Blood-brain barrier opening of the default mode network in Alzheimer's disease with magnetic resonance-guided focused ultrasound.

The blood-brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer's disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer's disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT04118764) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants [mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9] underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimer's disease pathology (P-tau181, amyloid-ß42/40 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery.

Mild hyperthermia with magnetic resonance- guided high intensity focused ultrasound combined with salvage chemoradiation for recurrent rectal cancer.

INTRODUCTION: Pelvic recurrences from rectal cancer present a challenging clinical scenario. Hyperthermia represents an innovative treatment option in combination with concurrent chemoradiation to enhance therapeutic effect. We provide the initial results of a prospective single center feasibility study (NCT02528175) for patients undergoing rectal cancer retreatment using concurrent chemoradiation and mild hyperthermia with MR-guided high intensity focused ultrasound (MR-HIFU). METHODS: All patients were deemed ineligible for salvage surgery and were evaluated in a multidisciplinary fashion with a surgical oncologist, radiation oncologist and medical oncologist. Radiation was delivered to a dose of 30.6 Gy in 1.8 Gy per fraction with concurrent capecitabine. MR-HIFU was delivered on days 1, 8 and 15 of concurrent chemoradiation. Our primary objective was feasibility and toxicity. RESULTS: Six patients (total 11 screened) were treated with concurrent chemoradiation and mild hyperthermia with MR-HIFU. Tumor size varied between 3.1-16.6 cm. Patients spent an average of 228 min in the MRI suite and sonication with the external transducer lasted an average of 35 min. There were no complications on the day of the MR-HIFU procedure and all acute toxicities (no grade >/=3 toxicities) resolved after completion of treatment. There were no late grade >/=3 toxicities. CONCLUSION: Mild hyperthermia with MR-HIFU, in combination with concurrent chemoradiation for appropriately selected patients, is safe for localized pelvic recurrences from rectal cancer. The potential for MR-HIFU to be applied in the recurrent setting in rectal cancer treatment requires further technical development and prospective evaluation.

Putaminal Recombinant Glucocerebrosidase Delivery with Magnetic Resonance-Guided Focused Ultrasound in Parkinson's Disease: A Phase I Study.

BACKGROUND: GBA1 mutation is the most common genetic risk factor for Parkinson's disease (PD). Replacement of the lysosomal enzyme glucocerebrosidase (GCase) slows neurodegeneration in PD models and may be a promising disease-modifying therapy in patients with PD. However, recombinant GCase has limited penetration through the blood-brain barrier (BBB). Microbubble-mediated magnetic resonance-guided focused ultrasound (MRgFUS) can reversibly disrupt the BBB for drug delivery. METHODS: This open-label phase I study investigated the safety and feasibility of MRgFUS putaminal delivery of intravenous GCase at escalating doses (15 to 30 to 60 IU/kg) every 2 weeks in four patients with PD with GBA1 mutations. RESULTS: BBB permeability was achieved and restored in all patients as quantified by dynamic contrast-enhanced magnetic resonance imaging after treatment. There were no serious adverse events. Two patients developed transient dyskinesia after treatment. Blinded Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor scores off medication decreased by 12% at 6 months from baseline (from 26 ± 9 to 22 ± 6). Standardized uptake value ratio on fluorodeoxyglucose positron emission tomography imaging in the treated putamen reduced from 1.66 ± 0.14 to 1.27 ± 0.08. CONCLUSIONS: Results from this study demonstrate the safety and feasibility of MRgFUS GCase delivery in PD and support further investigation of this approach. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Magnetic resonance-guided focused ultrasound capsulotomy for refractory obsessive compulsive disorder and major depressive disorder: clinical and imaging results from two phase I trials.

