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PDF file - 107K, Figure S1: (A) Experimental setup. (B) Beam steering pattern used during volumetric sonication. The order of the nine "subsonications" is indicated. (C) Pulsing scheme used during volumetric sonication. Three 50 s sonications were delivered with a 25 s pause between sonications. During each sonication, 10 ms bursts were delivered to the nine locations in sequence, typically every 200 ms

PDF file - 130K, Figure S3: MRI and histological effects of sonication delivered at an exposure level that produced tissue damage in addition to BBB disruption. (A) T2*-weighted imaging after volumetric sonication (nine locations in a 3�3 grid) in the thalamus at 249 kPa. At three of the nine sonicated locations, severe hypointense spots were observed in T2*-weighted imaging, and they were persistent for the next six months (B) Microphotograph of an H&E stained section showing parenchymal damage (box) evident six months after sonication. Macrophage accumulation and scattered brownish granules (hemosiderin deposits, arrows) are also evident. (C-D) High-magnification view of hemosiderin deposits from another part of this sonicated region. Prussian blue staining (D) was used to verify that the light brown clusters evident in H&E were hemosiderin (B-C: H&E; D: Prussian blue; scale bars: B: 100 Mum; C-D: 20 Mum)

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PDF file - 349K, Figure S2: Histology after volumetric sonication in the hippocampus/LGN in monkey 4. This target was sonicated ~2h before the animal was sacrificed and in seven prior sessions over several months. (A) Contrast-enhanced T1-weighted MRI showing BBB disruption. The region with contrast enhancement is indicated (red dotted line). Inset: Low-magnification microphotograph showing histology in the hippocampus/LGN. The approximate location of this section is indicated in the MR image by the white rectangle. (B) Low- and (C) high-magnification views of the LGN showing normal cell layers and undamaged nerve fibers, respectively. (D) Low and (E) high-magnification views showing normal-appearing granular cell layer of hippocampus. (F): Small capillaries in the LGN found with a few extravasated red blood cells, presumably from the last sonication session. Only a very small number of such extravasations were found. (B, F: H&E; C: H&E-LFB D, E: Nissl; scale bars: A: 1 cm, B, D: 1 mm, C,E-F: 200 Mum)

PDF file - 75K, Supplementary Methods including focused ultrasound system calibration, USCA infusion protocol and MRI sequences

We describe a 74-year-old male with intractable essential tremor (ET) and hyperostosis calvariae diffusa who was unsuccessfully treated with magnetic resonance-guided focused ultrasound (MRgFUS). A computed tomography performed prior to the procedure demonstrated a skull density ratio (SDR) of 0.37 and tricortical hyperostosis calvariae diffusa. No lesion was evident on post-MRgFUS MRI, and no improvement in the patient’s hand tremor was noted clinically. We systematically reviewed the literature to understand outcomes for those patients with hyperostosis who have undergone MRgFUS. A comprehensive literature search using the PubMed, Cochrane, and Google Scholar databases identified 3 ET patients with hyperostosis who failed treatment with MRgFUS. Clinical findings, skull characteristics, treatment parameters, and outcomes were summarized, demonstrating different patterns/degrees of bicortical hyperostosis and variable SDRs (i.e., from 0.38 to ≥0.45). Although we have successfully treated patients with bicortical hyperostosis frontalis interna (n = 50), tricortical hyperostosis calvariae diffusa appears to be a contraindication for MRgFUS despite acceptable SDRs.

