Neurological applications of focused ultrasound: an introduction and update on clinical and research trends

Abstract

Background

Focused ultrasound has emerged as a non-invasive technology with potential for treating various medical conditions, particularly neurological diseases. This article aims to explore recent advancements in the utilization of focused ultrasound for treating neurological conditions.

Results

A comprehensive literature review was conducted to explore current clinical applications and investigational uses of focused ultrasound, aiming to provide an up-todate overview of the field's progress. By employing different combinations of intensity and frequency, focused ultrasound can induce diverse interactions with soft tissues, including tissue ablation, cavitation, and mechanical effects. High-intensity focused ultrasound is utilized for tissue ablation and has received FDA approval for treating medication-refractory essential tremor. Conversely, low-intensity focused ultrasound is employed for neuromodulation and opening the blood–brain barrier, facilitating enhanced drug delivery for treating brain tumors and other neurological conditions. This article reviews ongoing clinical trials investigating focused ultrasound's role in neurological condition treatment.

Conclusion

Focused ultrasound holds significant promise for managing and treating various neurologic conditions. Whether employed for tissue ablation or transiently opening the blood–brain barrier to enhance drug delivery, numerous potential applications exist. Further research is necessary to evaluate its safe implementation and compare clinical outcomes with standard-of-care therapies.

Background

Ever since clinical ultrasound was first introduced in the 1930s, its clinical and diagnostic use has advanced rapidly. Early in ultrasound’s development, it was primarily used as a diagnostic tool for the imaging of body tumors [1]. Shortly thereafter, Lynn et al. started exploring the therapeutic applications of ultrasound through high Intensity focused ultrasound (HIFU), which utilizes significantly higher intensities compared to that of a diagnostic ultrasound. While these first attempts ultimately resulted in severe side effects such as small brain lesions and paralysis, it led to important discoveries of its future uses in tumor ablation [2]. In the 1980s, when the technology of medical imaging and ultrasound transducers had advanced, the U.S. Food and Drug Administration approved the first official therapeutic use of focused ultrasound (FUS): glaucoma. The indications have since expanded and currently, focused ultrasound is used for treatment of uterine fibroids, prostate cancer, and painful osseous metastasis, among other clinical applications [1].

The main setback towards the progression of focused ultrasound as a therapeutic tool was the lack of effective imaging. For example, precise targeting of a tumor is essential to avoid unnecessary off-target damage to surrounding structures. Additionally, the temperature must be closely monitored in real time, a feat that is highly challenging for diagnostic ultrasound. The relatively recent development of MRI has helped to overcome these barriers and is now used in conjunction with focused ultrasound [3]. Currently, focused ultrasound has many potential applications that are being studied in clinical trials. Our objective in this literature review is to specifically explore the recent and potential applications in neurology, including treatment of essential tremors, Alzheimer disease, Neuromodulation and opening of the Blood Brain Barrier (BBB).

Types and technique of focused ultrasound

Two main parameters determine the type of focused ultrasound and consequent interaction with soft tissues: Intensity and Frequency. With the appropriate intensity and frequency, focused ultrasound can have various therapeutic effects within the realm of neurologic pathologies. Low intensity ultrasound (< 3 W/cm²), especially when combined with low frequency (20–200 kHz), can be used for neuromodulation purposes. Models of FUS have shown that energy delivered through FUS results in oscillations of the intermembrane space and can generate either neuronal excitation or inhibition through changes in membrane capacitance to drive a current, ion flux from opening of the lipid bilayer, or activation of mechanosensitive ion channels [4]. This effect provides the base for investigating the use of FUS as a reversible neural activity modulator for treatment of pain with promising initial results [5].

On the other hand, high intensity ultrasound (≥ 3 W/CM²) produces a high-pressure wave upon interaction with soft tissues at the focus resulting in thermal, mechanical and cavitational effects (Figs. 1 and 2). This allows for non-invasive, precise tissue targeting with different effects on soft tissue according to the parameters selected [6,7,8,9]. Examples include tissue ablation and transient disruption of the blood–brain barrier.

Fig. 1

Diagram showing the interaction of HIFU with soft tissue. HIFU beams intersect in a small, focused area which results in precise tissue ablation at the focus. This provides accurate targeting of tumor tissue without damage to the surrounding healthy soft tissue. (Reused with permission from ter Haar & Coussios 2007 & Taylor & Francis Ltd, www.tandfonline.com [8])

Fig. 2

An illustrative representation of the cavitation effect of focused ultrasound. Upon interaction with soft tissues, focused ultrasound excites microbubbles to oscillate in a steady pattern. This stable cavitation induces shear forces which can disrupt the tight endothelial cell junctions, opening blood brain barrier and facilitating drug delivery. Above a specific cavitation threshold, bubbles collapse vigorously, known as inertial cavitation, resulting in a strong pressure wave which can destroy soft tissues. (Reprinted with permission from [9])

