Clinical aspects

Description

	• Focused ultrasound has many applications for neuromodulation in neurology and neurosurgery.
	• MRgFUS is approved for the treatment of essential tremor.
	• Focused ultrasound can be used to temporarily open the blood-brain barrier and facilitate drug delivery to the brain.
	• High frequency and intensity are used for thermoablation, eg, thalamotomy.

Magnetic resonance-guided focused ultrasound (MRgFUS), lying at the convergence of physics, engineering, imaging, biology, and neuroscience, offers an emerging tool for neurologic procedures applied to a wide range of indications. It can generate high-intensity energy at the focal fields deep in the body without requiring incision of soft tissues. The development of hemispheric distribution of ultrasound transducer phased arrays has overcome the problem of the skull as a barrier and enabled the performance of transcranial procedures and advanced imaging technologies, such as magnetic resonance thermometry, have enhanced the safety of MRgFUS (09). Some skull-related factors correlate with the maximal target area temperature. In brain applications, focused ultrasound is generally performed under MRI guidance, enabling targeted deposition of acoustic effects and real-time visualization of treatment, eg, thermal effect. MRgFUS planning requires a volumetric CT scan to account for bone thickness and density and correct the phase aberration that prevents exact focusing.

Although ultrasound has many diagnostic applications, this article focuses on the therapeutic applications of focused ultrasound. Focused ultrasound offers the ability to noninvasively and precisely intervene in key circuits that drive common and challenging brain conditions. The utility of focused ultrasound in the brain ranges from transient blood-brain barrier opening and neuromodulation to permanent thermoablation, depending on ultrasound frequency, intensity, and use of microbubbles (15). For example, low-frequency ultrasound is used for opening the blood-brain barrier with microbubbles, and low to high frequencies as well as low intensities are used for neuromodulation. High frequency and intensity are used for thermoablation, eg, MRgFUS thalamotomy, which has regulatory clinical approval.

The procedure can be done on an ambulatory basis while the patient is awake and can communicate with the treating physician, and improvement of symptoms, such as relief of tremor, can be observed. A preliminary, low-dose exposure of the planned target to focused ultrasound may be done. No surgical incision or burr holes are required. Usually, the team consists of a neurosurgeon, a neurologist who may be a specialist in the disease being treated (eg, movement disorders), an interventional neuroradiologist, a nurse, and a physiotherapist. The procedure is performed in an MRI scanner. The scanner enables the physicians to target a small area of the brain relevant to the disease being treated; it also precisely measures the increased temperature in the brain caused by the ultrasound energy. Precautions and contraindications are the same as for other procedures performed in the MRI scanner.

Clinical trials of focused ultrasound. As of November 2021, 590 clinical trials of focused ultrasound were listed on the United States Government website, and 82 of these were for neurologic disorders (ClinicalTrials.org).

A global post-approval study to collect safety and effectiveness data related to ExAblate Neuro for the treatment of certain disorders, such as essential tremor, parkinsonian movement disorders, or neuropathic pain, is active but not recruiting patients (ClinicalTrials.gov Identifier: NCT03100474).

Indications

Indications for the use of focused ultrasound are listed in Table 1.

Table 1. Indications for the Use of Focused Ultrasound

Drug delivery
	• Facilitate passage of drugs and genes across the blood-brain barrier
	• Combination of nanomaterials and ultrasound
	• Thermal combination therapies for local drug delivery by MRgFUS
Neurodegenerative disorders
	• Alzheimer disease
	• Parkinson disease
Neuromodulation in neurologic disorders
	• Epilepsy, control of seizures
	• Neuropathic pain
	• Tremor
Psychiatric disorders
	• Major depressive disorder
	• Obsessive-compulsive disorder
Stroke
	• Thrombolysis
Neurooncology
	• Brain tumor ablation
	• Intramedullary spinal cord tumor surgery

Opening of the blood-brain barrier and drug delivery. The potential of microbubble-mediated, focused ultrasound-induced opening of the blood-brain barrier for targeted drug delivery to the brain is being explored. Transcranial MRgFUS procedures are used for both thermoablation and blood-brain barrier opening.

