Focused Ultrasound for ALS: Results of First Clinical Trial Published
Published: 26 September 2019 Just posted on FUF website as new news
State of the Field report from FUSF
- FUS commercial treatment sites in the USA doubled
- FDA approval for tremor-dominant Parkinson’s disease
- CE Mark approval for epicondylitis and plantar fasciitis
- Expansion of FUS for veterinary usage
- 126 unique indications in various stages of development
- $218M invested in 6 FUS manufacturers
- Brainstem blood brain barrier disruption using focused ultrasound: A demonstration of feasibility and enhanced doxorubicin delivery.
Alli S, Figueiredo CA, Golbourn B, Sabha N, Wu MY, Bondoc A, Luck A, Coluccia D, Maslink C, Smith C, Wurdak H, Hynynen K, O’Reilly M, Rutka JT.
J Control Release. 2018 Jul 10;281:29-41. doi: 10.1016/j.jconrel.2018.05.005. Epub 2018 May 16.
Magnetic Resonance Image-guided Focused Ultrasound (MRgFUS) has been used to achieve transient blood brain barrier (BBB) opening without tissue injury. Delivery of a targeted ultrasonic wave causes an interaction between administered microbubbles and the capillary bed resulting in enhanced vessel permeability. The use of MRgFUS in the brainstem has not previously been shown but could provide value in the treatment of tumors such as Diffuse Intrinsic Pontine Glioma (DIPG) where the intact BBB has contributed to the limited success of chemotherapy. Our primary objective was to determine whether the use of MRgFUS in this eloquent brain region could be performed without histological injury and functional deficits. Our secondary objective was to select an effective chemotherapeutic against patient derived DIPG cell lines and demonstrate enhanced brainstem delivery when combined with MRgFUS in vivo. Female Sprague Dawley rats were randomized to one of four groups: 1) Microbubble administration but no MRgFUS treatment; 2) MRgFUS only; 3) MRgFUS + microbubbles; and 4) MRgFUS + microbubbles + cisplatin. Physiological assessment was performed by monitoring of heart and respiratory rates. Motor function and co-ordination were evaluated by Rotarod and grip strength testing. Histological analysis for hemorrhage (H&E), neuronal nuclei (NeuN) and apoptosis (cleaved Caspase-3) was also performed. A drug screen of eight chemotherapy agents was conducted in three patient-derived DIPG cell lines (SU-DIPG IV, SU-DIPG XIII and SU-DIPG XVII). Doxorubicin was identified as an effective agent. NOD/SCID/GAMMA (NSG) mice were subsequently administered with 5 mg/kg of intravenous doxorubicin at the time of one of the following: 1) Microbubbles but no MRgFUS; 2) MRgFUS only; 3) MRgFUS + microbubbles and 4) no intervention. Brain specimens were extracted at 2 h and doxorubicin quantification was conducted using liquid chromatography mass spectrometry (LC/MS). BBB opening was confirmed by contrast enhancement on T1-weighted MR imaging and positive Evans blue staining of the brainstem. Normal cardiorespiratory parameters were preserved. Grip strength and Rotarod testing demonstrating no decline in performance across all groups. Histological analysis showed no evidence of hemorrhage, neuronal loss or increased apoptosis. Doxorubicin demonstrated cytotoxicity against all three cell lines and is known to have poor BBB permeability. Quantities measured in the brainstem of NSG mice were highest in the group receiving MRgFUS and microbubbles (431.5 ng/g). This was significantly higher than in mice who received no intervention (7.6 ng/g). Our data demonstrates both the preservation of histological and functional integrity of the brainstem following MRgFUS for BBB opening and the ability to significantly enhance drug delivery to the region, giving promise to the treatment of brainstem-specific conditions.
- Blood-Brain Barrier Opening in Primary Brain Tumors with Non-invasive MR-Guided Focused Ultrasound: A Clinical Safety and Feasibility Study.
Mainprize T, Lipsman N, Huang Y, Meng Y, Bethune A, Ironside S, Heyn C, Alkins R, Trudeau M, Sahgal A, Perry J, Hynynen K.
Sci Rep. 2019 Jan 23;9(1):321. doi: 10.1038/s41598-018-36340-0.
