Design and Validation of a Patient-Specific Stereotactic Frame for Transcranial Ultrasound Therapy.

Transcranial-focused ultrasound (tFUS) procedures such as neuromodulation and blood-brain barrier (BBB) opening require precise focus placement within the brain. MRI is currently the most reliable tool for focus localization but can be prohibitive for procedures requiring recurrent therapies. We designed, fabricated, and characterized a patient-specific, 3-D-printed, stereotactic frame for repeated tFUS therapy. The frame is compact, with minimal footprint, can be removed and re-secured between treatments while maintaining sub-mm accuracy, and will allow for precise and repeatable transcranial FUS treatment without the need for MR-guidance following the initial calibration scan. Focus localization and repeatability were assessed via MR-thermometry and MR-acoustic radiation force imaging (ARFI) on an ex vivo skull phantom and in vivo nonhuman primates (NHPs), respectively. Focal localization, registration, steering, and re-steering were accomplished during the initial MRI calibration scan session. Keeping steering coordinates fixed in subsequent therapy and imaging sessions, we found good agreement between steered foci and the intended target, with target registration error (TRE) of 1.2 ± 0.3 ( n = 4 , ex vivo) and 1.0 ± 0.5 ( n = 3 , in vivo) mm. Focus position (steered and non-steered) was consistent, with sub-mm variation in each dimension between studies. Our 3-D-printed, patient-specific stereotactic frame can reliably position and orient the ultrasound transducer for repeated targeting of brain regions using a single MR-based calibration. The compact frame allows for high-precision tFUS to be carried out outside the magnet and could help reduce the cost of tFUS treatments where repeated application of an ultrasound focus is required with high precision.

Ultra-short time-echo based ray tracing for transcranial focused ultrasound aberration correction in human calvaria.

OBJECTIVE: Magnetic resonance guided transcranial focused ultrasound holds great promises for treating neurological disorders. This technique relies on skull aberration correction which requires computed tomography (CT) scans of the skull of the patients. Recently, ultra-short time-echo (UTE) magnetic resonance (MR) sequences have unleashed the MRI potential to reveal internal bone structures. In this study, we measure the efficacy of transcranial aberration correction using UTE images. Approach. We compare the efficacy of transcranial aberration correction using UTE scans to CT based correction on four skulls and two targets using a clinical device (Exablate Neuro, Insightec, Israel). We also evaluate the performance of a custom ray tracing algorithm using both UTE and CT estimates of acoustic properties and compare these against the performance of the manufacturer's proprietary aberration correction software. Main results. UTE estimated skull maps in Hounsfield units (HU) had a mean absolute error of 242 ± 20 HU (n=4). The UTE skull maps were sufficiently accurate to improve pressure at the target (no correction: 0.44 ± 0.10, UTE correction: 0.79 ± 0.05, manufacturer CT: 0.80 ± 0.05), pressure confinement ratios (no correction: 0.45 ± 0.10, UTE correction: 0.80 ± 0.05, manufacturer CT: 0.81 ± 0.05), and targeting error (no correction: 1.06 ± 0.42 mm, UTE correction 0.30 ± 0.23 mm, manufacturer CT: 0.32 ± 0.22) (n=8 for all values). When using CT, our ray tracing algorithm performed slightly better than UTE based correction with pressure at the target (UTE: 0.79 ± 0.05, CT: 0.84 ± 0.04), pressure confinement ratios (UTE: 0.80 ± 0.05, CT: 0.84 ± 0.04), and targeting error (UTE: 0.30 ± 0.23 mm, CT: 0.17 ± 0.15). Significance. These 3D transcranial measurements suggest that UTE sequences could replace CT scans in the case of MR guided focused ultrasound with minimal reduction in performance which will avoid ionizing radiation exposure to the patients and reduce procedure time and cost. .

Practical Targeting Errors During Optically Tracked Transcranial Focused Ultrasound Using MR-ARFI and Array- Based Steering.

