Introduction

Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel and non-invasive technology for functional neurosurgery. It uses geometric focusing of a high-intensity ultrasound beam through the intact skull to impact targeted tissue deep in the brain with the advantages of no anesthesia or ionizing radiation and real-time detection.[1] In addition to thermal ablation, it can also be used to reversibly open the blood-brain barrier (BBB) and induce neuromodulation, which significantly impacts the treatment of various neurological diseases.[2,3] Since 2016, MRgFUS has been approved for the treatment of medication-refractory essential tremor (ET), tremor-predominant Parkinson's disease (PD), and other neurological disorders.[4–6] It was also introduced into China in 2018 for the treatment of ET and PD.

PD is the second most common progressive neurodegenerative disorder that affects more than 1% of the population aged over 65 years globally.[7] Functional neurosurgery has developed rapidly in recent years.[8] Since the first report of MRgFUS for the treatment of PD in 2014, the field of MRgFUS has become a research hotspot.[9–11] Reviews have confirmed the effectiveness of MRgFUS-mediated thermal ablation.[12] Furthermore, non-thermal effects mediated by MRgFUS are gradually being implemented, such as the cavitation effect and neuromodulation. In combination with intravenous microbubbles, Gasca-Salas et al[13] found that MRgFUS can open the BBB via the cavitation effect and improve cognitive function in patients with PD. As for neuromodulation, a review has revealed that focused ultrasound (FUS) stimulation can modulate the brain activity of deep brain structures acutely and reversibly.[14]

In our review, we summarized advances in the application of MRgFUS for the treatment of PD, with a focus on thermal ablation, BBB opening, and neuromodulation, in the hope of informing clinicians regarding the current applications of MRgFUS.

MRgFUS Therapeutic Approaches for PD Treatment

MRgFUS can induce a variety of thermal and non-thermal effects (e.g., cavitation and mechanical effects) by adjusting the intensity, frequency, and pulse mode of ultrasound.

MRgFUS-mediated thermal effects in the treatment of PD

When ultrasound is focused on a target, the acoustic energy is absorbed into the target area to generate thermal energy, which increases the local temperature (tissue inactivation is typically achieved at temperatures above 55°C). Lower temperature heat exposure (i.e., temperatures of approximately 40–45°C) can be used for hyperthermia to sensitize tissues to radiation or chemotherapy,[15] activate genes for gene therapy,[16] and enable targeted drug delivery.[17] When the high-intensity ultrasound-focused area reaches a high temperature, protein denaturation, coagulation, and cell necrosis occurs, which results in tissue thermoablation.[18] MRgFUS uses magnetic resonance imaging (MRI) guidance to precisely locate the target, and high-intensity ultrasound beams emitted by a hemispherical transducer pass through the intact skull to ablate specific brain nuclei [Figure 1A]. Current research is primarily focused on MRgFUS thermal ablation of various targets for the treatment of various PD symptoms, which include the globus pallidus internus (GPi), the pallidothalamic tract (PTT), the ventral intermediate nucleus (Vim), and the subthalamic nucleus (STN).

Figure 1:

The mechanisms of thermoablation (A) and blood-brain barrier (BBB) opening (B) for magnetic resonance-guided focused ultrasound (MRgFUS). The mechanism of thermoablation using MRgFUS is the use of high-intensity focused ultrasound (FUS) to accurately locate the target and ablate specific brain nuclei. The mechanism of non-thermoablation using MRgFUS is the use of low-intensity FUS to open the BBB, which enables the microbubbles to undergo oscillations of expansion and contraction that cause the transient separation of endothelial tight junctions and enhances the localized delivery of therapeutic agents to the brain.

