We have no source of funding for this article to acknowledge.

All human experiments were approved by the Institutional Research Ethics Board at Sunnybrook Health Sciences Centre.
1. Patient Identification
<ol>
	<li>Administer informed consent with the patient or substitute decision maker. Explain potential adverse events related to the procedure, such as bleeding and neurological deficits, to the patient.</li>
	<li>Assess the candidate patient for MRgFUS thalamotomy. A physician with expertise in movement disorder should perform the assessment. 
	NOTE: It is important to rule out differential diagnoses such as dystonic tremor, Parkinson&#39;s Disease, and psychogenic tremor. Further, the neurologist should assess whether adequate trials of medical treatments have been attempted, and the patient deemed treatment-refractory.</li>
	<li>Check for contraindications such as an inability to tolerate an MRI.</li>
	<li>Assess the patient&#39;s medical fitness along with an anesthetist. 
	NOTE: Active heart disease, impaired kidney function, and propensity for bleeding are all contraindications for MRgFUS.</li>
	<li>Obtain bloodwork such as complete blood cell count, electrolytes, creatinine, and coagulation panel as part of the screening process.</li>
	<li>Perform a full neurological exam (Table 1) and use the clinical rating scale for tremor (CRST) to document tremor and disability. It is useful to also administer a standard quality of life scale to capture this information at baseline and to follow it over time.</li>
</ol>
2. Imaging Setup
<ol>
	<li>Obtain a CT scan prior to the day of treatment to assess for any intracranial calcifications and skull thickness. 
	NOTE: The CT scan should have at least 512 by 512 resolution, 1 mm thickness with zero spacing, covering the entire skull from the very top to the skull-base.</li>
	<li>Obtain an MR scan prior to the day of treatment to rule out contraindications such as previous intracranial hemorrhage or brain tumor.</li>
	<li>Use a commercially available helmet transducer with 1,024 independent elements, each with central frequency 650 kHz and integrated with a 3 Tesla MR scanner8. MRI thermometry is available to provide real time feedback of the target temperature.</li>
</ol>
3. Patient Preparation
<ol>
	<li>Advise the patient not to take their medication for essential tremor on the day of treatment and not to have anything by mouth beginning at midnight the night before surgery.</li>
	<li>Check the patient into the hospital, typically through Same Day Surgery.</li>
	<li>Ensure the entire team is present: neurosurgeon, movement disorder neurologist, physicist, imaging technician, and anesthetist. 
	NOTE: An anesthetist should be available to support the patient throughout the procedure in case of discomfort, anxiety, and vertigo/vomiting, while keeping the patient conscious at all times.</li>
	<li>Place suction equipment nearby for emergency airway maintenance and peripheral intravenous lines in case medications need to be administered urgently.</li>
	<li>Attach non-invasive monitors of heart rate, electrocardiogram, blood pressure, and oxygen saturation.</li>
	<li>Insert a Foley catheter, if necessary, for the patient to empty his/her bladder.</li>
	<li>Put graduated compression stockings on the patient to help prevent deep venous thrombosis in the lower limbs.</li>
	<li>Carefully shave the hair completely and check for scalp lesions.</li>
	<li>Place the stereotactic frame with the help of a neurosurgeon and apply local anesthetic (e.g., lidocaine or bupivicaine) at the 4 pin sites.</li>
	<li>Place the rubber diaphragm on the patient&#39;s head. 
	NOTE: Because the space between the transducer and scalp is filled with degassed water, a rubber diaphragm encircles the patient&#39;s head to prevent the water from leaking. Cool water is circulated, carrying away any excess heat from the scalp.</li>
	<li>Ensure the patient does not have any ferrous components before entering the procedure room.</li>
	<li>Have the patient lie flat, headfirst into the ultrasound helmet.</li>
	<li>Cover the patient with a warming blanket to prevent hypothermia. 
	NOTE: The temperature in the treatment room is approximately 15 &#176;C.</li>
</ol>
4. Target Selection of the Vim nucleus of the thalamus
<ol>
	<li>Perform a preliminary 3D localizer MR scan and T2-weighted sequence with at least axial and sagittal planes immediately prior to sonication to register the patient to pre-treatment CT/MRI scans.</li>