The technique for focused ultrasound varies based on the clinical application; however, in the setting of neurologic conditions, real-time imaging feedback is crucial to avoid any undesired side effects and to monitor key variables such as temperature. As such, MRI imaging is used in conjunction with focused ultrasound for neurologic conditions. One example is the ExAblate platform (Insightec Inc, Tirat Carmel, Israel) used for the treatment of essential tremor (Fig. 3). First, a stereotactic frame is placed on the patient’s head, which is surrounded with a bag of cooled degassed water to help prevent ultrasound-induced heating injury to the scalp. Then, the patient undergoes proper alignment with the MRI and ultrasound array. This then enables for the precise targeting of the desired tissue in the brain for FUS treatment [10]. While the indications for the use of FUS vary based on the pathology, contraindications of MRI guided FUS include patients with a pacemaker or those with other contraindications to MRI, those with a increased skull thickness, and patients who have undergone previous brain surgery [11].

Fig. 3

Image of ExAblate FUS machine used for treatment of essential tremor. Shown is the FUS transducer and MRI machine used during the procedure. (Reprinted with permission from Insightec Inc, Tirat Carmel, Israel)

Neurologic applications of focused ultrasound

Focused Ultrasound (FUS) applications in neurology have gained interest in recent years due to its wide range of utility. Its biological effect on tissue varies greatly based on the tissue type (ex. soft tissue vs blood vessels), the method of delivery (intermittent vs. consistent), and the intensity and frequency used [12, 13]. For this reason, there are ongoing clinical trials for a variety of clinical applications in different fields [5, 14]. In their literature review, Bretsztajn & Gedroyc outlined some of the potential uses of FUS in neurology, including essential tremor, Parkinson’s disease, chronic neuropathic pain, obsessive compulsive disorder, depression, brain tumors, epilepsy, Alzheimer’s, as well as opening the blood brain barrier and neuromodulation [15]. While only one of these (essential tremor) is currently FDA approved for clinical use, each of the other applications has supportive evidence and ongoing clinical trials that show promise for future use [15, 16]. In this review, we will focus on the main clinical applications of FUS in neurology including the treatment of essential tremor & Alzheimer’s, as well as the investigational use for opening the blood brain barrier and neuromodulation.

Essential tremor

Essential tremor (ET) is characterized by involuntary rhythmic trembling, or shaking, of the hands or feet. It normally presents later in life, and while it does not affect life expectancy, it poses a significant hindrance in performing everyday tasks [17]. As the most common movement disorder, ET is a condition which still lacks a definitive treatment [18]. It is estimated that approximately 25%-55% of individuals with ET cannot be treated with medications alone and require additional interventions to alleviate their symptoms. Focused ultrasound can be used to target specific responsible location in the brain, which current studies have identified as the ventral intermediate nucleus of the thalamus [13, 19].

In 2016, Elias et al. performed a clinical study in which they enrolled 76 patients to a randomized FUS unilateral thalamotomy or sham procedure. Only patients who were unresponsive to multiple medical treatment options were included, and the outcome measured was the standardized Clinical Rating Scale for Tremor (CRST) score. Upon completion of the trial, there was a significant improvement in hand tremors at 3 months and 12 months, with an increased ability to perform daily tasks such as drinking and writing. There were no severe side effects such as intracranial hemorrhage, but about 40% of patients experienced sensory or gait disturbances which persisted in about 10% after 12 months [18]. Two years after this study, Mohammed et al. conducted a meta-analysis including a total of nine studies with 160 patients with ET. In this study, FUS significantly improved the tremor scores and the quality of life [19]. Importantly, there were no severe side effects; however, ataxia was reported in 32.8% and paresthesia in 25.1%, both of which improved to about half at the 12-month mark. One limitation that Mohammed et al. addressed was the limited data on long term effects past 1 year [19]. In an effort to address this limitation, Park et al. obtained a four-year follow up on patients who were treated with MRI guided focused ultrasound (MRgFUS) thalamotomy for ET. Of the 15 patients enrolled, 12 completed the 4-year follow up. They found that all quality of life and tremor improvements remained statistically significant after the four years, and there were no sustained adverse effects [17].

Similar trends have been consistently found in recent studies. One research group summarized a 1-year follow up on 45 medication resistant essential tremor patients treated with MRgFUS; using forms that measure hand tremor scores and mental quality of life. All of these patients were treated with a unilateral thalamotomy. Results of the study showed an 82% improvement in the hand tremor score, with a significant decrease in depressive symptoms. The side effect profile consisted of some symptoms including paresthesias, gait disturbances & taste disturbances (78%), with 62% of these symptoms being transient [20].