The blood-brain barrier (BBB) has long limited therapeutic access to brain tumor and peritumoral tissue. In animals, MR-guided focused ultrasound (MRgFUS) with intravenously injected microbubbles can temporarily and repeatedly disrupt the BBB in a targeted fashion, without open surgery. Our objective is to demonstrate safety and feasibility of MRgFUS BBB opening with systemically administered chemotherapy in patients with glioma in a phase I, single-arm, open-label study. Five patients with previously confirmed or suspected high-grade glioma based on imaging underwent the MRgFUS in conjunction with administration of chemotherapy (n = 1 liposomal doxorubicin, n = 4 temozolomide) one day prior to their scheduled surgical resection. Samples of “sonicated” and “unsonicated” tissue were measured for the chemotherapy by liquid-chromatography-mass spectrometry. Complete follow-up was three months. The procedure was well-tolerated, with no adverse clinical or radiologic events related to the procedure. The BBB within the target volume showed radiographic evidence of opening with an immediate 15-50% increased contrast enhancement on T1-weighted MRI, and resolution approximately 20 hours after. Biochemical analysis of sonicated versus unsonicated tissue suggest chemotherapy delivery is feasible. In this study, we demonstrated transient BBB opening in tumor and peritumor tissue using non-invasive low-intensity MRgFUS with systemically administered chemotherapy was safe and feasible. The characterization of therapeutic delivery and clinical response to this treatment paradigm requires further investigation.
- First-in-human trial of blood-brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound.
Abrahao A, Meng Y, Llinas M, Huang Y, Hamani C, Mainprize T, Aubert I, Heyn C, Black SE, Hynynen K, Lipsman N, Zinman L.
Nat Commun. 2019 Sep 26;10(1):4373. doi: 10.1038/s41467-019-12426-9.
MR-guided focused ultrasound (MRgFUS) is an emerging technology that can accurately and transiently permeabilize the blood-brain barrier (BBB) for targeted drug delivery to the central nervous system. We conducted a single-arm, first-in-human trial to investigate the safety and feasibility of MRgFUS-induced BBB opening in eloquent primary motor cortex in four volunteers with amyotrophic lateral sclerosis (ALS). Here, we show successful BBB opening using MRgFUS as demonstrated by gadolinium leakage at the target site immediately after sonication in all subjects, which normalized 24 hours later. The procedure was well-tolerated with no serious clinical, radiologic or electroencephalographic adverse events. This study demonstrates that non-invasive BBB permeabilization over the motor cortex using MRgFUS is safe, feasible, and reversible in ALS subjects. In future, MRgFUS can be coupled with promising therapeutics providing a targeted delivery platform in ALS.
- A review of potential applications of MR-guided focused ultrasound for targeting brain tumor therapy.
Lamsam L, Johnson E, Connolly ID, Wintermark M, Hayden Gephart M.
Neurosurg Focus. 2018 Feb;44(2):E10. doi: 10.3171/2017.11.FOCUS17620. Review.
Magnetic resonance-guided focused ultrasound (MRgFUS) has been used extensively to ablate brain tissue in movement disorders, such as essential tremor. At a lower energy, MRgFUS can disrupt the blood-brain barrier (BBB) to allow passage of drugs. This focal disruption of the BBB can target systemic medications to specific portions of the brain, such as for brain tumors. Current methods to bypass the BBB are invasive, as the BBB is relatively impermeable to systemically delivered antineoplastic agents. Multiple healthy and brain tumor animal models have suggested that MRgFUS disrupts the BBB and focally increases the concentration of systemically delivered antitumor chemotherapy, immunotherapy, and gene therapy. In animal tumor models, combining MRgFUS with systemic drug delivery increases median survival times and delays tumor progression. Liposomes, modified microbubbles, and magnetic nanoparticles, combined with MRgFUS, more effectively deliver chemotherapy to brain tumors. MRgFUS has great potential to enhance brain tumor drug delivery, while limiting treatment toxicity to the healthy brain.
- Low-Intensity MR-Guided Focused Ultrasound Mediated Disruption of the Blood-Brain Barrier for Intracranial Metastatic Diseases.
Meng Y, Suppiah S, Surendrakumar S, Bigioni L, Lipsman N.
Front Oncol. 2018 Aug 28
Low-intensity MR-guided focused ultrasound in combination with intravenously injected microbubbles is a promising platform for drug delivery to the central nervous system past the blood-brain barrier. The blood-brain barrier is a key bottleneck for cancer therapeutics via limited inter- and intracellular transport. Further, drugs that cross the blood-brain barrier when delivered in a spatially nonspecific way, result in adverse effects on normal brain tissue, or at high concentrations, result in increasing risks to peripheral organs. As such, various anti-cancer drugs that have been developed or to be developed in the future would benefit from a noninvasive, temporary, and repeatable method of targeted opening of the blood-brain barrier to treat metastatic brain diseases. MR-guided focused ultrasound is a potential solution to these design requirements. The safety, feasibility and preliminary efficacy of MRgFUS aided delivery have been demonstrated in various animal models. In this review, we discuss this preclinical evidence, mechanisms of focused ultrasound mediated blood-brain barrier opening, and translational efforts to neuro-oncology patients.
- Magnetic Resonance-Guided Focused Ultrasound : Current Status and Future Perspectives in Thermal Ablation and Blood-Brain Barrier Opening.
Lee EJ, Fomenko A, Lozano AM.
