High-Intensity Focused Ultrasound: A Review of Mechanisms and Clinical Applications.

One of the most established applications of HIFU is in the female reproductive system. HIFU is FDA-approved for treatment of uterine leiomyomas and currently in the clinical trial stage for treatment of uterine adenomyosis 96 . Adenomyosis occurs when the inner endometrial lining of the uterus grows into the muscular wall and leads to a thickening of the organ. Though the cause has not been fully elucidated, it results in painful menstrual cramps and abnormal bleeding in many affected women. There are several current treatment protocols for adenomyosis include hysteroscopic resection, focal excision, uterine artery ligation, and myometrial electrocoagulation 70 . Yet, many of these procedures have not gained widespread acceptance due to negative side effects and serious contraindications in certain populations. Studies on the treatment of adenomyosis with HIFU have yielded positive results but still indicated the need to standardize protocols and optimize parameters. In a 2016 study, Gong et al. investigated factors affecting HIFU ablative efficiency in 245 patients diagnosed with adenomyosis. Increased abdominal wall thickness, distance from skin to lesion, richer blood supply, and high T2 signals on MRI scans were all found to be predictive factors for lower HIFU ablative efficiency 20 . Marques et al. released a meta-analysis of all English language studies examining HIFU-treatment of adenomyotic lesions between 2010 and 2020 45 . Results indicated that uterine volume and dysmenorrhea significantly decreased with a standard mean difference of 0.85 and 2.37 respectively at the 12 month-interval. Patients further reported a significant improvement in quality of life at both the 3 month and 12 month mark 45 . Still, comparative studies have not been conducted to evaluate HIFU treatment against more traditional standards of care 45 , indicating a need to assess direct impacts of treatment protocols prior to adjusting clinical decisions. In 2004, HIFU was approved by the Food and Drug Administration (FDA) for the treatment of leiomyomas, otherwise known as uterine fibroids 106 . Uterine leiomyomas are benign monoclonal tumors arising from smooth muscle cells of the myometrium. They are the most prevalent pelvic tumors in premenopausal females, currently affecting 11 million females in the United States 46 . Treatments for uterine fibroids include hysterectomy, myomectomy, endometrial ablation, myolysis, and MRgHIFU 59 . Compared to more traditional treatments, MRgHIFU has been theorized to be more safe and effective due to its noninvasiveness, rapid recovery time, and ability to spare the uterus 97 . In 2015 Shui et al. evaluated the long-term improvement of clinical symptoms of adenomyosis after USgHIFU. 224 patients were followed for two years ( Figure 3 ) 65 . All patients completed HIFU ablation without severe postoperative complications. Dysmenorrhea significantly decreased after treatment (P< 0.001) and the relief rate was 84.7%, 84.7%, and 82.3%, respectively at 3 months, 1 year, and 2 years after treatment. The menstrual volume in 109 patients with menorrhagia was also significantly improved after treatment (P< 0.001) with a relief rate of 79.8%, 80.7%, and 78.9%, respectively at 3 months, 1 year, and 2 years after HIFU treatment. This clinical follow up study determined that HIFU was a safe and effective treatment for adenomyosis. A retrospective observational trial published by Li et al. in 2020 analyzed long-term reintervention rates among their cohort of patients with uterine fibroids who were treated with ultrasound-guided HIFU 37 . With an overall reintervention rate of 20.7% and 86.4% of patients reporting relief from distressing symptoms, HIFU was concluded to be an effective treatment for leiomyomas 37 . Similarly, Wang et al. collected data on 245 women who were treated with ultrasound-guided HIFU for their uterine fibroids and 129 women who underwent uterus-sparing surgery for symptomatic fibroids 73 . The treatment resulted in reduced procedural complications and significantly higher symptom relief (p < 0.05). Furthermore, long-term clinical outcomes were reported to be better in the group that was administered HIFU as compared to the uterus-sparing surgical group 73 . While these studies are promising, larger-scale clinical trials should also be conducted to further validate these findings. There are two completed or currently active clinical trials examining the treatment effects of HIFU 98 on adenomyosis and 13 on uterine leiomyomas 99 . The vast majority of these trials are focused on HIFU as an ablative treatment in comparison with previously mentioned protocols such as uterine artery ligation, myomectomy, etc. The results of these ongoing trials will help to further elucidate the long-term effects of HIFU in the context of uterine leiomyomas/adenomyosis and aide in protocol optimization. Prostate cancer is the second most common cancer in men and a major cause of mortality due