Internal globus pallidus (GPi): The GPi, a component of the basal ganglia, relays information from the striatum, globus pallidus externus, and STN to the thalamus.[19] Abnormal activity of the GPi leads to dystonia in PD patients, and deep brain stimulation of the GPi reduces involuntary movements in dystonia patients.[20] Similarly, the GPi is an important ablation target for MRgFUS therapy in patients with PD, which is effective in improving patients’ movement disorders. In a prospective, single-arm clinical trial conducted by Jung et al[21], GPi-MRgFUS was successful in eight of ten participants. Clinical results showed that the “medication-off” Unified Parkinson's Disease Rating Scale (UPDRS) part III and Unified Dyskinesia Rating Scale scores increased significantly by 32.2% and 52.7%, respectively, at the 6-month follow-up, and improved by 39.1% and 42.7%, respectively, at the 1-year follow-up. One patient developed dysarthria and right motor hemiparesis because of the off-target effect of the internal capsule; however, they recovered 2 days after surgery. In addition, a recent clinical study examined the safety and feasibility of GPi-MRgFUS and found that the Movement Disorder Society (MDS) version of the UPDRS (MDS-UPDRS) part III score for the treated side improved by 44.5% from baseline to 3 months and by 45.2% from baseline to 12 months.[22]

Pallidothalamic tract (PTT): The PTT comprises the ansa lenticularis and fasciculus lenticularis, which originate from the GPi.[23] PTT-MRgFUS can effectively suppress the over-inhibited thalamic output from the globus pallidus.[24] In 2014, MRgFUS was first applied to nine PD patients using the PTT as the target.[25] The clinical outcomes of UPDRS score and global symptom relief improved by 60.9% and 56.7%, respectively, at the 3-month follow-up following surgical treatment. This study demonstrated the feasibility, safety, and accuracy of PTT-MRgFUS. Subsequently, Gallay and colleagues[26,27] conducted clinical studies using bilateral PTT-MRgFUS ablation for the treatment of PD and observed significant improvements in tremor, rigidity, distal hypobradykinesia, and dystonia at the 1-year follow-up.

Vim: The Vim is a key relay point of the striatal-thalamocortical and cerebello-thalamocortical circuits and is an important node that is affected in patients with tremor-predominant PD.[28] Therefore, tremor-predominant PD is a good indication for Vim-MRgFUS [Figure 2].[29] Bond et al[4] conducted a randomized, double-blind controlled study of 27 patients with tremor-predominant PD, of whom 20 patients received unilateral Vim-MRgFUS and seven patients received a sham procedure. They found that patients in the surgical group had a median improvement of 62% on the Clinical Rating Scale for Tremor score for hand tremor on the treated side, and the median UPDRS motor score increased by eight points for the on-medication state from baseline to the 3-month follow-up. The improvements were significantly different between the two groups. However, early in the study, unrecognized heating of the internal capsule resulted in mild hemiparesis in two patients. Other adverse events included finger paresthesias, ataxia, and orofacial paresthesias. Furthermore, a recent study by Yamamoto et al[30] showed consistent improvement in tremor symptoms in 11 patients at the 12-month follow-up following Vim-MRgFUS.

Figure 2:

The multiplanar images of the target ventral intermediate nucleus (Vim) using magnetic resonance-guided focused ultrasound (MRgFUS) at different time points. A 60-year-old male Parkinson's disease patient underwent right Vim-MRgFUS. T2-weighted images show changes in three-ring ablation lesions (indicated by the yellow arrow) in the axial, coronal, and sagittal please at three follow-up periods.

STN: The STN is a common surgical target for the treatment of PD. In PD, dopamine deficiency causes disinhibition and overactivity of the STN, which increases the activity of the GPi and substantia nigra (SNr), resulting in decreased cortical motor activity.[31] Therefore, stimulation or ablation of the STN can effectively ameliorate the abnormal movements of PD. A prospective open-label study conducted by Martínez-Fernández et al[32] examined the safety and preliminary efficacy of unilateral subthalamotomy using MRgFUS and found that the mean MDS-UPDRS part III scores for the treated hemibody improved by 53% from baseline to 6 months in the off-medication state versus 47% in the on-medication state. Common adverse events were gait ataxia, pin-site head pain, and high blood pressure, although most of these side effects were transient and resolved within a few weeks of treatment. Recently, Martínez-Fernández and colleagues[18] conducted a randomized controlled trial of STN-MRgFUS for the treatment of PD, in which 27 patients received the active treatment and 13 patients underwent a sham procedure. Results showed that the mean MDS-UPDRS III score decreased from 19.9 at baseline to 9.9 at the 4-month follow-up in the active treatment group and from 18.7 to 17.1 in the control group, which indicated that the active treatment was significantly more effective than the control group. However, several patients experienced frequent adverse events, including dyskinesia, motor weakness, and gait and speech disturbances. Thus, longer-term and larger trials are needed to determine the effects of STN-MRgFUS on patients with PD. The clinical trials conducted on MRgFUS for the treatment of PD are listed in Table 1.