OBJECTIVE: Transcranial focused ultrasound (tFUS) is being explored for neuroscience research and clinical applications due to its ability to affect precise brain regions noninvasively. The ability to target specific brain regions and localize the beam during these procedures is important for these applications to avoid damage and minimize off-target effects. Here, we present a method to combine optical tracking with magnetic resonance (MR) acoustic radiation force imaging to achieve targeting and localizing of the tFUS beam. This combined method provides steering coordinates to target brain regions within a clinically practical time frame. METHODS: Using an optically tracked hydrophone and bias correction with MR imaging we transformed the FUS focus coordinates into the MR space for targeting and error correction. We validated this method in vivo in 18 macaque FUS studies. RESULTS: Across these in vivo studies a single localization scan allowed for the average targeting error to be reduced from 4.8 mm to 1.4 mm and for multiple brain regions to be targeted with one transducer position. CONCLUSIONS: By reducing targeting error and providing the means to target multiple brain regions within a single session with high accuracy this method will allow further study of the effects of tFUS neuromodulation with more advanced approaches such as simultaneous dual or multi-site brain stimulation.

Small volume blood-brain barrier opening in macaques with a 1 MHz ultrasound phased array.

The use of focused ultrasound to open the blood-brain barrier (BBB) has the potential to deliver drugs to specific regions of the brain. The size of the BBB opening and ability to localize the opening determines the spatial extent and is a limiting factor in many applications of BBB opening where targeting a small brain region is desired. Here we evaluate the performance of a system designed for small opening volumes and highlight the unique challenges associated with pushing the spatial precision of this technique. To achieve small volume openings in cortical regions of the macaque brain, we tested a custom 1 MHz array transducer integrated into a magnetic resonance image-guided focused ultrasound system. Using real-time cavitation monitoring, we demonstrated twelve instances of single sonication, small volume BBB opening with average volumes of 59 ± 37 mm3 and 184 ± 2 mm3 in cortical and subcortical targets, respectively. We found high correlation between subject-specific acoustic simulations and observed openings when incorporating grey matter segmentation (R2 = 0.8577), and the threshold for BBB opening based on simulations was 0.53 MPa. Analysis of MRI-based safety assessment and cavitation signals indicate a safe pressure range for 1 MHz BBB opening and suggest that our system can be used to deliver drugs and gene therapy to small brain regions.

Evaluation of synthetically generated computed tomography for use in transcranial focused ultrasound procedures.

Purpose: Transcranial focused ultrasound (tFUS) is a therapeutic ultrasound method that focuses sound through the skull to a small region noninvasively and often under magnetic resonance imaging (MRI) guidance. CT imaging is used to estimate the acoustic properties that vary between individual skulls to enable effective focusing during tFUS procedures, exposing patients to potentially harmful radiation. A method to estimate acoustic parameters in the skull without the need for CT is desirable. Approach: We synthesized CT images from routinely acquired T1-weighted MRI using a 3D patch-based conditional generative adversarial network and evaluated the performance of synthesized CT (sCT) images for treatment planning with tFUS. We compared the performance of sCT with real CT (rCT) images for tFUS planning using Kranion and simulations using the acoustic toolbox, k-Wave. Simulations were performed for 3 tFUS scenarios: (1) no aberration correction, (2) correction with phases calculated from Kranion, and (3) phase shifts calculated from time reversal. Results: From Kranion, the skull density ratio, skull thickness, and number of active elements between rCT and sCT had Pearson's correlation coefficients of 0.94, 0.92, and 0.98, respectively. Among 20 targets, differences in simulated peak pressure between rCT and sCT were largest without phase correction (12.4%±8.1%) and smallest with Kranion phases (7.3%±6.0%). The distance between peak focal locations between rCT and sCT was <1.3 mm for all simulation cases. Conclusions: Real and synthetically generated skulls had comparable image similarity, skull measurements, and acoustic simulation metrics. Our work demonstrated similar results for 10 testing cases comparing MR-sCTs and rCTs for tFUS planning. Source code and a docker image with the trained model are available at https://github.com/han-liu/SynCT_TcMRgFUS.

Disrupting nociceptive information processing flow through transcranial focused ultrasound neuromodulation of thalamic nuclei.

