Focused Ultrasound Neuromodulation Research Articles

Functional Cerebral Neurovascular Mapping During Focused Ultrasound Peripheral Neuromodulation of Neuropathic Pain.

Nociceptive pain is required for healthy function, yet, neuropathic pain (disease or injury) can be severely debilitating. Though a wide-array of treatment options are available, they are often systemic and/or invasive. As a promising neuromodulation treatment, Focused ultrasound (FUS) is a noninvasive and highly spatially-targeted technique shown to stimulate neural activity, yet, effects on pain signaling are currently unknown. Develop and validate a method for studying FUS nerve stimulation modulation of pain-evoked neural responses in vivo. We developed a high-resolution functional ultrasound (fUS) method capable of mapping cortical responses in healthy and neuropathic pain mice in response to FUS neuromodulation treatment. FUS-evoked hemodynamic responses are correlated with the intensity of peripheral neuromodulation. We confirm functional connectivity is altered in neuropathic mice and demonstrate that FUS can modulate neuropathic pain-evoked hemodynamics. The findings presented herein provides evidence for an FUS-based nerve pain method and validates the fUS technique developed for monitoring pain-evoked hemodynamics. We anticipate that the findings presented herein describe a noninvasive and flexible nerve modulation technique for pain mitigation, furthering evidence for clinical translation.

Investigating the impact of skull vibrations on motor responses to focused ultrasound neuromodulation in small rodents and methods to mitigate them

Objective. Focused ultrasound (FUS) neuromodulation non-invasively alters brain activity, likely via acoustic radiation force with dynamics of the pulse repetition frequency (PRF). PRF impacts neuromodulation as well as indirect auditory activation, a confound linked to skull vibrations. This study aimed to minimize these vibrations, by adjusting and randomizing PRF, and determine their impact on FUS-induced motor activity. We hypothesized that: the skull would vibrate most at a specific PRF; randomizing PRF would reduce skull vibrations without affecting motor responses; and FUS would yield motor activity while actuator-induced skull vibrations would not. Approach. Three objectives were studied in parallel using C57Bl/6 mice (n = number of mice used per objective). First, skull vibration amplitude, measured as a percentage of maximum amplitude per treatment, was recorded via contact microphone over a range of PRFs to assess the PRF-dependency of skull vibrations (n = 19). Vibrations were then compared between random and fixed PRFs (n = 15). Lastly, motor responses were compared between fixed 1.5 kHz PRF FUS, random PRF FUS, air-puff stimulation, sham stimulation, and vibration induction via piezoelectric actuator (n = 30). Main Results. The study found amplitude peaked at 1.51 kHz (88.1 ± 11.5%), significantly higher than at 0.54 kHz (75.5 ± 15.1%; p = 0.0149). Random PRF reduced amplitude by 4.2% (p = 0.0181). Motor response rates to actuator-induced skull vibrations at the PRF (5.73 ± 6.96%) and its third harmonic (22.9 ± 22.7%) were not significantly different than sham (14.1 ± 11.6%), but lower than FUS (70.2 ± 16.3%; p < 0.0001). Significance. Based on these results, PRF near 0.5 kHz may best avoid skull vibrations, while random PRF could be utilized to slightly reduce vibration amplitude. The results also suggested that skull vibrations likely do not significantly impact motor responses to FUS neuromodulation.

Focused Ultrasound-Mediated Blood–Brain Barrier Opening Best Promotes Neuroimmunomodulation through Brain Macrophage Redistribution