Obsessive compulsive disorder (OCD) and major depressive disorder (MDD) are common, often refractory, neuropsychiatric conditions for which new treatment approaches are urgently needed. Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel surgical technique permitting incisionless ablative neurosurgery. We examined the safety profile, clinical response, and imaging correlates of MRgFUS bilateral anterior capsulotomy in patients with refractory obsessive compulsive disorder (OCD, N = 6) and major depressive disorder (MDD, n = 6). There were no serious adverse events. Nonserious adverse events included headaches and pin-site swelling in 7/12 patients. The response rate was 4/6 and 2/6 in the OCD and MDD cohorts respectively. To delineate the white-matter tracts impacted by capsulotomy, a normative diffusion MRI-based structural connectome was used, revealing tracts terminating primarily in the frontal pole, medial thalamus, striatum, and medial-temporal lobe. Positron emission tomography (PET) analysis (nine subjects) revealed widespread decreases in metabolism bilaterally in the cerebral hemispheres at 6 months post treatment, as well as in the right hippocampus, amygdala, and putamen. A pretreatment seed-to-voxel resting-state functional magnetic resonance imaging (rs-fMRI) analysis (12 subjects) revealed three voxel clusters significantly associated with eventual clinical response. MRgFUS capsulotomy appears to be safe, well tolerated, and according to these initial results, may be an important treatment option for patients with refractory OCD and MDD. MRgFUS capsulotomy results in both targeted and widespread changes in neural activity, and neuroimaging may hold potential for the prediction of outcome.

Technical Principles and Clinical Workflow of Transcranial MR-Guided Focused Ultrasound.

Transcranial MR-guided focused ultrasound (MRgFUS) is a rapidly developing technology in neuroscience for manipulating brain structure and function without open surgery. The effectiveness of transcranial MRgFUS for thermoablation is well established, and the technique is actively employed worldwide for movement disorders including essential tremor. A growing number of centers are also investigating the potential of microbubble-mediated focused ultrasound-induced opening of the blood-brain barrier (BBB) for targeted drug delivery to the brain. Here, we provide a technical overview of the principles, clinical workflow, and operator considerations of transcranial MRgFUS procedures for both thermoablation and BBB opening.

Glymphatics Visualization after Focused Ultrasound-Induced Blood-Brain Barrier Opening in Humans.

It is currently unclear whether the glymphatic system, a brain-wide interstitial fluid-cerebrospinal fluid exchange described in rodents, exists in humans. Focal blood-brain barrier disruption using magnetic resonance-guided focused ultrasound allows parenchymal penetration of gadobutrol contrast, creating an opportunity to study glymphatics in vivo noninvasively. We describe patterns of contrast distribution in the perivascular space, subarachnoid space, and space surrounding large veins draining toward the dural sinuses on fluid-attenuated inversion recovery in subjects with Alzheimer disease and amyotrophic lateral sclerosis. This is the first evidence suggesting glymphatic efflux persists in humans. It's relevance to proteinopathies and drug delivery is discussed. ANN NEUROL 2019;86:975-980.

Echo-Focusing in Transcranial Focused Ultrasound Thalamotomy for Essential Tremor: A Feasibility Study.

BACKGROUND: Transcranial magnetic resonance-guided focused ultrasound (TcMRgFUS) systems currently employ computed tomography (CT)-based aberration corrections, which may provide suboptimal trans-skull focusing. OBJECTIVES: The objective of this study was to evaluate a contrast agent microbubble imaging-based transcranial focusing method, echo-focusing (EF), during TcMRgFUS for essential tremor. METHODS: A clinical trial of TcMRgFUS thalamotomy using EF for the treatment of essential tremor was conducted (NCT03935581; funded by InSightec [Tirat Carmel, Israel]). Patients (n = 12) were injected with Definity (Lantheus Medical Imaging, North Billerica, MA) microbubbles, and EF was performed using a research feature add-on to a commercial TcMRgFUS system (ExAblate Neuro, InSightec). Subablative thermal sonications carried out using (1) EF and (2) CT-based aberration corrections were compared via magnetic resonance thermometry, and the optimal focusing method for each patient was employed for TcMRgFUS thalamotomy. RESULTS: EF aberration corrections provided increased sonication efficiency, decreased focal size, and equivalent targeting accuracy relative to CT-based focusing. EF aberration corrections were employed successfully for lesion formation in all 12 patients, 3 of whom had previously undergone unsuccessful TcMRgFUS thalamotomy via CT-based focusing. There were no adverse events related directly to the EF procedure. CONCLUSIONS: EF is feasible and appears safe during TcMRgFUS thalamotomy for essential tremor and improves on the trans-skull focal quality provided by existing CT-based focusing methods. © 2020 International Parkinson and Movement Disorder Society.

Magnetic resonance-guided focused ultrasound thalamotomy for treatment of essential tremor: A 2-year outcome study.