BACKGROUND: MRI-guided transcranial focused ultrasound (MRgFUS) as a next-generation neuromodulation tool can precisely target and stimulate deep brain regions with high spatial selectivity. Combined with MR-ARFI (acoustic radiation force imaging) and using fMRI BOLD signal as functional readouts, our previous studies have shown that low-intensity FUS can excite or suppress neural activity in the somatosensory cortex. OBJECTIVE: To investigate whether low-intensity FUS can suppress nociceptive heat stimulation-induced responses in thalamic nuclei during hand stimulation, and to determine how this suppression influences the information processing flow within nociception networks. FINDINGS: BOLD fMRI activations evoked by 47.5 °C heat stimulation of hand were detected in 24 cortical regions, which belong to sensory, affective, and cognitive nociceptive networks. Concurrent delivery of low-intensity FUS pulses (650 kHz, 550 kPa) to the predefined heat nociceptive stimulus-responsive thalamic centromedial_parafascicular (CM_para), mediodorsal (MD), ventral_lateral (VL_ and ventral_lateral_posteroventral (VLpv) nuclei suppressed their heat responses. Off-target cortical areas exhibited reduced, enhanced, or no significant fMRI signal changes, depending on the specific areas. Differentiable thalamocortical information flow during the processing of nociceptive heat input was observed, as indicated by the time to reach 10% or 30% of the heat-evoked BOLD signal peak. Suppression of thalamic heat responses significantly altered nociceptive processing flow and direction between the thalamus and cortical areas. Modulation of contralateral versus ipsilateral areas by unilateral thalamic activity differed. Signals detected in high-order cortical areas, such as dorsal frontal (DFC) and ventrolateral prefrontal (vlPFC) cortices, exhibited faster response latencies than sensory areas. CONCLUSIONS: The concurrent delivery of FUS suppressed nociceptive heat response in thalamic nuclei and disrupted the nociceptive network. This study offers new insights into the causal functional connections within the thalamocortical networks and demonstrates the modulatory effects of low-intensity FUS on nociceptive information processing.

Design of a 1-MHz Therapeutic Ultrasound Array for Small Volume Blood-Brain Barrier Opening at Cortical Targets in Macaques.

[[gabstract]][] Focused ultrasound (FUS) can temporarily open the blood-brain barrier (BBB) and increase the delivery of chemotherapeutics, viral vectors, and other agents to the brain parenchyma. To limit FUS BBB opening to a single brain region, the transcranial acoustic focus of the ultrasound transducer must not be larger than the region targeted. In this work, we design and characterize a therapeutic array optimized for BBB opening at the frontal eye field (FEF) in macaques. We used 115 transcranial simulations in four macaques varying f-number and frequency to optimize the design for focus size, transmission, and small device footprint. The design leverages inward steering for focus tightening, a 1-MHz transmit frequency, and can focus to a simulation predicted 2.5- ± 0.3-mm lateral and 9.5- ± 1.0-mm axial full-width at half-maximum spot size at the FEF without aberration correction. The array is capable of steering axially 35 mm outward, 26 mm inward, and laterally 13 mm with 50% the geometric focus pressure. The simulated design was fabricated, and we characterized the performance of the array using hydrophone beam maps in a water tank and through an ex vivo skull cap to compare measurements with simulation predictions, achieving a 1.8-mm lateral and 9.5-mm axial spot size with a transmission of 37% (transcranial, phase corrected). The transducer produced by this design process is optimized for BBB opening at the FEF in macaques.

Small volume blood-brain barrier opening in macaques with a 1 MHz ultrasound phased array.

Focused ultrasound blood-brain barrier (BBB) opening is a promising tool for targeted delivery of therapeutic agents into the brain. The volume of opening determines the extent of therapeutic administration and sets a lower bound on the size of targets which can be selectively treated. We tested a custom 1 MHz array transducer optimized for cortical regions in the macaque brain with the goal of achieving small volume openings. We integrated this device into a magnetic resonance image guided focused ultrasound system and demonstrated twelve instances of small volume BBB opening with average opening volumes of 59 ± 37 mm 3 and 184 ± 2 mm 3 in cortical and subcortical targets, respectively. We developed real-time cavitation monitoring using a passive cavitation detector embedded in the array and characterized its performance on a bench-top flow phantom mimicking transcranial BBB opening procedures. We monitored cavitation during in-vivo procedures and compared cavitation metrics against opening volumes and safety outcomes measured with FLAIR and susceptibility weighted MR imaging. Our findings show small BBB opening at cortical targets in macaques and characterize the safe pressure range for 1 MHz BBB opening. Additionally, we used subject-specific simulations to investigate variance in measured opening volumes and found high correlation (R 2 = 0.8577) between simulation predictions and observed measurements. Simulations suggest the threshold for 1 MHz BBB opening was 0.53 MPa. This system enables BBB opening for drug delivery and gene therapy to be targeted to more specific brain regions.

Generating Patient-Specific Acoustic Simulations for Transcranial Focused Ultrasound Procedures Based on Optical Tracking Information.

