Clinical aspects

Description

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 energy deep in the body without soft tissue incisions. The development of the hemispheric distribution of ultrasound transducer phased arrays has overcome the skull as a barrier and enabled the use of transcranial procedures, which has enhanced the safety of MRgFUS (16). MRgFUS is performed on an ambulatory basis, and the team usually consists of a neurosurgeon, nurse anesthetist, as well as radiology and ultrasound technicians. During the procedure, focused ultrasound is applied with increasing energy with MRI guidance. The patient remains awake during the procedure to monitor clinical response and side effects, which allows for more precise intraoperative lesioning (01). On the other hand, as LIFU involves nondestructive and more neuromodulatory effects, therapeutic benefits and side effects are not as readily appreciated in real-time. Planning requires a volumetric CT scan to account for bone thickness and density and correction of the phase aberration that prevents exact focusing. A high skull density ratio greater than 0.4 is typically preferred to achieve high temperature and large lesioning, but it may not be necessary and sufficient for clinical outcomes. A Japanese multicenter study showed similar effective results with lower ratios greater than 0.25 (03). This was also demonstrated by Vetkas and colleagues in a study using MRgFUS for tremor with skull density ratios less than 0.4 (33).

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.

Indications

MRgFUS is FDA-approved for bilateral essential tremor, tremor dominant Parkinson disease, as well as dyskinesias and other motor symptoms in Parkinson disease. Focused ultrasound is also being studied in many other neurologic conditions. Indications for the use of focused ultrasound are listed in Table 1.

Table 1. Indications for the Use of Focused Ultrasound

FDA-APPROVED INDICATIONS

Motor symptoms in Parkinson disease. Parkinson disease is a neurodegenerative disorder characterized by tremor, bradykinesia, rigidity, and postural instability. Dysfunction of the basal ganglia-thalamocortical circuitry is seen in Parkinson disease, and surgical treatments target these structures to improve motor function. Unilateral MRgFUS thalamotomy and pallidotomy are approved for the treatment for tremor dominant Parkinson disease, as well as dyskinesias and other motor symptoms in Parkinson disease. MRgFUS ventral intermediate nucleus of the thalamus (VIM) thalamotomy showed similar significant benefits and a favorable safety profile as shown with essential tremor. In a 1-year follow-up, hand tremor improvement scores remained high at 87.9% (30). Similar results were seen at follow-up at 5 years as well. Thalamotomy, however, does not significantly improve other motor symptoms in Parkinson disease, such as bradykinesia and rigidity. Thus, as Parkinson disease is a progressive disease, dopaminergic dosing was unchanged or increased in most cases during the follow-up period (35).

In a 1-year multicenter trial regarding focused ultrasound pallidotomy, UPDRS scores improved 44.5% at 3 months and 45.2% at 1 year (07). Similar and sustained results were seen with dyskinesias. Adverse events were mild as well. Ongoing studies are evaluating benefits with other target sites, such as the subthalamic nucleus and pallidothalamic tract. Gallay and colleagues investigated bilateral pallidothalamic tractotomy, with the second side surgery occurring 1 year after the first (10). Total UPDRS scores off-medication were reduced by 52% compared to on-medication baseline scores. The most improvement was seen with tremor at 91%, followed by 67% for distal rigidity and 54% for bradykinesia. There was also a significant improvement in pain reduction and decreased levodopa intake. Gait and postural instability were unchanged. Speech difficulties increased by 58% after the procedure. Cognitive function scores remained unchanged.

Deep brain stimulation remains the standard surgical treatment for medication refractory tremor and motor fluctuations in Parkinson disease. To date, no clinical trials have compared long-term outcomes for MRgFUS versus deep brain stimulation. Given progressive decline in Parkinson disease, it is unclear if and how long MRgFUS effects are sustained. The follow-up period in most studies has only ranged from 1 to 5 years. Deep brain stimulation Parkinson disease studies have shown efficacy for at least up to 10 to 15 years. Postoperative adjustments cannot be made with MRgFUS, but deep brain stimulation allows for continued stimulation adjustment for therapeutic benefits and reduction of dopaminergic medications. Deep brain stimulation treatment is also available bilaterally; MRgFUS treatments for Parkinson disease are only approved for unilateral treatment (17). MRgFUS may be preferred for patients who are apprehensive about surgery or hardware implantation or those unable to attend multiple appointments for deep brain stimulation programing and long-term device maintenance. Patients who have significant comorbidities and are poor surgical candidates and who have marked cognitive impairment might consider MRgFUS over deep brain stimulation (01).