to its high recurrence rates, necessitating extensive research into various potential tumor treatments to render affected patients disease-free 57 . HIFU has been examined and employed for several years as a treatment method for ablation of prostate cancer 69 . A multi-center study published in 2018 by Guillaumier and colleagues investigated 625 patients with nonmetastatic prostate cancer treated with HIFU between 2006 and 2015 21 . They found that at the five-year mark, metastasis-free survival was 98%, cancer-specific survival levels were 100%, and morbidities were low as compared to whole-gland radical prostatectomy and radical radiotherapy, which are interventions that though extremely successful are commonly known to have urinary, sexual function, and bowel side effects. The authors concluded that though long-term data is unavailable, HIFU is an advantageous therapy for prostate cancer care, lacking the morbidities of more aggressive and invasive therapies, and can be offered as a treatment to certain patients with nonmetastatic disease 21 . Glybochko et al. found similarly low morbidity rates in their 35-case retrospective study on patients who received HIFU hemiablation of the prostate cancer and too noted that HIFU shows promise as a low-risk and feasible procedure 19 ( Figure 4 ). Due to the high likelihood of recurrence of prostate cancer, the use of HIFU in prostate cancer has also been proposed and investigated as a salvage therapy after traditional therapy fails to prevent local recurrences. A study in 2017 by Crouzet and colleagues examined 418 patients with locally recurrent prostate cancer across several institutions treated with external beam radiotherapy followed by HIFU. The authors found that 7-year survival rates increased with the utilization of salvage HIFU 8 . Furthermore, a study the next year by von Hardenburg et al. examined 24 patients who underwent MRI and transrectal ultrasound (TRUS) guided HIFU (nineteen patients with focal HIFU and five with zonal HIFU) as an ablative therapy for prostate cancer. The study found that though HIFU was capable of achieving successful local tumor ablation, 40% of patients actually had a positive biopsy at short-term follow-up 26 , indicating a current need for a more robust treatment regimen as well as further investigation and development in the use of this technology before it can become a standalone therapy. A search of clinicaltrials.gov provides a robust list of over 30 completed or active clinical trials investigating the use of HIFU in the treatment of prostate cancer, particularly regarding different guidance techniques and the utility of PET scans for prostate cancer identification and HIFU ablation. A few such trials include NCT03350529 , investigating MRI guided transurethral ultrasound in prostate cancer and benign prostatic hyperplasia, and NCT03927521 and NCT04461509 , both investigating using PET-MRI as a selection tool for HIFU treatment. No current trials exist regarding enhancement of drug delivery with the use of HIFU in prostate cancer, but this is would be an interesting are to explore in future studies in the prostatic cancer care field. HIFU has undergone extensive examination in multiple cancer types as a technique for cancer ablation and drug delivery, and results from these studies provide encouragement for further exploration. One such cancer investigated is breast cancer, which is the most common cancer in women (276,480 new cases/yr and 42,170 deaths/yr) 100 ; Although it has a high survival rate (5-year survival of 89% between 2005 and 2011) 58 , there remains a significant population who suffer from more aggressive disease refractory to standard surgical intervention, radiation, and chemotherapy protocols, demanding the exploration of advanced techniques, including HIFU. Several studies have examined the use of HIFU as a method of ablation for breast cancer treatment. One of the earliest published results came from Wu et al. in 2003, who examined a cohort of 48 women with biopsy-proven breast cancer staged at T 1-2 , N 0-2 , M0 77 . The patients were randomized to either the control group, who received modified radical mastectomy, or the treatment group, who received ultrasound-guided HIFU and modified radical mastectomy within 1-2 weeks of ablation. The authors found that HIFU left no severe short-term side effects and that cells treated with HIFU underwent severe damage, achieving complete coagulative necrosis and losing the ability to proliferate and metastasize, indicating its worth as a potential noninvasive treatment of breast cancer 77 . Wu and colleagues further explored this technique in 2007, affirming its ability to achieve wide local ablation in localized breast cancer 76 , 78 . Other studies since have reinforced the value of HIFU as an ablative technique for breast cancer treatment 56 . In 2016, Knuttel et al. examined the histopathological changes of MR-guided HIFU versus that of traditional radiofrequency ablation (RFA) 34 . The authors found that there were several distinctions