The impact of pulse repetition frequency on microbubble activity and drug delivery during focused ultrasound-mediated blood-brain barrier opening.

Objective.Pulsed focused ultrasound (FUS) can deliver therapeutics to the brain by using intravenous microbubbles (MBs) to open the blood-brain barrier (BBB). MB emissions indicate treatment outcomes, like BBB opening (harmonics) and damage (broadband). Typically, a pulse repetition frequency (PRF) of 1 Hz is used, but the effect of PRF on MBs is not fully understood. We investigated the effect of PRF on MB activity and tracer delivery.Approach.The effect of PRF (0.125, 0.25, 0.5, 1, and 2 Hz) on MB activity was monitored through harmonic and wideband emissions during FUS sonications of the rat brain at 274.3 kHz. BBB opening was quantified through fluorescence imaging to estimate the concentration of Trypan Blue (TB) dye following a 75-pulse FUS exposure for PRFs of 1 and 0.25 Hz.Main results.At a fixed acoustic pressure, the percentage change in maximum harmonic amplitude compared to the control (PRF = 1 Hz) decreased with increasing PRF, with a median change of 73.8% at 0.125 Hz and -38.3% at 2 Hz. There was no difference in the pressure threshold for broadband emissions between PRFs of 0.25 and 1 Hz. PRF = 0.25 Hz, led to a 68.2% increase in the mean concentration of TB measured after FUS, with a 53.9% increase in the mean harmonic sum, compared with PRF = 1 Hz. Harmonic emissions-based control at PRF = 0.25 Hz yielded similar TB delivery, with less damage at histology, compared with 1 Hz.Significance.For a fixed number of FUS pulses, reducing the PRF was shown to increase the magnitude of harmonic emissions and TB delivery, but not the threshold for broadband emissions. While further research is necessary to understand the mechanisms involved, these results may be useful to improve clinical safety margins and sensitivity to detecting small harmonic signals from cavitating MBs.

Cavitation monitoring, treatment strategy, and acoustic simulations of focused ultrasound blood-brain barrier disruption in patients with glioblastoma.

PURPOSE: We report our experience disrupting the blood-brain barrier (BBB) to improve drug delivery in glioblastoma patients receiving temozolomide chemotherapy. The goals of this retrospective analysis were to compare MRI-based measures of BBB disruption and vascular damage to the exposure levels, acoustic emissions data, and acoustic simulations. We also simulated the cavitation detectors. METHODS: Monthly BBB disruption (BBBD) was performed using a 220 kHz hemispherical phased array focused ultrasound system (Exablate Neuro, InSightec) and Definity microbubbles (Lantheus) over 38 sessions in nine patients. Exposure levels were actively controlled via the cavitation dose obtained by monitoring subharmonic acoustic emissions. The acoustic field and sensitivity profile of the cavitation detection system were simulated. Exposure levels and cavitation metrics were compared to the level of BBBD evident in contrast-enhanced MRI and to hypointense regions in T2*-weighted MRI. RESULTS: Our treatment strategy evolved from using a relatively high cavitation dose goal to a lower goal and longer sonication duration and ultimately resulted in BBBD across the treatment volume with minimal petechiae. Subsonication-level feedback control of the exposure using acoustic emissions also improved consistency. Simulations of the acoustic field suggest that reflections and standing waves appear when the focus is placed near the skull, but their effects can be mitigated with aberration correction. Simulating the cavitation detectors suggest variations in the sensitivity profile across the treatment volume and between patients. A correlation was observed with the cavitation dose, BBBD and petechial hemorrhage in 8/9 patients, but substantial variability was evident. Analysis of the cavitation spectra found that most bursts did not contain wideband emissions, a signature of inertial cavitation, but biggest contribution to the cavitation dose - the metric used to control the procedure - came from bursts with wideband emissions. CONCLUSION: Using a low subharmonic cavitation dose with a longer duration resulted in BBBD with minimal petechiae. The correlation between cavitation dose and outcomes demonstrates the benefits of feedback control based on acoustic emissions, although more work is needed to reduce variability. Acoustic simulations could improve focusing near the skull and inform our analysis of acoustic emissions. Monitoring additional frequency bands and improving the sensitivity of the cavitation detection could provide signatures of microbubble activity associated with BBB disruption that were undetected here and could improve our ability to achieve BBB disruption without vascular damage.

