Noninvasive, transient, and local image-guided blood-brain barrier disruption (BBBD) has been demonstrated with focused ultrasound exposure in animal models. Most studies have combined low pressure ...amplitude and low time average acoustic power burst sonications with intravascular injection of pre-formed micro-bubbles to produce BBBD without damage to the neurons. The BBB has been shown to be healed within a few hours after the exposure. The combination of focused ultrasound beams with MR image guidance allows precise anatomical targeting as demonstrated by the delivery of several marker molecules in different animal models. This method may in the future have a significant impact on the diagnosis and treatment of central nervous system (CNS) disorders. Most notably, the delivery of the chemotherapy agents (liposomal Doxorubicin and Herceptin) has been shown in a rat model.
Focused ultrasound (FUS) is a disruptive medical technology, and its implementation in the clinic represents the culmination of decades of research. Lying at the convergence of physics, engineering, ...imaging, biology and neuroscience, FUS offers the ability to non-invasively and precisely intervene in key circuits that drive common and challenging brain conditions. The actions of FUS in the brain take many forms, ranging from transient blood-brain barrier opening and neuromodulation to permanent thermoablation. Over the past 5 years, we have seen a dramatic expansion of indications for and experience with FUS in humans, with a resultant exponential increase in academic and public interest in the technology. Applications now span the clinical spectrum in neurological and psychiatric diseases, with insights still emerging from preclinical models and human trials. In this Review, we provide a comprehensive overview of therapeutic ultrasound and its current and emerging indications in the brain. We examine the potential impact of FUS on the landscape of brain therapies as well as the challenges facing further advancement and broader adoption of this promising minimally invasive therapeutic alternative.
Focused ultrasound (FUS), in conjunction with circulating microbubbles (MBs), can be used to transiently increase the permeability of the blood-brain barrier (BBB) in a targeted manner, allowing ...therapeutic agents to enter the brain from systemic circulation. While promising preclinical work has paved the way for the initiation of 3 human trials, there remains concern regarding neuroinflammation following treatment. The aim of this study was to assess the magnitude of this response following sonication and explore the influence of MB dose.
Differential expression of NFκB signaling pathway genes was assessed in rats at 6 h and 4 days following a FUS-mediated increase in BBB permeability. Three sonication schemes were tested: (1) a clinical imaging dose of MBs + peak negative pressure (PNP) controlled by acoustic feedback, (2) 10x clinical imaging dose of MBs + constant PNP of 0.290 MPa, and (3) 10x clinical imaging dose of MBs + PNP controlled by acoustic feedback. Follow-up magnetic resonance imaging (MRI) was performed to assess edema and hemorrhage. Hematoxylin and eosin histology was used to evaluate general tissue health.
MB dose has a significant impact on the expression of several key genes involved in acute inflammation and immune activation, including Tnf, Birc3, and Ccl2. At a clinical imaging dose of MBs, there were no significant changes detected in the expression of any NFκB signaling pathway genes. Conversely, a high MB dose resulted in a clear activation of the NFκB signaling pathway, accompanied by edema, neuronal degeneration, neutrophil infiltration, and microhemorrhage. Results also suggest that post-FUS gadolinium enhancement may hold predictive value in assessing the magnitude of inflammatory response.
While a significant and damaging inflammatory response was observed at high MB doses, it was demonstrated that FUS can be used to induce increased BBB permeability without an associated upregulation of NFκB signaling pathway gene expression. This emphasizes the importance of employing optimized FUS parameters to mitigate the chances of causing injury to the brain at the targeted locations.
The presence of the blood-brain barrier (BBB) is a significant impediment to the delivery of therapeutic agents to the brain for treatment of brain diseases. Focused ultrasound (FUS) has been ...developed as a noninvasive method for transiently increasing the permeability of the BBB to promote drug delivery to targeted regions of the brain.
The present review briefly compares the methods used to promote drug delivery to the brain and describes the benefits and limitations of FUS technology. We summarize the experimental data which shows that FUS, combined with intravascular microbubbles, increases therapeutic agent delivery into the brain leading to significant reductions in pathology in preclinical models of disease. The potential for translation of this technology to the clinic is also discussed.
