Tag: focused ultrasound

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A Scoping Review of Focused Ultrasound- Blood-Brain Barrier Opening for Treatment of Chronic Pain

Neurosurgery 98:328–338, 2026

This scoping review evaluates focused ultrasound–mediated blood–brain barrier opening (FUS‑BBBO) as a targeted drug‑delivery strategy to treat chronic pain, summarizing systematic literature screening and preclinical evidence. It outlines how FUS parameters, microbubbles, and regional targeting can transiently permit delivery of drugs and particles otherwise excluded by the BBB, potentially improving efficacy and reducing systemic toxicity.

The document surveys candidate therapeutics (opioids, peptides, antibodies, gene therapies) and particle vehicles (nanoparticles, liposomes, niosomes, AAVs), highlights preclinical successes and delivery challenges, and stresses safety, parameter optimization, and the need for human trials. It concludes that FUS‑BBBO combined with advanced delivery platforms holds promise but requires systematic clinical evaluation.

Blood-brain barrier (BBB) challenge: The BBB restricts most drugs from entering the brain, impeding effective pharmacological treatment of chronic pain, with only small, lipophilic molecules (<400–500 Da) able to cross easily, while 98% of small molecules and nearly all large molecules are excluded.

Focused ultrasound (FUS)-mediated BBB opening (FUSBO): FUSBO uses low-intensity ultrasound and microbubbles to temporarily, noninvasively open the BBB, enabling targeted drug delivery to specific brain regions without thermal damage.

Current pain therapies’ limitations: Opioids, gabapentin, cannabinoids, and other agents have limited efficacy and significant systemic side effects due to poor BBB penetration and susceptibility to efflux mechanisms like p-glycoprotein pumps.

Preclinical evidence, lack of human trials: While FUSBO has shown success in animal models for delivering pain therapies directly to the CNS and enhancing efficacy, no human studies have yet assessed FUSBO for chronic pain treatment.

Advancements in drug delivery particles: Nanoparticles, niosomes, polymeric nanoparticles, gold nanoparticles, and liposomes can be engineered to carry drugs across the BBB, improve bioavailability, and reduce toxicity, especially when combined with FUSBO.

Potential for biologics and gene therapy: FUSBO may enable delivery of monoclonal antibodies, single-chain fragment variable antibodies, and adeno-associated virus (AAV) gene therapies to the CNS, overcoming size and immune barriers.

Safety and technical considerations: FUSBO is generally safe in animal and early human studies, but potential risks include microglial activation, microhemorrhage, and neuronal suppression at high intensities; optimal parameters for various drugs and delivery systems remain to be established.

Outlook and clinical promise: FUSBO combined with advanced drug delivery particles could transform chronic pain management by bypassing the BBB, expanding the range of usable therapies, and improving the therapeutic window, but clinical trials are needed to confirm efficacy and safety in humans.

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Brain Bleeding Associated With Cavitation During Focused Ultrasound Ablation

Neurosurgery 97:1215–1218, 2025

This report presents two cases of symptomatic intracranial hemorrhage occurring during MR-guided focused ultrasound (MRgFUS) ablation for movement disorders, associated with persistent cavitation activity despite power reductions. Both patients developed contralateral motor deficits after sonications; one recovered substantially, the other remained significantly disabled, and imaging confirmed hematomas at the targeted sites.

The authors review procedural variables, cavitation mechanisms, mitigation strategies, and institutional experience (~500 cases, 0.4% incidence), recommending a conservative approach—including treatment termination—when uncontrollable cavitation arises, and urging further study of patient- and system-related risk factors to minimize bleeding risk.

• MRgFUS Complication: Symptomatic brain bleeding can occur during magnetic resonance–guided focused ultrasound (MRgFUS) ablation for movement disorders, although it is a rare complication (approximately 0.4% incidence in a center with over 500 cases).

• Cavitation Risk: Persistent cavitation—microbubble formation and collapse during sonication—is strongly associated with the occurrence of brain hemorrhage in MRgFUS procedures, even when standard mitigation steps (such as lowering power) are taken.

• Case Outcomes: In two reported cases, both patients developed contralateral motor weakness and brain hematoma following persistent cavitation during MRgFUS; one patient recovered functional independence, while the other remained severely disabled.

• Technical Mitigation: When cavitation is detected, the recommended strategy is to reduce sonication power and, if needed, increase duration to maintain energy delivery; however, if uncontrollable cavitation persists, treatment termination should be considered.

• Patient Factors: Bleeding can occur even in patients without traditional vascular risk factors, suggesting procedural factors like cavitation may be more critical than patient comorbidities in these cases.

• Incidence and Reporting: Over 20,000 MRgFUS procedures have been performed globally with very few reports of symptomatic brain bleeding, highlighting the importance of continued reporting to refine safety practices.

• Clinical Implication: MRgFUS is an effective and generally safe treatment for movement disorders, but it is not without risk; both clinicians and patients should be aware that severe complications, though rare, are possible.