J Korean Neurosurg Soc. 2019 Jan
Magnetic resonance-guided focused ultrasound (MRgFUS) is an emerging new technology with considerable potential to treat various neurological diseases. With refinement of ultrasound transducer technology and integration with magnetic resonance imaging guidance, transcranial sonication of precise cerebral targets has become a therapeutic option. Intensity is a key determinant of ultrasound effects. High-intensity focused ultrasound can produce targeted lesions via thermal ablation of tissue. MRgFUS-mediated stereotactic ablation is non-invasive, incision-free, and confers immediate therapeutic effects. Since the US Food and Drug Administration approval of MRgFUS in 2016 for unilateral thalamotomy in medication-refractory essential tremor, studies on novel indications such as Parkinson’s disease, psychiatric disease, and brain tumors are underway. MRgFUS is also used in the context of blood-brain barrier (BBB) opening at low intensities, in combination with intravenously-administered microbubbles. Preclinical studies show that MRgFUS-mediated BBB opening safely enhances the delivery of targeted chemotherapeutic agents to the brain and improves tumor control as well as survival. In addition, BBB opening has been shown to activate the innate immune system in animal models of Alzheimer’s disease. Amyloid plaque clearance and promotion of neurogenesis in these studies suggest that MRgFUS-mediated BBB opening may be a new paradigm for neurodegenerative disease treatment in the future. Here, we review the current status of preclinical and clinical trials of MRgFUS-mediated thermal ablation and BBB opening, described their mechanisms of action, and discuss future prospects.
LeWitt PA, Lipsman N, Kordower JH.
Mov Disord. 2019 Sep
The expanding landscape of options for Parkinson’s disease (PD) therapeutics calls for novel ways to improve delivery of treatments to counteract neurodegeneration or enhance symptomatic control. This unmet need is particularly relevant for opportunities in gene therapy, which, in recent PD clinical trials, has required invasive neurosurgical approaches into the CNS. One of the promising techniques to bring new therapies into the brain for PD therapeutics involves an evolving technology, focused ultrasound. Focused ultrasound has been used to alleviate tremor by thermal ablation with high-energy sonication. Using similar equipment but much lower sonication energy, focused ultrasound assisted with micro-bubbles can temporarily open the blood-brain barrier at specific brain targets to facilitate real-time magnetic resonance-guided delivery of therapeutic agents. To explore the current status and future of focused ultrasound in transvascular therapeutics for PD, a November 2018 workshop reviewed its accomplishments and challenges. This report summarizes key points of discussion and provides further background to the promising roles focused ultrasound offers.
- Safety and efficacy of focused ultrasound induced blood-brain barrier opening, an integrative review of animal and human studies.
Meng Y, Pople CB, Lea-Banks H, Abrahao A, Davidson B, Suppiah S, Vecchio LM, Samuel N, Mahmud F, Hynynen K, Hamani C, Lipsman N.
J Control Release. 2019 Jul 18
The blood-brain barrier, while fundamental in maintaining homeostasis in the central nervous system, is a bottleneck to achieving efficacy for numerous therapeutics. Improved brain penetration is also desirable for reduced dose, cost, and systemic side effects. Transient disruption of the blood-brain barrier with focused ultrasound (FUS) can facilitate drug delivery noninvasively with precise spatial and temporal specificity. FUS technology is transcranial and effective without further drug modifications, key advantages that will accelerate adoption and translation of existing therapeutic pipelines. In this review, we performed a comprehensive literature search to build a database and provide a synthesis of ultrasound parameters and drug characteristics that influence the safety and efficacy profile of FUS to enhance drug delivery.
Lipsman N, Meng Y, Bethune AJ, Huang Y, Lam B, Masellis M, Herrmann N, Heyn C, Aubert I, Boutet A, Smith GS, Hynynen K, Black SE.
Nat Commun. 2018 Jul 25
Magnetic resonance-guided focused ultrasound in combination with intravenously injected microbubbles has been shown to transiently open the blood-brain barrier, and reduce beta-amyloid and tau pathology in animal models of Alzheimer’s disease. Here, we used focused ultrasound to open the blood-brain barrier in five patients with early to moderate Alzheimer’s disease in a phase I safety trial. In all patients, the blood-brain barrier within the target volume was safely, reversibly, and repeatedly opened. Opening the blood-brain barrier did not result in serious clinical or radiographic adverse events, as well as no clinically significant worsening on cognitive scores at three months compared to baseline. Beta-amyloid levels were measured before treatment using [18F]-florbetaben PET to confirm amyloid deposition at the target site. Exploratory analysis suggested no group-wise changes in amyloid post-sonication. The results of this safety and feasibility study support the continued investigation of focused ultrasound as a potential novel treatment and delivery strategy for patients with Alzheimer’s disease.
- Localized Blood-Brain Barrier Opening in Ovine Model Using Image-Guided Transcranial Focused Ultrasound.
Yoon K, Lee W, Chen E, Lee JE, Croce P, Cammalleri A, Foley L, Tsao AL, Yoo SS.
