Non-invasive transcranial ultrasound stimulation for neuromodulation.

Transcranial ultrasound stimulation (TUS) holds great potential as a tool to alter neural circuits non-invasively in both animals and humans. In contrast to established non-invasive brain stimulation methods, ultrasonic waves can be focused on both cortical and deep brain targets with the unprecedented spatial resolution as small as a few cubic millimeters. This focusing allows exclusive targeting of small subcortical structures, previously accessible only by invasive deep brain stimulation devices. The neuromodulatory effects of TUS are likely derived from the kinetic interaction of the ultrasound waves with neuronal membranes and their constitutive mechanosensitive ion channels, to produce short term and long-lasting changes in neuronal excitability and spontaneous firing rate. After decades of mechanistic and safety investigation, the technique has finally come of age, and an increasing number of human TUS studies are expected. Given its excellent compatibility with non-invasive brain mapping techniques, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), as well as neuromodulatory techniques, such as transcranial magnetic stimulation (TMS), systemic TUS effects can readily be assessed in both basic and clinical research. In this review, we present the fundamentals of TUS for a broader audience. We provide up-to-date information on the physical and neurophysiological mechanisms of TUS, available readouts for its neural and behavioral effects, insights gained from animal models and human studies, potential clinical applications, and safety considerations. Moreover, we discuss the indirect effects of TUS on the nervous system through peripheral co-stimulation and how these confounding factors can be mitigated by proper control conditions.

Transient acoustic vaporization signatures unique to low boiling point phase change contrast agents enable super-resolution ultrasound imaging without spatiotemporal filtering.

The unique activation signal of phase-change contrast agents (PCCAs or droplets) can be separated from the tissue signal and localized to generate super-resolution (SR) ultrasound (US) images. Lipid-shelled, perfluorocarbon PCCAs can be stochastically vaporized (activated) by a plane wave US transmission thereby enabling them to be used as separable targets for ultrasound localization microscopy. The unique signature of droplet vaporization imaging and the transient inherent nature of this signature increases signal contrast and therefore localization confidence, while the poor resolution of the low-frequency vaporization signal is overcome by the super-resolution result. Furthermore, our proposed PCCA SR technique does not require the use of user-dependent and flow-dependent spatio-temporal filtering via singular-value decomposition. Rather, matched filters selected by Fourier-domain analysis are able to identify and localize PCCA activations. Droplet SR was demonstrated in a crossed-microtube water phantom by localizing the activation signals of octafluoropropane nanodroplets (OFP, C3F8, -37 °C boiling point) to resolve 100 µm diameter fluorinated ethylene propylene tubes, which are ordinarily 35% smaller than the native diffraction-limited resolution of the imaging system utilized.

Numerical Simulation of Focused Shock Shear Waves in Soft Solids and a Two-Dimensional Nonlinear Homogeneous Model of the Brain.

Shear waves that propagate in soft solids, such as the brain, are strongly nonlinear and can develop into shock waves in less than one wavelength. We hypothesize that these shear shock waves could be responsible for certain types of traumatic brain injuries (TBI) and that the spherical geometry of the skull bone could focus shear waves deep in the brain, generating diffuse axonal injuries. Theoretical models and numerical methods that describe nonlinear polarized shear waves in soft solids such as the brain are presented. They include the cubic nonlinearities that are characteristic of soft solids and the specific types of nonclassical attenuation and dispersion observed in soft tissues and the brain. The numerical methods are validated with analytical solutions, where possible, and with self-similar scaling laws where no known solutions exist. Initial conditions based on a human head X-ray microtomography (CT) were used to simulate focused shear shock waves in the brain. Three regimes are investigated with shock wave formation distances of 2.54 m, 0.018 m, and 0.0064 m. We demonstrate that under realistic loading scenarios, with nonlinear properties consistent with measurements in the brain, and when the shock wave propagation distance and focal distance coincide, nonlinear propagation can easily overcome attenuation to generate shear shocks deep inside the brain. Due to these effects, the accelerations in the focal are larger by a factor of 15 compared to acceleration at the skull surface. These results suggest that shock wave focusing could be responsible for diffuse axonal injuries.

Estrogen receptor ß activation impairs mitochondrial oxidative metabolism and affects malignant mesothelioma cell growth in vitro and in vivo.

Estrogen receptor (ER)-ß has been shown to possess a tumor suppressive effect, and is a potential target for cancer therapy. Using gene-expression meta-analysis of human malignant pleural mesothelioma, we identified an ESR2 (ERß coding gene) signature. High ESR2 expression was strongly associated with low succinate dehydrogenase B (SDHB) (which encodes a mitochondrial respiratory chain complex II subunit) expression. We demonstrate that SDHB loss induced ESR2 expression, and that activated ERß, by over-expression or by selective agonist stimulation, negatively affected oxidative phosphorylation compromising mitochondrial complex II and IV activity. This resulted in reduced mitochondrial ATP production, increased glycolysis dependence and impaired cell proliferation. The observed in vitro effects were phenocopied in vivo using a selective ERß agonist in a mesothelioma mouse model. On the whole, our data highlight an unforeseen interaction between ERß-mediated tumor suppression and energy metabolism that may be exploited to improve on the therapy for clinical management of malignant mesothelioma.

Global approach for transient shear wave inversion based on the adjoint method: a comprehensive 2D simulation study.

Shear wave imaging (SWI) maps soft tissue elasticity by measuring shear wave propagation with ultrafast ultrasound acquisitions (10 000 frames s(-1)). This spatiotemporal data can be used as an input for an inverse problem that determines a shear modulus map. Common inversion methods are local: the shear modulus at each point is calculated based on the values of its neighbour (e.g. time-of-flight, wave equation inversion). However, these approaches are sensitive to the information loss such as noise or the lack of the backscattered signal. In this paper, we evaluate the benefits of a global approach for elasticity inversion using a least-squares formulation, which is derived from full waveform inversion in geophysics known as the adjoint method. We simulate an acoustic waveform in a medium with a soft and a hard lesion. For this initial application, full elastic propagation and viscosity are ignored. We demonstrate that the reconstruction of the shear modulus map is robust with a non-uniform background or in the presence of noise with regularization. Compared to regular local inversions, the global approach leads to an increase of contrast (∼+3 dB) and a decrease of the quantification error (∼+2%). We demonstrate that the inversion is reliable in the case when there is no signal measured within the inclusions like hypoechoic lesions which could have an impact on medical diagnosis.