The range of therapeutic treatment options for central nervous system (CNS) diseases is greatly limited by the blood-brain barrier (BBB). While a variety of strategies to circumvent the blood-brain barrier for drug delivery have been investigated, little clinical success has been achieved. Focused ultrasound (FUS) is a unique approach whereby the transcranial application of acoustic energy to targeted brain areas causes a noninvasive, safe, transient, and targeted opening of the BBB, providing an avenue for the delivery of therapeutic agents from the systemic circulation into the brain. There is a great need for viable treatment strategies for CNS diseases, and we believe that the preclinical success of this technique should encourage a rapid movement towards clinical testing. In this review, we address the versatile applications of FUS-mediated BBB opening, the safety profile of the technique, and the physical and biological mechanisms that drive this process.

Previous studies have demonstrated that temporarily increasing the permeability of the blood-brain barrier using focused ultrasound can reduce β-amyloid plaque load and improve cognitive function in animal models of Alzheimer’s disease. However, the underlying mechanism and duration for which the effects of one treatment persists for are unknown. Here, we used in vivo two-photon fluorescence microscopy to track changes in β-amyloid plaque sizes in the TgCRND8 mouse model of Alzheimer’s disease after one focused ultrasound treatment. We found that one treatment reduced plaques to 62 ± 16% (p ≤ 0.001) of their original volume two days post-sonication; this decrease in size persisted for two weeks. We then sought to evaluate the effectiveness of biweekly focused ultrasound treatments using magnetic resonance imaging-guided focused ultrasound treatments. Three to five biweekly treatments resulted in a 27 ± 7% (p ≤ 0.01) decrease in plaque number and 40 ± 10% (p ≤ 0.01) decrease in plaque surface area compared to untreated littermates. This study demonstrates that one focused ultrasound treatment reduces the size of existing β-amyloid plaques for two weeks, and that repeated biweekly focused ultrasound treatments is an effective method of reducing β-amyloid pathology in moderate-to-late stages of Alzheimer’s disease.

Introduction: Treatment of several diseases of the brain are complicated by the presence of the skull and the blood-brain barrier (BBB). Focused ultrasound (FUS) and microbubble (MB)mediated BBB treatment is a minimally invasive method to transiently increase the permeability of blood vessels in targeted brain areas. It can be used as a general delivery system to increase the concentration of therapeutic agents in the brain parenchyma.Areas covered: Over the past two decades, the safety of using FUS+MBs to deliver agents across the BBB has been interrogated through various methods of imaging, histology, biochemical assays, and behaviour analyses. Here we provide an overview of the factors that affect the safety profile these treatments, describe methods by which FUS+MB treatments are controlled, and discuss data that have informed the assessment of treatment risks. Expert opinion:There remains a need to assess the risks associated with clinically relevant treatment strategies, specifically repeated FUS+MB treatments, with and without therapeutic agent delivery. Additionally, efforts to develop metrics by which FUS+MB treatments can be easily compared across studies would facilitate a more rapid consensus on the risks associated with this intervention.