Ultrasound Med Biol. 2019 Sep
Transcranial application of focused ultrasound (FUS) combined with vascular introduction of microbubble contrast agents (MBs) has emerged as a non-invasive technique that can temporarily create a localized opening in the blood-brain barrier (BBB). Under image-guidance, we administered FUS to sheep brain after intravenous injection of microbubbles. BBB opening was confirmed by performing dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to detect the extravasated gadolinium-based magnetic resonance contrast agents. Through pharmacokinetic analysis as well as independent component analysis of the DCE-MRI data, we observed localized enhancement in BBB permeability at the area that subjected to acoustic pressure of 0.48 MPa (mechanical index = 0.96). On the other hand, application of a higher pressure at 0.58 MPa resulted in localized, minor cerebral hemorrhage. No animals exhibited abnormal behavior during the post-FUS survival periods up to 2 mo. Our data suggest that monitoring for excessive BBB disruption is important for safe translation of the method to humans.
- Three-dimensional transcranial microbubble imaging for guiding volumetric ultrasound-mediated blood-brain barrier opening.
Jones RM, Deng L, Leung K, McMahon D, O’Reilly MA, Hynynen K.
Theranostics. 2018 Apr 16
Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening recently entered clinical testing for targeted drug delivery to the brain. Sources of variability exist in the current procedures, motivating the development of real-time monitoring and control techniques to improve treatment safety and efficacy. Here we used three-dimensional (3D) transcranial microbubble imaging to calibrate FUS exposure levels for volumetric BBB opening. Methods: Using a sparse hemispherical transmit/receive ultrasound phased array, pulsed ultrasound was focused transcranially into the thalamus of rabbits during microbubble infusion and multi-channel 3D beamforming was performed online with receiver signals captured at the subharmonic frequency. Pressures were increased pulse-by-pulse until subharmonic activity was detected on acoustic imaging (psub), and tissue volumes surrounding the calibration point were exposed at 50-100%psub via rapid electronic beam steering. Results: Spatially-coherent subharmonic microbubble activity was successfully reconstructed transcranially in vivo during calibration sonications. Multi-point exposures induced volumetric regions of elevated BBB permeability assessed via contrast-enhanced magnetic resonance imaging (MRI). At exposure levels ≥75%psub, MRI and histological examination occasionally revealed tissue damage, whereas sonications at 50%psub were performed safely. Substantial intra-grid variability of FUS-induced bioeffects was observed via MRI, prompting future development of multi-point calibration schemes for improved treatment consistency. Receiver array sparsity and sensor configuration had substantial impacts on subharmonic detection sensitivity, and are factors that should be considered when designing next-generation clinical FUS brain therapy systems. Conclusion: Our findings suggest that 3D subharmonic imaging can be used to calibrate exposure levels for safe FUS-induced volumetric BBB opening, and should be explored further as a method for cavitation-mediated treatment guidance.
Neurotherapeutics. 2019 Jan
For more than 70 years, the promise of noninvasive neuromodulation using focused ultrasound has been growing while diagnostic ultrasound established itself as a foundation of clinical imaging. Significant technical challenges have been overcome to allow transcranial focused ultrasound to deliver spatially restricted energy into the nervous system at a wide range of intensities. High-intensity focused ultrasound produces reliable permanent lesions within the brain, and low-intensity focused ultrasound has been reported to both excite and inhibit neural activity reversibly. Despite intense interest in this promising new platform for noninvasive, highly focused neuromodulation, the underlying mechanism remains elusive, though recent studies provide further insight. Despite the barriers, the potential of focused ultrasound to deliver a range of permanent and reversible neuromodulation with seamless translation from bench to the bedside warrants unparalleled attention and scientific investment. Focused ultrasound boasts a number of key features such as multimodal compatibility, submillimeter steerable focusing, multifocal, high temporal resolution, coregistration, and the ability to monitor delivered therapy and temperatures in real time. Despite the technical complexity, the future of noninvasive focused ultrasound for neuromodulation as a neuroscience and clinical platform remains bright
Fini M, Tyler WJ.
Int Rev Psychiatry. 2017 Apr
Ultrasound (US) is widely known for its utility as a biomedical imaging modality. An abundance of evidence has recently accumulated showing that US is also useful for non-invasively modulating brain circuit activity. Through a series of studies discussed in this short review, it has recently become recognized that transcranial focused ultrasound can exert mechanical (non-thermal) bioeffects on neurons and cells to produce focal changes in the activity of brain circuits. In addition to highlighting scientific breakthroughs and observations that have driven the development of the field of ultrasonic neuromodulation, this study also provides a discussion of mechanisms of action underlying the ability of ultrasound to physically stimulate and modulate brain circuit activity. Exemplifying some forward-looking tools that can be developed by integrating ultrasonic neuromodulation with other advanced acoustic technologies, some innovative acoustic imaging, beam forming, and focusing techniques are briefly reviewed. Finally, the future outlook for ultrasonic neuromodulation is discussed, specifically in the context of applications employing transcranial focused ultrasound for the investigation, diagnosis, and treatment of neuropsychiatric disorders.
