Focal Volume, Acoustic Radiation Force, and Strain in Two-Transducer Regimes.

Transcranial focused ultrasound stimulation (TUS) holds promise for non-invasive neural modulation in treating neurological disorders. Most clinically relevant targets are deep within the brain (near or at its geometric center), surrounded by other sensitive regions that need to be spared clinical intervention. However, in TUS, increasing frequency with the goal of improving spatial resolution reduces the effective penetration depth. We show that by using a pair of 1 MHz, orthogonally arranged transducers we improve the spatial resolution afforded by each of the transducers individually, by nearly 40 fold, achieving a sub-cubic millimeter target volume of $0.24\ mm^3$. We show that orthogonally placed transducers generate highly localized standing waves with Acoustic Radiation Force (ARF) arranged into periodic regions of compression and tension near the target. We further present an extended capability of the orthogonal setup, which is to impart selective pressures--either positive or negative, but not both--on the target. Lastly, we share our preliminary findings that strain can arise from both particle motion and ARF with the former reaching its maximum value at the focus, and the latter remaining null at the focus and reaching its maximum around the focus. As the field is investigating the mechanism of interaction in TUS by way of elucidating the mapping between ultrasound parameters and neural response, orthogonal transducers expand our toolbox by making it possible to conduct these investigations at much finer spatial resolutions, with localized and directed (compression vs. tension) ARF and the capability of applying selective pressures at the target.

Focal Volume, Acoustic Radiation Force, and Strain in Two-Transducer Regimes.

Transcranial ultrasound stimulation (TUS) holds promise for noninvasive neural modulation in treating neurological disorders. Most clinically relevant targets are deep within the brain (near or at its geometric center), surrounded by other sensitive regions that need to be spared clinical intervention. However, in TUS, increasing frequency with the goal of improving spatial resolution reduces the effective penetration depth. We show that by using a pair of 1-MHz orthogonally arranged transducers, we improve the spatial resolution afforded by each of the transducers individually, by nearly 40 folds, achieving a subcubic millimeter target volume of [Formula: see text]. We show that orthogonally placed transducers generate highly localized standing waves with acoustic radiation force (ARF) arranged into periodic regions of compression and tension near the target. We further present an extended capability of the orthogonal setup, which is to impart selective pressures-either positive or negative, but not both-on the target. Finally, we share our preliminary findings that strain can arise from both particle motion (PM) and ARF with the former reaching its maximum value at the focus and the latter remaining null at the focus and reaching its maximum around the focus. As the field is investigating the mechanism of interaction in TUS by way of elucidating the mapping between ultrasound parameters and neural response, orthogonal transducers expand our toolbox by making it possible to conduct these investigations at much finer spatial resolutions, with localized and directed (compression versus tension) ARF and the capability of applying selective pressures at the target.

Application of Data-Driven computing to patient-specific prediction of the viscoelastic response of human brain under transcranial ultrasound stimulation.

We present a class of model-free Data-Driven solvers that effectively enable the utilization of in situ and in vivo imaging data directly in full-scale calculations of the mechanical response of the human brain to sonic and ultrasonic stimulation, entirely bypassing the need for analytical modeling or regression of the data. The well-posedness of the approach and its convergence with respect to data are proven analytically. We demonstrate the approach, including its ability to make detailed spatially resolved patient-specific predictions of wave patterns, using public-domain MRI images, MRE data and commercially available solid-mechanics software.

Effects of focused ultrasound in a "clean" mouse model of ultrasonic neuromodulation.

Recent studies on ultrasonic neuromodulation (UNM) in rodents have shown that focused ultrasound (FUS) can activate peripheral auditory pathways, leading to off-target and brain-wide excitation, which obscures the direct activation of the target area by FUS. To address this issue, we developed a new mouse model, the double transgenic Pou4f3+/DTR × Thy1-GCaMP6s, which allows for inducible deafening using diphtheria toxin and minimizes off-target effects of UNM while allowing effects on neural activity to be visualized with fluorescent calcium imaging. Using this model, we found that the auditory confounds caused by FUS can be significantly reduced or eliminated within a certain pressure range. At higher pressures, FUS can result in focal fluorescence dips at the target, elicit non-auditory sensory confounds, and damage tissue, leading to spreading depolarization. Under the acoustic conditions we tested, we did not observe direct calcium responses in the mouse cortex. Our findings provide a cleaner animal model for UNM and sonogenetics research, establish a parameter range within which off-target effects are confidently avoided, and reveal the non-auditory side effects of higher-pressure stimulation.

Effects of focused ultrasound in a "clean" mouse model of ultrasonic neuromodulation.

Recent studies on ultrasonic neuromodulation (UNM) in rodents have shown that focused ultrasound (FUS) can activate peripheral auditory pathways, leading to off-target and brain-wide excitation, which obscures the direct activation of the target area by FUS. To address this issue, we developed a new mouse model, the double transgenic Pou4f3+/DTR × Thy1-GCaMP6s, which allows for inducible deafening using diphtheria toxin and minimizes off-target effects of UNM while allowing effects on neural activity to be visualized with fluorescent calcium imaging. Using this model, we found that the auditory confounds caused by FUS can be significantly reduced or eliminated within a certain pressure range. At higher pressures, FUS can result in focal fluorescence dips at the target, elicit non-auditory sensory confounds, and damage tissue, leading to spreading depolarization. Under the acoustic conditions we tested, we did not observe direct calcium responses in the mouse cortex. Our findings provide a cleaner animal model for UNM and sonogenetics research, establish a parameter range within which off-target effects are confidently avoided, and reveal the non-auditory side effects of higher-pressure stimulation.