MRI-guided focused ultrasound thalamotomy has been shown to be an effective treatment for medication refractory essential tremor. Here, we report a clinical-radiological analysis of 123 cases of MRI-guided focused ultrasound thalamotomy, and explore the relationships between treatment parameters, lesion characteristics and outcomes. All patients undergoing focused ultrasound thalamotomy by a single surgeon were included. The procedure was performed as previously described, and patients were followed for up to 1 year. MRI was performed 24 h post-treatment, and lesion locations and volumes were calculated. We retrospectively evaluated 118 essential tremor patients and five tremor-dominant Parkinson’s disease patients who underwent thalamotomy. At 24 h post-procedure, tremor abated completely in the treated hand in 81 essential tremor patients. Imbalance, sensory disturbances and dysarthria were the most frequent acute adverse events. Patients with any adverse event had significantly larger lesions, while inferolateral lesion margins were associated with a higher incidence of motor-related adverse events. Twenty-three lesions were identified with irregular tails, often extending into the internal capsule; 22 of these patients experienced at least one adverse event. Treatment parameters and lesion characteristics changed with increasing surgeon experience. In later cases, treatments used higher maximum power (normalized to skull density ratio), accelerated more quickly to high power, and delivered energy over fewer sonications. Larger lesions were correlated with a rapid rise in both power delivery and temperature, while increased oedema was associated with rapid rise in temperature and the maximum power delivered. Total energy and total power did not significantly affect lesion size. A support vector regression was trained to predict lesion size and confirmed the most valuable predictors of increased lesion size as higher maximum power, rapid rise to high-power delivery, and rapid rise to high tissue temperatures. These findings may relate to a decrease in the energy efficiency of the treatment, potentially due to changes in acoustic properties of skull and tissue at higher powers and temperatures. We report the largest single surgeon series of focused ultrasound thalamotomy to date, demonstrating tremor relief and adverse events consistent with reported literature. Lesion location and volume impacted adverse events, and an irregular lesion tail was strongly associated with adverse events. High-power delivery early in the treatment course, rapid temperature rise, and maximum power were dominant predictors of lesion volume, while total power, total energy, maximum energy and maximum temperature did not improve prediction of lesion volume. These findings have critical implications for treatment planning in future patients.

Pulsed low-intensity focused ultrasound (PLIFUS) has shown promise in inducing neuromodulation in several animal and human studies. Therefore, it is of clinical interest to develop experimental platforms to test repetitive PLIFUS as a therapeutic modality in humans with neurologic disorders. In the study described here, our aim was to develop a laboratory-built experimental device platform intended to deliver repetitive PLIFUS across the hippocampus in seizure onset zones of patients with drug-resistant temporal lobe epilepsy. The system uses neuronavigation targeting over multiple therapeutic sessions. PLIFUS (548 kHz) was emitted across multiple hippocampal targets in a human subject with temporal lobe epilepsy using a mechanically steered piezoelectric transducer. Stimulation was delivered up to 2.25 W/cm2 spatial peak temporal average intensity (free-field equivalent), with 36%-50% duty cycle, 500-ms sonications and 7-s inter-stimulation intervals lasting 140 s per target and repeated for multiple sessions. A first-in-human PLIFUS course of treatment was successfully delivered using the device platform with no adverse events.

The effect of local anesthetics, particularly those which are hydrophilic, such as tetrodotoxin, is impeded by tissue barriers that restrict access to individual nerve cells. Methods of enhancing penetration of tetrodotoxin into nerve include co-administration with chemical permeation enhancers, nanoencapsulation, and insonation with very low acoustic intensity ultrasound and microbubbles. In this study, we examined the effect of acoustic intensity on nerve block by tetrodotoxin and compared it to the effect on nerve block by bupivacaine, a more hydrophobic local anesthetic. Anesthetics were applied in peripheral nerve blockade in adult Sprague-Dawley rats. Insonation with 1-MHz ultrasound at acoustic intensity greater than 0.5 W/cm2 improved nerve block effectiveness, increased nerve block reliability, and prolonged both sensory and motor nerve blockade mediated by the hydrophilic ultra-potent local anesthetic, tetrodotoxin. These effects were not enhanced by microbubbles. There was minimal or no tissue injury from ultrasound treatment. Insonation did not enhance nerve block from bupivacaine. Using an in vivo model system of local anesthetic delivery, we studied the effect of acoustic intensity on insonation-mediated drug delivery of local anesthetics to the peripheral nerve. We found that insonation alone (at intensities greater than 0.5 W/cm2) enhanced nerve blockade mediated by the hydrophilic ultra-potent local anesthetic, tetrodotoxin. Graphical abstract.