BACKGROUND: Magnetic resonance-guided focused ultrasound is an emerging, minimally invasive thermoablation technique for medically refractory essential tremor. Beyond the initial year, data regarding efficacy and potential predictors of efficacy are still preliminary. OBJECTIVES: The objective of this study was to assess the outcome at 2 years and the association between lesion volume and outcome 1 year after treatment. METHODS: We reviewed data from 37 patients who underwent unilateral magnetic resonance-guided focused ultrasound thalamotomy, with primary outcome being dominant tremor subscore of the Clinical Rating Scale for Tremor. We used multivariable linear regression to model initial lesion volume with 1-year outcome, adjusting for other clinically relevant variables. RESULTS: Although we detected a trend in loss of clinical benefit within the first year, the dominant tremor score at 2 years continued to be significantly improved (43.4%, 95% confidence interval 27.8%-59.0%) from baseline. Secondarily, initial lesion volume is significantly associated with 1-year outcome. CONCLUSION: Our findings show that magnetic resonance-guided focused ultrasound thalamotomy results in sustained tremor reduction for medically refractory essential tremor even in the long term, and we highlight areas for improvement.

Opening the Blood-Brain Barrier with MR Imaging-guided Focused Ultrasound: Preclinical Testing on a Trans-Human Skull Porcine Model.

Purpose To develop and test a protocol in preparation for a clinical trial on opening the blood-brain barrier (BBB) with magnetic resonance (MR) imaging-guided focused ultrasound for the delivery of chemotherapy drugs to brain tumors. Materials and Methods The procedures were approved by the institutional animal care committee. A trans-human skull porcine model was designed for the preclinical testing. Wide craniotomies were applied in 11 pigs (weight, approximately 15 kg). A partial human skull was positioned over the animal's brain. A modified clinical MR imaging-guided focused ultrasound brain system was used with a 3.0-T MR unit. The ultrasound beam was steered during sonications over a 3 × 3 grid at 3-mm spacing. Acoustic power levels of 3-20 W were tested. Bolus injections of microbubbles at 4 µL/kg were tested for each sonication. Levels of BBB opening, hemorrhage, and cavitation signal were measured with MR imaging, histologic examination, and cavitation receivers, respectively. A cavitation safety algorithm was developed on the basis of logistic regression of the measurements and tested to minimize the risk of hemorrhage. Results BBB openings of approximately 1 cm3 in volume were visualized with gadolinium-enhanced MR imaging after sonication at an acoustic power of approximately 5 W. Gross examination of histologic specimens helped confirm Evans blue (bound to macromolecule albumin) extravasation, and hematoxylin-eosin staining helped detect only scattered extravasation of red blood cells. In cases where cavitation signals were higher than thresholds, sonications were terminated immediately without causing hemorrhage. Conclusion With a trans-human skull porcine model, this study demonstrated BBB opening with a 230-kHz system in preparation for a clinical trial. © RSNA, 2016 Online supplemental material is available for this article.

A computerized tablet system for evaluating treatment of essential tremor by magnetic resonance guided focused ultrasound.

BACKGROUND: Transcranial magnetic resonance guided focused ultrasound is an emerging technology under evaluation for treatment of essential tremor, a prevalent movement disorder. A qualitative evaluation is performed by a clinician periodically during the procedure to maximize treatment effects and minimize adverse effects. The present work demonstrates a magnetic resonance-compatible method to enable more precise, quantitative measurement of tremor severity. METHODS: Tremor severity was measured in 12 patients pre-, post-, and intra-operatively, using a magnetic resonance-compatible tablet and a computerized adaptation of drawing tasks from the widely-used Fahn-Tolosa-Marin Tremor Rating Scale. Tremor metrics based on spectral analysis were calculated for each drawing and compared using Wilcoxon signed rank tests. RESULTS: Tremor metrics in the dominant (treated) hand were significantly and consistently lower post-operatively compared to pre-operatively, but there was no significant difference in the non-dominant (untreated) hand, as expected. Intra-operative metrics were intermediate between pre- and post-operative metrics. CONCLUSIONS: Use of the tablet for quantitative tremor measurement was demonstrated pre-, post-, and intra-operatively during treatment of essential tremor, complementing standard qualitative assessment. With additional work, the system has potential to add objectivity to clinical trials and to aid treatment decision-making by providing a metric for optimization during the procedure, which may eventually lead to more optimal treatment. Enhancements and further studies are suggested, and extensions to fMRI studies of essential tremor and Parkinson's disease are also likely.

