Sonogenetic stimulation of the brain at a spatiotemporal resolution suitable for vision restoration

Abstract

Remote, precisely controlled activation of the brain is a fundamental challenge in the development of brain-machine interfaces providing feasible rehabilitation strategies for neurological disorders. Low-frequency ultrasound stimulation can be used to modulate neuronal activity deep in the brain1–7, but this approach lacks spatial resolution and cellular selectivity and loads the brain with high levels of acoustic energy. The combination of the expression of ultrasound-sensitive proteins with ultrasound stimulation (‘sonogenetic stimulation’) can provide cellular selectivity and higher sensitivity, but such strategies have been subject to severe limitations in terms of spatiotemporal resolution in vivo8–10, precluding their use for real-life applications. We used the expression of large-conductance mechanosensitive ion channels (MscL) with high-frequency ultrasonic stimulation for a duration of milliseconds to activate neurons selectively at a relatively high spatiotemporal resolution in the rat retina ex vivo and the primary visual cortex of rodents in vivo. This spatiotemporal resolution was achieved at low energy levels associated with negligible tissue heating and far below those leading to complications in ultrasound neuromodulation6,11. We showed, in an associative learning test, that sonogenetic stimulation of the visual cortex generated light perception. Our findings demonstrate that sonogenetic stimulation is compatible with millisecond pattern presentation for visual restoration at the cortical level. They represent a step towards the precise transfer of information over large distances to the cortical and subcortical regions of the brain via an approach less invasive than that associated with current brain-machine interfaces and with a wide range of applications in neurological disorders.

Sonogenetics: Recent advances and future directions

“…At the same time, Cadoni et al utilized the same mediator MscL-G22s to make retinal ganglion cells and visual cortex neurons sensitive to ultrasound stimulation. The study confirmed the feasibility of MscL-G22s sonogenetics with low frequency ultrasound [43]. In addition, the results showed that higher frequency ultrasound at 2.2 MHz and 15MHz can also be used to improve the spatial resolution.…”

“…On the other hand, the specificity of sonogenetic neural activation defined by eq (6) and eq (7) mainly relies on how the off-target effects were suppressed. Qiu et al (2020) and Cadoni et al (2021), showed that MscL-G22s based Sonogenetics are specific to targeted cells with 500kHz ultrasound stimulation below 0.45…”

“…Interestingly, Cadoni et al (2021) showed that sonogenetics with 2.25 MHz ultrasound dose have minimal stimulatory effects on WT neurons compares to 0.5 MHz and 15 MHz ultrasound in the ultrasound pressure range they tested [64]. Similarly, the hsTRPA1 based showed unspecific neural activation in vitro, while the in vivo EMG response is specific to sonogenetic stimulation [63].…”

Ultrasound stimulation for non-invasive visual prostheses

“…To overcome these issues, sonogenetics approach was explored ( Ibsen et al, 2015 ). For example, a recent sonogenetics study expressed mechanosensitive ion channels (MscL) in the primary visual cortex of rodents; they achieved high spatial (∼100 μm) and temporal (<50 ms) resolution ( Cadoni et al, 2021 ). It has been known that the activation of 100 μm area in diameter would result in the restored visual acuity of 20/400 ( Palanker et al, 2020 ).…”

“…It has been known that the activation of 100 μm area in diameter would result in the restored visual acuity of 20/400 ( Palanker et al, 2020 ). The increased sensitivity of neuronal cells to UST was observed by heterogeneously expressed MscL, which increases Ca 2+ influx ( Cadoni et al, 2021 ). Considering these results, the sonogenetic strategy may open a new door for the application of engineered mechanosensitive channels for vision restoration in blind patients.…”