Background A key challenge in the medical treatment of brain tumors is the limited penetration of most chemotherapeutic agents across the blood-brain barrier (BBB) into the tumor and the infiltrative margin around the tumor. Magnetic resonance-guided focused ultrasound (MRgFUS) is a promising tool to enhance the delivery of chemotherapeutic agents into brain tumors. Objective To review the mechanism of FUS, preclinical evidence, and clinical studies that used low-frequency FUS for a BBB opening in gliomas. Methods Literature review. Results The potential of externally delivered low-intensity ultrasound for a temporally and spatially precise and predictable disruption of the BBB has been investigated for over a decade, yielding extensive preclinical literature demonstrating that FUS can disrupt the BBB in a spatially targeted and temporally reversible manner. Studies in animal models documented that FUS enhanced the delivery of numerous chemotherapeutic and investigational agents across the BBB and into brain tumors, including temozolomide, bevacizumab, 1,3-bis (2-chloroethyl)-1-nitrosourea, doxorubicin, viral vectors, and cells. Chemotherapeutic interventions combined with FUS slowed tumor progression and improved animal survival. Recent advances of MRgFUS systems allow precise, temporally and spatially controllable, and safe transcranial delivery of ultrasound energy. Initial clinical evidence in glioma patients has shown the efficacy of MRgFUS in disrupting the BBB, as demonstrated by an enhanced gadolinium penetration. Conclusion Thus far, a temporary disruption of the BBB followed by the administration of chemotherapy has been both feasible and safe. Further studies are needed to determine the actual drug delivery, including the drug distribution at a tissue-level scale, as well as effects on tumor growth and patient prognosis.

OBJECTIVE The objective of this study was to evaluate, at 4 and 5 years posttreatment, the long-term safety and efficacy of unilateral MRI-guided focused ultrasound (MRgFUS) thalamotomy for medication-refractory essential tremor in a cohort of patients from a prospective, controlled, multicenter clinical trial. METHODS Outcomes per the Clinical Rating Scale for Tremor (CRST), including postural tremor scores (CRST Part A), combined hand tremor/motor scores (CRST Parts A and B), and functional disability scores (CRST Part C), were measured by a qualified neurologist. The Quality of Life in Essential Tremor Questionnaire (QUEST) was used to assess quality of life. CRST and QUEST scores at 48 and 60 months post-MRgFUS were compared to those at baseline to assess treatment efficacy and durability. All adverse events (AEs) were reported. RESULTS Forty-five and 40 patients completed the 4- and 5-year follow-ups, respectively. CRST scores for postural tremor (Part A) for the treated hand remained significantly improved by 73.3% and 73.1% from baseline at both 48 and 60 months posttreatment, respectively (both p < 0.0001). Combined hand tremor/motor scores (Parts A and B) also improved by 49.5% and 40.4% (p < 0.0001) at each respective time point. Functional disability scores (Part C) increased slightly over time but remained significantly improved through the 5 years (p < 0.0001). Similarly, QUEST scores remained significantly improved from baseline at year 4 (p < 0.0001) and year 5 (p < 0.0003). All previously reported AEs remained mild or moderate, and no new AEs were reported. CONCLUSIONS Unilateral MRgFUS thalamotomy demonstrates sustained and significant tremor improvement at 5 years with an overall improvement in quality-of-life measures and without any progressive or delayed complications. Clinical trial registration no.: NCT01827904 (ClinicalTrials.gov)

Focused ultrasound single-element piezoelectric transducers constitute a promising method to deliver ultrasound to the brain in low-intensity applications, but are subject to defocusing and high attenuation because of transmission through the skull. Here, a novel virtual brain projection method is used to superimpose a magnetic resonance image of the brain in ex vivo human skulls to provide targets during trans-skull focused ultrasound single-element piezoelectric transducer pressure field mapping. Positions of the transducer, skull and hydrophone are tracked in real time using a stereoscopic navigation camera and 3-D Slicer software. Virtual targets of the left dorsolateral prefrontal cortex, left hippocampus and cerebellar vermis were chosen to illustrate the method's flexibility in evaluating focal-zone beam distortion and attenuation. The regions are of interest as non-invasive brain stimulation targets in the treatment of neuropsychiatric disorders via repeated ultrasound exposure. The technical approach can facilitate the assessment of transcranial ultrasound device operator positioning reliability, intracranial beam behavior and computational model validation.