Tractography-Based Ventral Intermediate Nucleus Targeting: Novel Methodology and Intraoperative Validation.

BACKGROUND: The ventral intermediate nucleus of the thalamus is not readily visible on structural magnetic resonance imaging. Therefore, a method for its visualization for stereotactic targeting is desirable. OBJECTIVE: The objective of this study was to define a tractography-based methodology for the stereotactic targeting of the ventral intermediate nucleus. METHODS: The lateral and posterior borders of the ventral intermediate nucleus were defined by tracking the pyramidal tract and medial lemniscus, respectively. A thalamic seed was then created 3 mm medial and anterior to these borders, and its structural connections were analyzed. The application of this method was assessed in an imaging cohort of 14 tremor patients and 15 healthy controls, in which we compared the tractography-based targeting to conventional targeting. In a separate surgical cohort (3 tremor and 3 tremor-dominant Parkinson's disease patients), we analyzed the accuracy of this method by correlating it with intraoperative neurophysiology. RESULTS: Tractography of the thalamic seed revealed the tracts corresponding to cerebellar input and motor cortical output fibers. The tractography-based target was more lateral (12.5 [1.2] mm vs 11.5 mm for conventional targeting) and anterior (8.5 [1.1] mm vs 6.7 [0.3] mm, anterior to the posterior commissure). In the surgical cohort, the Euclidian distance between the ventral intermediate nucleus identified by tractography and the surgical target was 1.6 [1.1] mm. The locations of the sensory thalamus, lemniscus, and pyramidal tracts were concordant within <1 mm between tractography and neurophysiology. INTERPRETATION: The tractography-based methodology for identification of the ventral intermediate nucleus is accurate and useful. This method may be used to improve stereotactic targeting in functional neurosurgery procedures. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

A Fully Electronically Steerable Therapeutic Ultrasound Phased Array With MR-Guidance.

Recently, MRI-guided focused ultrasound (FUS) has shown great promise in treating various conditions non-invasively. OBJECTIVE: The focus of this article is to introduce an MRI-guided FUS device, which can provide full electronic steering range without mechanical movement and with low near-field heating. A pilot study was conducted in order to investigate the feasibility, and safety of the device in a large animal model and a pilot clinical trial. METHODS: A flat, fully steerable FUS phased array with 4096 elements was designed and manufactured to be compatible with an MR scanner. Pre-clinical experiments were carried out for testing the accuracy of the focus at different steering angles as well as evaluating the ablation efficiency using MR thermometry. Eleven patients with uterine fibroids were treated in the pilot clinical trial. RESULTS: Pre-clinical results showed successful ablation at various steering angles with reasonable targeting accuracy and no off-target heating. During the pilot clinical study, effective fibroid ablation was achieved with significant symptom reduction observed over time. In general, the treatment results showed the system to be effective in ablating deep tissue volumes. The device was successful at efficiently ablating large volumes with minimal near-field heating and eliminating the need for mechanical translation. CONCLUSIONS: Being capable of providing high acoustic power, full electronic steering range in 3D for large volume ablations, this device can provide a safe and efficient treatment option as an outpatient procedure for uterine fibroids and other pelvic and abdominal tumors.

Current Progress in Magnetic Resonance-Guided Focused Ultrasound to Facilitate Drug Delivery across the Blood-Brain Barrier.

This review discusses the current progress in the clinical use of magnetic resonance-guided focused ultrasound (MRgFUS) and other ultrasound platforms to transiently permeabilize the blood-brain barrier (BBB) for drug delivery in neurological disorders and neuro-oncology. Safety trials in humans have followed on from extensive pre-clinical studies, demonstrating a reassuring safety profile and paving the way for numerous translational clinical trials in Alzheimer's disease, Parkinson's disease, and primary and metastatic brain tumors. Future directions include improving ultrasound delivery devices, exploring alternative delivery approaches such as nanodroplets, and expanding the application to other neurological conditions.

Comparison of computer simulations and clinical treatment results of magnetic resonance-guided focused ultrasound surgery (MRgFUS) of uterine fibroids.