Neuroimmunomodulation is a promising form of drug-free treatment for neurological diseases ranging from Alzheimer’s disease to depression. The evidence supporting the efficacy of focused ultrasound (FUS) neuroimmunomodulation is encouraging; however, the method has yet to be standardized, and its mechanism remains poorly understood. Methods of FUS neuroimmunomodulation can be categorized into three paradigms based on the parameters used. In the first paradigm, focused ultrasound blood–brain barrier opening (FUS-BBBO) combines FUS with microbubbles (MB) to transiently and safely induce BBB opening. In the second paradigm, focused ultrasound neuromodulation (FUS-N) harnesses the acoustic effects of FUS alone (without MB). In the third paradigm, focused ultrasound with microbubbles without BBBO (FUS + MB) combines MB with FUS below the BBBO pressure threshold—harnessing the mechanical effects of FUS without opening the barrier. Due to the recent evidence of brain macrophage modulation in response to FUS-BBBO, we provide the first direct comparison of brain macrophage modulation between all three paradigms both in the presence and absence of Alzheimer’s disease (AD) pathology. Flow cytometry and single-cell sequencing are employed to identify FUS-BBBO as the FUS paradigm, which maximizes brain macrophage modulation, including an increase in the population of neuroprotective, disease-associated microglia and direct correlation between treatment cavitation dose and brain macrophage phagocytosis. Next, we combine spatial and single-cell transcriptomics with immunohistochemical validation to provide the first characterization of brain macrophage distribution in response to FUS-BBBO. Given their relevance within neurodegeneration and perturbation response, we emphasize the analysis of three brain macrophage populations—disease- and interferon-associated microglia and central-nervous-system-associated macrophages. We find and validate the redistribution of each population with an overall trend toward increased interaction with the brain–cerebrospinal fluid barrier (BCSFB) after FUS-BBBO, an effect that is found to be more pronounced in the presence of disease pathology. This study addresses the prior lack of FUS neuroimmunomodulation paradigm optimization and mechanism characterization, identifying that FUS-BBBO best modulates brain macrophage response via complex redistribution.

SPatiotemporal-ENcoded acoustic radiation force imaging of focused ultrasound.

Neuromodulation technology has provided novel therapeutic approaches for diseases caused by neural circuit dysfunction. Transcranial focused ultrasound (FU) is an emerging neuromodulation approach that combines noninvasiveness with relatively sharp focus, even in deep brain regions. It has numerous advantages such as high precision and good safety in neuromodulation, allowing for modulation of both peripheral and central nervous systems. To ensure accurate treatment targeting in FU neuromodulation, a magnetic resonance acoustic radiation force imaging (MR-ARFI) sequence is crucial for the visualization of the focal point. Currently, the commonly used 2D Spin Echo ARFI (2D SE-ARFI) sequence suffers from the long acquisition time, while the echo planar imaging ARFI (EPI-ARFI) sequence with a shorter acquisition time is vulnerable to the magnetic field inhomogeneities. To address these problems, we proposed a spatiotemporal-encoded acoustic radiation force imaging sequence (i.e., SE-SPEN-ARFI, shortened to SPEN-ARFI) in this study. The displacement at the focal spot obtained was highly consistent with that of the SE-ARFI sequence. Our research shows that SPEN-ARFI allows for rapid image acquisition and has less image distortions even under great field inhomogeneities. Therefore, a SPEN-ARFI sequence is a practical alternative for the treatment planning in ultrasound neuromodulation.

Oscillatory effects of ketamine using focused ultrasound sensitive liposomes

The blood brain barrier (BBB) poses a significant challenge in the treatment of neurological disorders by preventing the diffusion of medications into the brain. Focused ultrasound (FUS) enables noninvasive modulation of the central nervous system by targeting millimeter-sized regions of the cortical and sub-cortical brain. We have synthesized ultrasound-sensitive nanoparticles (NPs) to encapsulate small, hydrophobic neuromodulators. Recent data has shown that our NPs deliver pharmacological drugs across the BBB when paired with FUS to the desired region of the brain with targeted accuracy. This method enables us to study the impact of small hydrophobic anesthetics across different regions of the brain. The aim of the study is to determine the electrophysiological effects of FUS neuromodulation in an awake small animal model. Specifically, we aim to understand the oscillatory effects of localized ketamine activity on the thalamocortical system. We hypothesized that localized delivery of ketamine in the central thalamus (CL) will induce slow-delta and gamma oscillations comparable to the recorded frequencies obtained from systemic delivery of ketamine. Using in-house electrocorticogram (ECoG) hardware, we recorded signals from the prefrontal cortex, CL, and visual cortex in awake-restraint rats. Preliminary results suggest that FUS-only neuromodulation of the brain induced undetectable oscillatory differences from baseline signals. We then investigated the electrophysiologic signatures of localized ketamine activity. Ketamine-loaded NPs were administered intravenously to rats via bolus injection and FUS was applied to the desired brain region for site-specific drug uncaging. Initial evidence indicated localized delivery of ketamine induced similar slow-delta and gamma oscillations in a smaller timeframe than those recorded after systemic ketamine administration. These results provide insight into the impacts of pharmacological modulation in relation to brain activity. Future directions include analyzing the thalamocortical system as a potential binding site for ketamine to induce anesthetic-specific oscillations.