Table 1 - The clinical trials on MRgFUS conducted in patients with PD. Authors, years Type of study Design Conclusions Magara et al, 2014[25] Open-label prospective case series Unilateral PTT-MRgFUS in 13 patients (3 months follow-up) 60.9% improvement in UPDRS
56.7% improvement in GSR (9 patients) No serious clinical side effects Gallay et al, 2021[26] Open-label prospective case series Bilateral PTT-MRgFUS in 10 patients (12 months follow-up) 52% improvement in off-medication UPDRS
Adverse effect including speech difficulties Bond et al, 2017[4] Randomized controlled trial Unilateral Vim-MRgFUS in 27 patients (12 months follow-up) 62% improvement in CRST (hand tremor score) in the thalamotomy group
22% improvement in CRST (hand tremor score) in the sham group
Adverse effects include paresthesia and ataxia Yamamoto et al, 2021[30] Open-label prospective case series Unilateral Vim-MRgFUS in 11 patients (12 months follow-up) 87.9% improvement in CRST (hand tremor score) No serious clinical side effects Jung et al, 2018[21] Open-label prospective case series Unilateral GPi-MRgFUS in 10 patients (12 months follow-up) 39.1% improvement in off-medication UPDRS part III
42.7% improvement in off-medication UdysRS
No serious clinical side effects Eisenberg et al, 2020[22] Open-label prospective case series Unilateral GPi-MRgFUS in 20 patients (12 months follow-up) 43% improvement in off-medication UdysRS
45.2% improvement in off-medication MDS-UPDRS part III
No serious clinical side effects Martínez-Fernández et al, 2018[32] Open-label prospective case series Unilateral STN-MRgFUS in 10 patients (6 months follow-up) 53% improvement in off-medication MDS-UPDRS part III
47% improvement in on-medication MDS-UPDRS part III
Adverse effects: gait ataxia, pin-site head pain, and high blood pressure Martínez-Fernández et al, 2020[18] Randomized controlled trial Unilateral STN-MRgFUS in 27 patients (12 months follow-up) 50.3% improvement in MDS-UPDRS part III in thalamotomy group at 4 months
8.5% improvement in MDS-UPDRS part III in sham group at 4 months
Adverse effects including dyskinesia, motor weakness, and gait and speech disturbances

CRST: Clinical rating scale for tremor; GPi: Internal globus pallidus; GSR: Global symptom relief; MDS-UPDRS: Movement Disorder Society version of the United Parkinson's Disease Rating Scale; MRgFUS: Magnetic resonance-guided focused ultrasound; PD: Parkinson's disease; PTT: Pallidothalamic tract; STN: Subthalamic nucleus; UdysRS: Unified Dyskinesia Rating Scale; UPDRS: Unified Parkinson's Disease Rating Scale; Vim: Ventral intermediate nucleus.

Selecting appropriate brain targets for PD is crucial for relieving symptoms. According to the clinical trials mentioned above, the PTT, GPi, and STN are targets for treating almost all motor features of PD, whereas the Vim is the target for the treatment of tremor-predominant PD.[26,30] PTT-MRgFUS can relieve all symptoms of PD without impairing cognitive function.[24] You et al[33] found that stimulation of the STN improves not only motor symptoms but also cognitive function to a certain extent in patients with PD. STN-MRgFUS is effective in improving the symptoms of tremor and rigidity and reducing post-operative drug dose, although transient or persistent adverse events may also occur.[18] Previous findings have suggested that GPi stimulation is more effective for controlling levodopa-induced dyskinesia.[34] Because the determination of PD therapeutic targets remains controversial, further clinical studies using large sample sizes and long-term follow-ups are needed to evaluate the safety and efficacy of ablating different targets.