	<li>Fuse the new scans with the pre-treatment MRI and CT.</li>
	<li>Contour any lesions on the scalp, calcifications in the brain, sinuses, and air volumes as no-pass zones so the transducers can avoid these specific areas.</li>
	<li>Choose the target on the axial T2 weighted image cutting through the anterior commissure (AC) and posterior commissure (PC). 
	NOTE: There are different approaches to identifying and targeting the Vim nucleus of the thalamus. Given that the Vim is not visible even on 3T images, its location is deduced relative to known anatomic landmarks (i.e., indirect targeting).
	<ol>
		<li>At the level of the AC-PC line, begin at 25% of the intercommissural distance, anterior to PC. This is typically approximately 6 mm. 
		NOTE: The average AC-PC distance in humans is 24 - 28 mm, and can range from 20 - 30 mm. Dividing the distance into quarters, one begins by defining the point that is &#188; the distance of the anterior-posterior distance, anterior to PC.</li>
		<li>Laterally, select a point midway between the point 14 mm lateral to midline and the point 11.5 mm lateral to the lateral edge of the ventricle at the level of the AC-PC plane.</li>
		<li>Make small adjustments according to the actual length and width of the specific patient&#39;s third ventricle and regional anatomy. 
		NOTE: Third ventricular width can vary widely, especially in elderly patients. It is important to be mindful of internal capsule fibers when determining the laterality of the proposed target. An individualized approach, taking into consideration the patient&#39;s specific anatomy, is critical.</li>
	</ol>
	</li>
</ol>
5. Ultrasound Delivery
<ol>
	<li>Provide a stop button for the patient so they can abort energy delivery at any time.</li>
	<li>Perform a test sonication at low energy by raising the temperature in the target region to around 45 &#176;C.</li>
	<li>Verify the alignment of the heating volume to the target and correct in all three dimensions</li>
	<li>Raise the temperature further to approximately 50 &#176;C.</li>
	<li>After each sonication, perform a screening exam of motor power and sensation to light touch along with a test for the patient&#39;s tremor. 
	NOTE: At this point, the patient may experience transient dizziness, tingling and/or numbness.</li>
	<li>Adjust the target (i.e., moving anterior if the patient reports parasthesias) according to the patient&#39;s responses before increasing the energy to make the permanent lesion around 55-60 oC.</li>
	<li>Repeat the sonication until the tremor is reduced to a satisfactory level. 
	NOTE: 12 - 29 sonications each with a duration of 10 - 25 s are typically administered in increments of 0, 1, or 2 &#176;C in an awake patient.</li>
</ol>
6. Post-treatment
<ol>
	<li>Immediately after treatment, perform a T2-weighted MRI to assess for lesion size and associated radiologic findings such as edema.</li>
	<li>Once satisfactory, take the patient out of the scanner and remove the frame.</li>
	<li>Check pin sites for bleeding. A few minutes of pressure will usually stop this.</li>
	<li>Perform another neurologic exam (Table 1). 
	NOTE: This exam is important to rule out any neurologic deficits such as paresthesia, weakness, speech or visual deficits.</li>
	<li>Admit the patient to a post-surgical unit overnight for observation.</li>
	<li>Perform an MRI on day one post-treatment to confirm the presence of the lesion and rule out any adverse events.</li>
	<li>Request assessment by a neurosurgeon if an adverse event (e.g., mass effect on imaging, intracranial hemorrhage, or decreased level of consciousness) is detected.</li>
	<li>Discharge the patient in the morning if they are doing well.</li>
</ol>
7. Follow-up
<ol>
	<li>Schedule the patient for their first follow-up visit approximately 1 week after treatment.</li>
	<li>Review the patient&#39;s tremor symptoms, side effects, medication changes, and neurologic exam.</li>
	<li>Perform the CRST and quality of life measure to document and follow tremor and disability.</li>
	<li>Document any adverse events including pin-site infection, motor deficits, sensory disturbances, and speech problems.</li>
	<li>Request assessment of an adverse event by a physician, if necessary. Request a CT scan if the patient has a new neurological deficit to rule out intracranial etiology such as hemorrhage.</li>
</ol>