MRI guided thalamotomywith FUS as a treatment for ET is  currently the only FDA approved treatment within the realm of neurological pathologies, with a recent expansion to include treating debilitating symptoms of those with Parkinson’s. FUS treatment shows promise for patients with ET as an alternative to the current medical and surgical (aka Deep Brain Stimulation) therapies. One review article compared outcomes in two separate clinical trials for treatment of ET with FUS or Deep Brain Stimulation (DBS), shown in (Fig. 4) [21]. Future studies should evaluate a longer follow up post treatment with FUS to determine its long-term efficacy. Additionally, a randomized control trial should be performed to determine if there is a significant difference between treatment with Deep Brain Stimulation vs Focused Ultrasound. Most ongoing clinical trials are seeking to understand the effects of a bilateral thalamotomy in the treatment of bilateral ET and ensuring there are no lasting adverse effects (NCT04112381, NCT03465761).

Fig. 4

Comparison between results of DPS and FUS A Tremor scores for DPS versus FUS over a 12 month period. There was significant improvement in tremor scores in both trials that lasted for 12 month. When comparing these two studies results against each other, there was no statistical significant difference in tremors between DBS and FUS. B Quality of life scores after treatment over a 12 month period are shown. Both treatments result in an improvement in quality of life. The clinical trial with DBS did not include standard deviation for this data, as such, it cannot be statistically compared to that of FUS. (Reused with permission from [21])

Opening the blood brain barrier (BBB)

One of the most exciting applications of FUS is its ability to increase vascular permeability in the BBB and facilitate drug delivery to the brain. When used at a lower intensity and pulsed rather than continuous mode, FUS can create a temporary mechanical effect on vasculature. Through this pulsating low intensity “dose”, microbubbles are created which oscillate within the vasculature and create a shearing effect which stretches the endothelial tight junctions and increases permeability [15]. A myriad of studies focused on finding the optimal intensity and pulse frequency in animal models which will be helpful in using it in a safe and efficient way [22,23,24,25]. Because the effects are transient, it is being considered for several conditions that require temporary increased permeability of the BBB to allow for delivery of high concentration of medications into the brain (Fig. 5). Fishman & Frenkel outlined the pertinent diseases that are currently being studied, namely brain tumors, Alzheimer’s disease, and Parkinson’s disease [13]. Other attempts at opening the BBB have been made using intraarterial Mannitol, electroporation or ultrashort-pulsed laser. However, all of these methods are more invasive than FUS and each have specific limitations. The use of mannitol, for example, has a diffuse effect and is unable to target a specific region of the brain to induce increased BBB permeability [26].

Fig. 5

Illustration of Blood-Brain Barrier (BBB) Opening with Focused Ultrasound (FUS). Focused ultrasound (FUS) offers a non-invasive transcranial approach to precisely target deep intracranial structures in a safe and precise manner. A The BBB, composed of tightly adherent endothelial cells lining brain blood vessels, acts as a protective barrier, limiting the permeation of microorganisms into the brain. However, it also restricts the penetration of high medication doses, reducing the efficacy of intravenous systemic medications. B Focused ultrasound, often combined with microbubble contrast agents, induces steady stable cavitation, disrupting the tight junctions in between the endothelial cells. This allows therapeutic agents (green beads), such as chemotherapy or immunotherapy, to diffuse into brain tissue at higher concentrations, potentially leading to improved therapeutic outcomes. BBB opening is temporary and occurs without significant damage to adjacent brain tissues

Treatment of brain tumors has been the most studied application of BBB manipulation. While direct tumor ablation with HIFU is another area of study, opening the BBB to allow for easier delivery of chemotherapy is also undergoing clinical trials [13]. In a 2018 clinical trial including 5 patients with high-grade gliomas, Mainprize et al. showed a 15–50% increase in contrast enhancement on MRI following FUS application, suggesting the BBB opened effectively. Additionally, there were no adverse reactions, and all the patients tolerated the treatment well [27]. While there are limitations to this study, such as population size, this suggests that FUS can safely open the BBB and facilitate the delivery of chemotherapeutic agents to brain tumors. A recent preclinical study used mice models to observe the effects of FUS on chemotherapeutic delivery through a transiently disrupted BBB. Results showed a successful opening of the BBB, a decrease in tumor growth by 45%, and an increased survival rate of 30% [28].

In a review of current studies on the topic, Arsiwala et al. stated that many preclinical trials have proved the effectiveness of FUS in opening the BBB, but that there were too few clinical trials with enough power to affirm FUS as an option for treatment of brain tumors in humans [29]. To date, there are a number of clinical trials ongoing to determine if this proposed mechanism of increasing chemotherapeutic delivery to brain tumors through FUS-mediated BBB disruption is effective and safe. One of these clinical trials is evaluating the ability of FUS to deliver albumin-bound paclitaxel in a study with an estimated 57 glioma patients (NCT04528680). Another clinical trial is looking to do the same, but with intravenous carboplatin in an estimated 50 participants (NCT04440358). These are just two examples of the relevant clinical trials that are in progress. While there seems to be promise, the results of these future studies will need to be evaluated to make the claim that FUS is a viable treatment option in humans.

