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.

On the accuracy of optically tracked transducers for image-guided transcranial ultrasound.

PURPOSE: Transcranial focused ultrasound (FUS) is increasingly being explored to modulate neuronal activity. To target neuromodulation, researchers often localize the FUS beam onto the brain region(s) of interest using spatially tracked tools overlaid on pre-acquired images. Here, we quantify the accuracy of optically tracked image-guided FUS with magnetic resonance imaging (MRI) thermometry, evaluate sources of error and demonstrate feasibility of these procedures to target the macaque somatosensory region. METHODS: We developed an optically tracked FUS system capable of projecting the transducer focus onto a pre-acquired MRI volume. To measure the target registration error (TRE), we aimed the transducer focus at a desired target in a phantom under image guidance, heated the target while imaging with MR thermometry and then calculated the TRE as the difference between the targeted and heated locations. Multiple targets were measured using either an unbiased or bias-corrected calibration. We then targeted the macaque S1 brain region, where displacement induced by the acoustic radiation force was measured using MR acoustic radiation force imaging (MR-ARFI). RESULTS: All calibration methods enabled registration with TRE on the order of 3 mm. Unbiased calibration resulted in an average TRE of 3.26 mm (min-max: 2.80-4.53 mm), which was not significantly changed by prospective bias correction (TRE of 3.05 mm; 2.06-3.81 mm, p = 0.55). Restricting motion between the transducer and target and increasing the distance between tracked markers reduced the TRE to 2.43 mm (min-max: 0.79-3.88 mm). MR-ARFI images showed qualitatively similar shape and extent as projected beam profiles in a living non-human primate. CONCLUSIONS: Our study describes methods for image guidance of FUS neuromodulation and quantifies errors associated with this method in a large animal. The workflow is efficient enough for in vivo use, and we demonstrate transcranial MR-ARFI in vivo in macaques for the first time.