<ol>
	<li>Louis, E. D., Ottman, R., Hauser, W. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=How+common+is+the+most+common+adult+movement+disorder?+Estimates+of+the+prevalence+of+essential+tremor+throughout+the+world.">How common is the most common adult movement disorder? Estimates of the prevalence of essential tremor throughout the world.</a> Mov Disord. 13, 5-10 (1998).</li><li>Louis, E. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Treatment+of+essential+tremor:+are+there+issues+we+are+overlooking?.">Treatment of essential tremor: are there issues we are overlooking?.</a> Front Neurol. 2, 91 (2011).</li><li>Zesiewicz, T. A., Encarnacion, E., Hauser, R. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Management+of+essential+tremor.">Management of essential tremor.</a> Curr Neurol Neurosci Rep. 2 (4), 324-330 (2002).</li><li>Yu, H., Neimat, J. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+treatment+of+movement+disorders+by+deep+brain+stimulation.">The treatment of movement disorders by deep brain stimulation.</a> Neurotherapeutics. 5 (1), 26-36 (2008).</li><li>Niranjan, A., Raju, S. S., Kooshkabadi, A., Monaco, E., Flickinger, J. C., Lunsford, L. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stereotactic+radiosurgery+for+essential+tremor:+Retrospective+analysis+of+a+19-year+experience.">Stereotactic radiosurgery for essential tremor: Retrospective analysis of a 19-year experience.</a> Movement Disorders: Mov Disord. , (2017).</li><li>Lipsman, N., Schwartz, M. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=MR-guided+focused+ultrasound+thalamotomy+for+essential+tremor:+a+proof-of-concept+study.">MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study.</a> The Lancet. Neurology. 12 (5), 462-468 (2013).</li><li>Elias, W. J., Lipsman, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+Randomized+Trial+of+Focused+Ultrasound+Thalamotomy+for+Essential+Tremor.">A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor.</a> N Engl J Med. 375 (8), 730-739 (2016).</li><li>Hynynen, K., Jolesz, F. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Demonstration+of+potential+noninvasive+ultrasound+brain+therapy+through+an+intact+skull.">Demonstration of potential noninvasive ultrasound brain therapy through an intact skull.</a> Ultrasound Med Biol. 24 (2), 275-283 (1998).</li><li>Hamani, C., Lozano, A. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hardware-related+complications+of+deep+brain+stimulation:+a+review+of+the+published+literature.">Hardware-related complications of deep brain stimulation: a review of the published literature.</a> Stereotact Funct Neurosurg. 84, 248-251 (2006).</li><li>Lim, S. Y., Hodaie, M., Fallis, M., Poon, Y. Y., Mazzella, F., Moro, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Gamma+knife+thalamotomy+for+disabling+tremor:+a+blinded+evaluation.">Gamma knife thalamotomy for disabling tremor: a blinded evaluation.</a> Arch Neurol. 67, 584-588 (2010).</li><li>King, N. K. K., Krishna, V., Basha, D., Elias, G., Sammartino, F., Hodaie, M., Lozano, A. M., Hutchison, W. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Microelectrode+recording+findings+within+the+tractography-defined+ventral+intermediate+nucleus.">Microelectrode recording findings within the tractography-defined ventral intermediate nucleus.</a> J Neurosurg. 126, 1669-1675 (2017).</li></ol>

