MRgFUS has been investigated most commonly in movement disorders. Lesioning via stereotactic radiofrequency (RF) ablation has effectively alleviated movement disorder symptoms in ET, PD, and dystonia. Therefore, it was thought that lesioning using HIFU would work in a similar way in these diseases. Contrary to conventional RF lesioning methods, lesioning via MRgFUS is noninvasive, that is, no incision, no burr hole trephination, and no electrode insertion are required. Moreover, as stereotactic targets of movement disorder are located near the center of the skull, it is feasible to make a discrete lesion at the target while minimizing thermal damage to the overlying skull and scalp. In addition, since the procedure is performed in awake patients and in a stepwise fashion, immediate clinical feedback is available from the patients, encouraging the application of MRgFUS to movement disorders. Since MRgFUS unilateral thalamotomy in medication-refractory ET patients was approved by FDA in 2016, its application has bloomed, and clinical indications have expanded. MRg-FUS uses a protocol for lesioning which is transferable across its many clinical indications. First, escalating doses of lowpower sonication are applied to raise target temperatures to around 45℃, below the threshold leading to coagulation necrosis. At this time, radiological evaluation of thermal lesioning location and clinical evaluation for safety is performed. After accuracy at the desired target is determined, several high-power sonications are applied under the guidance of MR thermometry, gradually escalating the acoustic power and energy until the temperature at the target reaches 55–60℃ [72,76]. MRgFUS parameters across various intracranial applications are summarized in Table 1.

ET is the most common movement disorder affecting 4% of the population over 40 years old, characterized by postural and intentional tremors at 8–12 Hz [34,82]. The primary treatment for ET is medication such as propranolol and primidone, but surgical treatment targeting the ventral intermediate nucleus (Vim) of the thalamus may be considered in patients who are refractory or intolerant of medication. RF ablation, radiosurgery, or deep brain stimulation (DBS) are options that may be considered for the patients [82,89,127]. The first two pilot studies of MRgFUS thalamotomy were published in 2013. One proof of concept study, in which four ET patients were enrolled, showed favorable outcome of 81.3% reduction of tremor in the dominant hand and 51.1% reduction in functional disability, as measured on the Clinical Rating Scale for Tremor (CRST) score, at 3 months after surgery [72]. Another study was performed in 15 patients and also demonstrated promising results of significant improvement of the contralateral hand tremor by 75% (p=0.001) and functional disability related to tremor by 85% (p=0.001) at 12 months after surgery [34]. A subsequent randomized trial in 76 patients (20 sham-treated patients) with ET confirmed the efficacy of MRgFUS thalamotomy with improvement of hand tremor score by 47% and by 62% reduction in disability score at 3 months [35]. Recently, the same group has reported the long-term robustness of MRg-FUS thalamotomy [19]. At 2 years after surgery (67 patients), the mean hand tremor and functional disability scores improved by 56% and 60%, respectively, with two patients reporting complete resolution of hand tremor. Commonly reported acute adverse effects included numbness/paresthesia (38%), taste disturbances, headache, and ataxia [21,58,97,128]. The vast majority of side effects recovered within 3 months after treatment [21,48,58,128]. Long-term side effects persisting at 2 years included gait disturbance, dysgeusia, dysmetria, muscle weakness, and dizziness, while all events were reported mild to moderate [19]. The adjustable and titratable properties of DBS have certain advantages over lesioning surgery [111]. However, DBS is an invasive procedure that can be associated with infection (1–3%) or hemorrhage (0.5–2.0%), and hardware problems including electrode migration, fracture (1–3%), and malfunction (1–3%) [38,39,96,108]. Also, DBS patients with primary cells require periodic replacement of the implanted pulse generator when the batteries are depleted. GammaKnife radiosurgery (GKRS) is another non-invasive technique for lesioning but can be associated with some unpredictability of the response and delayed effects of radiation, often requiring weeks to months to detect a clinical benefit [39,82]. Moreover, since it is not possible to monitor the patients’ clinical symptoms during the procedure, determining an optimized target with GKRS can be challenging. Several clinical trials are underway to further evaluate the effectiveness and safety of MRgFUS unilateral thalamotomy (NCT01827904, NCT02289560, NCT03253991). The current status of clinical investigation of MRgFUS in various intracranial diseases is presented in Table 2.