Long term study of motivational and cognitive effects of low-intensity focused ultrasound neuromodulation in the dorsal striatum of nonhuman primates

Noninvasive brain stimulation using transcranial focused ultrasound (FUS) has many potential applications as a research and clinical tool, including incorporation into neural prosthetics for cognitive rehabilitation. To develop this technology, it is necessary to evaluate the safety and efficacy of FUS neuromodulation for specific brain targets and cognitive functions. It is also important to test whether repeated long-term application of FUS to deep brain targets improves or degrades behavioral and cognitive function. To this end, we investigated the effects of FUS in the dorsal striatum of nonhuman primates (NHP) performing a visual-motor decision-making task for small or large rewards. Over the course of 2 years, we performed 129 and 147 FUS applications, respectively, in two NHP. FUS (0.5 MHz @ 0.2–0.8 MPa) was applied to the putamen and caudate in both hemispheres to evaluate the effects on movement accuracy, motivation, decision accuracy, and response time. Sonicating the caudate or the putamen unilaterally resulted in modest but statistically significant improvements in motivation and decision accuracy, but at the cost of slower reaction times. The effects were dose (i.e., FUS pressure) and reward dependent. There was no effect on reaching accuracy, nor was there long-term behavioral impairment or neurological trauma evident on T1-weighted, T2-weighted, or susceptibility-weighted MRI scans. Sonication also resulted in significant changes in resting state functional connectivity between the caudate and multiple cortical regions. The results indicate that applying FUS to the dorsal striatum can positively impact the motivational and cognitive aspects of decision making. The capability of FUS to improve motivation and cognition in NHPs points to its therapeutic potential in treating a wide variety of human neural diseases, and warrants further development as a novel technique for non-invasive deep brain stimulation.

Mechanical and mechanothermal effects of focused ultrasound elicited distinct electromyographic responses in mice

The objective of this study was to compare focused ultrasound (FUS) neuromodulation-induced motor responses under two physical mechanisms: mechanical and mechanothermal effects. Mice were divided into two groups. One group was subjected to short-duration FUS stimulation (0.3 s) that induced mechanical effects (mechanical group). The other group underwent long-duration FUS stimulation (15 s) that produced not only mechanical but also thermal effects (mechanothermal group). FUS was targeted at the deep cerebellar nucleus in the cerebellum to induce motor responses, which were evaluated by recording the evoked electromyographic (EMG) signals and tail movements. Brain tissue temperature rise associated with the FUS stimulation was quantified by noninvasive magnetic resonance thermometry in vivo. Temperature rise was negligible for the mechanical group (0.2 °C ± 0.1 °C) but did rise within the range of 0.6 °C ± 0.2 °C−3.3 °C ± 0.9 °C for the mechanothermal group. The elongated FUS beam also induced heating in the dorsal brain (below the top skull) and ventral brain (above the bottom skull) along the beam path for the mechanothermal group. Both mechanical and mechanothermal groups achieved successful FUS neuromodulation. EMG response latencies were within the range of 0.03–0.1 s at different intensity levels for the mechanical group. The mechanothermal effect of FUS could induce both short-latency EMG (0.2–1.4 s) and long-latency EMG (8.7–13.0 s) under the same intensity levels as the mechanical group. The different temporal dynamics of evoked EMG suggested that FUS-induced mechanical and mechanothermal effects could evoke different responses in the brain.

Focused ultrasound neuromodulation.

Focused ultrasound (FUS) is an emerging modality for performing incisionless neurosurgical procedures including thermoablation and blood-brain barrier (BBB) modulation. Emerging evidence suggests that low intensity FUS can also be used for neuromodulation with several benefits, including high spatial precision and the possibility of targeting deep brain regions. Here we review the existing data regarding the biological mechanisms of FUS neuromodulation, the characteristics of neuronal activity altered by FUS, emerging indications for FUS neuromodulation, as well as the strengths and limitations of this approach.

Displacement Imaging for Focused Ultrasound Peripheral Nerve Neuromodulation.