between histopathologic changes in HIFU and RFA. For HIFU, there were more necrotic-type changes in vivo that were more subtle ex vivo , whereas for RFA, in vivo and ex vivo histopathologic changes were similar in character, with hyper-eosinophilic stroma and elongated nuclei. Further, RFA created large transition zones, while HIFU created smaller ones, suggesting a more defined area of effect with HIFU 34 . Several ongoing clinical trials ( NCT02407613 , NCT03560102 , NCT03342625 , and NCT00008437 ) are continuing to examine both short- and long-term effects of HIFU as a method of noninvasive tumor ablation and will continue to guide clinical practice as their results are determined in the coming years. HIFU has also been examined as a method to enhance drug delivery in breast cancer. Based on prior research indicating that pulsed HIFU could enhance systemic delivery of various drugs, Frenkel and colleagues in 2006 performed one of the earliest experiments by examining the delivery of liposome-encapsulated doxorubicin in a murine breast cancer model using pulsed HIFU. These authors injected a cell suspension of either a mouse mammary adenocarcinoma or squamous cell carcinoma into the bilateral flanks of their mice, and unilaterally treated with pulsed HIFU and/or doxorubicin as compared to a saline control on day 21 of tumor growth via tail-vein injection. Their aim was to use HIFU to enhance uptake, but not specifically through hyperthermia. The results from this study indicated that HIFU did not sensitize tissue to doxorubicin delivery 16 . Although such results were not immediately promising, other tumor types investigated have shown HIFU to be a viable method of enhancing doxorubicin delivery via induction of hyperthermia in rabbits with a unilateral Vx2 tumor in the thigh. The rabbits were treated at 11-13 days after inoculation with the tumor, with thermosensitive liposomal doxorubicin via ear-vein injection. For rabbits receiving the hyperthermia variable, this was injected once the HIFU created a mild hyperthermia state of 40-43°C, with a target mean of 42°C. The rabbits who underwent hyperthermia-focused HIFU treatment had better uptake of doxorubicin into their tumors and longer survival times. 2 , 67 An ongoing clinical trial ( NCT03749850 ) is taking place to further examine how MR-guided HIFU can enhance doxorubicin delivery in breast cancer. Another mechanism by which HIFU may enhance drug delivery is through the disruption of microbubbles; a study by Lee and colleagues found that HIFU burst chemically-generated microbubbles containing the chemotherapeutic drug methotrexate, allowing for highly targeted local delivery 35 . A final mechanism by which HIFU may augment drug delivery is through enhancing antigen presentation. Specifically, HIFU can cause in situ tumor emulsification, facilitating an increased breakdown of antigenic proteins and stimulating an inflammatory response. This response upregulates chemoattractants and allows for local delivery of exogenous drug-carrier molecules 44 . A current trial ( NCT03237572 ) is examining the mechanisms behind this therapeutic regimen, specific to pembrolizumab therapy in patients with metastatic breast cancer. With careful titration and examination, HIFU may become a useful tactic to enhance drug delivery to treat multiple types of solid tumors. With neurological disorders a major cause of death and disability globally, dysfunction in the central nervous system (CNS) is associated with serious consequences 71 . Comprising the brain and spinal cord, the CNS is responsible for sensory integration, response coordination, and motor output. High intensity focused ultrasound was first applied to the human CNS when the Fry brothers discovered its ability to treat neurological disorders in the early 1950s 30 . Since then, it has been utilized to treat essential tremor (ET), neuropathic pain, and CNS tumors. HIFU has also been used as a technique to transiently make the brain more accessible for the delivery of systemically administered agents. In 2016, focused ultrasound was approved in the United States as a treatment for essential tremor (ET) by the FDA 109 . In this treatment, the ventral intermediate nucleus of the thalamus is ablated, selectively creating brain lesions at the focal point of soundwave convergence. With structures in the wave path largely unaffected, HIFU is relatively safe for non-targeted regions and results in lower risk of thrombosis and lower risk of infection as compared to traditional ET treatments such as deep brain stimulation and radiofrequency ablation 24 , 36 , 60 . A study by Ito et al. explored long-term clinical outcomes of MRgFUS in patients with medication-refractory ET 29 . Focal left-sided thalamotomy resulted in a 60% reduction of clinical rating scale for tremor scores (CRST) in the right hand. Though patients reported significant symptoms including headache during treatment and sensory disturbances post-treatment, the study validated MRgFUS unilateral thalamotomy as a viable choice for refractory