Essential tremor. Essential tremor is a common movement disorder that typically presents as a bilateral upper limb action tremor. Tremors are slowly progressive and can affect the head, neck, jaw, voice, or legs over time as well. By limiting functional capacity, essential tremor impacts activities of daily living, such as eating, drinking, and writing, that can lead to reduced quality of life. MRgFUS is approved by the Food and Drug Administration (FDA) for medically refractory (> 2 medications) essential tremor. The primary target is the ventral intermediate nucleus of the thalamus (VIM), which is important in tremor circuitry. Studies of MRgFUS VIM lesioning have shown significant reductions in appendicular tremor, improvement in quality of life, and mild to moderate adverse side effects. Initial trials showed a 47% improvement at 3 months compared to the sham control group and a 62% reduction in total disability scores. Adverse events included gait disturbances in 36% of patients and paresthesias in 38%. These side effects persisted at 1 year in 9% and 14% of patients, respectively (08). Other adverse effects noted have also included mild to moderate weakness, ataxia, and dysgeusia. Notably, cognitive function remains stable with MRgFUS thalamotomy (29). Subsequent studies have shown sustained benefit for MRgFUS thalamotomy in essential tremor at 5 years, without progressive or additional complications (04).

Previously, MRgFUS was only indicated for unilateral refractory tremors. This limited its application in a syndrome of tremor symmetry and favored bilateral deep brain stimulation over unilateral MRgFUS thalamotomy for essential tremor. As of 2023, MRgGUS is now approved for bilateral essential tremor, with the second treatment occurring at least 9 months after the first. Bilateral MRgFUS thalamotomy has shown similar benefits, disability reduction, and safety profile as seen with unilateral thalamotomy. In addition, bilateral focused ultrasound demonstrated a mild benefit with voice and head tremors as well (22). There was no additional risk of gait difficulties, speech, or other side effects with bilateral lesioning (14).

Studies to date have only compared unilateral MRgFUS thalamotomy to unilateral or bilateral deep brain stimulation; there have been no comparisons between bilateral deep brain stimulation and bilateral MRgFUS thalamotomy. A systemic review comparing unilateral MRgFUS thalamotomy versus deep brain stimulation found no significant difference in tremor improvement. Postoperative quality of life was significantly improved in the focused ultrasound group, but persistent complications were more common (12). In deep brain stimulation, electrode reprogramming is used after initial lead implantation to address and reduce the frequency of stimulation-related adverse events. Focused ultrasound adverse effects are dependent on the location and size of the lesion, and postoperative adjustments cannot be made. Most procedure-related complications can be detected with intra-operative monitoring and mitigated with target repositioning. However, some complications cannot be assessed in this manner, such as gait disturbances and dysgeusia (29). Adverse effects are typically mild to moderate and may improve as perilesional edema resolves.

INVESTIGATORY STUDIES

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 disease-modifying therapies have been developed for these conditions, efficacy is thought to be limited by reduced neuroaxis penetration. Low-intensity pulsed ultrasound coupled with microbubbles can reversibly open the blood-brain barrier and facilitate the delivery of targeted brain therapeutics. Preclinical studies have successfully delivered growth factors, antibodies, genes, viral vectors, and nanoparticles in rodent models of Alzheimer disease and Parkinson disease (09). Small clinical trials support the safety and feasibility of this strategy in these vulnerable patients. Further studies are needed to establish safety as MRI-guided blood-brain barrier opening enhances the delivery of newly developed molecular therapies.

Alzheimer disease. Results from a 1-year follow-up trial evaluating safety, imaging, and clinical outcomes after MRgFUS blood-brain barrier targeted opening to the hippocampus, frontal lobe, and parietal lob in participants with mild Alzheimer disease showed promising results (27). The blood-brain barrier opening was confirmed by contrast enhancement in the treatment area and did not occur in untreated regions. Blood-brain barrier opening was transient, and closure occurred in 24 to 48 hours. Position emission tomography (PET) scans demonstrated an average B-amyloid plaque decrease of 14% in treated regions. At the 1-year follow-up, decline in cognition was comparable to matched control groups with Alzheimer disease. There were no serious adverse events. Meng and colleagues also investigated blood-brain barrier opening in patients with Alzheimer disease. Cognitive decline was similarly not worsened, and there were no serious adverse events. This provides a unique translational opportunity to investigate therapeutic delivery in Alzheimer disease.