Structure of Anabaena flos-aquae gas vesicles revealed by cryo-ET.

Gas vesicles (GVs) are gas-filled protein nanostructures employed by several species of bacteria and archaea as flotation devices to enable access to optimal light and nutrients. The unique physical properties of GVs have led to their use as genetically encodable contrast agents for ultrasound and MRI. Currently, however, the structure and assembly mechanism of GVs remain unknown. Here we employ cryoelectron tomography to reveal how the GV shell is formed by a helical filament of highly conserved GvpA subunits. This filament changes polarity at the center of the GV cylinder, a site that may act as an elongation center. Subtomogram averaging reveals a corrugated pattern of the shell arising from polymerization of GvpA into a ß sheet. The accessory protein GvpC forms a helical cage around the GvpA shell, providing structural reinforcement. Together, our results help explain the remarkable mechanical properties of GVs and their ability to adopt different diameters and shapes.

Geometric effects in gas vesicle buckling under ultrasound.

Acoustic reporter genes based on gas vesicles (GVs) have enabled the use of ultrasound to noninvasively visualize cellular function in vivo. The specific detection of GV signals relative to background acoustic scattering in tissues is facilitated by nonlinear ultrasound imaging techniques taking advantage of the sonomechanical buckling of GVs. However, the effect of geometry on the buckling behavior of GVs under exposure to ultrasound has not been studied. To understand such geometric effects, we developed computational models of GVs of various lengths and diameters and used finite element simulations to predict their threshold buckling pressures and postbuckling deformations. We demonstrated that the GV diameter has an inverse cubic relation to the threshold buckling pressure, whereas length has no substantial effect. To complement these simulations, we experimentally probed the effect of geometry on the mechanical properties of GVs and the corresponding nonlinear ultrasound signals. The results of these experiments corroborate our computational predictions. This study provides fundamental insights into how geometry affects the sonomechanical properties of GVs, which, in turn, can inform further engineering of these nanostructures for high-contrast, nonlinear ultrasound imaging.

Mechanics Of Ultrasonic Neuromodulation In A Mouse Subject.

Ultrasound neuromodulation (UNM), where a region in the brain is targeted by focused ultrasound (FUS), which, in turn, causes excitation or inhibition of neural activity, has recently received considerable attention as a promising tool for neuroscience. Despite its great potential, several aspects of UNM are still unknown. An important question pertains to the off-target sensory effects of UNM and their dependence on stimulation frequency. To understand these effects, we have developed a finite-element model of a mouse, including elasticity and viscoelasticity, and used it to interrogate the response of mouse models to focused ultrasound (FUS). We find that, while some degree of focusing and magnification of the signal is achieved within the brain, the induced pressure-wave pattern is complex and delocalized. In addition, we find that the brain is largely insulated, or 'cloaked', from shear waves by the cranium and that the shear waves are largely carried away from the skull by the vertebral column, which acts as a waveguide. We find that, as expected, this waveguide mechanism is strongly frequency dependent, which may contribute to the frequency dependence of UNM effects. Our calculations further suggest that off-target skin locations experience displacements and stresses at levels that, while greatly attenuated from the source, could nevertheless induce sensory responses in the subject.

Transcranial focused ultrasound generates skull-conducted shear waves: Computational model and implications for neuromodulation.

Focused ultrasound (FUS) is an established technique for non-invasive surgery and has recently attracted considerable attention as a potential method for non-invasive neuromodulation. While the pressure waves in FUS procedures have been extensively studied in this context, the accompanying shear waves are often neglected due to the relatively high shear compliance of soft tissues. However, in bony structures such as the skull, acoustic pressure can also induce significant shear waves that could propagate outside the ultrasound focus. Here, we investigate wave propagation in the human cranium by means of a finite-element model that accounts for the anatomy, elasticity, and viscoelasticity of the skull and brain. We show that, when a region on the scalp is subjected to FUS, the skull acts as a waveguide for shear waves that propagate with a speed close to 1500 m/s, reaching off-target structures such as the cochlea. In particular, when a sharp onset of FUS is introduced in a zone proximal to the intersection of the parietal and temporal cranium, the bone-propagated shear waves reach the inner ear in about 40 µ s , leading to cumulative displacements of about 1 µ m . We further quantify the effect of ramped and sharp application of FUS on the cumulative displacements in the inner ear. Our results help explain the off-target auditory responses observed during neuromodulation experiments and inform the development of mitigation and sham control strategies.

Multi-scale mechanical and transport properties of a hydrogel.

In this paper, molecular dynamic simulation was used to study the effect of water on the equilibrated structure and mechanical properties of cross-linked hydrogel at multiple scales. The hydrogel consisted of Polyethylene glycol diglycidyl ether (PEGDGE) as epoxy and the Jeffamine, poly-oxy-alkylene-amines, as curing agent. The results for systems with various water contents indicated that the cross-links were more hydrophilic within the hydrogel structure. Effects of cross-linking on the transport properties were also investigated by computing diffusion coefficients of water molecules. A new Coarse-Grained (CG) scheme for hydrogels is proposed, and validated by comparing the transport properties with the all-atom method, demonstrating the capability of the model to capture the correct dynamic evolution of the system. The all-atom model of the hydrogel was mapped to the CG model using the MARTINI force field. This method resulted in a more realistic representation of the stiffness of the system, compared to the previous experimental studies in the literature. The variation of the stiffness of the hydrogel as a function of the water content showed that 40% water content is the optimal value for mechanical performance of the hydrogel.