Magnetic resonance image-guided focused ultrasound has emerged as a viable non-invasive technique for the treatment of central nervous system-related diseases/disorders. Application of mechanical and thermal effects associated with focused transcranial ultrasound has been studied extensively in pre-clinical models, which has paved the way for clinical trials. However, in vivo treatment evaluation techniques on drug delivery application via blood–brain barrier opening has not been fully explored. Current treatment evaluation techniques via magnetic resonance imaging are hindered by systemic toxicity resulting from free gadolinium delivery. Here we propose a novel treatment evaluation strategy to overcome limitations by (i) synthesizing liposomes that are dually labeled with gadolinium, a magnetic resonance imaging (MRI) contrast agent, and rhodamine, a fluorophore; (ii) applying a focused ultrasound (FUS)-mediated BBB opening technique to deliver the liposomes across vascular barriers, achieving local gadolinium enhancement while reducing systemic and unwanted regional toxic effects associated with free gadolinium; and (iii) utilizing the MRI modality to confirm the delivery as it is already included in the FUS treatment in clinic. Liposomes were secondarily labeled with a fluorescent marker to confirm results obtained by MRI quantification postmortem. Two different sizes, 77.5 nm (group A) and 140 nm (group B), of gadolinium- and fluorescence-labeled liposomes were fabricated using thin-film hydration followed by extrusion methods and determined their stability up to 6 h under physiologic conditions. Gadolinium signal was detected on contrast-enhanced T1-weighted MRI 5 h after the delivery of liposomes via the BBB opening approach with an ultrasound pulse of 0.42 MPa (estimate in water) combined with microbubbles. MRI contrast was enhanced significantly in sonicated regions compared with non-sonicated regions of the brain. This was due to the accumulation of labeled liposomes, which was confirmed by detection of rhodamine fluorescence in histologic sections. The relative increase in MRI signal intensity was greater for smaller liposomes (mean diameter = 77.5 nm) than larger liposomes (mean diameter = 140 nm), which suggested a greater accumulation of the smaller liposomes in the brain after ultrasound-mediated opening of the BBB. Our findings suggest that the dual-labeled nanocarrier platform can be established, the FUS-mediated BBB opening approach can be used to deliver it through vascular barriers and MRI can be used to evaluate the extent of nanocarrier delivery.

The technology of transcranial focused ultrasound (FUS) enables a novel approach to neuromodulation, a tool for selective manipulation of brain function to be used in neurobiology research and with potential applications in clinical treatment. The method uses transcranial focused ultrasound to non-invasively open the blood-brain barrier (BBB) in a localized region such that a systemically injected neurotransmitter chemical can be delivered to the targeted brain site. The approach modulates the chemical signaling that occurs in and between neurons, making it complimentary to most other neuromodulation techniques that affect the electrical properties of neuronal activity. Here, we report delivering the inhibitory neurotransmitter GABA to the right somatosensory cortex of the rat brain during bilateral hind paw electrical stimulation and measure the inhibition of activation using functional MRI (fMRI). In a 2 × 2 factorial design, we evaluated conditions of BBB Closed vs BBB Open and No GABA vs GABA. Results from fMRI measurements of the blood oxygen level-dependent (BOLD) signal show: 1) intravenous GABA injection without FUS-mediated BBB opening does not have an effect on the BOLD response; 2) FUS-mediated BBB opening alone significantly alters the BOLD signal response to the stimulus, both in amplitude and shape of the time course; 3) the combination of FUS-mediated BBB opening and GABA injection further reduces the peak amplitude and spatial extent of the BOLD signal response to the stimulus. The data support the thesis that FUS-mediated opening of the BBB can be used to achieve non-invasive delivery of neuroactive substances for targeted manipulation of brain function.

Objective: Phase aberration correction is essential in transcranial histotripsy to compensate for focal distortion caused by the heterogeneity of the intact skull bone. This paper improves the 2-step aberration correction (AC) method that has been previously presented and develops an AC workflow that fits in the clinical environment, in which the computed tomography (CT)-based analytical approach was first implemented, followed by a cavitation-based approach using the shockwaves from the acoustic cavitation emission (ACE). Approach: A 700 kHz, 360-element hemispherical transducer array capable of transmit-and-receive on all channels was used to transcranially generate histotripsy-induced cavitation and acquire ACE shockwaves. For CT-AC, two ray-tracing models were investigated: a forward ray-tracing model (transducer-to-focus) in the open-source software Kranion, and an in-house backward ray-tracing model (focus-to-transducer) accounting for refraction and the sound speed variation in skulls. Co-registration was achieved by aligning the skull CT data to the skull surface map reconstructed using the acoustic pulse-echo method. For ACE-AC, the ACE signals from the collapses of generated bubbles were aligned by cross-correlation to estimate the corresponding time delays. Main results: The performance of the 2-step method was tested with 3 excised human calvariums placed at 2 different locations in the transducer array. Results showed that the 2-step AC achieved 90 ± 7% peak focal pressure compared to the gold standard hydrophone correction. It also reduced the focal shift from 0.84 to 0.30 mm and the focal volume from 10.6 to 2.0 mm3 on average compared to the no AC cases. Significance: The 2-step AC yielded better refocusing compared to either CT-AC or ACE-AC alone and can be implemented in real-time for transcranial histotripsy brain therapy.