Hyperthermia-triggered local drug delivery is possible through the use of MRgFUS in combination with temperature-sensitive liposomes. A study compared different MR-high-intensity focused ultrasound treatment schemes comprising ablation and hyperthermia-triggered drug delivery with respect to drug distribution and therapeutic efficacy and showed that a combination protocol of hyperthermia-induced drug delivery followed by ablation resulted in homogeneous drug distribution and the highest therapeutic effect (07).

Neuromodulation in neurologic disorders

Neurodegenerative disorders. The blood-brain barrier is an obstacle to the delivery of potential molecular therapies for neurodegenerative diseases, such as Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis. Although several potential disease-modifying therapies have been developed for these conditions, methods for delivering these large molecules remain limited. High-intensity MRI-guided focused ultrasound has already been approved by the U.S. Food and Drug Administration to lesion brain targets to treat movement disorders, whereas lower intensity pulsed ultrasound coupled with microbubbles commonly used as contrast agents can create transient safe opening of the blood-brain barrier. Preclinical studies have successfully delivered growth factors, antibodies, genes, viral vectors, and nanoparticles in rodent models of Alzheimer disease and Parkinson disease (03). Small clinical trials support the safety and feasibility of this strategy in these vulnerable patients. Further study is needed to establish safety as MRI-guided blood-brain barrier opening enhances the delivery of newly developed molecular therapies.

Alzheimer disease. The blood-brain barrier presents a significant challenge for treating brain disorders. For example, the hippocampus is a key target for novel therapeutics in Alzheimer disease. Preclinical studies have shown that MR-guided low-intensity focused ultrasound can reversibly open the blood-brain barrier and facilitate the delivery of targeted brain therapeutics. Initial clinical trial results evaluating the safety, feasibility, and reversibility of blood-brain barrier opening with focused ultrasound treatment of the hippocampus and entorhinal cortex in patients with early Alzheimer disease have been reported (18). Post-FUS contrast MRI revealed immediate and sizable hippocampal parenchymal enhancement indicating blook-brain barrier opening, followed by closure within 24 hours. The average opening was 95% of the targeted focused ultrasound volume, which corresponds to 29% of the overall hippocampus volume. The authors demonstrated that focused ultrasound can safely, noninvasively, transiently, reproducibly, and focally mediate blood-brain barrier opening in the human hippocampus and entorhinal cortex. This provides a unique translational opportunity to investigate therapeutic delivery in Alzheimer disease and other conditions. Focused MRgFUS in combination with intravenously injected microbubbles has been shown to transiently open the blood-brain barrier in patients with early to moderate Alzheimer disease in a phase I safety trial (12). In all patients, the blood-brain barrier within the target volume was safely, reversibly, and repeatedly opened. Opening the blood-brain barrier did not result in serious clinical or radiographic adverse events, and there was no clinically significant worsening on cognitive scores at 3 months compared to baseline. Aβ levels were measured before treatment using [18F]-florbetaben PET to confirm amyloid deposition at the target site. Exploratory analysis suggested no group-wise changes in amyloid postsonication. The results of this safety and feasibility study support the continued investigation of focused ultrasound as a potential novel treatment strategy for patients with Alzheimer disease.

Parkinson disease. MRgFUS is a minimally invasive technique for ablation of cerebral structures, such as the substantia nigra, internal globus pallidus, and ventral intermediate nucleus, during thalamotomy for relief of tremor with a lower risk of infection and cerebral hemorrhage than seen in invasive procedures. A prospective, single-arm, nonrandomized, proof-of-concept safety and feasibility phase I clinical trial (NCT03608553) was started for Parkinson disease dementia and is still in progress. The primary outcomes of the study demonstrated the safety, feasibility, and reversibility of blood-brain barrier disruption in Parkinson disease dementia, targeting the right parieto occipitotemporal cortex where cortical pathology is foremost in this clinical state. Changes in Aβ burden, brain metabolism after treatments, and neuropsychological assessments were analyzed as exploratory measurements. In all cases, the procedures were uneventful, and no side effects associated with blood-brain barrier opening were encountered. From pre- to post-treatment, mild cognitive improvement was observed, and no major changes were detected in amyloid or fluorodeoxyglucose PET. MRgFUS blood-brain-barrier opening in Parkinson disease dementia is, thus, safe, reversible, and can be performed repeatedly. This study provides encouragement for the concept of blood-brain barrier opening for drug delivery to treat dementia in Parkinson disease and other neurodegenerative disorders (04).

