as ultrasound surgery, drug delivery and pain management. This work thus underlines the potential for OFUS to be utilised as a valuable technology in neuroscience research and clinical therapies.”