ET 29 . Furthermore, Park et al. demonstrated sustained clinical mitigation of refractory ET by unilateral MRgFUS thalamotomy 4 years after initial treatment 54 . Current clinical trials include NCT04112381 in which scientists are examining the effect of bilateral thalamotomies on left and right-sided tremors 101 . NCT03465761 is another similar prospective single-arm trial, studying outcomes of bilateral focused ultrasound ablative treatment to treat drug-refractory ET 102 . These larger-scale studies will set the stage for further treatment optimization of HIFU technology. Neuropathic pain is generally caused by abnormalities in the somatosensory system and impacts 7-10% of the population 7 . Dealing with a chronic issue, those affected report a lower quality of life due to persistent symptoms and limited treatment options. Primary central neuropathic pain is frequently a result of injury to the spinal cord whereas peripheral neuralgias can be due to an array of disease states including diabetes, inherited disorders, autoimmune diseases, etc 103 . Conventional methods to treat neuropathic pain include medications, nerve blocks, and invasive surgery, yet many patients are unable to find long-term relief. Focused ultrasound was first theorized to have an effect on neuropathic pain in 1996 10 . A prospective clinical trial released in 2012 followed 12 patients who suffered from treatment-resistant chronic neuropathic pain. MRgFUS was utilized to perform central lateral thalamotomies, with patients reporting a mean pain relief score of 57% at the 1-year follow-up interval 31 . In a 2020 study, Ma et al. further concluded the high potential of HIFU to become a non-invasive treatment modality for primary trigeminal neuralgia 42 . There are currently 8 clinical trials underway to examine the short- and long-term effects of focused ultrasound on neuropathic pain, including trigeminal neuralgia ( NCT04579692 ), phantom limb pain ( NCT03111277 ), and craniofacial neuralgias ( NCT04202783 ). Though preliminary studies have speculated the ability of HIFU to relieve neuropathic pain, the results of these trials will dictate its potential to become a mainstay treatment in the field. In 2020, approximately 23,890 malignant tumors of the brain and spinal cord will be diagnosed 66 . Current strategies for treating brain tumors include a combination of surgery, radiation, and chemotherapy. Yet, the most promising chemotherapies have been unable to demonstrate as much success in the central nervous system as they have in other systemic locations 75 . This is due to the blood-brain barrier (BBB), which is a tight layer of cells lining vessels in the brain that serve to protect the brain from potentially harmful substances in the circulation. In addition to functioning in an ablative capacity, HIFU has been shown to open this endothelial barrier in a safe, minimally invasive, and regional manner by means of cavitation and other physical mechanisms 104 . The ability to non-destructively penetrate the blood-brain barrier in a targeted manner and deliver appropriate concentrations of select drugs has the potential to revolutionize the way we treat some of our most vulnerable patients. The utilization of focused ultrasound to transiently and reversibly open the blood-brain barrier poses several advantages over traditional delivery methods. Transcranial application eradicates the need for invasive procedures, reducing mechanical shift of brain tissue and infection risk. Tandem MRI use would allow for focal application of FUS, increasing the precision of treatment. And furthermore, current research has indicated no long-term deficits in blood-brain barrier function 4 . Proof of concept has been shown in multiple in vivo trials, demonstrating targeted delivery of nanoparticles to selective brain regions in animal models 6 , 39 , 72 . Recently, human trials are emerging evaluating the feasibility of focused ultrasound applications in this regard. A clinical trial published by Mainprize et al. reported a 15-50% transient contrast enhancement in five patients who were administrated chemotherapy after MRgFUS pulses for high-grade glioma 43 . Barrier function reportedly returned to normal within 20 hours, affirming the transient and reversible nature of the treatment modality. Sattiraju et al. further posited on the compounded treatment effects of focused ultrasound to bypass the blood-brain barrier and surpass the efficacy of therapeutic drugs 62 . Chan et al. delivered varying sizes of Cy5-DNA-Au nanoparticles across the BBB using focused ultrasound and showed smaller NPs were delivered 6 times more efficiently than the largest ones tested, even though the difference in diameter between the particles was < 5nm), suggesting that optimizing NPs for intracranial delivery needs to be precisely fine-tuned ( Figure 5 ) 6 . To establish translational data and substantiate theorized efficacy in humans, there are currently four clinical trials examining the effect of focused ultrasound on blood-brain barrier disruptions. One