KH is an inventor on patents and patent applications related to neuroablation with focused ultrasound. NL and KH have served as paid consultants for Focused Ultrasound Foundation (FUSF). FUSF is an independent, non-profit organization whose objective is the advancement of research in focused ultrasound technology and its applications. YM, YH, BS, MLS, and NS have no conflicts to declare.

MRgFUS at high-intensity can noninvasively create an intracranial lesion. Current high-intensity MRgFUS with continuous wave mode at 650 kHz has been optimized for thermal ablation of deep brain structures, such as the Vim thalamus. The use of MRgFUS has some advantages over existing techniques such as DBS, gamma knife radiosurgery, or radiofrequency ablation for treatment-refractory ET. DBS is an open surgical procedure that can be associated with potential device-related complications, including hardware malfunctions, ...

Essential tremor (ET) is the most common movement disorder, with a prevalence of up to 4% among individuals 40 year of age or older1. It is characterized by a postural and intention tremor at a frequency of approximately 4 - 7 Hz. It typically affects the upper extremities as well as the head and voice but can also be seen in the legs. ET can be severely debilitating, affecting the ability to manage simple activities of daily living. 15 - 25% of patients are forced to retire prematurely as a result of ET, and 60% of patients do not apply for jobs or promotions due to uncontrollable shaking2. Despite the effectiveness of first line medical therapies, such as propranolol or primidone3, a significant proportion of patients cannot tolerate or are resistant to medical treatments. Patients who remain symptomatic and significantly disabled after trying at least two medications, or who develop intolerable side effects, are considered medication-refractory.
Medically-refractory cases of ET are eligible for surgical interventions. Targeting of the ventralis intermedius (Vim) nucleus of the thalamus, a key cerebello-motor relay structure, with deep brain stimulation (DBS)4 electrodes or radiofrequency ablation can help alleviate tremors5,6. However, both are open neurosurgical procedures, with potential complications including infection and hemorrhage. DBS further involves chronic implantation of an intracranial electrode and battery over the pectoralis major. Furthermore, patients require anesthetics, and in the case of DBS a general anesthetic, as well as hospital stays ranging from one to several days.
MR-guided Focused ultrasound (MRgFUS) is an emerging noninvasive technique to treat various neurologic and psychiatric disorders. The device consists of a helmet that focuses over 1000 ultrasound beams from independent transducers through the intact skull. High-intensity MRgFUS can generate heat at the target leading to coagulative necrosis. A multi-centered randomized sham-controlled trial of thalamotomy for essential tremor demonstrated 47% improvement in tremor score that was durable at 12 months7. This result has led to regulatory approval of MRgFUS as a treatment modality and the subsequent addition of MRgFUS to the clinician&#39;s armamentarium for tremor management. This protocol details the steps of patient selection, preparation, and sonication, as well as the important elements of patient follow-up.

<table><tbody><tr><td>InSightec ExAblate Neuro system</td><td>InSightec</td><td></td><td>The ExAblate Neuro consists of a helmet transducer with 1,024 independent elements, each with central frequency 650 kHz and is integrated with a 3 Tesla MR scanner.</td></tr><tr><td>3 Tesla MRI scanner</td><td></td><td></td><td></td></tr><tr><td>MRI compatible Cosman-Roberts-Wells (CRW) stereotactic frame</td><td></td><td></td><td></td></tr><tr><td>20 mL of 1% lidocaine with 1:100,000 epinephrine</td><td></td><td></td><td></td></tr><tr><td>hair shaver/clipper</td><td></td><td></td><td></td></tr><tr><td>warming blanket</td><td></td><td></td><td></td></tr><tr><td>compression stockings</td><td></td><td></td><td></td></tr></tbody></table>

mri-guided focused ultrasound thalamotomy for patients with medically-refractory essential tremor

Essential tremor (ET) is the most common type of tremor in adults. While ET does not result in decreased life expectancy, the disabilities associated with ET can have a significant impact on quality of life, mood, functional activities, and socialization. Patients suffering from ET not sufficiently treated with first line medications may be eligible for alternative strategies such as deep brain stimulation, radiofrequency ablation, and MRI guided focused ultrasound (MRgFUS). High-intensity MRgFUS is an emerging modality to treat ET, its attraction for patients being that it is noninvasive and associated with short recovery time, as patients are home the day after treatment. While MRgFUS centers are still limited, it will become important for clinicians to consider MRgFUS as a treatment alternative, particularly in the case of a patient for whom open surgery is contraindicated. This article outlines the steps of patient selection, equipment setup, sonication, and post-treatment follow-up, as well as critical steps to be aware of when performing a MRgFUS procedure.

Long-term reduction in tremor in the treated extremity is on average 50% at 3 months and 40% at 12 months. Treatment success can be immediately evaluated after sonication through radiologic findings of a lesion at the Vim (Figure 1) and performance on clinical measures such as the hand-drawn spiral test (Figure 2). Additionally, intraoperative MR thermography provides real-time feedback to the target temperature. A permanent lesi...

Watch this Scientific Journal Video about MRI-guided Focused Ultrasound Thalamotomy for Patients with Medically-refractory Essential Tremor at JoVE.com

MRI-guided Focused Ultrasound Thalamotomy for Patients with Medically-refractory Essential Tremor

High-intensity MRI guided focused ultrasound is an emerging noninvasive technique to precisely ablate brain tissue. It has been shown to be safe and effective in treating medically-refractory essential tremor. This article describes the protocol for thalamotomy from patient selection to equipment setup to post-treatment follow-up.

Essential tremor (ET) is the most common type of tremor in adults. While ET does not result in decreased life expectancy, the disabilities associated with ...

mri-guided-focused-ultrasound-thalamotomy-for-patients-with-medically

Research

JoVE Journal

Medicine

13.9K Views.  Sunnybrook Health Sciences Centre. Hoge intensiteit MRI geleide gericht echografie is een opkomende noninvasive techniek om juist lasertherapie hersenweefsel. Het is aangetoond dat het veilig en effectief in het behandelen van medisch-vuurvaste essentiële tremor. Dit artikel beschrijft het protocol voor thalamotomy van PATIËNTSELECTIE apparatuur Setup om de follow-up van de nabehandeling.