Focused ultrasound (FUS) is an emerging technique for neuromodulation due to its noninvasive application and high depth penetration. Recent studies have reported success in modulation of brain circuits, peripheral nerves, ion channels, and organ structures. In particular, neuromodulation of peripheral nerves and the underlying mechanisms remain comparatively unexplored in vivo. Lack of methodologies for FUS targeting and monitoring impede further research in in vivo studies. Thus, we developed a method that non-invasively measures nerve engagement, via tissue displacement, during FUS neuromodulation of in vivo nerves using simultaneous high frame-rate ultrasound imaging. Using this system, we can validate, in real-time, FUS targeting of the nerve and characterize subsequent compound muscle action potentials (CMAPs) elicited from sciatic nerve activation in mice using 0.5 to 5 ms pulse durations and 22 - 28 MPa peak positive stimulus pressures at 4 MHz. Interestingly, successful motor excitation from FUS neuromodulation required a minimum interframe nerve displacement of 18 μm without any displacement incurred at the skin or muscle levels. Moreover, CMAPs detected in mice monotonically increased with interframe nerve displacements within the range of 18 to 300 μm . Thus, correlation between nerve displacement and motor activation constitutes strong evidence FUS neuromodulation is driven by a mechanical effect given that tissue deflection is a result of highly focused acoustic radiation force.

Displacement Imaging During Focused Ultrasound Median Nerve Modulation: A Preliminary Study in Human Pain Sensation Mitigation.

Focused ultrasound (FUS)-based viscoelastic imaging techniques using high frame rate (HFR) ultrasound to track tissue displacement can be used for mechanistic monitoring of FUS neuromodulation. However, a majority of techniques avoid imaging during the active push transmit (interleaved or postpush acquisitions) to mitigate ultrasound interference, which leads to missing temporal information of ultrasound effects when FUS is being applied. Furthermore, critical for clinical translation, use of both axial steering and real-time (<1 s) capabilities for optimizing acoustic parameters for tissue engagement are largely missing. In this study, we describe a method of noninterleaved, single Vantage imaging displacement within an active FUS push with simultaneous axial steering and real-time capabilities using a single ultrasound acquisition machine. Results show that the pulse sequence can track micron-sized displacements using frame rates determined by the calculated time-of-flight (TOF), without interleaving the FUS pulses and imaging acquisition. Decimation by 3-7 frames increases signal-to-noise ratio (SNR) by 15.09±7.03 dB. Benchmarking tests of CUDA-optimized code show increase in processing speed of 35- and 300-fold in comparison with MATLAB parallel processing GPU and CPU functions, respectively, and we can estimate displacement from steered push beams ±10 mm from the geometric focus. Preliminary validation of displacement imaging in humans shows that the same driving pressures led to variable nerve engagement, demonstrating important feedback to improve transducer coupling, FUS incident angle, and targeting. Regarding the use of our technique for neuromodulation, we found that FUS altered thermal perception of thermal pain by 0.9643 units of pain ratings in a single trial. Additionally, 5 [Formula: see text] of nerve displacement was shown in on-target versus off-target sonications. The initial feasibility in healthy volunteers warrants further study for potential clinical translation of FUS for pain suppression.

Ultrasound neuromodulation: mechanisms and the potential of multimodal stimulation for neuronal function assessment.

Focused ultrasound (FUS) neuromodulation has shown that mechanical waves can interact with cell membranes and mechanosensitive ion channels, causing changes in neuronal activity. However, the thorough understanding of the mechanisms involved in these interactions are hindered by different experimental conditions for a variety of animal scales and models. While the lack of complete understanding of FUS neuromodulation mechanisms does not impede benefiting from the current known advantages and potential of this technique, a precise characterization of its mechanisms of action and their dependence on experimental setup (e.g., tuning acoustic parameters and characterizing safety ranges) has the potential to exponentially improve its efficacy as well as spatial and functional selectivity. This could potentially reach the cell type specificity typical of other, more invasive techniques e.g., opto- and chemogenetics or at least orientation-specific selectivity afforded by transcranial magnetic stimulation. Here, the mechanisms and their potential overlap are reviewed along with discussions on the potential insights into mechanisms that magnetic resonance imaging sequences along with a multimodal stimulation approach involving electrical, magnetic, chemical, light, and mechanical stimuli can provide.