Optical tracking is a real-time transducer positioning method for transcranial focused ultrasound (tFUS) procedures, but the predicted focus from optical tracking typically does not incorporate subject-specific skull information. Acoustic simulations can estimate the pressure field when propagating through the cranium but rely on accurately replicating the positioning of the transducer and skull in a simulated space. Here, we develop and characterize the accuracy of a workflow that creates simulation grids based on optical tracking information in a neuronavigated phantom with and without transmission through an ex vivo skull cap. The software pipeline could replicate the geometry of the tFUS procedure within the limits of the optical tracking system (transcranial target registration error (TRE): 3.9 ± 0.7 mm). The simulated focus and the free-field focus predicted by optical tracking had low Euclidean distance errors of 0.5±0.1 and 1.2±0.4 mm for phantom and skull cap, respectively, and some skull-specific effects were captured by the simulation. However, the TRE of simulation informed by optical tracking was 4.6±0.2, which is as large or greater than the focal spot size used by many tFUS systems. By updating the position of the transducer using the original TRE offset, we reduced the simulated TRE to 1.1 ± 0.4 mm. Our study describes a software pipeline for treatment planning, evaluates its accuracy, and demonstrates an approach using MR-acoustic radiation force imaging as a method to improve dosimetry. Overall, our software pipeline helps estimate acoustic exposure, and our study highlights the need for image feedback to increase the accuracy of tFUS dosimetry.

Differential dose responses of transcranial focused ultrasound at brain regions indicate causal interactions.

We have previously shown that focused ultrasound (FUS) pulses in low pressure range exerted bidirectional and brain state-dependent neuromodulation in the nonhuman primate somatosensory cortices by fMRI. Here we aim to gain insights about the proposed neuron selective modulation of FUS and probe feedforward versus feedback interactions by simultaneously quantifying the stimulus (FUS pressures: 925, 425, 250 kPa) and response (% BOLD fMRI changes) function at the targeted area 3a/3b and off-target cortical areas at 7T. In resting-state, lowered intensities of FUS resulted in decreased fMRI signal changes at the target area 3a/3b and off-target area 1/2, S2, MCC, insula and auditory cortex, and no signal difference in thalamic VPL and MD nuclei. In activated states, concurrent high-intensity FUS significantly enhanced touch-evoked signals in area 1/2. Medium- and low-intensity FUS significantly suppressed touch-evoked BOLD signals in all areas except in the auditory cortex, VPL and MD thalamic nuclei. Distinct state dependent and dose-response curves led us to hypothesize that FUS's neuromodulatory effects may be mediated through preferential activation of different populations of neurons. Area 3a/3b may have distinct causal feedforward and feedback interactions with Area 1/2, S2, MCC, insula, and VPL. FUS offers a noninvasive neural stimulation tool for dissecting brain circuits and probing causal functional connections.

Anterior cingulate cortex causally supports flexible learning under motivationally challenging and cognitively demanding conditions.

Anterior cingulate cortex (ACC) and striatum (STR) contain neurons encoding not only the expected values of actions, but also the value of stimulus features irrespective of actions. Values about stimulus features in ACC or STR might contribute to adaptive behavior by guiding fixational information sampling and biasing choices toward relevant objects, but they might also have indirect motivational functions by enabling subjects to estimate the value of putting effort into choosing objects. Here, we tested these possibilities by modulating neuronal activity in ACC and STR of nonhuman primates using transcranial ultrasound stimulation while subjects learned the relevance of objects in situations with varying motivational and cognitive demands. Motivational demand was indexed by varying gains and losses during learning, while cognitive demand was varied by increasing the uncertainty about which object features could be relevant during learning. We found that ultrasound stimulation of the ACC, but not the STR, reduced learning efficiency and prolonged information sampling when the task required averting losses and motivational demands were high. Reduced learning efficiency was particularly evident at higher cognitive demands and when subjects experienced loss of already attained tokens. These results suggest that the ACC supports flexible learning of feature values when loss experiences impose a motivational challenge and when uncertainty about the relevance of objects is high. Taken together, these findings provide causal evidence that the ACC facilitates resource allocation and improves visual information sampling during adaptive behavior.

Reduced-field of view three-dimensional MR acoustic radiation force imaging with a low-rank reconstruction for targeting transcranial focused ultrasound.