Video: MRI-guided Focused Ultrasound Thalamotomy for Patients with Medically-refractory Essential Tremor

Contrast Ultrasound Targeted Treatment of Gliomas in Mice via Drug-Bearing Nanoparticle Delivery and Microvascular Ablation

We are developing minimally-invasive contrast agent microbubble based therapeutic approaches in which the permeabilization and/or ablation of the microvasculature are controlled by varying ultrasound pulsing parameters.  Specifically, we are testing whether such approaches may be used to treat malignant brain tumors through drug delivery and microvascular ablation.  Preliminary studies have been performed to determine whether targeted drug-bearing nanoparticle delivery can be facilitated by the ultrasound mediated destruction of "composite" delivery agents comprised of 100nm poly(lactide-co-glycolide) (PLAGA) nanoparticles that are adhered to albumin shelled microbubbles. We denote these agents as microbubble-nanoparticle composite agents (MNCAs). When targeted to subcutaneous C6 gliomas with ultrasound, we observed an immediate 4.6-fold increase in nanoparticle delivery in MNCA treated tumors over tumors treated with microbubbles co-administered with nanoparticles and a 8.5 fold increase over non-treated tumors. Furthermore, in many cancer applications, we believe it may be desirable to perform targeted drug delivery in conjunction with ablation of the tumor microcirculation, which will lead to tumor hypoxia and apoptosis. To this end, we have tested the efficacy of non-theramal cavitation-induced microvascular ablation, showing that this approach elicits tumor perfusion reduction, apoptosis, significant growth inhibition, and necrosis. Taken together, these results indicate that our ultrasound-targeted approach has the potential to increase therapeutic efficiency by creating tumor necrosis through microvascular ablation and/or simultaneously enhancing the drug payload in gliomas.

Insonation of microbubbles is a promising strategy for tumor ablation at reduced time-averaged acoustic powers, as well as for the targeted delivery of therapeutics. The purpose of the present study is to develop low duty cycle ultrasound pulsing strategies and nanocarriers to maximize non-thermal microvascular ablation and payload delivery to subcutaneous C6 gliomas.

We are developing minimally-invasive contrast agent microbubble based therapeutic approaches in which the permeabilization and/or ablation of the ...

Bioengineering

Evaluation of the Feasibility, Safety, and Accuracy of an Intraoperative High-intensity Focused Ultrasound Device for Treating Liver Metastases

Today, the only potentially curative option in patients with colorectal liver metastases is surgery. However, liver resection is feasible in less than 20% of patients. Surgery has been widely used in association with radiofrequency, cryotherapy, or microwaves to expand the number of treatments performed with a curative intent. Nevertheless, several limitations have been documented when using these techniques (i.e., a traumatic puncture of the parenchyma, a limited size of lesions, and an inability to monitor the treatment in real-time).High-intensity focused ultrasound (HIFU) technology can achieve precise ablations of biological tissues without incisions or radiation. Current HIFU devices are based on an extracorporeal approach with limited access to the liver. We have developed a HIFU device designed for intraoperative use. The use of a toroidal transducer enables an ablation rate (10 cm3&#183;min-1) higher than any other treatment and is independent of perfusion.
The feasibility, safety, and accuracy of intraoperative HIFU ablation were evaluated during an ablate-and-resect prospective study. This clinical phase I and IIa study was performed in patients undergoing hepatectomy for liver metastases. The HIFU treatment was performed on healthy tissue scheduled for resection.Liver metastases measuring less than 20 mm will be targeted during phase IIb (currently ongoing). This set-up allows the real-time evaluation of HIFU ablation while protecting participating patients from any adverse effects related to this new technique.
Fifteen patients were included in phase I&#8211;IIa and 30 HIFU ablations were safely created within 40 s and with a precision of 1&#8211;2 mm. The average dimensions of the HIFU ablations were 27.5 x 21.0 mm2, corresponding to a volume of approximately 7.5 cm3. The aim of the ongoing phase IIb is to ablate metastases of less than 20 mm in diameter with a 5 mm margin.

Here, we present an ablate-and-resect prospective study to evaluate the feasibility, safety, and accuracy of intraoperative high-intensity focused ultrasound ablation in patients undergoing hepatectomy for liver metastases.

Today, the only potentially curative option in patients with colorectal liver metastases is surgery. However, liver resection is feasible in less than 20% ...