Histologic safety of transcranial focused ultrasound neuromodulation and magnetic resonance acoustic radiation force imaging in rhesus macaques and sheep

BackgroundNeuromodulation by transcranial focused ultrasound (FUS) offers the potential to non-invasively treat specific brain regions, with treatment location verified by magnetic resonance acoustic radiation force imaging (MR-ARFI). ObjectiveTo investigate the safety of these methods prior to widespread clinical use, we report histologic findings in two large animal models following FUS neuromodulation and MR-ARFI. MethodsTwo rhesus macaques and thirteen Dorset sheep were studied. FUS neuromodulation was targeted to the primary visual cortex in rhesus macaques and to subcortical locations, verified by MR-ARFI, in eleven sheep. Both rhesus macaques and five sheep received a single FUS session, whereas six sheep received repeated sessions three to six days apart. The remaining two control sheep did not receive ultrasound but otherwise underwent the same anesthetic and MRI procedures as the eleven experimental sheep. Hematoxylin and eosin-stained sections of brain tissue (harvested zero to eleven days following FUS) were evaluated for tissue damage at FUS and control locations as well as tissue within the path of the FUS beam. TUNEL staining was used to evaluate for the presence of apoptosis in sheep receiving high dose FUS. ResultsNo FUS-related pre-mortem histologic findings were observed in the rhesus macaques or in any of the examined sheep. Extravascular red blood cells (RBCs) were present within the meninges of all sheep, regardless of treatment group. Similarly, small aggregates of perivascular RBCs were rarely noted in non-target regions of neural parenchyma of FUS-treated (8/11) and untreated (2/2) sheep. However, no concurrent histologic abnormalities were observed, consistent with RBC extravasation occurring as post-mortem artifact following brain extraction. Sheep within the high dose FUS group were TUNEL-negative at the targeted site of FUS. ConclusionsThe absence of FUS-related histologic findings suggests that the neuromodulation and MR-ARFI protocols evaluated do not cause tissue damage.

Real-time imaging of brain displacement during FUS neuromodulation in rodents in vivo

Focused ultrasound (FUS) is capable of modulating the central and peripheral nervous system. Temperature increase, cavitation, and acoustic radiation force have been proposed as potential mechanisms. Thus, tissue displacement imaging during FUS modulation is critical to understanding its physical mechanism. A cranial window was formed to perform imaging during FUS neuromodulation in C57BL/6 mice. FUS sonications were performed with a 4 MHz single-element transducer with a focal volume 0.2 × 0.9 mm (Sonic Concepts, WA), an applied tone burst of 0.5 ms and peak positive pressures varying from 1.9 to 6.7 MPa. Real-time channel data using plane wave sequences were acquired with an 18 MHz linear array (Vermon, France) and axial displacements throughout the entire brain were estimated using 1D cross-correlation (9λ window, 99% overlap) at 1 kHz frame rate. Downward displacements were only detected during FUS within the focal region. During modulation, the cumulative displacement ranged from 0.021 ± 0.017 μm (n = 3) at 3.1 MPa to 0.24 ± 0.004 μm at 6.7 MPa (n = 3). Displacement decreased post-FUS and returned to null within 1–2 ms. Unlike in a preliminary phantom study, no shear waves were detected. Real-time displacement imaging could thus provide effective targeting and monitoring as well as unveil the mechanism during FUS modulation.Focused ultrasound (FUS) is capable of modulating the central and peripheral nervous system. Temperature increase, cavitation, and acoustic radiation force have been proposed as potential mechanisms. Thus, tissue displacement imaging during FUS modulation is critical to understanding its physical mechanism. A cranial window was formed to perform imaging during FUS neuromodulation in C57BL/6 mice. FUS sonications were performed with a 4 MHz single-element transducer with a focal volume 0.2 × 0.9 mm (Sonic Concepts, WA), an applied tone burst of 0.5 ms and peak positive pressures varying from 1.9 to 6.7 MPa. Real-time channel data using plane wave sequences were acquired with an 18 MHz linear array (Vermon, France) and axial displacements throughout the entire brain were estimated using 1D cross-correlation (9λ window, 99% overlap) at 1 kHz frame rate. Downward displacements were only detected during FUS within the focal region. During modulation, the cumulative displacement ranged from 0.021 ± 0.017 μm (n ...