- Low-intensity ultrasound neuromodulation: An overview of mechanisms and emerging human applications.
Fomenko A, Neudorfer C, Dallapiazza RF, Kalia SK, Lozano AM.
Brain Stimul. 2018 Nov – Dec
There is an emerging need for noninvasive neuromodulation techniques to improve patient outcomes while minimizing adverse events and morbidity. Low-intensity focused ultrasound (LIFUS) is gaining traction as a non-surgical experimental approach of modulating brain activity. Several LIFUS sonication parameters have been found to potentiate neural firing, suppress cortical and epileptic discharges, and alter behavior when delivered to cortical and subcortical mammalian brain regions.
This review introduces the elements of an effective sonication protocol and summarizes key preclinical studies on LIFUS as a neuromodulation modality. The state of the art in human ultrasound neuromodulation is then comprehensively summarized, and current hypotheses regarding the underlying mechanism of action on neural activity are presented.
Peer-reviewed literature on human ultrasound neuromodulation was obtained by searching several electronic databases. The abstracts of all reports were read and publications which examined low-intensity transcranial ultrasound applied to human subjects were selected for review.
LIFUS can noninvasively influence human brain activity by suppressing cortical evoked potentials, influencing cortical oscillatory dynamics, and altering outcomes of sensory/motor tasks compared to sham sonication. Proposed mechanisms include cavitation, direct effects on neural ion channels, and plasma membrane deformation.
Though optimal sonication paradigms and transcranial delivery methods are still being established, future applications may include non-invasive human brain mapping experiments, and nonsurgical treatments for functional neurological disorders.
Tyler WJ, Lani SW, Hwang GM.
Curr Opin Neurobiol. 2018 Jun
Ultrasound (US) is recognized for its use in medical imaging as a diagnostic tool. As an acoustic energy source, US has become increasingly appreciated over the past decade for its ability to non-invasively modulate cellular activity including neuronal activity. Data obtained from a host of experimental models has shown that low-intensity US can reversibly modulate the physiological activity of neurons in peripheral nerves, spinal cord, and intact brain circuits. Experimental evidence indicates that acoustic pressures exerted by US act, in part, on mechanosensitive ion channels to modulate activity. While the precise mechanisms of action enabling US to both stimulate and suppress neuronal activity remain to be clarified, there are several advantages conferred by the physics of US that make it an appealing option for neuromodulation. For example, it can be focused with millimeter spatial resolutions through skull bone to deep-brain regions. By increasing our engineering capability to leverage such physical advantages while growing our understanding of how US affects neuronal function, the development of a new generation of non-invasive neurotechnology can be developed using ultrasonic methods.
Neurosurg Focus. 2018 Feb
The understanding of brain function and the capacity to treat neurological and psychiatric disorders rest on the ability to intervene in neuronal activity in specific brain circuits. Current methods of neuromodulation incur a tradeoff between spatial focus and the level of invasiveness. Transcranial focused ultrasound (FUS) is emerging as a neuromodulation approach that combines noninvasiveness with focus that can be relatively sharp even in regions deep in the brain. This may enable studies of the causal role of specific brain regions in specific behaviors and behavioral disorders. In addition to causal brain mapping, the spatial focus of FUS opens new avenues for treatments of neurological and psychiatric conditions. This review introduces existing and emerging FUS applications in neuromodulation, discusses the mechanisms of FUS effects on cellular excitability, considers the effects of specific stimulation parameters, and lays out the directions for future work.
- Neuromodulation and ablation with focused ultrasound – toward the future of noninvasive brain therapy.
Fomenko A, Lozano AM.
Neural Regen Res. 2019 Sep
Roet M, Hescham SA, Jahanshahi A, Rutten BPF, Anikeeva PO, Temel Y.
Prog Neurobiol. 2019 Jun
The field of neuromodulation is developing rapidly. Current techniques, however, are still limited as they i) either depend on permanent implants, ii) require invasive procedures, iii) are not cell-type specific, iv) involve slow pharmacokinetics or v) have a restricted penetration depth making it difficult to stimulate regions deep within the brain. Refinements into the different fields of neuromodulation are thus needed. In this review, we will provide background information on the different techniques of neuromodulation discussing their latest refinements and future potentials including the implementation of nanoparticles (NPs). In particular we will highlight the usage of magnetic nanoparticles (MNPs) as transducers in advanced neuromodulation. When exposed to an alternating magnetic field (AMF), certain MNPs can generate heat through hysteresis. This MNP heating has been promising in the field of cancer therapy and has recently been introduced as a method for remote and wireless neuromodulation. This indicates that MNPs may aid in the exploration of brain functions via neuromodulation and may eventually be applied for treatment of neuropsychiatric disorders. We will address the materials chemistry of MNPs, their biomedical applications, their delivery into the brain, their mechanisms of stimulation with emphasis on MNP heating and their remote control in living tissue. The final section compares and discusses the parameters used for MNP heating in brain cancer treatment and neuromodulation. Concluding, using MNPs for nanomaterial-mediated neuromodulation seem promising in a variety of techniques and could be applied for different neuropsychiatric disorders when more extensively investigated.