Pyroglutamate-3 amyloid-β (pGlu3 Aβ) is an N-terminally modified, pathogenic form of amyloid-β that is present in cerebral amyloid plaques and vascular deposits. Here, for the first time, wee used focused ultrasound (FUS) with microbubbles to enhance the intravenous delivery of an Fc-competent anti-pGlu3 Aβ monoclonal antibody, 07/2a mAb, across the blood brain barrier (BBB) in an attempt to improve Aβ removal and memory in aged APP/PS1dE9 mice, an Alzheimer’s disease-like model of amyloidogenesis. First, we demonstrated that bilateral hippocampal FUS-BBBD led to a 5.5-fold increase of 07/2a mAb in the brains of sonicated aged APP/PS1dE9 mice compared to non-sonicated mice 72 hours following a single treatment. Then, we determined that three weekly treatments with 07/2a mAb alone improved spatial learning and memory in aged, plaque-rich APP/PS1dE9 mice, and that this improvement occurred faster and in a higher percentage of animals when combined with FUS-BBBD. APP/PS1dE9 mice given the combination treatment had reduced hippocampal plaque burden compared to PBS-treated APP/PS1dE9 mice. Furthermore, synaptic protein levels were higher in hippocampal synaptosomes from APP/PS1 mice given the combination treatment compared to sham controls, and there were more CA3 synaptic puncta labeled in the APP/PS1dE9 mice given the combination treatment compared to those given mAb alone. Plaque-associated microglia were present in the hippocampi of APP/PS1dE9 mice treated with 07/2a mAb with and without FUS-BBBD. However, we discovered that plaque-associated Ly6G+ monocytes were only present in the hippocampi of APP/PS1dE9 mice that were given FUS-BBBD alone or even more so, the combination treatment. Lastly, FUS- BBBD did not increase the incidence of microhemorrhage in mice with or without 07/2a mAb treatment. Our findings suggest that FUS is a useful tool to enhance delivery and efficacy of an anti-pGlu3 Aβ mAb for immunotherapy either via an additive effect or an independent mechanism. We revealed a potential novel mechanism wherein the combination of 07/2a mAb with FUS-BBBD led to greater monocyte infiltration and recruitment to plaques in this AD-like model. Overall, these effects resulted in greater plaque removal, sparing of synapses and improved cognitive function without causing overt damage, suggesting the possibility of FUS-BBBD as a noninvasive method to increase the therapeutic efficacy of drugs or biologics in AD patients.

Neurosurgery targets in the thalamus can be challenging to identify during transcranial MRI-guided focused ultrasound (MRgFUS) thermal ablation due to poor image quality. They also neighbor structures that can result in side effects if damaged. Here we demonstrate that the phase data obtained during MRgFUS for MR temperature imaging (MRTI) contains anatomic information that could be useful in guiding this procedure. This approach was evaluated in 68 thalamotomies for essential tremor (ET). We found that we could readily visualize the red nucleus and subthalamic nucleus, and those nuclei were consistently aligned with the sonication target coordinates. We also could consistently visualize the internal capsule, which needs to be protected from thermal damage to prevent side effects. Preliminary results from four pallidotomies in Parkinson's disease patients suggest that this approach might also be useful in visualizing the optic tract in addition to the internal capsule. Overall, this approach can visualize anatomic landmarks that may be useful to refine atlas-based targeting for MRgFUS. Since the same data is used for MRTI and anatomic visualization, there are no errors induced by registration to previously obtained planning images or image distortion, and no additional time is needed.

Focused ultrasound (FUS) is a promising technology for facilitating treatment of brain diseases including chronic pain. Focused ultrasound is a unique modality for delivering therapeutic levels of energy into the body, including the central nervous system (CNS). It is non-invasive and can target spatially localized effects through the intact skull to cortical or subcortical regions of the brain. FUS can achieve three different mechanisms of action in the brain that are relevant for chronic pain treatment: (1) localized thermal ablation of neural tissue; (2) localized and transient disruption of the blood-brain barrier for targeted drug delivery to CNS structures; and (3) inhibition or stimulation of neuronal activity in targeted regions. This review provides an in-depth look at the technology of FUS with emphasis placed on applications to CNS-based treatments of chronic pain. While still in the early stages of clinical translation and with some technical challenges remaining, we suggest that FUS has great potential as a novel approach for manipulating CNS networks involved in pain treatment.