Several cell transplantation and gene therapy trials to restore function in Parkinson disease have been performed during the past 3 decades. Innovations such as design of cannula, iMRI-guided surgery, and an evolution in delivery strategy have radically changed the ways investigators approach clinical trial design. Future therapeutic strategies may employ newer delivery methods, such as chronically implanted infusion devices and focal opening of the blood-brain barrier with focused ultrasound (10).

Control of epileptic seizures. The role of MRI in epilepsy is mainly diagnostic. Resection of an epileptic focus is an evidence-based curative treatment option for patients with drug-resistant focal epilepsy. The major preoperative predictor of a good surgical outcome is the detection of an epileptogenic lesion by ultra-high-field MRI (ie, field strengths ≥ 7 Tesla MRI may increase the sensitivity to detect such a lesion). Whether this results in improved seizure control after surgical treatment remains to be proven. Besides technical improvements, a correlation of imaging features with histopathology and clinical outcome must be established (19).

Neuropathic pain. Focused ultrasound can influence several mechanisms relevant for neuropathic pain management, such as modulation of ion channels, glutamatergic neurotransmission, cerebral blood flow, inflammation and neurotoxicity, neuronal morphology and survival, nerve regeneration, and remyelination. Results in experimental models have shown that low-intensity focused ultrasound may reduce pain after peripheral nerve damage. A few clinical studies also support the beneficial effects of thalamic ablation by focused ultrasound on reducing pain in neuropathic pain syndromes (16); better controlled clinical trials are needed to determine the safety and efficacy.

Tremor. There has been no breakthrough drug for the treatment of essential tremor, but there are several remarkable achievements in the noninvasive neuromodulation and minimally invasive surgical fields, such as radiofrequency thalamotomy, thalamic deep-brain stimulation, transcranial magnetic stimulation, and Gamma Knife thalamotomy. The most recent advance in this area is magnetic resonance-guided focused ultrasound.

Technically, a transducer with 1024 elements emits ultrasound beams that are focused on the target with a phase control, resulting in optimal ablation by thermal coagulation (14). The technical advantages of MRgFUS are continuous intraoperative monitoring of clinical symptoms and MR images and fine adjustment of the target by the steering function. Postoperative tremor control is compatible with other modalities, although long-term follow-up is necessary.

A high skull density ratio is needed to achieve high temperature and large lesioning, but it may not be necessary and sufficient for clinical outcomes. Deep-brain stimulation may be recommended for patients with advanced symptoms, such as bilateral tremor or head/neck tremor, because of the adjustability of stimulation and the possibility of bilateral treatment. To perform this treatment safely and effectively, physicians need to understand the technological aspects and the physiological principles. To choose the appropriate modality, physicians also should recognize the clinical advantages and disadvantages of MRgFUS compared to other modalities.

Deep-brain stimulation remains the current standard surgical treatment for medication-resistant essential tremor, but the introduction of incisionless techniques, such as MRgFUS thalamotomy, has led to a systematic review comparing the results from these two techniques in terms of tremor severity and quality-of-life improvement (05). Tremor improvement was greater following deep-brain stimulation than MRgFUS thalamotomy, but postoperative quality-of-life was significantly more improved following MRgFUS thalamotomy than after deep-brain stimulation. Persistent complications were significantly more common in the MRgFUS group. Although bilateral deep-brain stimulation proves superior to unilateral MRgFUS thalamotomy in the treatment of essential tremor, a subgroup analysis suggests that treatment laterality is the most significant determinant of tremor improvement, thus, highlighting the importance of future investigations of bilateral staged MRgFUS thalamotomy.

Another systematic review of comparative trials showed that subthalamic deep-brain stimulation ranked first, followed by combined deep-brain stimulation of pedunculopontine nucleus and caudal zona incerta; pedunculopontine nucleus deep-brain stimulation ranked last (11). MRIgFUS, an effective intervention for improving parkinsonian tremor, was not demonstrated to be inferior to deep-brain stimulation in suppressing parkinsonian tremor. Therefore, clinicians should distinguish individual patients' symptoms to ensure appropriate intervention and therapeutic targets are used.