PD is another main indication for MRgFUS. The success of MRgFUS-mediated Vim thalamotomy trials in ET patients inspired investigators to target the Vim in tremor-dominant PD patients [37,102,128]. Zaaroor et al. [128] reported that in 9 tremordominant PD patients undergoing MRgFUS Vim thalamotomy, the total motor Unified Parkinson’s Disease Rating Scale (UPDRS) score improved by 46.2% at 6 months after surgery, while resting and postural tremors (assessed by the item 20 and 21 of UPDRS) alleviated by 90% and 80%, respectively (NCT03300193). A randomized double-blind sham-controlled study in 27 patients (seven sham-treated patients) followed up to 1 year also demonstrated long-term efficacy of MRgFUS Vim thalamotomy in tremor-dominant PD (NCT01772693) [10]. On medication, the CRST score improved by 62% following MRgFUS thalamotomy versus 22% after sham procedure at 3 months after surgery, while motor UPDRS score improved by 35% versus 4% after MRgFUS thalamotomy and sham procedure, respectively, at 3 months after surgery. At 1 year, 65% of patients (13 out of 20) had a positive outcome, defined as at least 50% reduction in the on-medication hand tremor subscores of the CRST from a baseline. At 1-year follow-up, paresthesia remained in 19% of patients, while 4% reported persistent ataxia. Further long-term studies are needed to determine whether MRgFUS thalamotomy for PD has lasting effectiveness and if patient side effects eventually resolve. The globus pallidus interna can be another important target for MRgFUS. In an early report of MRgFUS unilateral pallidotomy in a PD patient suffering from severe dyskinesias, the motor UPDRS score in on-medication state was reduced by 60% at 6 months after surgery, whereas score in the off-medication state was reduced by 55% [87]. The unified dyskinesia rating scale score was also significantly improved by 70% at 6 months postoperatively. Several clinical trials of MRgFUS unilateral pallidotomy are in progress (NCT02003248, NCT02263885, NCT02347254, NCT03319485). Because of the high incidence of adverse effects with bilateral lesions, MRgFUS pallidotomy has been limited in only one hemisphere [52,107]. Meanwhile, despite the subthalamic nucleus (STN) is a well-established DBS target, stereotactic lesioning surgery targeting the STN had been limited because of concerns about incidence of postoperative involuntary movement such as hemichorea and hemiballismus, which were reported as high as 15% [6,39,67]. However, subthalamotomy with FUS is being examined [39]. A pilot study of unilateral subthalamotomy using MRgFUS in 10 patients has recently reported that motor UPDRS scores improved by 53% in the off-medication state and by 47% in the on-medication state at 6 months after surgery [77]. Over 6 months follow-up, a total of 38 adverse events were recorded, including three persisting events that were directly STN-related, namely, off-medication choreic dyskinesia, on-medication non-disabling dyskinesia, and subjective speech disturbance. The two aforementioned patients suffering from involuntary movements after subthalamotomy had resolution of symptoms by 6 months postoperatively after adjusting medication. Currently, other phase I subthalamotomy studies are also underway (NCT02246374, NCT03454425) (Table 2).

The feasibility of MRgFUS in obsessive-compulsive disorder (OCD) and major depressive disorder (MDD) is being investigated. A common surgical target in treatment-resistant patients include the anterior limb of the internal capsule (ALIC) [41,82]. ALIC fiber tracts carry information between the limbic cortices and thalamus and are thought to be associated with mood and anxiety disorders [25,60,103]. The first reported clinical trial for MRgFUS bilateral capsulotomy was completed in in four medically refractory OCD patients [58]. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score gradually improved by 33% over 6-month follow-up period, while Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAM-A) scores were immediately relieved by 61.1% and 69.4%, respectively, after surgery in all patients and such effects were sustained during the same period. A recent study by the same group in 11 OCD patients has shown that the above-mentioned clinical effects were maintained for 2 years, with Y-BOCS, HAM-D, and HAM-A scores being improved by 38%, 60%, and 65%, respectively [63]. Meanwhile, the first MRgFUS lesioning for MDD was also performed with the ALIC as the target, reporting significant improvements of HAM-D and Beck Depression Inventory scores by 73% and 54%, respectively, at 12 months after surgery [62]. Clinical trials (NCT02348411, NCT03421574) are underway to further evaluate the safety and initial effectiveness of MRgFUS bilateral capsulotomy for medically refractory MDD patients.

In chronic neuropathic pain, RF ablative surgery of the central thalamus has been successfully performed in medicationrefractory patients, spurring the application of MRgFUS to this condition [123,126]. One study that performed MRgFUS-mediated central lateral thalamotomy reported mean pain relief of 57% at 12 months follow-up in eight patients [54]. Clinical trials continue to investigate the effects of MRgFUS thalamotomy for chronic neuropathic pain (NCT03255395, NCT03309813) [82].

Pilot studies are underway for MRgFUS-mediated ablation for epilepsy : one study aims to ablate subcortical lesion using MRgFUS for secondary generalized epilepsy due to subcortical lesion (NCT02804230). Another study plans to target the anterior thalamic nucleus to prevent secondary generalization in focal onset epilepsy patients (NCT03417297).