- Neuromodulation of sensory networks in monkey brain by focused ultrasound with MRI guidance and detection.
Yang PF, Phipps MA, Newton AT, Chaplin V, Gore JC, Caskey CF, Chen LM.
Sci Rep. 2018 May 22
Focused ultrasound (FUS) has gained recognition as a technique for non-invasive neuromodulation with high spatial precision and the ability to both excite and inhibit neural activity. Here we demonstrate that MRI-guided FUS is capable of exciting precise targets within areas 3a/3b in the monkey brain, causing downstream activations in off-target somatosensory and associated brain regions which are simultaneously detected by functional MRI. The similarity between natural tactile stimulation-and FUS- evoked fMRI activation patterns suggests that FUS likely can excite populations of neurons and produce associated spiking activities that may be subsequently transmitted to other functionally related touch regions. The across-region differences in fMRI signal changes relative to area 3a/3b between tactile and FUS conditions also indicate that FUS modulated the tactile network differently. The significantly faster rising (>1 sec) fMRI signals elicited by direct FUS stimulation at the targeted cortical region suggest that a different neural hemodynamic coupling mechanism may be involved in generating fMRI signals. This is the first demonstration of imaging neural excitation effects of FUS with BOLD fMRI on a specific functional circuit in non-human primates.
Dallapiazza R, McKisic MS, Shah B, Elias WJ.
Neurosurg Clin N Am. 2014 Jan
Surgical neuromodulation has emerged as the primary method to treat the medically refractory symptoms of essential tremor and Parkinson disease. With reversible manipulation of CNS neurons, neuromodulation can be used to intraoperatively localize and verify a stereotactic target, and to chronically treat movement disorders. This article discusses the historical advances in stereotactic surgery using various modalities of neuromodulation leading to contemporary treatment. Electrical neuromodulation, or deep brain stimulation, is emphasized as the major surgical intervention with a discussion of the technique, surgical targets, and clinical outcomes. A comparison of neuromodulation techniques is presented.
- Development of a subject-specific guide system for Low-Intensity Focused Ultrasound (LIFU) brain stimulation.
Joe H, Pahk KJ, Park S, Kim H.
Comput Methods Programs Biomed. 2019 Jul
Low-Intensity Focused Ultrasound (LIFU) has recently been considered as a promising neuromodulation technique because it can noninvasively stimulate the brain with a high spatial resolution. As spatial resolution is improved, there is a growing demand for developing more accurate and convenient guide systems. Therefore, in the present study, we have developed and prototyped a 3D printed wearable subject-specific helmet for LIFU stimulation that is guaranteed to be accurate. The spatial relationship between the target position and the full-width at half-maximum (FWHM) of acoustic pressure of the transducer, i.e. focal volume, was compared using the conventional image-guided navigation system. According to the distribution of positional errors, the target position was located well within the focal volume.
Davidson B, Meng Y, Giacobbe P, Hamani C, Lipsman N.
Clin Pharmacol Ther. 2019 Oct
Chen SG, Tsai CH, Lin CJ, Lee CC, Yu HY, Hsieh TH, Liu HL.
Brain Stimul. 2019 Sep 24
Epilepsy is a neurological disorder characterized by abnormal neuron discharge, and one-third of epilepsy patients suffer from drug-resistant epilepsy (DRE). The current management for DRE includes epileptogenic lesion resection, disconnection, and neuromodulation. Neuromodulation is achieved through invasive electrical stimulus including deep brain stimulation, vagus nerve stimulation, or responsive neurostimulation (RNS). As an alternative therapy, transcranial focused ultrasound (FUS) can transcranially and non-invasively modulate neuron activity.
This study seeks to verify the use of FUS pulsations to suppress spikes in an acute epileptic small-animal model, and to investigate possible biological mechanisms by which FUS pulsations interfere with epileptic neuronal activity.
The study used a total of 76 Sprague-Dawley rats. For the epilepsy model, rats were administered pentylenetetrazol (PTZ) to induce acute epileptic-like abnormal neuron discharges, followed by FUS exposure. Various ultrasound parameters were set to test the epilepsy-suppressing effect, while concurrently monitoring and analyzing electroencephalogram (EEG) signals. Animal behavior was monitored and histological examinations were conducted to evaluate the hazard posed by ultrasound exposure and the expression of neuronal activity markers. Western blotting was used to evaluate the correlation between FUS-induced epileptic suppression and the PI3K-mTOR signaling pathway.