• Best Practice: A conservative approach is advised if cavitation cannot be controlled during MRgFUS, and further study into both technical and patient-related risk factors for hemorrhage is warranted.

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Bilateral focused ultrasound medial thalamotomies for trigeminal neuropathic pain: a randomized controlled study

J Neurosurg 140:1799–1809, 2024

Medial thalamotomy has been shown to benefit patients with neuropathic pain, but widespread adoption of this procedure has been limited by reporting of clinical outcomes in studies without a control group. This study aimed to minimize confounders associated with medial thalamotomy for treating chronic pain by using modern MRI-guided stereotactic lesioning and a rigorous clinical design.

METHODS This prospective, double-blinded, randomized controlled trial in 10 patients with trigeminal neuropathic pain used sham procedures as controls. Participants underwent assessments by a pain psychologist and pain management clinician, including use of the following measures: the Numeric Pain Rating Scale (NPRS); patient-reported outcome measures; and patient’s impression of improvement at baseline, 1 day, 1 week, 1 month, and 3 months postprocedure. Patients in the treated group underwent bilateral focused ultrasound (FUS) medial thalamotomy targeting the central lateral nucleus. Patients in the control group underwent sham procedures with energy output disabled. The primary efficacy outcome measure was between-group differences in pain intensity (using the NPRS) at baseline and at 3 months postprocedure. Adverse events were measured for safety and included MRI analysis. Exploratory measures of connectivity and metabolism were analyzed using diffusion tensor imaging, functional MRI, and PET, respectively.

RESULTS There were no serious complications from the FUS procedures. MRI confirmed bilateral medial thalamic ablations. There was no significant improvement in pain intensity from baseline to 3 months, either for patients undergoing FUS medial thalamotomy or for sham controls; and the between-group change in NPRS score as the primary efficacy outcome measure was not significantly different. Patient-reported outcome assessments demonstrated improvement (i.e., a decrease) only in pain interference with enjoyment of life at 3 months. There was a perception of benefit at 1 week, but only for patients treated with FUS and not for the sham cohort. Advanced neuroimaging showed that these medial thalamic lesions altered structural connectivity with the postcentral gyrus and demonstrated a trend toward hypometabolism in the insula and amygdala.

CONCLUSIONS This randomized controlled trial of bilateral FUS medial thalamotomy did not reduce the intensity of trigeminal neuropathic pain, although it should be noted that the ability to estimate the magnitude of treatment effects is limited by the small cohort.

Clinical trial registration no.: NCT03309813 (ClinicalTrials.gov)

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Patient-Reported Outcomes After Focused Ultrasound Thalamotomy for Tremor-Predominant Parkinson’s Disease

Neurosurgery 93:884–891, 2023

Magnetic resonance–guided focused ultrasound (MRgFUS) has emerged as a precise, incisionless approach to cerebral lesioning and an alternative to neuromodulation in movement disorders. Despite rigorous clinical trials, long-term patient-centered outcome data after MRgFUS for tremor-predominant Parkinson’s Disease (TPPD) are relatively lacking.

OBJECTIVE: To report long-term data on patient satisfaction and quality of life after MRgFUS thalamotomy for TPPD.

METHODS: In a retrospective study of patients who underwent MRgFUS thalamotomy for TPPD at our institution between 2015 and 2022, a patient survey was administered to collect self-reported measures of tremor improvement, recurrence, Patients’ Global Impression of Change (PGIC), and side effects. Patient demographics, FUS parameters, and lesion characteristics were analyzed.

RESULTS: A total of 29 patients were included with a median follow-up of 16 months. Immediate tremor improvement was achieved in 96% of patients. Sustained improvement was achieved in 63% of patients at last follow-up. Complete tremor recurrence to baseline occurred for 17% of patients. Life quality improvement denoted by a PGIC of 1 to 2 was reported by 69% of patients. Long-term side effects were reported by 38% of patients and were mostly mild. Performing a secondary anteromedial lesion to target the ventralis oralis anterior/posterior nucleus was associated with higher rates of speech-related side effects (56% vs 12%), without significant improvement in tremor outcomes.

CONCLUSION: Patient satisfaction with FUS thalamotomy for tremor-predominant PD was very high, even at longer term. Extended lesioning to target the motor thalamus did not improve tremor control and may contribute to greater frequency of postoperative motor- and speech-related side effects.

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Initial experience with magnetic resonance–guided focused ultrasound stereotactic surgery for central brain lesions in young adults

J Neurosurg 137:760–767, 2022

Magnetic resonance–guided focused ultrasound (MRgFUS) is an incisionless procedure capable of thermoablation through the focus of multiple acoustic beams. Although MRgFUS is currently approved for the treatment of tremor in adults, its safety and feasibility profile for intracranial lesions in the pediatric and young adult population remains unknown.