Non-invasive Blood-Brain Barrier Disruption using Acoustic Holography with a Clinical Focused Ultrasound System.

OBJECTIVE: Holographic methods can be used with phased array transducers to shape an ultrasound field. We tested a simple method to create holograms with a hemispherical 1024-element phased array transducer and explored how it could benefit ultrasound-mediated blood-brain barrier (BBB) disruption. METHODS: With this method, individual acoustic simulations for each element of the transducer were simultaneously loaded into computer memory. Each element's phase was systematically modulated until the combined field matched a desired pattern. The method was evaluated with a 220 kHz transducer being tested clinically to enhance drug delivery via BBB disruption. The holograms were evaluated in a tissue-mimicking phantom and in vivo in experiments disrupting the BBB in rats and in a macaque. We also explored whether this approach could mitigate secondary reflections from the skull using simulations of transcranial focusing in clinical treatments of transcranial sonication for BBB disruption. RESULTS: This approach can enlarge the focal volume in a patient-specific manner and could reduce the number of sonication targets needed to disrupt large volumes, improve the homogeneity of the disruption, and improve our ability to detect microbubble activity in tissues with low vascular density. Simulations suggest that the method could also mitigate secondary reflections during transcranial sonication.

A study combining microbubble-mediated focused ultrasound and radiation therapy in the healthy rat brain and a F98 glioma model.

Focused Ultrasound (FUS) has been shown to sensitize tumors outside the brain to Radiotherapy (RT) through increased ceramide-mediated apoptosis. This study investigated the effects of FUS + RT in healthy rodent brains and F98 gliomas. Tumors, or striata in healthy rats, were targeted with microbubble-mediated, pulsed FUS (220 kHz, 102-444 kPa), followed by RT (4, 8, 15 Gy). FUS + RT (8, 15 Gy) resulted in ablative lesions, not observed with FUS or RT only, in healthy tissue. Lesions were visible using Magnetic Resonance Imaging (MRI) within 72 h and persisted until 21 days post-treatment, indicating potential applications in ablative neurosurgery. In F98 tumors, at 8 and 15 Gy, where RT only had significant effects, FUS + RT offered limited improvements. At 4 Gy, where RT had limited effects compared with untreated controls, FUS + RT reduced tumor volumes observed on MRI by 45-57%. However, survival benefits were minimal (controls: 27 days, RT: 27 days, FUS + RT: 28 days). Histological analyses of tumors 72 h after FUS + RT (4 Gy) showed 93% and 396% increases in apoptosis, and 320% and 336% increases in vessel-associated ceramide, compared to FUS and RT only. Preliminary evidence shows that FUS + RT may improve treatment of glioma, but additional studies are required to optimize effect size.

Transferrin Receptor-Targeted Nonspherical Microbubbles for Blood-Brain Barrier Sonopermeation.

Microbubbles (MB) are widely used for ultrasound (US) imaging and drug delivery. MB are typically spherically shaped, due to surface tension. When heated above their glass transition temperature, polymer-based MB can be mechanically stretched to obtain an anisotropic shape, endowing them with unique features for US-mediated blood-brain barrier (BBB) permeation. It is here shown that nonspherical MB can be surface-modified with BBB-specific targeting ligands, thereby promoting binding to and sonopermeation of blood vessels in the brain. Actively targeted rod-shaped MB are generated via 1D stretching of spherical poly(butyl cyanoacrylate) MB and via subsequently functionalizing their shell with antitransferrin receptor (TfR) antibodies. Using US and optical imaging, it is demonstrated that nonspherical anti-TfR-MB bind more efficiently to BBB endothelium than spherical anti-TfR-MB, both in vitro and in vivo. BBB-associated anisotropic MB produce stronger cavitation signals and markedly enhance BBB permeation and delivery of a model drug as compared to spherical BBB-targeted MB. These findings exemplify the potential of antibody-modified nonspherical MB for targeted and triggered drug delivery to the brain.