We observed that FUS pulsations effectively suppressed epileptic activity and observed EEG spectrum oscillations; the spike-suppressing effect depended on the selection of ultrasound parameters and highly correlated with FUS exposure level. Expression level changes of c-Fos and GAD65 were confirmed in the cortex and hippocampus, indicating that FUS pulsations deactivated excitatory cells and activated GABAergic terminals. No tissue damage, inflammatory response, or behavioral abnormalities were observed in rats treated with FUS under these exposure parameters. We also found that the FUS pulsations down-regulated the S6 phosphorylation and decreased pAKT expression.
Our results suggest that pulsed FUS exposure effectively suppresses epileptic spikes in an acute epilepsy animal model, and finds that ultrasound pulsation interferes with neuronal activity and affects the PTZ-induced PI3K-Akt-mTOR pathway, which might help explain the mechanism underlying ultrasound-related epileptic spike control.
- Effects of sonication parameters on transcranial focused ultrasound brain stimulation in an ovine model.
Yoon K, Lee W, Lee JE, Xu L, Croce P, Foley L, Yoo SS.
PLoS One. 2019 Oct 24
Low-intensity focused ultrasound (FUS) has significant potential as a non-invasive brain stimulation modality and novel technique for functional brain mapping, particularly with its advantage of greater spatial selectivity and depth penetration compared to existing non-invasive brain stimulation techniques. As previous studies, primarily carried out in small animals, have demonstrated that sonication parameters affect the stimulation efficiency, further investigation in large animals is necessary to translate this technique into clinical practice. In the present study, we examined the effects of sonication parameters on the transient modification of excitability of cortical and thalamic areas in an ovine model. Guided by anatomical and functional neuroimaging data specific to each animal, 250 kHz FUS was transcranially applied to the primary sensorimotor area associated with the right hind limb and its thalamic projection in sheep (n = 10) across multiple sessions using various combinations of sonication parameters. The degree of effect from FUS was assessed through electrophysiological responses, through analysis of electromyogram and electroencephalographic somatosensory evoked potentials for evaluation of excitatory and suppressive effects, respectively. We found that the modulatory effects were transient and reversible, with specific sonication parameters outperforming others in modulating regional brain activity. Magnetic resonance imaging and histological analysis conducted at different time points after the final sonication session, as well as behavioral observations, showed that repeated exposure to FUS did not damage the underlying brain tissue. Our results suggest that FUS-mediated, non-invasive, region-specific bimodal neuromodulation can be safely achieved in an ovine model, indicating its potential for translation into human studies.
Leung SA, Webb TD, Bitton RR, Ghanouni P, Butts Pauly K.
Sci Rep. 2019 May 28
Transcranial focused ultrasound is a non-invasive therapeutic modality that can be used to treat essential tremor. Beams of energy are focused into a small spot in the thalamus, resulting in tissue heating and ablation. Here, we report on a rapid 3D numeric simulation framework that can be used to predict focal spot characteristics prior to the application of ultrasound. By comparing with magnetic resonance proton resonance frequency shift thermometry (MR thermometry) data acquired during treatments of essential tremor, we verified that our simulation framework can be used to predict focal spot position, and with patient-specific calibration, predict focal spot temperature rise. Preliminary data suggests that lateral smearing of the focal spot can be simulated. The framework may also be relevant for other therapeutic ultrasound applications such as blood brain barrier opening and neuromodulation.
- Improved Target Specificity of Transcranial Focused Ultrasound Stimulation (TFUS) using Double-Crossed Ultrasound Transducers.
Kim S, Kim H, Shim C, Lee HJ.
Conf Proc IEEE Eng Med Biol Soc. 2018 Jul
Ultrasound neuromodulation is a promising stimulation modality because of its non-invasiveness, focusing and steering capability, and relatively high spatial resolution compared to the other stimulation modalities. However, despite the high lateral resolution, the ultrasound beam in the axial direction is relatively long, especially when compared to the small size of the mouse brain. Here, we report a new ultrasound focusing technique for small animal in vivo experiments where a high spatial resolution in both lateral and axial directions is achieved by crossing two ultrasound beams. The focal volume of a full width half maximum (FWHM) of our proposed system is only 0.161 mm3 and the focal diameter in the axial direction is about 1 mm, which is ten times smaller than the previously reported ultrasound neuromodulation system. Thus, the proposed system enables targeting a sub-region of a mouse brain using ultrasound for the first time. We also demonstrate successful stimulation of the motor cortex through in vivo mice experiments where the movement of forepaw of the mouse was observed using the double-crossed ultrasound transducers. Moreover, by sweeping the focal point in the z-axis and measuring the success rate of stimulated movements, we show that our double-transducer system targeted a region with 2 mmresolution in the dorsal-ventral (DV) coordinates. The success rate of the double-crossed ultrasound stimulation was quantified by recording the electromyography (EMG) signals during the stimulation. Our results show that the double-crossed ultrasound transducer system with a ten times higher spatial resolution enables highly specific and noninvasive stimulation of small animals and thus enables versatile in vivo experiments to study functional connectivities of brain circuits
Aubry JF, Tanter M.