trial ( NCT02343991 ) is examining the potential of MRgFUS to facilitate doxorubicin accumulation in the brain tumors of ten patients. Another prospective, single arm, non-randomized trial ( NCT03714243 ) will evaluate focused ultrasound as a tool to intentionally disrupt the blood-brain barrier in a transient and targeted manner in patients with breast cancer and brain metastases. The larger goal of both trials is to examine and determine safety factors in order to provide quantitative parameters when assessing treatment efficacy in the future. As evidenced throughout this discussion, the application of HIFU in a therapeutic rather than diagnostic method has invigorated the medical community in recent years. Though published literature on HIFU as a treatment modality on humans is limited, several clinical trials are underway in the hopes to introduce HIFU into common practice ( Table 3 ). Promising preliminary results from a number of these trials indicate that HIFU will become a valuable therapeutic tool in the years to come. High-intensity focused ultrasound is an emerging treatment modality with ground-breaking potential. Since its integration with imaging software in the early 2000s, HIFU’s applicability has increased as both an ablative treatment and technique to improve drug delivery of multiple agents. Significant applications of HIFU have been demonstrated clinically for CNS disorders, pain, and cancer. For oncological diseases in particular, including uterine leiomyomas, adenomyosis, breast, prostate, and CNS cancers, the field has significantly advanced over the last decade and has great promise. Despite these gains, larger clinical trials are still needed to further substantiate results and increase the therapeutic options to best utilize this innovative modality.

Due to its heating effects, the most commonly explored utilization of HIFU is thermal ablation ( Figure 1 ) 94 . The idea was first introduced by Lynn et al. in the 1940s when exploring inducible hyperthermia 108 , and further expanded upon in the 1980s when Wang et al. correlated the scope of ablative injury with wave intensity and irradiation time in porcine liver tissue 74 . Since its first application, ablation has become a popular therapeutic option for treatment in the bone, liver, pancreas, breast, and kidney 15 . To adequately ablate an area with high-intensity focused ultrasound, certain parameters are determined including the treatment zone, safety margins, radiation dose, and duration of ablation. The treatment zone is the most variable and includes both the target tumor volume and a surrounding perimeter of normal tissue as a safety margin, which is similar to the surgical excising approach 13 . Lesion depth is taken into account as well; deeper structures (>10 cm) result in more attenuation of the acoustic waves as they pass through the body and are less effective at depositing the set energy dose 13 . Reflective interfaces between tissues and dense structure obstruction may lead to under-treatment of the target region. In addition, the delivery path should avoid gas-filled organs due to their muffling of HIFU effects through focal point displacement and sound wave modulation 27 . Monitoring lesion formation during ablative pulses is of the utmost importance from an efficacy and safety standpoint. Transducer dose deposition is actively adjusted to control temperature fluctuations, allowing those delivering care to optimize ablative impact within safety limits. Because of its ability to monitor lesion formation and tissue temperature in real time, MRI and thermometry is preferred over diagnostic ultrasound. For accurate delivery, anxiolytic, analgesic, and antispasmodic medications are administered to decrease movement during the procedure and temporarily block digestive peristaltic motion 83 . Though traditionally used in an ablative setting, HIFU has more recently been explored as an adjunct to drug delivery due to its effect on membrane permeability. Specifically, there are two leading justifications for nanoparticles to be utilized in conjunction with ultrasound. First, nanoparticles can serve as nucleation sites, lowering the cavitation threshold during the formation of microbubbles; this potentiates the mechanical effects of HIFU and results in more efficient treatment applications. A 2019 study by Khirallah et al. demonstrated the increased capacity of perfluorohexane nanoparticles in reducing the cavitation threshold during ablation of tissue phantoms contained red blood cells 33 . Second, carrier particles themselves can be loaded with drug molecules and ablated at the appropriate delivery site by selectively applying HIFU to the region. Thus, externally triggered drug release can be accomplished with spatiotemporal control, with HIFU “activating” select particles via thermal and/or mechanical effects 1 . A description of select nanoparticles used with HIFU for cancer therapy shown in Table 2 . To rely on the thermal effects of HIFU, particles must be temperature-sensitive such that above