PURPOSE: Magnetic resonance-guided focused ultrasound surgery (MRgFUS) can be used to noninvasively treat symptomatic uterine fibroids by heating with focused ultrasound sonications while monitoring the temperature with magnetic resonance (MR) thermometry. While prior studies have compared focused ultrasound simulations to clinical results, studies involving uterine fibroids remain scarce. In our study, we perform such a comparison to assess the suitability of simulations for treatment planning. METHODS: Sonications (N = 67) were simulated retrospectively using acoustic and thermal models based on the Rayleigh integral and Pennes bioheat equation followed by MR-thermometry simulation in seven patients who underwent MRgFUS treatment for uterine fibroids. The spatial accuracy of simulated focus location was assessed by evaluating displacements of the centers of mass of the thermal dose distributions between simulated and treatment MR thermometry slices. Temperature-time curves and sizes of 240 equivalent minutes at 43°C (240EM43 ) volumes between treatment and simulation were compared. RESULTS: The simulated focus location showed errors of 2.7 ± 4.1, -0.7 ± 2.0, and 1.3 ± 1.2 mm (mean ± SD) in the anterior-posterior, foot-head, and right-left directions for a fibroid absorption coefficient of 4.9 Np m-1  MHz-1 and perfusion parameter of 1.89 kg m-3 s-1 . Linear regression of 240EM43 volumes of 67 sonications of patient treatments and simulations utilizing these parameters yielded a slope of 1.04 and a correlation coefficient of 0.54. The temperature rise ratio of simulation to treatment near the end of sonication was 0.47 ± 0.22, 1.28 ± 0.60, and 1.49 ± 0.71 for 66 sonications simulated utilizing fibroid absorption coefficient of 1.2, 4.9, and 8.6 Np m-1  MHz-1 , respectively, and the aforementioned perfusion value. The impact of perfusion on peak temperature rise is minimal between 1.89 and 10 kg m-3 s-1 , but became more substantial when utilizing a value of 100 kg m-3 s-1 . CONCLUSIONS: The results of this study suggest that perfusion, while in some cases having a substantial impact on thermal dose volumes, has less impact than ultrasound absorption for predicting peak temperature elevation at least when using perfusion parameter values up to 10 kg m-3 s-1 for this particular array geometry, frequencies, and tissue target which is good for clinicians to be aware of. The results suggest that simulations show promise in treatment planning, particularly in terms of spatial accuracy. However, in order to use simulations to predict temperature rise due to a sonication, knowledge of the patient-specific tissue parameters, in particular the absorption coefficient is important. Currently, spatially varying patient-specific tissue parameter values are not available during treatment, so simulations can only be used for planning purposes to estimate sonication performance on average.

Clinical value of M1 macrophage-related genes identification in bladder urothelial carcinoma and in vitro validation.

Background: Tumor microenvironment (TME) takes a non-negligible role in the progression and metastasis of bladder urothelial carcinoma (BLCA) and tumor development could be inhibited by macrophage M1 in TME. The role of macrophage M1-related genes in BLCA adjuvant therapy has not been studied well. Methods: CIBERSOR algorithm was applied for identification tumor-infiltrating immune cells (TICs) subtypes of subjects from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data sets. We identified potential modules of M1 macrophages by weighted gene co-expression network analysis (WGCNA). Nomogram was determined by one-way Cox regression and lasso regression analysis for M1 macrophage genes. The data from GEO are taken to verify the models externally. Kaplan-Meier and receiver operating characteristic (ROC) curves validated prognostic value of M1 macrophage genes. Finally, we divided patients into the low-risk group (LRG) and the high-risk group (HRG) based on the median risk score (RS), and the predictive value of RS in patients with BLCA immunotherapy and chemotherapy was investigated. Bladder cancer (T24, 5637, and BIU-87) and bladder uroepithelial cell line (SV-HUC-1) were used for in vitro validation. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was employed to validate the associated genes mRNA level. Results: 111 macrophage M1-related genes were identified using WGCNA. RS model containing three prognostically significant M1 macrophage-associated genes (FBXO6, OAS1, and TMEM229B) was formed by multiple Cox analysis, and a polygenic risk model and a comprehensive prognostic line plot was developed. The calibration curve clarified RS was a good predictor of prognosis. Patients in the LRG were more suitable for programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte associate protein-4 (CTLA4) combination immunotherapy. Finally, chemotherapeutic drug models showed patients in the LRG were more sensitive to gemcitabine and mitomycin. RT-qPCR result elucidated the upregulation of FBXO6, TMEM229B, and downregulation of OAS1 in BLCA cell lines. Conclusion: A predictive model based on M1 macrophage-related genes can help guide us in the treatment of BLCA.