Psychiatric indications. Obsessive-compulsive disorder and major depressive disorder are common, often refractory, neuropsychiatric conditions. A study of MRgFUS bilateral anterior capsulotomy in patients with refractory obsessive-compulsive disorder and major depressive disorder revealed no serious adverse events. To delineate the white-matter tracts impacted by capsulotomy, a normative diffusion MRI-based structural connectome revealed tracts terminating primarily in the frontal pole, medial thalamus, striatum, and medial-temporal lobe. PET analysis revealed widespread decreases in metabolism bilaterally in the cerebral hemispheres at 6 months posttreatment as well as in the right hippocampus, amygdala, and putamen. A pretreatment seed-to-voxel resting-state functional magnetic resonance imaging (rs-fMRI) analysis in 12 subjects revealed three voxel clusters significantly associated with eventual clinical response. MRgFUS capsulotomy appears to be safe and well-tolerated and, according to these initial results, may be an important treatment option for patients with refractory obsessive-compulsive disorder and major depressive disorder (01). MRgFUS capsulotomy results in both targeted and widespread changes in neural activity, and neuroimaging may hold potential for predicting outcome.

Stroke. In a thrombotic stroke, lysis or removal of thrombus is required promptly to restore blood flow to the affected area. The combination of laser and ultrasound can significantly improve the efficiency of thrombolysis through an enhanced cavitation effect. Jo and colleagues developed a fiber optics-based laser-ultrasound thrombolysis device; they tested the feasibility and efficiency of this technology for restoring blood flow in an in vitro blood clot model (08). The laser and ultrasound pulses were synchronized and delivered to the blood clot concurrently. The laser pulses of 532 nm were delivered to the blood clot endovascularly through an optical fiber, whereas the ultrasound pulses of 0.5 MHz were applied noninvasively to the same region. Thus, effective thrombolysis can be achieved by combining endovascular laser with noninvasive ultrasound at relatively low power and pressure levels, potentially improving both the clinical treatment efficiency and safety in stroke patients.

Brain tumors. Treatment of malignant primary brain tumors, particularly glioblastoma, is limited. Focused ultrasound can improve the management of malignant primary tumors by the actions and rationale shown in Table 2 (17).

Table 2. Focused Ultrasound-Mediated Improvement of Management of Glioblastoma

Focused ultrasound-mediated action	Rationale
Thermal ablation	Ultrasound contrast agents, such as intravascular microbubbles, can enhance tissue ablation by exploiting cavitation, permitting a reduction in time-averaged acoustic power, and overcoming the limitation of bone heating compared to standard thermal tumor ablation.
Blood-brain barrier disruption using focused ultrasound	Focused ultrasound enables selective opening of the blood-brain barrier for delivery of therapeutic concentrations of chemotherapy without systemic side effects.
Focused ultrasound-mediated targeted drug across blood-brain barrier engineered nanoparticles with dense poly(ethylene glycol) coating	Focused ultrasound in combination with nanoparticles could overcome the diffusion limitations of the blood-brain barrier and deliver a drug to the target in the brain.
Interstitial focused ultrasound (catheter-based focused ultrasound)	Multi-elemental cooled catheter with cylindrical elements enables precise shaping of the ablative field of large tumors.
Sonoporation as stable cavitation to induce transient pore opening in cell membrane	An increase of fluid motions in cell micro-environment through acoustic streaming enables enhanced drug/gene penetration and actions.
Focused ultrasound immunomodulation	Focused ultrasound is synergistic with immunotherapy as it leads to superior blood-brain barrier permeability for antigens, immune cells, and pro-inflammatory molecules. Tumor mechanical disruption also generates a bulk of tumor-related debris, and antigens activate dendritic cells. Focused ultrasound can moderate tumor-related immunosuppression, enhance tumor-infiltrating cell population, and facilitate neuroglial cell activation.
Sensitization to radiotherapy	Focused ultrasound induces a sensitization to radiotherapy that could require a lower dose of radiation to be effective and reduce radiation-induced side effects. Biologically, focused ultrasound and radiation are complementary, and cells in S phase of cell cycle are more sensitive to hyperthermia whereas they are relatively resistant to radiation.
Sensitization to chemotherapy.	Ultrasound can enhance the sensitivity to chemotherapy due to several mechanisms: (1) Local hyperthermia induces a local increase in blood flow, allowing greater delivery of drugs, oxygen, and trophic molecules. This leads to an augmented metabolic activity and, as a result, to a sensitization to chemotherapeutic agents. (2) Focused ultrasound could revert tumor-acquired resistance to certain drugs, thus, regaining a therapeutic efficacy. (3) Local hyperthermia is particularly effective in tumor cells because of their reduced ability to scatter heat. (4) Focused ultrasound offers a noninvasive method to induce an enhanced sensitivity to chemotherapy as it has been demonstrated in preclinical studies supporting the potential application in numerous types of tumors in the clinical setting.
Need for repeated opening of the blood-brain barrier	The principal limitation to focused ultrasound application in brain tumors is the thickness of the skull, which absorbs up to 90% of an ultrasound beam, complicating repetitive applications of FUS and especially for the treatment of superficial tumors. A solution to this problem is represented by an implantable ultrasound device, ie, SonoCloud, which permits repeatable, diffuse blood-brain barrier opening. SonoCloud implantation has been used in recurrent glioblastoma patients to obtain monthly blood-brain barrier opening before systemic administration of carboplatin.