METHODS The long-term outcomes of a prospective single-center, single-arm trial of MRgFUS at Nicklaus Children’s Hospital in Miami, Florida, are presented. Patients 15–22 years of age with centrally located lesions were recruited, clinically consistent with WHO grade I tumors that require surgical intervention. This cohort consisted of 4 patients with hypothalamic hamartoma (HH), and 1 patient with tuberous sclerosis complex harboring a subependymal giant cell astrocytoma (SEGA).

RESULTS In each case, high-intensity FUS was used to target the intracranial lesion. Real-time MRI was used to monitor the thermoablations. Primary outcomes of interest were tolerability, feasibility, and safety of FUS. The radiographic ablation volume on intra- and postoperative MRI was also assessed. All 5 patients tolerated the procedure without any complications. Successful thermoablation was achieved in 4 of the 5 cases; the calcified SEGA was undertreated due to intratumor calcification, which prevented attainment of the target ablation temperature. The HHs underwent target tissue thermoablations that led to MR signal changes at the treatment site. For the patients harboring HHs, FUS thermoablations occurred without procedure-related complications and led to improvement in seizure control or hypothalamic hyperphagia. All 5 patients were discharged home on postoperative day 1 or 2, without any readmissions. There were no cases of hemorrhage, electrolyte derangement, endocrinopathy, or new neurological deficit in this cohort.

CONCLUSIONS This experience demonstrates that FUS thermoablation of centrally located brain lesions in adolescents and young adults can be performed safely and that it provides therapeutic benefit for associated symptoms. Clinical trial registration no.: NCT03028246

 

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Prospective Tractography-Based Targeting for Improved Safety of Focused Ultrasound Thalamotomy

Neurosurgery 84:160–168, 2019

Focused ultrasound thalamotomy (FUS-T) was recently approved for the treatment of refractory essential tremor (ET). Despite its noninvasive approach, FUS-T reinitiated concerns about the adverse effects and long-term efficacy after lesioning.

OBJECTIVE: To prospectively assess the outcomes of FUS-T in 10 ET patients using tractography-based targeting of the ventral intermediate nucleus (VIM).

METHODS: VIM was identified at the intercommissural plane based on its neighboring tracts: the pyramidal tract and medial lemniscus. FUS-T was performed at the center of tractography-defined VIM. Tremor outcomes, at baseline and 3 mo, were assessed independently by the Tremor Research Group.We analyzed targeting coordinates, clinical outcomes, and adverse events. The FUS-T lesion location was analyzed in relation to unbiased thalamic parcellation using probabilisitic tractography. Quantitative diffusionweighted imaging changes were also studied in fiber tracts of interest.

RESULTS: The tractography coordinates were more anterior than the standard. Intraoperatively, therapeutic sonications at the tractography target improved tremor (>50% improvement) without motor or sensory side effects. Sustained improvement in tremor was observed at 3mo(tremor score: 18.3±6.9 vs 8.1±4.4, P=.001).Nomotorweakness and sensory deficits after FUS-T were observed during 6-mo follow-up. Ataxia was observed in 3 patients. FUS-T lesions overlapped with the VIM parcellated with probablisitic tractography. Significant microstructural changes were observed in the white matter connecting VIM with cerebellum and motor cortex.

CONCLUSION: This is the first report of prospective VIM targeting with tractography for FUS-T. These results suggest that tractography-guided targeting is safe and has satisfactory short-term clinical outcomes.

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Minimally invasive treatment of intracerebral hemorrhage with magnetic resonance–guided focused ultrasound

Sonothrombolysis in ICH

J Neurosurg 118:1035–1045, 2013

Intracerebral hemorrhage (ICH) is a major cause of death and disability throughout the world. Surgical techniques are limited by their invasive nature and the associated disability caused during clot removal. Preliminary data have shown promise for the feasibility of transcranial MR-guided focused ultrasound (MRgFUS) sonothrombolysis in liquefying the clotted blood in ICH and thereby facilitating minimally invasive evacuation of the clot via a twist-drill craniostomy and aspiration tube.

Methods and Results. In an in vitro model, the following optimum transcranial sonothrombolysis parameters were determined: transducer center frequency 230 kHz, power 3950 W, pulse repetition rate 1 kHz, duty cycle 10%, and sonication duration 30 seconds. Safety studies were performed in swine (n = 20). In a swine model of ICH, MRgFUS sonothrombolysis of 4 ml ICH was performed. Magnetic resonance imaging and histological examination demonstrated complete lysis of the ICH without additional brain injury, blood-brain barrier breakdown, or thermal necrosis due to sonothrombolysis. A novel cadaveric model of ICH was developed with 40-ml clots implanted into fresh cadaveric brains (n = 10). Intracerebral hemorrhages were successfully liquefied (> 95%) with transcranial MRgFUS in a highly accurate fashion, permitting minimally invasive aspiration of the lysate under MRI guidance.

Conclusions. The feasibility of transcranial MRgFUS sonothrombolysis was demonstrated in in vitro and cadaveric models of ICH. Initial in vivo safety data in a swine model of ICH suggest the process to be safe. Minimally invasive treatment of ICH with MRgFUS warrants evaluation in the setting of a clinical trial.

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