Parkinson disease dementia. Studies investigating blood-brain barrier opening in Parkinson disease and Parkinson disease dementia have shown similar results as those with Alzheimer disease. Pineda-Pardo and colleagues treated seven Parkinson disease patients with cognitive impairment with blood-brain barrier opening in the posterior putamen (26). The procedure was well tolerated without any serious side effects or changes in cognitive function. Another study investigated the use of MRgFUS blood-brain barrier opening with drug delivery: lysosomal enzyme glucocerebrosidase (23). The GBA1 mutation encodes this enzyme, and carriers have an increased risk of developing Parkinson disease. This variant is also one of the most common mutations in the Parkinson disease population. Results from the trial showed decreased Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores off medication by 12% at 6 months compared to baseline. There was metabolic reduction in the treated putamen as noted on PET scans, which was of unclear clinical significance. Cognitive scores were unchanged. Adverse events included headaches, post-procedure–related pain, vasovagal reaction, and dyskinesias. These were all transient, and mild to moderate in severity.

Epilepsy. Epilepsy is a prevalent neurologic condition. Antiepileptic drugs are the first line of treatment. For drug-resistant epilepsy, options may include surgical procedures versus neuromodulation devices, such as responsive neurostimulation, deep brain stimulation, or vagus nerve stimulation. Focused ultrasound, particularly LIFU for neuromodulation, is currently being investigated as an additional treatment modality in epilepsy (20). Lee and colleagues examined the effect of LIFU on six patients undergoing stereo-electroencephalography (sEEG) (19). There were mixed results; two patients had a decrease in seizure frequency, whereas one showed an increase in (subclinical) seizure frequency. Four patients had a decrease in interictal epileptiform discharges, and two patients had an increase. sEEG changes indicated that the focused ultrasound effect stayed within target leads. There were no radiologic changes seen after focused ultrasound treatment. One patient experienced uncomfortable scalp heating, and another had transient difficulties with naming and memory after focused ultrasound. Another study by Stern and colleagues further examined the safety of LIFU in eight patients with drug-resistant epilepsy that were due to undergo surgical resection (31). Focused ultrasound was performed at least a day prior to resection surgery. Histological analysis showed no tissue damage, except for one patient in which the findings were inconclusive. Neuropsychological testing showed decreases in verbal memory but were overall inconclusive. HIFU for tissue ablation has also been researched for epilepsy. A small trial by Krishna and colleagues showed improvement in seizure frequency (18). Additional research is needed regarding both therapeutic benefit and safety in LIFU and HIFU for epilepsy.

Neuropathic pain. The nonpharmacological treatment of chronic neuropathic pain is an active area of interest. MRgFUS thalamotomy has shown beneficial effects in several studies with rare and mild adverse effects. The thalamus is a key mediator involved in pain pathways. A systemic review by Taranta and colleagues discussed studies with improvement in chronic neuropathic pain, including patients with trigeminal neuralgia, amputations, spinal cord lesions, and root compression (32). There was an increase in cognitive scores after MRgFUS, which was attributed to general improvement in functional status. Serious adverse events were rare. However, studies have been limited due to small patient populations, heterogenicity of patients included, and follow-up times making results not easily comparable. Additional higher-quality studies are needed to further investigate effectiveness and safety. MRgFUS for neuropathic pain has obtained international regulatory approval in some countries but is not approved in the United States. FDA-focused ultrasound approval for pain applications is currently limited to bone pain related to metastatic cancer. LIFU is another modality that is being investigated for neuropathic pain.

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. PET analysis revealed decreases in metabolism at 6 months posttreatment and was more widespread than the white matter tracts affected by the capsulotomy. Functional connectivity tests also displayed changes in the treatment group. Cognitive tests showed mild but significant improvements, but it was unclear if there was a relation to improved quality of life. 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 (05). MRgFUS capsulotomy results in both targeted and widespread changes in neural activity. Aberrant functional connectivity is thought to have a role in obsessive compulsive disorder and major depressive disorder.

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 (15). 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 focused ultrasound, potentially improving both the clinical treatment efficiency and safety in stroke patients.