Adv Exp Med Biol. 2016
Previous chapters introduced the ability of using focused ultrasound to ablate tissues. It has led to various clinical applications in the treatment of uterine fibroid, prostate or liver cancers. Nevertheless, treating the brain non-invasively with focused ultrasound has been considered beyond reach for almost a century: The skull bone protects the brain from mechanical injuries, but it also reflects and refracts ultrasound, making it difficult to target the brain with focused ultrasound. Fortunately, aberration correction techniques have been developed recently and thermal lesioning in the thalamus has been achieved clinically. This chapter introduces the aberration effect of the skull bone and how it can be corrected non-invasively. It also presents the latest clinical results obtained with thermal ablation and introduces novel non-thermal approaches that could revolutionize brain therapy in the future.
Jolesz FA, McDannold NJ.
Neurol Clin. 2014 Feb
Transcranial MRI-guided focused ultrasound (TcMRgFUS) is an old idea but a new technology that may change the entire clinical field of the neurosciences. TcMRgFUS has no cumulative effect, and it is applicable for repeatable treatments, controlled by real-time dosimetry, and capable of immediate tissue destruction. Most importantly, it has extremely accurate targeting and constant monitoring. It is potentially more precise than proton beam therapy and definitely more cost effective. Neuro-oncology may be the most promising area of future TcMRgFUS applications.
Chaplin V, Phipps MA, Jonathan SV, Grissom WA, Yang PF, Chen LM, Caskey CF.
Int J Comput Assist Radiol Surg. 2019 Aug
Transcranial focused ultrasound (FUS) is increasingly being explored to modulate neuronal activity. To target neuromodulation, researchers often localize the FUS beam onto the brain region(s) of interest using spatially tracked tools overlaid on pre-acquired images. Here, we quantify the accuracy of optically tracked image-guided FUS with magnetic resonance imaging (MRI) thermometry, evaluate sources of error and demonstrate feasibility of these procedures to target the macaque somatosensory region.
We developed an optically tracked FUS system capable of projecting the transducer focus onto a pre-acquired MRI volume. To measure the target registration error (TRE), we aimed the transducer focus at a desired target in a phantom under image guidance, heated the target while imaging with MR thermometry and then calculated the TRE as the difference between the targeted and heated locations. Multiple targets were measured using either an unbiased or bias-corrected calibration. We then targeted the macaque S1 brain region, where displacement induced by the acoustic radiation force was measured using MR acoustic radiation force imaging (MR-ARFI).
All calibration methods enabled registration with TRE on the order of 3 mm. Unbiased calibration resulted in an average TRE of 3.26 mm (min-max: 2.80-4.53 mm), which was not significantly changed by prospective bias correction (TRE of 3.05 mm; 2.06-3.81 mm, p = 0.55). Restricting motion between the transducer and target and increasing the distance between tracked markers reduced the TRE to 2.43 mm (min-max: 0.79-3.88 mm). MR-ARFI images showed qualitatively similar shape and extent as projected beam profiles in a living non-human primate.
Our study describes methods for image guidance of FUS neuromodulation and quantifies errors associated with this method in a large animal. The workflow is efficient enough for in vivo use, and we demonstrate transcranial MR-ARFI in vivo in macaques for the first time.
Prada F, Kalani MYS, Yagmurlu K, Norat P, Del Bene M, DiMeco F, Kassell NF.
Neurotherapeutics. 2019 Jan
Oncology and cerebrovascular disease constitute two of the most common diseases afflicting the central nervous system. Standard of treatment of these pathologies is based on multidisciplinary approaches encompassing combination of interventional procedures such as open and endovascular surgeries, drugs (chemotherapies, anti-coagulants, anti-platelet therapies, thrombolytics), and radiation therapies. In this context, therapeutic ultrasound could represent a novel diagnostic/therapeutic in the armamentarium of the surgeon to treat these diseases. Ultrasound relies on mechanical energy to induce numerous physical and biological effects. The application of this technology in neurology has been limited due to the challenges with penetrating the skull, thus limiting a prompt translation as has been seen in treating pathologies in other organs, such as breast and abdomen. Thanks to pivotal adjuncts such as multiconvergent transducers, magnetic resonance imaging (MRI) guidance, MRI thermometry, implantable transducers, and acoustic windows, focused ultrasound (FUS) is ready for prime-time applications in oncology and cerebrovascular neurology. In this review, we analyze the evolution of FUS from the beginning in 1950s to current state-of-the-art. We provide an overall picture of actual and future applications of FUS in oncology and cerebrovascular neurology reporting for each application the principal existing evidences.