The introduction of magnetic resonance imaging guidance and intravascular administration of microbubbles to FUS treatments permits the consistent, transient and targeted opening of the BBB. The development of feedback systems and real-time monitoring techniques improve the safety of BBB opening. Successful clinical translation of FUS has the potential to revolutionize the treatment of brain disease resulting in effective, less-invasive treatments without the need for expensive drug development.
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.
Despite recent advances in blood-brain barrier (BBB) research, it remains a significant hurdle for the pharmaceutical treatment of brain diseases. Focused ultrasound (FUS) is one method to ...transiently increase permeability of the BBB to promote drug delivery to specific brain regions. An introduction to the BBB and a brief overview of the methods, which can be used to circumvent the BBB to promote drug delivery, is provided. In particular, we discuss the advantages and limitations of FUS technology and the efficacy of FUS-mediated drug delivery in models of disease. MRI for targeting and evaluating FUS treatments, combined with administration of microbubbles, allows for transient, reproducible BBB opening. The integration of a real-time acoustic feedback controller has improved treatment safety. Successful clinical translation of FUS has the potential to transform the treatment of brain disease worldwide without requiring the development of new pharmaceutical agents.
Therapeutic treatment options for central nervous system diseases are greatly limited by the blood-brain barrier (BBB). Focused ultrasound (FUS), in conjunction with circulating microbubbles, can be ...used to induce a targeted and transient increase in BBB permeability, providing a unique approach for the delivery of drugs from the systemic circulation into the brain. While preclinical research has demonstrated the utility of FUS, there remains a large gap in our knowledge regarding the impact of sonication on BBB gene expression. This work is focused on investigating the transcriptional changes in dorsal hippocampal rat microvessels in the acute stages following sonication. Microarray analysis of microvessels was performed at 6 and 24 hrs post-FUS. Expression changes in individual genes and bioinformatic analysis suggests that FUS may induce a transient inflammatory response in microvessels. Increased transcription of proinflammatory cytokine genes appears to be short-lived, largely returning to baseline by 24 hrs. This observation may help to explain some previously observed bioeffects of FUS and may also be a driving force for the angiogenic processes and reduced drug efflux suggested by this work. While further studies are necessary, these results open up intriguing possibilities for novel FUS applications and suggest possible routes for pharmacologically modifying the technique.
Summary Background Essential tremor is the most common movement disorder and is often refractory to medical treatment. Surgical therapies, using lesioning and deep brain stimulation in the thalamus, ...have been used to treat essential tremor that is disabling and resistant to medication. Although often effective, these treatments have risks associated with an open neurosurgical procedure. MR-guided focused ultrasound has been developed as a non-invasive means of generating precisely placed focal lesions. We examined its application to the management of essential tremor. Methods Our study was done in Toronto, Canada, between May, 2012, and January, 2013. Four patients with chronic and medication-resistant essential tremor were treated with MR-guided focused ultrasound to ablate tremor-mediating areas of the thalamus. Patients underwent tremor evaluation and neuroimaging at baseline and 1 month and 3 months after surgery. Outcome measures included tremor severity in the treated arm, as measured by the clinical rating scale for tremor, and treatment-related adverse events. Findings Patients showed immediate and sustained improvements in tremor in the dominant hand. Mean reduction in tremor score of the treated hand was 89·4% at 1 month and 81·3% at 3 months. This reduction was accompanied by functional benefits and improvements in writing and motor tasks. One patient had postoperative paraesthesias which persisted at 3 months. Another patient developed a deep vein thrombosis, potentially related to the length of the procedure. Interpretation MR-guided focused ultrasound might be a safe and effective approach to generation of focal intracranial lesions for the management of disabling, medication-resistant essential tremor. If larger trials validate the safety and ascertain the efficacy and durability of this new approach, it might change the way that patients with essential tremor and potentially other disorders are treated. Funding Focused Ultrasound Foundation.
PDF