Cavitation Feedback Control of Focused Ultrasound Blood-Brain Barrier Opening for Drug Delivery in Patients with Parkinson's Disease.

Magnetic resonance-guided focused ultrasound (MRgFUS), in conjunction with circulating microbubbles, is an emerging technology that can transiently enhance the permeability of the blood-brain barrier (BBB) locally and non-invasively to facilitate targeted drug delivery to the brain. In this clinical trial, the feasibility and safety of BBB modulation in the putamen were evaluated for biweekly therapeutic agent delivery in patients with Parkinson's disease. The performance of the clinical MRgFUS system's cavitation feedback controller for active power modulation throughout the exposures was examined. The putamen was targeted unilaterally by an ExAblate Neuro MRgFUS system operating at 220 kHz. Definity microbubbles were infused via a saline bag gravity drip at a rate of 4 µL/kg per 5 min. A cavitation emissions-based feedback controller was employed to modulate the acoustic power automatically according to prescribed target cavitation dose levels. BBB opening was measured by Gadolinium (Gd)-enhanced T1-weighted MR imaging, and the presence of potential micro-hemorrhages induced by the exposures was assessed via T2*-weighted MR imaging. A total of 12 treatment sessions were carried out across four patients, with target cavitation dose levels ranging from 0.20-0.40. BBB permeability in the targeted putamen was elevated successfully in all treatments, with a 14% ± 6% mean increase in Gd-enhanced T1-weighted MRI signal intensity relative to the untreated contralateral side. No indications of red blood cell extravasations were observed on MR imaging scans acquired one day following each treatment session. The cavitation emissions-based feedback controller was effective in modulating acoustic power levels to ensure BBB permeability enhancement while avoiding micro-hemorrhages, however, further technical advancements are warranted to improve its performance for use across a wide variety of brain diseases.

Implementation of a Skull-Conformal Phased Array for Transcranial Focused Ultrasound Therapy.

OBJECTIVE: To implement a skull-conformal phased array for ultrasound-guided transcranial focused ultrasound therapy with improved patient comfort. METHODS: Using patient-specific computed tomography and MRI neuroimaging data, tightly-conforming helmet scaffolds were designed computationally. The helmet scaffolds were designed to hold reusable transducer modules at near-normal incidence in an optimal configuration for the treatment location(s) of interest. Numerical simulations of trans-skull ultrasound propagation were performed to evaluate different conformal array designs and to compare with hemispherical arrays similar to those employed clinically. A 4096-element phased array was constructed by 3D printing a helmet scaffold optimised for an ex vivo human skullcap, and its performance was evaluated via benchtop and in vivo experiments. RESULTS: Acoustic field measurements confirmed the system's ability to focus through human skull bone using simulation-based transcranial aberration corrections. Preliminary in vivo testing demonstrated safe trans-human skull blood-brain barrier (BBB) opening in rodents. CONCLUSION: Patient-specific conformal ultrasound phased arrays appear to be a feasible and safe approach for conducting transcranial BBB opening procedures. SIGNIFICANCE: Skull-conformal phased arrays stand to improve patient comfort and have the potential to accelerate the adoption of transcranial FUS therapy by improving access to the technology.

MR-guided focused ultrasound enhances delivery of trastuzumab to Her2-positive brain metastases.

The blood-brain barrier (BBB) is an important factor limiting the effectiveness of central nervous system (CNS) therapeutics. MR-guided focused ultrasound (MRgFUS) is a noninvasive, spatially precise technology that enhances drug delivery across a temporarily permeable BBB. However, despite promising preclinical data, successful drug delivery has yet to be proven in human patients. In this study, we provide primary evidence of enhanced brain penetration of trastuzumab with MRgFUS in patients with Her2-positive breast cancer and brain metastases (NCT03714243). Four patients with progressive intracranial disease and stable systemic disease were enrolled in a single-arm open-labeled study. Twenty treatments combining transcranial MRgFUS with concomitant standard-of-care intravenous trastuzumab-based therapies were administered as outpatient procedures. The primary outcome was safety, and there were no treatment-related serious adverse events. The efficacy of trastuzumab delivery was demonstrated using 111In-BzDTPA-NLS-trastuzumab SPECT imaging. The standardized uptake value ratio (SUVR) of MRgFUS-treated lesions increased, on average, by 101 ± 71%, compared to −18 ± 26% in control lesions. MRgFUS enhanced drug uptake in 87 ± 17% of sonicated voxels (>20% increase in SUVR), with up to a 450% voxel-wise increase detected. Control lesions had 8 ± 8% voxels with >20% increase in SUVR. With treatment, unidimensional tumor measurements decreased by 19 ± 12%. This study provides first-in-human evidence of noninvasive, spatially targeted monoclonal antibody delivery across the BBB using MRgFUS, demonstrating the promise of this technology for a broad range of CNS diseases.