Neuromodulation

Neuromodulation is defined as the manipulation of neurons to either inhibit or activate neural activity. This can have many implications, such as stimulating muscle movements or inhibiting pain signals. Through a low intensity FUS, many of these neuromodulation effects can be implemented. For example, animal studies have shown the capability of FUS to stimulate specific muscle contraction or the inhibition of epileptic attacks [13]. Using FUS for pain management, however, is currently the most popular area of study. In a study involving swine with induced neuropathic pain, FUS was utilized to treat that pain. In all the swine enrolled in the study, each stopped exhibiting pain guarding behavior after treatment, suggesting effective treatment of the neuropathic pain. Additionally, there was no evidence of histological damage after treatment [30]. While this and many other animal studies have been successful, very few published clinical trials exist to show the necessary evidence to approve this treatment in humans.

Currently, there are approximately 21 ongoing clinical trials studying the effectiveness and safety of FUS as a treatment for pain. These trials include treatment for pain due to phantom limb, bone metastases, knee osteoarthritis, disc herniation and chronic neuropathic pain. Currently, FUS thalamotomy and ablations of bone metastasis are heavily investigated, with ablation of painful bone metastasis being FDA approved currently [5]. These ongoing clinical trials hold promise because FUS has the unique capability of non-invasively targeting deep tissue in the brain with a high accuracy [31]. However, there is still the necessity to establish the safety of FUS use for neuromodulation in humans due to potential side effects [32].

Alzheimer’s

As mentioned before, opening the BBB presents a potential treatment for patients with Alzheimer’s, which is the primary neurodegenerative disease in the world. While the current underlying pathogenic mechanism is not entirely understood, the main hypothesis is that the disease is caused by amyloid-beta plaque deposition and tau phosphorylation in the brain [33]. As such, opening the BBB provides an opportunity for larger immunotherapies and therapeutic agents to cross the BBB with higher concentration. In a phase I trial, Lipsman et al. successfully and safely opened the BBB in five patients with Alzheimer’s disease via a purely noninvasive FUS procedure [34] (Fig. 6). This study has opened the door to then implement medication administration which will help treat this currently untreatable disease. Similarly, Liu et al. conducted a systematic review of FUS treatment for Alzheimer’s and found that FUS with infused microbubbles was safe and efficient at opening the BBB, which in turn can allow for the future implementation of medicine coadministration. They even discussed two clinical trials which showed potential benefit in cognitive ability with sustained FUS stimulation alone in Alzheimer’s patients [35]. A more recent study showed 63 successful transient disruptions of the BBB in 9 different patients with Alzheimer’s without any adverse effects noted [36]. There are also a few ongoing clinical trials that are observing the safe and effective BBB opening with FUS in Alzheimer’s patients (NCT03739905, NCT03671889).

Fig. 6

MRI showing the successful opening and closure of the blood brain barrier. Image a is this patient’s baseline, b is after sonication treatment resulting in contrast extravasation in the 10 × 10 × 7 mm³ area in the right frontal cortex, and c shows appropriate closure with resolved extravasation. This suggests transient BBB opening. (Reprinted from open access article [34])

There are other potential benefits that FUS can have on Alzheimer’s patients that are not as a result of BBB disruption enabling immunotherapy delivery. One of these was evaluated in a clinical trial performed by Jeong et al., where 8 patients with Alzheimer’s received low intensity ultrasound to the right hippocampus. The study aimed to measure the effect of BBB opening, the metabolic use of glucose in the targeted area and on short-term memory. There was no sign of opening of the BBB, but there was an increase of glucose absorption and use in the right hippocampus. Additionally, the patients immediately showed improved short-term memory and recognition memory [37]. This finding of improved cognitive abilities with FUS treatment alone has been shown in preclinical studies already [38]. Currently, there are a few ongoing clinical trials to further examine the potential positive effect FUS has on the cognitive decline in Alzheimer’s disease and other neurodegenerative conditions (NCT04250376, NCT03347084). If the findings continue to prove effective for cognitive improvement, then FUS will likely be an important treatment modality for many related neurodegenerative diseases.

Conclusions

FUS is an innovative, non-invasive, treatment modality that has many potential clinical applications especially in the field of neurology. Different biological effects can be achieved using high or low intensity focused ultrasound. This opens doors for unlimited opportunities to treat various diseases and disorders using different mechanisms and through a non-invasive approach. This fits very well in the current paradigm of personalized medicine and brings hope to treat many medical conditions which currently have very limited treatment options.