A preclinical study investigated the feasibility of MRgFUS-mediated thrombolysis of intracerebral hemorrhage (ICH) [85]. In a swine model of ICH, the authors demonstrated that implanted clots with a volume of 4 mL (n=5) were completely lysed by MRgFUS (parameters : 230 kHz, pulse repetition rate 1 kHz, duty cycle 10%, and sonication duration 30 seconds) that was performed after 3 hours of clot dwell time. Sonication at 750 W was applied in craniotomized pigs, whereas 1500 W was required in pigs with the skull intact. There was neither evidence of blood-brain barrier disruption nor necrosis caused by thermal injury in the adjacent normal brain. In cadaveric model of ICH, all clots with a mean ICH volume of 27 mL (n=4) were liquefied over 95% of each clot after transcranial MRgFUS (parameters : 230 kHz, power of 3950 W, sonication duration 30 seconds, 1 kHz pulse repetition rate, and 10% duty cycle), except for one ICH in which ultrasound energy could not reach its target due to interaction of the dissolved gas generated by the decay of specimen. The researchers also studied the feasibility of MRgFUS thrombolysis for intraventricular hemorrhage using a cadaveric model (n=1), reporting that significant volume of thrombus was lysed after a single sonication using the same parameters as described above.

One study demonstrated the technical feasibility of noninvasive third ventriculostomy using MRgFUS in pigs. Inertial cavitation was generated, resulting in tissue fractionation, with higher peak rarefaction pressures than those used in thermal ablation [4]. Seven pigs underwent sonication at 650 kHz via craniectomy, while two underwent sonication (one at 650 kHz and another at 230 kHz) through an ex vivo human skull placed over the beam pathway after craniectomy was performed. Third ventriculostomy was successfully performed in 6 of 9 swine including one treated at 230 kHz through the skull. A small amount of subarachnoid hemorrhage was observed around the successful ventriculostomies, and in the animal treated transcranially at 650 kHz, microhemorrhage was identified at a site distal from the target. Therefore, in future studies, optimization of ultrasonic parameters to improve the safety and efficacy of this procedure is of paramount importance.

Over the past decade, many preclinical studies on FUS-mediated BBB opening to enhance drug delivery and to improve the treatment efficacy for various intracranial diseases have been conducted. Several animal studies have taken place including : targeted therapies of malignant gliomas and metastatic brain tumors using various types of therapeutic agents including monoclonal antibodies (e.g., trastuzumab for HER 2-positive breast cancer brain metastasis), gene therapy agents, and immune cells as well as conventional chemotherapeutic agents including doxorubicin and temozolomide. These studies consistently showed enhanced drug delivery into tumors, which led to inhibition of tumor growth as well as improved survival (Table 3). Though ultrasound parameters varied in the literature, the acoustic negative peak pressure generally ranged between 0.3–1.0 MPa, and as pressure increased beyond 0.8 MPa, erythrocyte extravasation was observed more frequently [18,64]. These promising preclinical results have promoted translation to clinical application of FUS-mediated BBB opening and enhanced drug delivery to the brain, with several phase I or I/IIa clinical trials for malignant brain tumors underway (NCT02253212, NCT03551249, NCT03616860, NCT02343991) (Table 4). Carpentier et al. [17] have recently reported the interim results of a clinical trial on the safety of ultrasound dose-escalation ranging from 0.5 to 1.1 MPa using SonoCloud^® (Car-Thera, Paris, France), an implantable pulsed ultrasound system in the recurrent glioblastoma patients. The authors demonstrated that repeated monthly BBB opening was safe up to 1.1 MPa, with the extent of BBB opening being most effective with acoustic pressures of ≥0.8 MPa (NCT02253212).