MR-guided focused ultrasound liquid biopsy enriches circulating biomarkers in patients with brain tumors.

BACKGROUND: Liquid biopsy is promising for early detection, monitoring of response, and recurrence of cancer. The blood-brain barrier (BBB) limits the shedding of biomarker, such as cell-free DNA (cfDNA), into the blood from brain tumors, and their detection by conventional assays. Transcranial MR-guided focused ultrasound (MRgFUS) can safely and transiently open the BBB, providing an opportunity for less-invasive access to brain pathology. We hypothesized that MRgFUS can enrich the signal of circulating brain-derived biomarkers to aid in liquid biopsy. METHODS: Nine patients were treated in a prospective single-arm, open-label trial to investigate serial MRgFUS and adjuvant temozolomide combination in patients with glioblastoma (NCT03616860). Blood samples were collected as an exploratory measure within the hours before and after sonication, with control samples from non-brain tumor patients undergoing BBB opening (BBBO) alone (NCT03739905). RESULTS: Brain regions averaging 7.8 ± 6.0 cm3 (range 0.8-23.1 cm3) were successfully treated within 111 ± 39 minutes without any serious adverse events. We found MRgFUS acutely enhanced plasma cfDNA (2.6 ± 1.2-fold, P < .01, Wilcoxon signed-rank test), neuron-derived extracellular vesicles (3.2 ± 1.9-fold, P < .01), and brain-specific protein S100b (1.4 ± 0.2-fold, P < .01). Further comparison of the cfDNA methylation profiles suggests a signature that is disease- and post-BBBO-specific, in keeping with our hypothesis. We also found cfDNA-mutant copies of isocitrate dehydrogenase 1 (IDH1) increased, although this was in only one patient known to harbor the tumor mutation. CONCLUSIONS: This first-in-human proof-of-concept study shows MRgFUS enriches the signal of circulating brain-derived biomarkers, demonstrating the potential of the technology to support liquid biopsy for the brain.

Focused ultrasound-mediated bbb disruption is associated with an increase in activation of AKT: experimental study in rats.

BACKGROUND: The Blood Brain Barrier (BBB) maintains the homeostasis of central nervous system by preventing the free passage of macromolecules from the systemic circulation into the brain. This normal physiological function of the BBB presents a challenge for delivery of therapeutic compounds into the brain. Recent studies have shown that the application of focused ultrasound together with ultrasound contrast agent (microbubbles) temporarily increases the permeability of the BBB. This effect is associated with breakdown of tight junctions, the structures that regulate the paracellular permeability of the endothelial cell layer. The influence of this ultrasound effect on the activation of intracellular signaling proteins is currently not well understood. Therefore, the aim of this study was to investigate the activation of cell survival signaling molecules in response to ultrasound-mediated BBB opening; METHODS: The BBB was disrupted in two four-spot lines (1-1.5 mm spacing) along the right hemisphere of rat brain with ultrasound beams (0.3 MPa, 120 s, 10 ms bursts, repetition frequency = 1 Hz) in the presence Definity microbubbles. Contrast-enhanced MRI images were acquired to assess the extent of BBB opening upon which the animals were sacrificed and the brains removed and processed for biochemical and immunohistochemical analyses; RESULTS: Immunoblotting of sonicated brain lysates resolved by SDS-PAGE demonstrated an increase in phosphorylation of Akt and its downstream signaling molecule, GSK3ß, while the phosphorylation of MAPK remained unchanged. The elevated levels of pAkt and pGSK3ß are still evident after 24 hours post-sonication, a time point where the integrity of the BBB is known to be re-established. Furthermore, immunofluoresence staining localized this increase in pAkt and pGSK3ß levels to neuronal cells flanking the region of the disrupted BBB; CONCLUSIONS: Our data demonstrates that ultrasound-mediated BBB disruption causes an activation of the Akt signaling pathway in neuronal cells surrounding the disrupted BBB.