We investigated controlled blood-brain barrier (BBB) disruption using a low-frequency clinical transcranial MRI-guided focused ultrasound (TcMRgFUS) device and evaluated enhanced delivery of irinotecan chemotherapy to the brain and a rat glioma model. Animals received three weekly sessions of FUS, FUS and 10 mg/kg irinotecan, or irinotecan alone. In each session, four volumetric sonications targeted 36 locations in one hemisphere. With feedback control based on recordings of acoustic emissions, 98% of the sonication targets (1045/1071) reached a pre-defined level of acoustic emission, while the probability of wideband emission (a signature for inertial cavitation) was than 1%. BBB disruption, evaluated by mapping the R1 relaxation rate after administration of an MRI contrast agent, was significantly higher in the sonicated hemisphere (P

We address the recent controversy over whether focused ultrasound (FUS) activates cortical neurons directly or indirectly by initially activating auditory pathways. We obtained two types of evidence that FUS can directly activate cortical neurons. The depth profile of the local field potential (LFP) in the barrel cortex of the rat in vivo indicated a generator was located within the cortical gray matter. The onset and peak latencies of the initial component p1 were 3.2 ± 0.25 ms (mean ± standard error of the mean) and 7.6 ± 0.12 ms, respectively, for the direct cortical response (DCR), 6.8 ± 0.40 and 14.3 ± 0.54 ms for the FUS-evoked LFP (4 MHz, 3.2 MPa, 50 or 300 µs/pulse, 1–20 pulses at 1 kHz) and 6.9 ± 0.51 and 15.8 ± 0.94 ms for the LFP evoked by 1-ms deflection of the C2 whisker projecting to the same area. The peak latency of the FUS p1 was statistically (t-test) longer than the DCR, but shorter than the whisker p1 at p

Focused ultrasound (FUS) is a technology capable of delivering therapeutic levels of energy through the intact skull to a tightly localized brain region. Combining the FUS pressure wave with intravenously injected microbubbles creates forces on blood vessel walls that open the blood-brain barrier (BBB). This noninvasive and localized opening of the BBB allows for targeted delivery of pharmacological agents into the brain for use in therapeutic development. It is possible to use FUS power levels such that the BBB is opened without damaging local tissues. However, open questions remain related to the effects that FUS-induced BBB opening has on brain function including local physiology and vascular hemodynamics. We evaluated the effects that FUS-induced BBB opening has on resting state functional magnetic resonance imaging (rs-fMRI) metrics. Data from rs-fMRI was acquired in rats that underwent sham FUS BBB vs. FUS BBB opening targeted to the right primary somatosensory cortex hindlimb region (S1HL). FUS BBB opening reduced the functional connectivity between the right S1HL and other sensorimotor regions, including statistically significant reduction of connectivity to the homologous region in the left hemisphere (left S1HL). The effect was observed in all three metrics analyzed: functional connectivity between anatomically defined regions, whole brain voxel-wise correlation maps based on anatomical seeds, and spatial patterns from independent component analysis. Connectivity metrics for other regions where the BBB was not perturbed were not affected. While it is not clear whether the effect is vascular or neuronal in origin, these results suggest that even safe levels of FUS BBB opening have an effect on the physiological processes that drive the signals measured by BOLD fMRI. As such these effects must be accounted for when carrying out studies using fMRI to evaluate the effects of pharmacological agents delivered via FUS-induced BBB opening.