Cancer Research

MRI-guided Disruption of the Blood-brain Barrier using Transcranial Focused Ultrasound in a Rat Model

Focused ultrasound (FUS) disruption of the blood-brain barrier (BBB) is an increasingly investigated technique for circumventing the BBB1-5. The BBB is a significant obstacle to pharmaceutical treatments of brain disorders as it limits the passage of molecules from the vasculature into the brain tissue to molecules less than approximately 500 Da in size6. FUS induced BBB disruption (BBBD) is temporary and reversible4 and has an advantage over chemical means of inducing BBBD by being highly localized. FUS induced BBBD provides a means for investigating the effects of a wide range of therapeutic agents on the brain, which would not otherwise be deliverable to the tissue in sufficient concentration. While a wide range of ultrasound parameters have proven successful at disrupting the BBB2,5,7, there are several critical steps in the experimental procedure to ensure successful disruption with accurate targeting. This protocol outlines how to achieve MRI-guided FUS induced BBBD in a rat model, with a focus on the critical animal preparation and microbubble handling steps of the experiment.

Microbubble-mediated focused ultrasound disruption of the blood-brain barrier (BBB) is a promising technique for non-invasive targeted drug delivery in the brain1-3. This protocol outlines the experimental procedure for MRI-guided transcranial BBB disruption in a rat model.

Focused ultrasound (FUS) disruption of the blood-brain barrier (BBB) is an increasingly investigated technique for circumventing the BBB1-5. The BBB is a ...

Magnetic Resonance-Guided High Intensity Focused Ultrasound Generated Hyperthermia: A Feasible Treatment Method in a Murine Rhabdomyosarcoma Model

Magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) is an established method for producing localized hyperthermia. Given the real-time imaging and acoustic energy modulation, this modality enables precise temperature control within a defined area. Many thermal applications are being explored with this noninvasive, nonionizing technology, such as hyperthermia generation, to release drugs from thermosensitive liposomal carriers. These drugs can include chemotherapies such as doxorubicin, for which targeted release is desired due to the dose-limiting systemic side effects, namely cardiotoxicity. Doxorubicin is a mainstay for treating a variety of malignant tumors and is commonly used in relapsed or recurrent rhabdomyosarcoma (RMS). RMS is the most common solid soft tissue extracranial tumor in children and young adults. Despite aggressive, multimodal therapy, RMS survival rates have remained the same for the past 30 years. To explore a solution for addressing this unmet need, an experimental protocol was developed to evaluate the release of thermosensitive liposomal doxorubicin (TLD) in an immunocompetent, syngeneic RMS mouse model using MRgHIFU as the source of hyperthermia for drug release.

Presented here is a protocol to use controlled hyperthermia, generated by magnetic resonance-guided high intensity focused ultrasound, to trigger drug release from temperature-sensitive liposomes in a rhabdomyosarcoma mouse model.

Magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) is an established method for producing localized hyperthermia. Given the real-time ...

Sonodynamic Therapy for the Treatment of Glioblastoma Multiforme in a Mouse Model Using a Portable Benchtop Focused Ultrasound System

Sonodynamic therapy (SDT) is an application of focused ultrasound (FUS) that enables a sonosensitizing agent to prime tumors for increased sensitivity during sonication. Unfortunately, current clinical treatments for glioblastoma (GBM) are lacking, leading to low long-term survival rates among patients. SDT is a promising method for treating GBM in an effective, noninvasive, and tumor-specific manner. Sonosensitizers preferentially enter tumor cells compared to the surrounding brain parenchyma. The application of FUS in the presence of a sonosensitizing agent generates reactive oxidative species resulting in apoptosis. Although this therapy has been shown previously to be effective in preclinical studies, there is a lack of established standardized parameters. Standardized methods are necessary to optimize this therapeutic strategy for preclinical and clinical use. In this paper, we detail the protocol to perform SDT in a preclinical GBM rodent model using magnetic resonance-guided FUS (MRgFUS). MRgFUS is an important feature of this protocol, as it allows for specific targeting of a brain tumor without the need for invasive surgeries (e.g., craniotomy). The benchtop device used here can focus on a specific location in three dimensions by clicking on a target on an MRI image, making target selection a straightforward process. This protocol will provide researchers with a standardized preclinical method for MRgFUS SDT, with the added flexibility to change and optimize parameters for translational research.

Here, we describe a protocol that details how to perform sonodynamic therapy in an in vivo mouse glioblastoma model using magnetic resonance-guided focused ultrasound.