PURPOSE: To rapidly image and localize the focus in MR-guided focused ultrasound (FUS) while maintaining a low ultrasound duty cycle to minimize tissue effects. METHODS: MR-acoustic radiation force imaging (ARFI) is key to targeting FUS procedures such as neuromodulation, and works by encoding ultrasound-induced displacements into the phase of MR images. However, it can require long scan times to cover a volume of tissue, especially when minimizing the FUS dose during targeting is paramount. To simultaneously minimize scan time and the FUS duty cycle, a 2-min three-dimensional (3D) reduced-FOV spin echo ARFI scan with two-dimensional undersampling was implemented at 3T with a FUS duty cycle of 0.85%. The 3D k-space sampling scheme incorporated uniform undersampling in one phase-encoded axis and partial Fourier (PF) sampling in the other. The scan interleaved FUS-on and FUS-off data collection to improve displacement map quality via a joint low-rank image reconstruction. Experiments in agarose and graphite phantoms and living macaque brains for neuromodulation and blood-brain barrier opening studied the effects of the sampling and reconstruction strategy on the acquisition, and evaluated its repeatability and accuracy. RESULTS: In the phantom, the distances between displacement centroids of 10 prospective reconstructions and a fully sampled reference were below 1 mm. In in vivo brain, the distances between centroids ranged from 1.3 to 2.1 mm. Results in phantom and in vivo brain both showed that the proposed method can recover the FUS focus compared to slower fully sampled scans. CONCLUSION: The proposed 3D MR-ARFI reduced-FOV method enables rapid imaging of the FUS focus while maintaining a low FUS duty cycle.

Ultrasound neuromodulation depends on pulse repetition frequency and can modulate inhibitory effects of TTX.

Ultrasound is gaining traction as a neuromodulation method due to its ability to remotely and non-invasively modulate neuronal activity with millimeter precision. However, there is little consensus about optimal ultrasound parameters required to elicit neuromodulation and how specific parameters drive mechanisms that underlie ultrasound neuromodulation. We address these questions in this work by performing a study to determine effective ultrasound parameters in a transgenic mouse brain slice model that enables calcium imaging as a quantitative readout of neuronal activity for ultrasound neuromodulation. We report that (1) calcium signaling increases with the application of ultrasound; (2) the neuronal response rate to ultrasound is dependent on pulse repetition frequency (PRF); and (3) ultrasound can reversibly alter the inhibitory effects of tetrodotoxin (TTX) in pharmacological studies. This study offers mechanistic insight into the PRF dependence of ultrasound neuromodulation and the nature of ultrasound/ion channel interaction.

Taylor Dispersion Analysis of Polysaccharides Using Backscattering Interferometry.

Taylor dispersion analysis (TDA) allows the determination of the molecular diffusion coefficient (D) or the hydrodynamic radius (Rh) of a solute from the peak broadening of a plug of solute in a laminar Poiseuille flow. The main limitation plaguing the broader applicability of TDA is the lack of a sensitive detection modality. UV absorption is typically used with TDA but is only suitable for UV-absorbing or derivatized compounds. In this work, we present a development of the TDA method for non-UV absorbing compounds by using a universal detector based on refractive index (RI) sensing with backscattering interferometry (BSI). BSI was interfaced to a capillary electrophoresis-UV instrument using a polyimide coated fused silica capillary and an in-house designed flow-cell assembly. Polysaccharides were selected to demonstrate the application of TDA-BSI for size characterization. Under the conditions of validity of TDA, D and Rh average values and the entire Rh distributions were obtained from the (poly)saccharide taylorgrams, including non-UV absorbing polymers.

An Electrochemistry Study of Cryoelectrolysis in Frozen Physiological Saline.

Cryoelectrolysis is a new minimally invasive tissue ablation surgical technique that combines the processes of electrolysis and solid/liquid phase transformation (freezing). This study investigated this new technique by measuring the pH front propagation and the changes in resistance in a tissue simulant made of physiological saline gel with a pH dye as a function of the sample temperature in the high subzero range above the eutectic. Results demonstrated that effective electrolysis can occur in a high subzero freezing milieu and that the propagation of the pH front is only weakly dependent on temperature. These observations are consistent with a mechanism involving ionic movement through the concentrated saline solution channels between ice crystals at subfreezing temperatures above the eutectic. Moreover, results suggest that Joule heating in these microchannels may cause local microscopic melting, the observed weak dependence of pH front propagation on temperature, and the large changes in resistance with time. A final insight provided by the results is that the pH front propagation from the anode is more rapid than from the cathode, a feature indicative of the electro-osmotic flow from the cathode to the anode. The findings in this paper may be critical for designing future cryoelectrolytic ablation surgery protocols.