FUS is being examined for its potential role in neurodegenerative diseases including Alzheimer’s disease (AD), PD, and Huntington’s disease (HD). In 2008, Raymond et al. [98] reported that using a transgenic mouse model of AD, FUS-mediated BBB opening increased anti-amyloid beta (Aβ) antibodies bound to Aβ plaques 2.7-fold in targeted areas. Another study using a transgenic mouse model of AD also demonstrated enhanced delivery of anti-Aβ monoclonal antibody (BAM-10) following MRgFUS application and significant reduction in Aβ plaques number and size (both 12%) as well as the surface area covered by Aβ plaques (23%) in the FUS-treated areas [56]. These results were seen in 4 days with only one treatment. Surprisingly, FUS-mediated BBB opening alone has also proven to induce significant Aβ plaque reduction [12,57,69]. Studies showed that endogenous immunoglobulins (IgG and IgM), which were present in the blood circulation, entered the brain after FUS-mediated BBB opening and bound to Aβ plaques, leading to activation of the innate immune system against pathologic proteins. Through such mechanism, FUS seems to assist in clearing Aβ plaques even without externally-administered antibodies. Also, activation of astrocytes and microglia was found, as well as increased internalization of Aβ within these cells following FUS treatment [57]. After a single treatment with FUS alone, Aβ plaque size and total surface area decreased significantly by 20% and 13%, respectively, and Aβ plaque number trended to decrease by 9%, which were comparable to the results of previous studies of FUS treatment with antibodies [56,57]. In addition, and even more surprisingly, sonication was reported to increase neurogenesis in the hippocampus [12,101]. Scarcelli et al. [101] demonstrated that pulsed LIFU combined with microbubbles applied at typical parameters for BBB opening (10 ms bursts, 1 Hz pulse repetition frequency, mean peak pressures of 0.96 MPa, and duration of 120 seconds) is able to stimulate neurogenesis (228% increase) in the dentate gyrus of the hippocampus of adult mice. Another study by the same group also verified the ability of inducing neurogenesis of pulsed LIFU. The authors applied MRgFUS (10 ms bursts, 1 Hz pulse repetition frequency, mean peak pressure of 1.18 MPa, and duration of 120 seconds) targeting the dorsal hippocampus with microbubbles using transgenic mouse model of AD and demonstrated that the number of newborn neurons in the dentate gyrus of the hippocampus significantly increased by 252% after 4 weekly ultrasound treatment [12]. Also, total dendrite length (323%) and branching were significantly greater in the ultrasound treated animals compared with untreated controls. Along with significant decrease in the Aβ plaque burden (size, number, and the surface area loaded by Aβ by 20%, 29%, and 19%, respectively) in the hippocampus after MRgFUS treatment, the neuronal proliferation and maturation in the dentate gyrus was correlated with spatial memory improvement. The mechanism by which FUS mediates the hippocampal neurogenesis at the BBB opening parameter has not yet been established. One potential mechanism may be illustrated with mechanical bioeffect of pulsed LIFU on stimulation of neurons, which is accompanied by activation of cellular molecular signaling cascade and in turn upregulation of trophic cytokine such as brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor which are essential for promoting hippocampal neurogenesis [12,16,99,101,117]. Tufail et al. [117] reported that pulsed LIFU (0.35 MHz, 50 cycles per pulse, 1.5 kHz pulse repetition frequencies, 500 pulses) without microbubble contrast agents targeted on the hippocampus of mouse significantly increased the density of BDNF in CA1 (148%) and CA3 regions (158%) of the hippocampus. Although the ultrasound parameters to elicit neuromodulatory effects are typically different from those for BBB opening, these observations suggest that pulsed LIFU may promote neurogenesis through a similar mechanism, even at BBB opening parameters, though further confirmatory studies are needed. Another potential mechanism might be explained as activation of PI3K-Akt-mTOR signaling pathway, which promotes cellular survival and growth, in response to FUS-mediated BBB opening [12]. Indeed, activation of PI3K-Akt-mTOR signaling leads to improve survival of newborn neurons in the dentate gyrus in the adult mouse model of AD, rescuing newborn neurons from Aβ-induced dendritic growth deficits [70]. Jalali et al. [53] demonstrated that ultrasoundmediated BBB opening combined with microbubbles in rats induced activation of PI3K-Akt signaling pathway in the neurons. Taken together, these findings suggest that FUS-mediated BBB opening has interesting potential as a therapeutic strategy for AD treatment. Recently, the results of a phase I safety and feasibility trial for FUS-mediated BBB opening in mild AD patients have been published (NCT02986932) [72]. In conjunction with intravenous microbubble contrast, MRgFUS was applied to a small volume of white matter in the frontal lobe in five patients. In all patients, BBB opening was successful without serious adverse events, but without any evidence of amyloid clearance as measured by positron emission tomography. Another phase I/II trial of BBB opening in mild AD patients is being underway (NCT03119961) (Table 4). For other neurodegenerative diseases such as PD and HD, preclinical and clinical trials are underway (Tables 3 and 4). Burgess et al. studied the feasibility of MRgFUS-facilitated non-invasive gene therapy to silence the mutant Huntingtin (Htt) gene that results in expression of abnormal Htt protein causing progressive neuronal damage in HD [13]. Decrease in Htt protein expression had proven to correlate with improved motor function and neuronal survival in the mouse model of HD, however, cholesterol-conjugated small interfering RNA against Htt (cc-siRNA-Htt), which reverses pathology, was injected into the striatum in an invasive manner in the previous study [31]. Instead, Burgess et al. [13] used MRgFUS to enhance the delivery of intravenously administered cc-siRNA-Htt into the striatum and demonstrated significant Htt knockdown. These results suggest that MRgFUS-mediated gene therapy could be a promising therapeutic approach for genetic neurological disorders.