Sonodynamic therapy (SDT) is an application of focused ultrasound (FUS) that enables a sonosensitizing agent to prime tumors for increased sensitivity ...

A Benchtop Approach to the Location Specific Blood Brain Barrier Opening using Focused Ultrasound in a Rat Model

Stereotaxic surgery is the gold standard for localized drug and gene delivery to the rodent brain. This technique has many advantages over systemic delivery including precise localization to a target brain region and reduction of off target side effects. However, stereotaxic surgery is highly invasive which limits its translational efficacy, requires long recovery times, and provides challenges when targeting multiple brain regions. Focused ultrasound (FUS) can be used in combination with circulating microbubbles to transiently open the blood brain barrier (BBB) in millimeter sized regions. This allows intracranial localization of systemically delivered agents that cannot normally cross the BBB. This technique provides a noninvasive alternative to stereotaxic surgery. However, to date this technique has yet to be widely adopted in neuroscience laboratories due to the limited access to equipment and standardized methods. The overall goal of this protocol is to provide a benchtop approach to FUS BBB opening (BBBO) that is affordable and reproducible and can therefore be easily adopted by any laboratory.

Focused ultrasound with microbubble agents can open the blood brain barrier focally and transiently. This technique has been used to deliver a wide range of agents across the blood brain barrier. This article provides a detailed protocol for the localized delivery to the rodent brain with or without MRI guidance.

Stereotaxic surgery is the gold standard for localized drug and gene delivery to the rodent brain. This technique has many advantages over systemic ...

Neuroscience

A High-Throughput Image-Guided Stereotactic Neuronavigation and Focused Ultrasound System for Blood-Brain Barrier Opening in Rodents

The blood-brain barrier (BBB) has been a major hurdle for the treatment of various brain diseases. Endothelial cells, connected by tight junctions, form a physiological barrier preventing large molecules (&#62;500 Da) from entering the brain tissue. Microbubble-mediated focused ultrasound (FUS) can be used to induce a transient local BBB opening, allowing larger drugs to enter the brain parenchyma.
In addition to large-scale clinical devices for clinical translation, preclinical research for therapy response assessment of drug candidates requires dedicated small animal ultrasound setups for targeted BBB opening. Preferably, these systems allow high-throughput workflows with both high-spatial precision as well as integrated cavitation monitoring, while still being cost effective in both initial investment and running costs.
Here, we present a bioluminescence and X-ray guided stereotactic small animal FUS system that is based on commercially available components and fulfills the aforementioned requirements. A particular emphasis has been placed on a high degree of automation facilitating the challenges typically encountered in high-volume preclinical drug evaluation studies. Examples of these challenges are the need for standardization in order to ensure data reproducibility, reduce intra-group variability, reduce sample size and thus comply with ethical requirements and decrease unnecessary workload. The proposed BBB system has been validated in the scope of BBB opening facilitated drug delivery trials on patient-derived xenograft models of glioblastoma multiforme and diffuse midline glioma.

The blood-brain barrier (BBB) can be temporarily disrupted with microbubble-mediated focused ultrasound (FUS). Here, we describe a step-by-step protocol for high-throughput BBB opening in vivo using a modular FUS system accessible for non-ultrasound experts.

The blood-brain barrier (BBB) has been a major hurdle for the treatment of various brain diseases. Endothelial cells, connected by tight junctions, form a ...

Targeted Neuronal Injury for the Non-Invasive Disconnection of Brain Circuitry

Surgical intervention can be quite effective for treating certain types of medically intractable neurological diseases. This approach is particularly useful for disorders in which identifiable neuronal circuitry plays a key role, such as epilepsy and movement disorders. Currently available surgical modalities, while effective, generally involve an invasive surgical procedure, which can result in surgical injury to non-target tissues. Consequently, it would be of value to expand the range of surgical approaches to include a technique that is both non-invasive and neurotoxic.
Here, a method is presented for producing focal, neuronal lesions in the brain in a non-invasive manner. This approach utilizes low-intensity focused ultrasound together with intravenous microbubbles to transiently and focally open the Blood Brain Barrier (BBB). The period of transient BBB opening is then exploited to focally deliver a systemically administered neurotoxin to a targeted brain area. The neurotoxin quinolinic acid (QA) is normally BBB-impermeable, and is well-tolerated when administered intraperitoneally or intravenously. However, when QA gains direct access to brain tissue, it is toxic to the neurons. This method has been used in rats and mice to target specific brain regions. Immediately after MRgFUS, successful opening of the BBB is confirmed using contrast enhanced T1-weighted imaging. After the procedure, T2 imaging shows injury restricted to the targeted area of the brain and the loss of neurons in the targeted area can be confirmed post-mortem utilizing histological techniques. Notably, animals injected with saline rather than QA do demonstrate opening of the BBB, but dot not exhibit injury or neuronal loss. This method, termed Precise Intracerebral Non-invasive Guided surgery (PING) could provide a non-invasive approach for treating neurological disorders associated with disturbances in neural circuitry.