or below a certain heat or energy threshold, drug is released. Dromi et al. explored the use of thermo-sensitive liposomes 12 ; in vitro and in vivo mouse models demonstrated a more rapid and concentrated release of doxorubicin following administration of HIFU pulses and injection of low temperature-sensitive liposomes. In contrast, Liang et al. demonstrated that high temperature-sensitive cerasomes underwent a burst-release of drug molecules over a 5 °C temperature increase in their target region when administered to treat adenocarcinoma of the breast in mice 38 . The study of inducible characteristics relying on the mechanical effects of HIFU has centered on nanoparticles; this is due to their capacity to present as additional nucleation sites and also act as carrier molecules, allowing for increased drug unloading via sonoporation at the site of HIFU application. These nanoparticles can be organic, such as lipid- or polymer-based, or they can be inorganic, such as metallic, or they can be a hybrid combination. You et al. explored the use of a metal oxide conjugated polymeric nanoparticle to unload perfluorohexane and treat hepatocellular carcinoma in a xenograft rabbit model. In addition to demonstrating in vitro efficacy, the nanoparticle + HIFU experimental group demonstrated a significantly (p < 0.05) lower tumor proliferative index than the HIFU alone control group 82 . Along with its efficacy in rabbit liver tumor xenograft tissue, nanoparticles in combination with HIFU has also been successfully utilized in mouse models. For example, researchers have demonstrated that pulsed HIFU (administered across burst intervals) effectively synergized with glycol chitosan nanoparticles in murine models 84 . Furthermore, in a study by You et al, specific HIFU pulsed dosing of 10, 20, and 50 W resulted in leaky murine femoral vasculature, demonstrated by increased fluorescence signals as compared to untreated tissue 81 . HIFU treatment has increasingly been shown to increased extravasation of drug-loaded carrier nanoparticles, overcoming tissue penetration, one of the critical obstacles to nanoparticle use. Limitations of HIFU in facilitating drug delivery include its short duration of effect and variable drug uptake. In clinical practice, solid tumors benefit from sustained release of chemotherapeutic agents to most fully penetrate the mass. Because the delivery mechanism of HIFU has inherent limitations in the number of pulses per session due to safety, large tumors may require longer and more complicated treatment protocols 55 . Additionally, the delivery of nanoparticles depends on transport through extracellular barriers to reach the target area. With variance within heterogenous tumors as well as from patient to patient, there can be dramatic differences in drug penetration and uptake based on tumor type, treatment area, and other biological characteristics. In addition to ablative and drug delivery applications, focused ultrasound techniques have the potential to be used in neuromodulation therapies especially when administered at a lower intensity. Neuromodulation ( Figure 1 , Figure 2 ) refers to the alteration of neuronal activity by a therapeutic agent, including electrical stimulation and pharmacologic chemicals 95 . With the FDA having only recently approved therapeutic ultrasound, neuromodulatory treatments are a newly emerging target of investigation with limited current literature. In contrast with the ablation caused by high intensity focused ultrasound (HIFU), low intensity focused ultrasound (LIFU) has been theorized to play a useful role in neuromodulation 14 . Mechanistically, LIFU creates a nonthermal mechanical disturbance in voltage-gated ion channels, affecting electrical signaling across membranes and therefore impacting neuronal activity 14 . In order for neuromodulation to occur as opposed to thermal ablation, ultrasound must be delivered at lower energy (< 3 W/cm 2 ) and provide marginally enough stimulation to modify channels short of causing mechanical damage 79 . The reversibility of this mechanism, as first demonstrated by the Fry brothers 17 , provided the basis for the investigation of ultrasound for neuromodulation. Furthermore, the resulting changes in neuronal activity are not limited to the duration of the LIFU therapy and can last for hours to days 14 , 25 . HIFU, conversely, is believed to not function through this neuromodulation mechanism, given its overt thermal destruction of tissue at higher frequencies 3 , 14 . Preclinical animal studies have repeatedly suggested the relative safety and efficacy of LIFU for neuromodulation. A study by Deffieux and colleagues in 2017 investigated LIFU as a tool to modulate prefrontal cortex activity, specifically visuomotor actions, in awake macaque rhesus monkeys 11 . By training the monkeys to initiate specific saccade movements based on a stimulus, they found that this behavior could be modified through the application of LIFU, suggesting potential for similar behavior-modifying capacity in humans 11 . A