Longitudinal MR imaging after unilateral MR-guided focused ultrasound thalamotomy: clinical and radiological correlation.

Introduction: Magnetic-resonance-guided focused ultrasound (MRgFUS) thalamotomy uses multiple converging high-energy ultrasonic beams to produce thermal lesions in the thalamus. Early postoperative MR imaging demonstrates the location and extent of the lesion, but there is no consensus on the utility or frequency of postoperative imaging. We aimed to evaluate the evolution of MRgFUS lesions and describe the incidence, predictors, and clinical effects of lesion persistence in a large patient cohort. Methods: A total of 215 unilateral MRgFUS thalamotomy procedures for essential tremor (ET) by a single surgeon were retrospectively analyzed. All patients had MR imaging 1 day postoperatively; 106 had imaging at 3 months and 32 had imaging at 1 year. Thin cut (2 mm) axial and coronal T2-weighted MRIs at these timepoints were analyzed visually on a binary scale for lesion presence and when visible, lesion volumes were measured. SWI and DWI sequences were also analyzed when available. Clinical outcomes including tremor scores and side effects were recorded at these same time points. We analyzed if patient characteristics (age, skull density ratio), preoperative tremor score, and sonication parameters influenced lesion evolution and if imaging characteristics correlated with clinical outcomes. Results: Visible lesions were present in all patients 1 day post- MRgFUS and measured 307.4 ± 128.7 mm3. At 3 months, residual lesions (excluding patients where lesions were not visible) were 83.6% smaller and detectable in only 54.7% of patients (n = 58). At 1 year, residual lesions were detected in 50.0% of patients (n = 16) and were 90.7% smaller than 24 h and 46.5% smaller than 3 months. Lesions were more frequently visible on SWI (100%, n = 17), DWI (n = 38, 97.4%) and ADC (n = 36, 92.3%). At 3 months, fewer treatment sonications, higher maximum power, and greater distance between individual sonications led to larger lesion volumes. Volume at 24 h did not predict if a lesion was visible later. Lesion visibility at 3 months predicted sensory side effects but was not correlated with tremor outcomes. Discussion: Overall, lesions are visible on T2-weighted MRI in about half of patients at both 3 months and 1 year post-MRgFUS thalamotomy. Certain sonication parameters significantly predicted persistent volume, but residual lesions did not correlate with tremor outcomes.

Focused Ultrasound Thalamotomy for Tremor in Parkinson's Disease: Outcomes in a Large, Prospective Cohort.

BACKGROUND: Magnetic resonance guided focused ultrasound (MRgFUS) is United States Food and Drug Administration approved for the treatment of tremor-dominant Parkinson's disease (TdPD), but only limited studies have been described in practice. OBJECTIVES: To report the largest prospective experience of unilateral MRgFUS thalamotomy for the treatment of medically refractory TdPD. METHODS: Clinical outcomes of 48 patients with medically refractory TdPD who underwent MRgFUS thalamotomy were evaluated. Tremor outcomes were assessed using the Fahn-Tolosa-Marin scale and adverse effects were categorized using a structured questionnaire and clinical exam at 1 month (n = 44), 3 months (n = 34), 1 year (n = 22), 2 years (n = 5), and 3 years (n = 2). Patients underwent magnetic resonance imaging <24 hours post-procedure. RESULTS: Significant tremor control persisted at all follow-ups (P < 0.001). All side effects were mild. At 3 months, these included gait imbalance (38.24%), sensory deficits (26.47%), motor weakness (17.65%), dysgeusia (5.88%), and dysarthria (5.88%), with some persisting at 1 year. CONCLUSIONS: MRgFUS thalamotomy is an effective treatment for sustained tremor control in patients with TdPD. © 2023 International Parkinson and Movement Disorder Society.