The goal of the protocol is to provide a method for producing non-invasive neuronal lesions in the brain. The method utilizes Magnetic Resonance-guided Focused Ultrasound (MRgFUS) to open the Blood Brain Barrier in a transient and focal manner, in order to deliver a circulating neurotoxin to the brain parenchyma.

Surgical intervention can be quite effective for treating certain types of medically intractable neurological diseases. This approach is particularly ...

Focused Ultrasound Induced Blood-Brain Barrier Opening for Targeting Brain Structures and Evaluating Chemogenetic Neuromodulation

Acoustically Targeted Chemogenetics (ATAC) allows for the noninvasive control of specific neural circuits. ATAC achieves such control through a combination of focused ultrasound (FUS) induced blood-brain barrier opening (FUS-BBBO), gene delivery with adeno-associated viral (AAV) vectors, and activation of cellular signaling with engineered, chemogenetic, protein receptors and their cognate ligands. With ATAC, it is possible to transduce both large and small brain regions with millimeter precision using a single noninvasive ultrasound application. This transduction can later allow for a long-term, noninvasive, device-free neuromodulation in freely moving animals using a drug. Since FUS-BBBO, AAVs, and chemogenetics have been used in multiple animals, ATAC should also be scalable for the use in other animal species. This paper expands upon a previously published protocol and outlines how to optimize the gene delivery with FUS-BBBO to small brain regions with MRI-guidance but without a need for a complicated MRI-compatible FUS device. The protocol, also, describes the design of mouse targeting and restraint components that can be 3D-printed by any lab and can be easily modified for different species or custom equipment. To aid reproducibility, the protocol describes in detail how the microbubbles, AAVs, and venipuncture were used in ATAC development. Finally, an example data is shown to guide the preliminary investigations of studies utilizing ATAC.

This protocol delineates steps necessary for the gene delivery through focused ultrasound blood brain barrier (BBB) opening, evaluation of the resulting gene expression, and measurement of neuromodulation activity of chemogenetic receptors through histological tests.

Acoustically Targeted Chemogenetics (ATAC) allows for the noninvasive control of specific neural circuits. ATAC achieves such control through a ...

Real-Time Magnetic Resonance Guided Focused Ultrasound for Painful Bone Metastases

Bones are one of the most common sites of cancer metastasis, which usually causes pain and impairs quality of life. Radiation therapy combined with opioids is the standard treatment for painful bone metastases. This treatment achieves effective pain control in 60&#8722;74% of patients, but limited treatment choices with limited benefits are available for recurrent or residual painful bone metastases after radiotherapy. More than 40% of patients still experience moderate to severe bone pain after reirradiation. Magnetic resonance-guided focused ultrasound (MRgFUS) combines high-intensity focused ultrasound, which achieves thermal ablation of bone metastases and subsequent pain reduction, with real-time magnetic resonance (MR) thermometry to monitor the temperature of anatomic MR images, with an accuracy of 1 &#176;C, spatial resolution of 1 mm, and temporal resolution within 3 s. As well as being increasingly used clinically for controlling metastatic bone pain, the use of MRgFUS for other diseases has also been tested. However, the use of MR software as a thermometer is the only technique available to verify the accuracy of the software and assure energy delivery. Here, we describe an efficient method of quality assurance we developed for thermal detection and energy delivery before each MRgFUS treatment and also propose a modified workflow to expedite the treatment course as well as to reduce patients&#39; pain during the procedure.

Magnetic resonance could offer real-time monitoring of the position and temperature of focused ultrasound in thermal ablation for painful bone metastases, regardless of cancer type or previous local treatments. Our innovative method of quality assurance could facilitate the application of this effective and safe treatment.

Bones are one of the most common sites of cancer metastasis, which usually causes pain and impairs quality of life. Radiation therapy combined with ...

MRI-guided Focused Ultrasound Thalamotomy for Patients with Medically-refractory Essential Tremor

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