MRgFUS-mediated cavitation effect in the treatment of PD

The BBB is generated by microvascular endothelial cells that form the walls of the capillaries.[35] Because of the BBB, most drugs have a limited ability to penetrate the brain parenchyma. MRgFUS can instantaneously disrupt the tight junctions of the BBB for up to 24 h via the oscillation of microbubbles (called stable cavitation), after which the BBB is restored to its original state.[36] While high-intensity, pulsed FUS can open the BBB mechanically, the required acoustic energy levels can cause local tissue damage.[37] Subsequent research has revealed that when FUS is combined with microbubbles, only lower acoustic energy is required to achieve reversible BBB opening.[38] The interaction of acoustic energy and microbubbles at capillary endothelial cells causes microbubbles to oscillate and grow, which leads to stretching of the endothelial cell membrane, allowing for temporary disruption of the BBB and diffusion of macromolecules [Figure 1B]. Because MRgFUS can reversibly open the BBB, it is considered a safe and feasible treatment for patients with amyotrophic lateral sclerosis and Alzheimer's disease.[2,39] Furthermore, long-term studies have shown that MRgFUS-mediated BBB disruption has little effect on brain tissue with no significant histological or functional impairment.[40,41]

MRgFUS coupled with the administration of microbubbles has been applied to focal temporary BBB opening for the treatment of PD. An animal study by Long et al[42] showed that nuclear factor E2-related factor 2 (Nrf2) is introduced into the SNr of PD rats following MRgFUS. Nrf2 is a neuroprotective gene that activates the antioxidant response element pathway and protects the brain by regulating the redox status. Results showed that Nrf2 is overexpressed in the PD rat model, which suggests that the delivery of nanomicrobubble gene vectors using MRgFUS could non-invasively open a target region of the BBB and thus allow the region to overexpress neuroprotective genes. A recent study demonstrated the safety, feasibility, and reversibility of BBB disruption in PD patients with dementia.[13] Five PD patients underwent MRgFUS targeting the right parietal-occipitotemporal cortex twice. The study reported that the BBB opened at the parietal-occipitotemporal junction in the PD patients after the treatments. Improvements were observed on the Montreal Cognitive Assessment (MoCA) test (from 14.4 to 15.0), short-term visual memory (from 7.8 to 14.4), long-term visual memory (from 0.6 to 5.6), and executive and visuospatial function after the second treatment. Moreover, no hemorrhages, edema, or other serious adverse events were reported during the study. Overall, the procedure is considered feasible and reversible, with no serious clinical or radiological side effects. This study provided empirical support for BBB opening to treat PD and other neurodegenerative diseases.

Previous studies have also reported that FUS-mediated BBB opening promotes hippocampal neurogenesis.[43,44] However, the mechanism underlying hippocampal neurogenesis induced by FUS-mediated BBB opening is unclear. One potential mechanism is that FUS stimulates neurons and activates the cellular molecular signaling cascade, which in turn leads to the upregulation of trophic cytokine and vascular endothelial growth factor.[43,45] Accumulating evidence has shown that adult hippocampal neurogenesis plays a key role in cognition.[46,47] Cognitive decline is associated with neurodegenerative diseases. Therefore, the prevention of reduced hippocampal neurogenesis using MRgFUS has emerged as a potential therapy for PD.

Taken together, the abovementioned studies suggest that MRgFUS-mediated BBB opening has great potential in the treatment of neurodegenerative diseases, such as PD. Because the safety of MRgFUS-mediated BBB opening has been demonstrated, molecular therapies will likely develop rapidly.