Focused ultrasound enhances transgene expression of intranasal hGDNF DNA nanoparticles in the sonicated brain regions.

The therapeutic potential of many gene therapies is limited by their inability to cross the blood brain barrier (BBB). While intranasal administration of plasmid DNA nanoparticles (NPs) offers a non-invasive approach to bypass the BBB, it is not targeted to disease-relevant brain regions. Here, our goal was to determine whether focused ultrasound (FUS) can enrich intranasal delivery of our plasmid DNA NPs to target deeper brain regions, in this case the regions most affected in Parkinson's disease. Combining FUS with intranasal administration resulted in enhanced delivery of DNA NPs to the rodent brain, by recruitment and transfection of microglia. FUS increased transgene expression by over 3-fold after intranasal administration compared to intravenous administration. Additionally, FUS with intranasal delivery increased transgene expression in the sonicated hemisphere by over 80%, altered cellular transfection patterns at the sonication sites, and improved penetration of plasmid NPs into the brain parenchyma (with a 1-fold and 3-fold increase in proximity of transgene expression to neurons in the forebrain and midbrain respectively, and a 40% increase in proximity of transgene expression to dopaminergic neurons in the substantia nigra). These results provide evidence in support of using FUS to improve transgene expression after intranasal delivery of non-viral gene therapies.

Nonspherical ultrasound microbubbles.

Surface tension provides microbubbles (MB) with a perfect spherical shape. Here, we demonstrate that MB can be engineered to be nonspherical, endowing them with unique features for biomedical applications. Anisotropic MB were generated via one-dimensionally stretching spherical poly(butyl cyanoacrylate) MB above their glass transition temperature. Compared to their spherical counterparts, nonspherical polymeric MB displayed superior performance in multiple ways, including i) increased margination behavior in blood vessel-like flow chambers, ii) reduced macrophage uptake in vitro, iii) prolonged circulation time in vivo, and iv) enhanced blood-brain barrier (BBB) permeation in vivo upon combination with transcranial focused ultrasound (FUS). Our studies identify shape as a design parameter in the MB landscape, and they provide a rational and robust framework for further exploring the application of anisotropic MB for ultrasound-enhanced drug delivery and imaging applications.

Ultrasound-mediated delivery of flexibility-tunable polymer drug conjugates for treating glioblastoma.

Effective chemotherapy delivery for glioblastoma multiforme (GBM) is limited by drug transport across the blood-brain barrier and poor efficacy of single agents. Polymer-drug conjugates can be used to deliver drug combinations with a ratiometric dosing. However, the behaviors and effectiveness of this system have never been well investigated in GBM models. Here, we report flexible conjugates of hyaluronic acid (HA) with camptothecin (CPT) and doxorubicin (DOX) delivered into the brain using focused ultrasound (FUS). In vitro toxicity assays reveal that DOX-CPT exhibited synergistic action against GBM in a ratio-dependent manner when delivered as HA conjugates. FUS is employed to improve penetration of DOX-HA-CPT conjugates into the brain in vivo in a murine GBM model. Small-angle x-ray scattering characterizations of the conjugates show that the DOX:CPT ratio affects the polymer chain flexibility. Conjugates with the highest flexibility yield the highest efficacy in treating mouse GBM in vivo. Our results demonstrate the association of FUS-enhanced delivery of combination chemotherapy and the drug-ratio-dependent flexibility of the HA conjugates. Drug ratio in the polymer nanocomplex may thus be employed as a key factor to modulate FUS drug delivery efficiency via controlling the polymer flexibility. Our characterizations also highlight the significance of understanding the flexibility of drug carriers in ultrasound-mediated drug delivery systems.

Trial of Globus Pallidus Focused Ultrasound Ablation in Parkinson's Disease.