study by Dallapiazza et al. in 2018 explored the use of LIFU to modulate the swine sensory thalamus as a means of noninvasively mapping the brain 9 . The authors found success in inhibiting specific thalamic nuclei without affecting neighboring nuclei, creating any tissue damage, or inducing any thermal effects, affirming the safety and specificity of delivered ultrasound signals and opening the possibility of developing neuromodulation as a brain-mapping tool pending future investigation in patients 9 . A setup and analysis of FU-guided neuromodulation is exemplified in Figure 2 , in which Airan et al. in 2017 demonstrated that sonication can safely deliver seizure-silencing nanoparticles without brain parenchymal damage in a rat model 1 . Several studies have investigated the use of ultrasound for neuromodulation in patients. A recent study by Sanguinetti and colleagues demonstrated the application of transcranial focused ultrasound to the right prefrontal cortex in healthy patients through a randomized, placebo-controlled, double-blind study; the authors found that this ultrasound use improved mood and affected the connectivity of neural networks related to emotional regulation 61 . These results provide a positive projection for future studies that may investigate the potential use of LIFU as a psychiatric neuromodulation treatment in patients suffering from mood disorders. An active clinical trial ( NCT04197921 ), is examining LIFU as an adjunctive treatment in opioid use disorder. As researchers further develop an understanding of the mechanisms of LIFU as a neuromodulator, these studies will shed light on both the utilities of neuromodulation with LIFU and the impact this therapeutic modality could have on the treatment of various neurologic disorders.

Ultrasound technology was first discovered in 1880 by Pierre and Jacques Curie when examining the effects of mechanical vibration on quartz crystals 86 . While early applications included underwater visualization during World War I and metal impurity testing for industrial uses, ultrasound was eventually introduced to the medical setting 87 . Since then, it has broadly grown into a fundamental clinical modality ( Table 1 ). From fetal imaging and bone sonometry to echocardiograms and biopsy guidance, ultrasound technology has become a diagnostic mainstay in many medical fields 88 . Diagnostic ultrasound is usually delivered at 0.1 W/cm 2 with higher energy dose administration categorized as either high intensity (1,000 W/cm 2 - 10,000 W/cm 2 ) 108 , medium intensity, or low intensity (< 3 W/cm 2 ) 79 . This review focuses on the applications of high intensity focused ultrasound (HIFU) in which acoustic waves are administered at the highest energy level and converge at a focal point. HIFU was first therapeutically suggested in 1932 when H. Freundlich, K. Collner, and F. Rogowski discovered the medium’s propensity to heat tissue 40 . In 1942, Lynn et al. explored the localized impact of targeted beams on tissue blocks and live animal organs 40 . The researchers specifically noted the method’s ability to cause intense change at the energy’s focal point while leaving tissue in the path of the beams unharmed 40 . In the 1960s, interest in HIFU greatly increased due to contributions by the Fry brothers, who created cortical lesions in patients with Parkinson’s and other hyperkinetic disorders 18 in an effort to slow disease progression. HIFU further gained momentum as a viable treatment option in the fields of ophthalmology and neurosurgery through the later 1900s, but research was stalled due to limited imaging modalities and the temperature-monitoring software required for precision during treatment 80 . The advent of Magnetic Resonance Imaging (MRI) technology in the 1980s led to a renewed interest in high-intensity focused ultrasound due to the potential for precise spatial guidance via imaging and the development of MR-thermometry, allowing for accurate temperature tracking 30 . The first coupled MR-guided focused ultrasound machine (MRgFUS) in 2003 80 , set the stage for HIFU to become a useful treatment option with broader applications. While HIFU is increasingly being used across disparate areas of medicine, one field of particular interest is oncology. Current strategies for treating malignant neoplasms include a combination of surgery, radiation, chemotherapy, and immunotherapy. Chemotherapy is the most widely employed systemic treatment, yet, even the most promising chemotherapies have been unable to demonstrate desired efficacy due in large part to barriers in delivery, tumor heterogeneity, and cancer resistance. In the pursuit to optimize cancer treatment, HIFU is emerging as a promising and versatile technology that presents itself as both a novel standalone treatment and also one that can enhance the effectiveness of currently available agents. Modulating the intensity of ultrasound treatment allows for its usage as either a drug delivery mechanism or ablative modality, both of which show promise as treatments for neoplasms.