Low intensity, continuous wave focused ultrasound reversibly depresses heart rate in anesthetized mice

Focused ultrasound (FUS) can noninvasively and reversibly modulate brain activity. Observed motor activity or behavioral changes are commonly used to infer neuromodulatory effects. Changes in autonomic nervous system regulation such as heart and respiratory function can potentially be used for studying the effects of FUS neuromodulation that do not produce outwardly observable motor or behavioral activity. In this study, low pressure (850 kPa), long duration (120 s) continuous-wave (CW) FUS at 2 MHz was targeted such that the focus spanned the visual cortex, hippocampus, and thalamus. These parameters were shown to reversibly depress heart rate in in vivo mice anesthetized with sodium pentobarbital by an average of 8.1 ± 3.7%. Following stimulus offset, heart rate either increased or varied in trend. Higher pressure (2 MPa), short duration (0.3 s) pulses at the same frequency resulted in either small, transient increases in heart rate or no change. Thermocouple measurements show the peak temperature elevation in the dura to be approximately 2 °C. Thermal simulations predict a peak temperature increase in the brain of 2.3 °C. These results indicate that CW FUS can alter autonomic nervous system regulation through very low heating and show that cardiorespiratory responses can be altered as a result of FUS neuromodulation.

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

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. 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). All calibration methods enabled registration with TRE on the order of 3mm. Unbiased calibration resulted in an average TRE of 3.26mm (min-max: 2.80-4.53mm), which was not significantly changed by prospective bias correction (TRE of 3.05mm; 2.06-3.81mm, p = 0.55). Restricting motion between the transducer and target and increasing the distance between tracked markers reduced the TRE to 2.43mm (min-max: 0.79-3.88mm). MR-ARFI images showed qualitatively similar shape and extent as projected beam profiles in a living non-human primate. 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.

Focused ultrasound neuromodulation of cortical and subcortical brain structures using 1.9 MHz.

Ultrasound neuromodulation is a promising noninvasive technique for controlling neural activity. Previous small animal studies suffered from low targeting specificity because of the low ultrasound frequencies (<690 kHz) used. In this study, the authors demonstrated the capability of focused ultrasound (FUS) neuromodulation in the megahertz-range to achieve superior targeting specificity in the murine brain as well as demonstrate modulation of both motor and sensory responses. FUS sonications were carried out at 1.9 MHz with 50% duty cycle, pulse repetition frequency of 1 kHz, and duration of 1 s. The robustness of the FUS neuromodulation was assessed first in sensorimotor cortex, where elicited motor activities were observed and recorded on videos and electromyography. Deeper brain regions were then targeted where pupillary dilation served as an indicative of successful modulation of subcortical brain structures. Contralateral and ipsilateral movements of the hind limbs were repeatedly observed when the FUS was targeted at the sensorimotor cortex. Induced trunk and tail movements were also observed at different coordinates inside the sensorimotor cortex. At deeper targeted-structures, FUS induced eyeball movements (superior colliculus) and pupillary dilation (pretectal nucleus, locus coeruleus, and hippocampus). Histological analysis revealed no tissue damage associated with the FUS sonications. The motor movements and pupillary dilation observed in this study demonstrate the capability of FUS to modulate cortical and subcortical brain structures without inducing any damage. The variety of responses observed here demonstrates the capability of FUS to perform functional brain mapping.

Towards multifocal ultrasonic neural stimulation: pattern generation algorithms

Focused ultrasound (FUS) waves directed onto neural structures have been shown to dynamically modulate neural activity and excitability, opening up a range of possible systems and applications where the non-invasiveness, safety, mm-range resolution and other characteristics of FUS are advantageous. As in other neuro-stimulation and modulation modalities, the highly distributed and parallel nature of neural systems and neural information processing call for the development of appropriately patterned stimulation strategies which could simultaneously address multiple sites in flexible patterns. Here, we study the generation of sparse multi-focal ultrasonic distributions using phase-only modulation in ultrasonic phased arrays. We analyse the relative performance of an existing algorithm for generating multifocal ultrasonic distributions and new algorithms that we adapt from the field of optical digital holography, and find that generally the weighted Gerchberg–Saxton algorithm leads to overall superior efficiency and uniformity in the focal spots, without significantly increasing the computational burden. By combining phased-array FUS and magnetic-resonance thermometry we experimentally demonstrate the simultaneous generation of tightly focused multifocal distributions in a tissue phantom, a first step towards patterned FUS neuro-modulation systems and devices.