BACKGROUND: Unilateral focused ultrasound ablation of the internal segment of globus pallidus has reduced motor symptoms of Parkinson's disease in open-label studies. METHODS: We randomly assigned, in a 3:1 ratio, patients with Parkinson's disease and dyskinesias or motor fluctuations and motor impairment in the off-medication state to undergo either focused ultrasound ablation opposite the most symptomatic side of the body or a sham procedure. The primary outcome was a response at 3 months, defined as a decrease of at least 3 points from baseline either in the score on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III), for the treated side in the off-medication state or in the score on the Unified Dyskinesia Rating Scale (UDysRS) in the on-medication state. Secondary outcomes included changes from baseline to month 3 in the scores on various parts of the MDS-UPDRS. After the 3-month blinded phase, an open-label phase lasted until 12 months. RESULTS: Of 94 patients, 69 were assigned to undergo ultrasound ablation (active treatment) and 25 to undergo the sham procedure (control); 65 patients and 22 patients, respectively, completed the primary-outcome assessment. In the active-treatment group, 45 patients (69%) had a response, as compared with 7 (32%) in the control group (difference, 37 percentage points; 95% confidence interval, 15 to 60; P = 0.003). Of the patients in the active-treatment group who had a response, 19 met the MDS-UPDRS III criterion only, 8 met the UDysRS criterion only, and 18 met both criteria. Results for secondary outcomes were generally in the same direction as those for the primary outcome. Of the 39 patients in the active-treatment group who had had a response at 3 months and who were assessed at 12 months, 30 continued to have a response. Pallidotomy-related adverse events in the active-treatment group included dysarthria, gait disturbance, loss of taste, visual disturbance, and facial weakness. CONCLUSIONS: Unilateral pallidal ultrasound ablation resulted in a higher percentage of patients who had improved motor function or reduced dyskinesia than a sham procedure over a period of 3 months but was associated with adverse events. Longer and larger trials are required to determine the effect and safety of this technique in persons with Parkinson's disease. (Funded by Insightec; ClinicalTrials.gov number, NCT03319485.).

Focused Ultrasound Thalamotomy: Correlation of Postoperative Imaging with Neuropathological Findings.

Magnetic resonance-guided high-intensity focused ultrasound (MRgFUS) is a rapidly developing technique used for tremor relief in tremor-predominant Parkinson's disease (PD) and essential tremor that has demonstrated successful results. Here, we describe the neuropathological findings in a woman who died from a fall 10 days after successful MRgFUS for tremor-predominant PD. Histological analysis demonstrates the characteristic early postoperative MRI findings including 3 distinct zones on T2-weighted imaging: (1) a hypointense core, (2) a hyperintense region with hypointense rim, and (3) a slightly hyperintense, poorly marginated surrounding area. Histopathological analyses also demonstrate the suspected cellular processes composing each of these regions including central hemorrhagic necrosis with surrounding cytotoxic edema and a rim of mostly unaffected vasogenic edema with some reactive and reparative processes. Overall, this case demonstrates the correlation of postoperative imaging findings with the subacute neuropathological findings after MRgFUS for PD.

Magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor: 5-year follow-up results.

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).

Transcranial MR-Guided Focused Ultrasound and Hyperostosis Calvariae Diffusa: Case Report and Systematic Review of the Literature.

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.

Low Intensity Focused Ultrasound for Epilepsy- A New Approach to Neuromodulation.

Patients with drug-resistant epilepsy (DRE) who are not surgical candidates have unacceptably few treatment options. Benefits of implanted electrostimulatory devices are still largely palliative, and many patients are not eligible to receive them. A new form of neuromodulation, low intensity focused ultrasound (LIFUS), is rapidly emerging, and has many potential intracranial applications. LIFUS can noninvasively target tissue with a spatial distribution of highly focused acoustic energy that ensures a therapeutic effect only at the geometric focus of the transducer. A growing literature over the past several decades supports the safety of LIFUS and its ability to noninvasively modulate neural tissue in animals and humans by positioning the beam over various brain regions to target motor, sensory, and visual cortices as well as frontal eye fields and even hippocampus. Several preclinical studies have demonstrated the ability of LIFUS to suppress seizures in epilepsy animal models without damaging tissue. Resection after sonication to the antero-mesial lobe showed no pathologic changes in epilepsy patients, and this is currently being trialed in serial treatments to the hippocampus in DRE. Low intensity focused ultrasound is a promising, novel, incisionless, and radiation-free alternative form of neuromodulation being investigated for epilepsy. If proven safe and effective, it could be used to target lateral cortex as well as deep structures without causing damage, and is being studied extensively to treat a wide variety of neurologic and psychiatric disorders including epilepsy.