Neuro-oncology. Primary and secondary brain malignancies can be difficult to treat given their distinct cellular composition, as well as blood-brain and blood-tumor barriers. Focused ultrasound is being investigated in various treatment approaches, including ablation, drug delivery enhancement, radiosensitization, and immunomodulation.

MRgFUS thermal ablation investigations have not gained traction in brain tumors given their larger volume. Sonodynamic therapy is an alternative modality being studied for ablative-like therapy. Focused ultrasound is combined with a sonosensitizing agent, which preferentially enters tumor cells and causes neoplastic cell death when ultrasound is applied. The agents used are nontoxic, and the proposed advantages to this technique are maximizing target responses while minimizing damage to normal tissue and, thus, adverse effects (02). Sonodynamic therapy clinical trials are ongoing. One trial is evaluating the effects of sonodynamic therapy with 5-aminoleveulinic acid in adult patients with recurrent glioblastoma undergoing planned re-resection (28). Preliminary data showed increased oxidative stress and apoptosis biomarkers in treated tumor versus controls, and no changes to nontargeted tissue were observed.

Another promising approach in neuro-oncology treatments involves blood-brain barrier disruption to increase tumor response to drugs as well as radiation. The blood-brain barrier is a barrier formed by tight junctions and endothelial cells, which limits molecular passage. Due to these characteristics, standard tumor management (such as in glioblastoma) uses a combination of surgery, radiation, and chemotherapy with temozolomide. Temozolomide can pass through the blood-brain barrier, but concentration still remains low, and levels may only rise up to 35% of the plasma level with concomitant radiation. LIFU can temporarily disrupt tight junctions between endothelial cells and increase permeability as well as increase uptake of immune cells. Park and colleagues examined blood-brain barrier disruption with temozolomide for the treatment of glioblastoma (25). At 1-year follow-up, 4 out of 6 patients had no recurrence. For the two patients who had recurrence, this occurred later when compared to usual glioblastoma progression rates. There were no immediate or delayed complications. Another study used MRgFUS to deliver the monoclonal antibody trastuzumab in four patients with Her2-positive brain metastases (24). There were no serious adverse events as well. Single-photon emission computed tomography (SPECT) imaging with sensitivity to trastuzumab showed increased SPECT signal for all treated lesions, and signals were unchanged in nonsonicated areas. All target tumors were either stable or reduced in size on follow up-MRI. Additional trials are being conducted with blood-brain barrier disruption and other chemotherapy and immunomodulatory agents as well.

Sonobiopsy (liquid biopsy). Biomarkers for neurologic conditions, such as Parkinson disease, neurodegenerative diseases, and gliomas, have been researched as a diagnostic and monitoring tool. Blood-based biomarkers offer an alternative, less invasive approach to obtain information on a neurologic condition without the need for a biopsy or lumbar puncture for cerebrospinal fluid. However, these are generally found in low numbers, which is attributed to the blood-brain barrier. This barrier limits biomarker permeability into the peripheral circulation and decreases detection. Sonobiopsy utilizes LIFU to increase blood-brain barrier permeability, with the aim of increasing biomarker levels. A clinical trial used sonobiopsy in high-grade gliomas and noted significantly increased plasma circulating tumor DNA after focused ultrasound sonication (36).

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 (34). 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 who have contraindications to contrasted MRI, ie, noncompatible implanted devices or implants, certain metallic foreign bodies, MRI contrast allergies, pregnancy, advanced kidney disease, and size limitations, are not eligible for MRI-guided focused ultrasound. Patients with mild-to-moderate claustrophobia may still be able to tolerate MRgFUS procedures in MRI chambers 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 mild to moderate in severity. Side effects depend on the targeted site but most commonly include sensory and gait disturbances. Other adverse events may include decreased taste sensation, speech difficulties, headaches, and post-procedure–related pain.

Scientific basis

Future outlook of focused ultrasound. Focused ultrasound therapy is only currently approved for a few neurologic conditions (essential tremor and Parkinson disease). They offer another therapeutic modality to patients, along with deep brain stimulation and radiofrequency ablation. Focused ultrasound also has potential for wider applications as seen in investigatory studies with neurodegenerative diseases, epilepsy, neuro-oncologic disorders, neuropathic pain, and stroke, and may become more widespread in the future.