This work explored an elementwise approach to model transcranial MRI-guided focused ultrasound (TcMRgFUS) thermal ablation, a noninvasive approach to neurosurgery. Each element of the phased array transducer was simulated individually and could be simultaneously loaded into computer memory, allowing for rapid (~2.5 s) calculation of the pressure field for different phase offsets used for beam steering and aberration correction. We simulated the pressure distribution for 431 sonications in 32 patients, applied the phase and magnitude values used during treatment, and estimated the resulting temperature rise. We systematically varied the relationship between CT (computerized tomography)-derived skull density and the acoustic attenuation and sound speed to obtain the best agreement between the predictions and MR temperature imaging (MRTI). The optimization was validated with simulations of 396 sonications from 40 additional treatments. After optimization, the predicted and measured heating agreed well (R 2: 0.74 patients 1-32; 0.71 patients 33-72). The dimensions and obliquity of the heating in the simulated temperature maps were correlated with the MRTI (R 2: 0.62, 0.74, respectively), but the measured heating was more spatially diffuse. The energy needed to achieve ablation varied by an order of magnitude (3.3-36.1 kJ). While this elementwise approach required more computation time up front (the combined simulation matrices were approximately 4.6 times higher than a single large simulation), it could be performed in parallel on a computing cluster. It allows for rapid calculation of the three-dimensional heating at the focus for different phase and magnitude values on the array. We also show how this approach can be used to optimize the relationship between CT-derived skull density and acoustic properties. While the relationships found here need further validation in a larger patient population, these results demonstrate the promise of this approach to model TcMRgFUS.

In wireless power transfer systems, the transmitting coil dimensions can substantially affect the transmission range and alignment sensitivity. We found that a transmitting coil with larger inner and outer diameter has a wider transmission range and lower alignment sensitivity. Thus, we developed a larger coil (24×30 cm2) designed to be embedded in the back of a vest to power DC pumps for artificial hearts or LVADs. To significantly reduce the required voltage, the coil was divided into 8 segments with resonant capacitors. The coil was operated at 6.78 MHz and evaluated with a 5.3-cm diameter receiving coil. A circuit model for the energy coupling coils was developed to predict the output power and efficiency. Having a coil separation of 7.7 cm, the output power and efficiency of the energy coupling coils are higher than 48 W and 80%, respectively. The system was experimentally tested with a DC pump, demonstrating that the proposed coil segmentation technique can significantly reduce the transmitter voltage to a safe level (∼10 Vrms).

The R. Bruce Lindsay Award (formerly the Biennial Award) is presented in the Spring to a member of the Society who is under 35 years of age on 1 January of the year of the Award and who, during a period of two or more years immediately preceding the award, has been active in the affairs of the Society and has contributed substantially, through published papers, to the advancement of theoretical or applied acoustics, or both. The award was presented biennially until 1986. It is now an annual award.

In the present proof of principle study, we evaluated the homogenous angular spectrum method for passive acoustic mapping (AS-PAM) of microbubble oscillations using simulated and experimental data. In the simulated data we assessed the ability of AS-PAM to form 3D maps of a single and multiple point sources. Then, in the two dimensional limit, we compared the 2D maps from AS-PAM with alternative frequency and time domain passive acoustic mapping (FD- and TD-PAM) approaches. Finally, we assessed the ability of AS-PAM to visualize microbubble activity in vivo with data obtained during 8 different experiments of FUS-induced blood-brain barrier disruption in 3 nonhuman primates, using a clinical MR-guided FUS system. Our in silico results demonstrate AS-PAM can be used to perform 3D passive acoustic mapping. 2D AS-PAM as compared to FD- PAM and TD-PAM is 10 and 200 times faster respectively and has similar sensitivity, resolution, and localization accuracy, even when the noise was 10-fold higher than the signal. In-vivo , the AS-PAM reconstructions of emissions at frequency bands pertinent to the different types of microbubble oscillations were also found to be more sensitive than TD-PAM. AS-PAM of harmonic-only components predicted safe blood-brain barrier disruption, whereas AS-PAM of broadband emissions correctly identified MR-evident tissue damage. The disparity (3.2 mm) in the location of the cavitation activity between the three methods was within their resolution limits. These data clearly demonstrate that AS-PAM is a sensitive and fast approach for PAM, thus providing a clinically relevant method to guide therapeutic ultrasound procedures.

Numerous researchers are investigating the use of microbubble-enhanced ultrasound to disrupt the blood-brain barrier (BBB) disruption and deliver drugs to the brain. This study investigated the impact of using oxygen as a carrier gas for anesthesia on microbubble activity and BBB disruption. Targets in mice were sonicated in combination with administration of Optison microbubbles (100 μl/kg) under isoflurane anesthesia with either oxygen or medical air. A 690 kHz focused ultrasound transducer applied 10 ms bursts at peak pressure amplitudes of 0.46-0.54 MPa (N=2) or 0.34-0.36 MPa (N=5). After sonication of two locations in one hemisphere, the carrier gas for the anesthesia was changed, and the sonications were repeated in the contralateral hemisphere. The BBB disruption, measured via contrast-enhanced MRI, was significantly greater (P