Intramedullary spinal cord tumors. Intraoperative contrast-enhanced ultrasound is a relatively standardized procedure in neurosurgery, but it is still underused in spinal cord and intramedullary tumor evaluation. Review and analysis of the intraoperative data from a surgical series of patients harboring intramedullary spinal cord tumors who underwent surgery under contrast-enhanced ultrasound guidance showed peritumoral cysts at preliminary intraoperative B-mode ultrasound (20). Contrast-enhanced ultrasound highlighted the tumors in all cases. The contrast agent's spinal distribution revealed different phases as observed in the brain, but these appeared to be slower and less intense. In the authors’ experience, intraoperative contrast-enhanced ultrasound allows surgeons to assess spinal cord perfusion and highlight intramedullary tumors in real-time. As for other imaging modalities, ultrasound contrast agents add valuable information over baseline imaging, and they should be used to better understand microbubble distribution dynamics.

Contraindications

Patients with mild-to-moderate claustrophobia may still be able to tolerate MRgFUS procedures in MRI chambers on on a case-by-case basis. Medical contraindications for MRgFUS procedures include uncorrected coagulopathy, which should be corrected such that the international normalized ratio is less than 1.2. Platelet count should also be above 100,000/μL. Patients on anticoagulation or antiplatelet therapies can be asked to hold these medications for the procedures if the associated risks for doing so are low.

Results

Results are described with each application.

Adverse effects

The adverse effects of focused ultrasound are usually transient and acceptable.

Scientific basis

• Low-intensity transcranial focused ultrasound has nondestructive pressure effects on cellular membranes and ion channels.

Low-intensity transcranial focused ultrasound exerts nondestructive mechanical pressure effects on cellular membranes and ion channels and has been shown to modulate the activity of neural structures in the cortex and even deep-brain nuclei, such as the thalamus (22). Because of these advantages, this technology has prospects of broad application in treating neurodegenerative and neuropsychiatric disorders.

High-intensity ultrasound cavitation consists of the formation and oscillation of gas bubbles originating from stable gas nuclei and propagates as a wave of positive and negative components; the first leads to compression and the second to the expansion of gas bubbles. The bubbles oscillate depending on the positive and negative components of the ultrasound wave and cause pressure on the surrounding tissues.

Future outlook of focused ultrasound. Future applications of focused ultrasound therapy have a favorable, potentially competitive role against established technologies, including deep-brain stimulation and stereotactic radiosurgery, particularly regarding tissue ablation, blood-brain-barrier opening, and gene therapy (21). However, some hurdles must be overcome before focused ultrasound becomes widely accepted by neurologists and neurosurgeons.