Acute Effects of Focused Ultrasound-Induced Blood-Brain Barrier Opening on Anti-Pyroglu3 Abeta Antibody Delivery and Immune Responses.

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain. Currently, therapeutic agents targeting amyloid appear promising for AD, however, delivery to the CNS is limited due to the blood-brain-barrier (BBB). Focused ultrasound (FUS) is a method to induce a temporary opening of the BBB to enhance the delivery of therapeutic agents to the CNS. In this study, we evaluated the acute effects of FUS and whether the use of FUS-induced BBB opening enhances the delivery of 07/2a mAb, an anti-pyroglutamate-3 Aß antibody, in aged 24 mo-old APP/PS1dE9 transgenic mice. FUS was performed either unilaterally or bilaterally with mAb infusion and the short-term effect was analyzed 4 h and 72 h post-treatment. Quantitative analysis by ELISA showed a 5-6-fold increase in 07/2a mAb levels in the brain at both time points and an increased brain-to-blood ratio of the antibody. Immunohistochemistry demonstrated an increase in IgG2a mAb detection particularly in the cortex, enhanced immunoreactivity of resident Iba1+ and phagocytic CD68+ microglial cells, and a transient increase in the infiltration of Ly6G+ immune cells. Cerebral microbleeds were not altered in the unilaterally or bilaterally sonicated hemispheres. Overall, this study shows the potential of FUS therapy for the enhanced delivery of CNS therapeutics.

Two-step aberration correction: application to transcranial histotripsy.

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 mm3on 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.

Magnetic Resonance Image Guided Focused Ultrasound Thalamotomy. A Single Center Experience With 160 Procedures.

INTRODUCTION: MRgFUS thalamotomy has gained popularity as an FDA approved, non-invasive treatment for patients with Essential Tremor and tremor predominant Parkinson's Disease. We present our initial clinical experience with 160 consecutive cases of MRgFUS thalamotomy and describe the clinical outcomes with long term follow-up. METHODS: A retrospective chart review of all patients who underwent MRgFUS thalamotomy at our institution was performed. CRST Part A tremor scores were obtained pre-operatively and at each follow-up visit along with an assessment of side effects (SE). All patients had a post-operative MRI within 24 h to determine the location, size, and extent of the MRgFUS lesion. RESULTS: One hundred and sixty unilateral MRgFUS Thalamotomies (Left, n = 128; Right, n = 32) were performed for medically refractory essential Tremor (n = 150) or tremor predominant Parkinson's disease (n = 10). Mean age at surgery was 75 Years (range: 48-93) and the mean skull density ratio (SDR) was 0.48 (range: 0.32-0.75; median: 0.46). In ET patients, both rest and postural tremor was abolished acutely and remained so at follow-up whereas intention tremor was reduced acutely by 93% below baseline, 87% at 3 months, 83.0% at 1-year, and 78% at 2 years. On post-operative day 1, the most common SE's included imbalance (57%), sensory disturbances (25%), and dysmetria (11%). All adverse events were rated as mild on the Clavien-Dindo Scale and improved over time. At 2-years follow-up, imbalance was seen in 18%, sensory disturbance in 10% and dysmetria in 8% patients. Mean clinical follow-up for all patients was 14 months (range: 1-48 months). CONCLUSION: MRgFUS thalamotomy is a safe and effective procedure for long term improvement of unilateral tremor symptoms, with the most common side-effects being imbalance and sensory disturbance.

Lesion location and lesion creation affect outcomes after focused ultrasound thalamotomy.

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.