MRgFUS-mediated neuromodulation in the treatment of PD

Since Fry et al[48] discovered in 1958 that ultrasound affects neuronal activity by reversibly suppressing ultrasound-induced visual evoked potentials, research on ultrasound-induced neuromodulation has increased. However, the neurological mechanism underlying ultrasound neuromodulation is not fully understood. Low-intensity FUS can alter membrane fluidity and permeability via mechanical energy or intra-membrane cavitation, which leads to the depolarization of neurons.[3,49] It has also been proposed that low-intensity FUS induces bursts of action potentials through the mechanical alteration of voltage-sensitive ion channels.[50] Tyler et al[50] showed that ultrasound application triggers the opening of voltage-dependent sodium (Na+) channels and free calcium (Ca2+) channels, thereby stimulating electrical activity in neurons. In addition, low-intensity FUS-induced changes in neuronal activity are sufficient to trigger soluble N-ethylmaleimide sensitive fusion protein attachment receptor-mediated synaptic vesicle exocytosis and synaptic transmission.

Low-intensity transcranial FUS has the advantage of high spatial resolution, allowing the neuromodulation of specific brain regions. Dallapiazza et al[3] targeted the porcine sensory thalamus using ultrasound and found that low-intensity FUS with a spatial resolution of 2 mm inhibits sensory evoked potentials. This method could be used to inhibit the ventromedial thalamic nucleus without affecting the ventrolateral nucleus. The study mentioned above illustrated that low-intensity FUS could be used for non-invasive neuromodulation and brain mapping, with potential value in future human brain research. In human studies, the transcranial application of low-intensity FUS to the primary somatosensory cortex elicits explicit tactile sensations, which indicates that low-intensity FUS can be used to locally modulate human cortical function.[51,52]

Various studies have shown that low-intensity FUS-mediated neuromodulation is a safe new therapy for PD. Nicodemus et al[53] used focused transcranial ultrasound combined with MRI to target the SNr in patients with PD. Patients achieved mild improvements in cognitive, fine motor and gross motor scores. Furthermore, Lee et al[14] found that low-intensity ultrasound stimulation in animal models of PD did not cause tissue bleeding or damage in vivo.

The abovementioned studies demonstrated the safety of low-intensity FUS-mediated neuromodulation for the treatment of PD. However, further research is needed to investigate the potential value of this method.

Prospects and Limitations of MRgFUS

Although MRgFUS has significant advantages in treating a variety of neurological diseases via thermal ablation mechanisms, it still has several limitations. The most important limitation is the relatively high post-operative recurrence rate. Zaaroor et al[54] reported that of the 30 patients with PD and essential tremor who underwent MRgFUS thalamotomy, six patients experienced a recurrence of tremor during the 6 to 24 month post-operative follow-up. In another clinical trial of Vim-MRgFUS, post-operative tremor recurrence was observed in one patient (1/11, follow-up of 12 months).[30] Moreover, there is currently no gold standard for the selection of therapeutic targets or the direct target visualization method for the nucleus. Indeed, reviews have shown that clinicians select different targets for PD according to the clinical symptoms of the patient.[55,56] The initial target for FUS thalamotomy relies on indirect coordinate localization; that is, 25% posterior to the midpoint of the anterior/posterior commissure and 14.0 mm lateral to the midline.[4] Finally, some patients experience persistent complications following treatment. For example, Mohammed et al[57] reported that approximately 15.3% of patients continue to have paresthesias 12 months after MRgFUS thalamotomy.

To ensure the therapeutic stability of MRgFUS, investigators have actively explored the methods for target visualization. Vassal et al[58] observed the Vim using a white matter attenuation inversion recovery sequence and found that the shape, spatial orientation, and signal contrast of the Vim were similar to those of the atlas. Several studies have also shown that the tractography technique can be used to directly identify targets for MRgFUS.[59,60] Nevertheless, additional studies are needed to explore target visualization methods to enable more precise targeting of MRgFUS ablation.

Conclusion

MRgFUS is an effective therapy for the treatment of PD via both thermal and non-thermal effects. Thermal ablation is mediated by high-intensity FUS, whereas BBB opening and neuromodulation are mediated by low-intensity FUS; both offer new treatments for PD. However, further clinical trials are required to assess the long-term efficacy and potential risks of MRgFUS.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 82151309, 81825012).

Conflicts of interest

None.

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