Transcranial focused ultrasound (FUS) has been investigated for >60 years, with seminal studies by John Lynn and Tracy Putnam in the 1940s and William and Francis Fry in the 1950s establishing the potential of applying ultrasound to cerebral tissue.1-3 Early explorations of FUS for clinical use, however, were limited by the need for a craniectomy owing to beam distortion and energy absorption by the intact skull. In the 1990s, hemispheric phased arrays of transducers were developed, along with software that corrects for the phase aberrations produced by the variable thickness of the skull. This development revolutionized the field by allowing the noninvasive transmission of ultrasound beams to focal regions across irregular bone and tissue interfaces.4 Additionally, advances in magnetic resonance (MR) imaging, specifically the development of MR thermometry, allowed temperature changes to be visualized in real time, thereby enabling safety monitoring and confirmation of the energy being applied at the acoustic focus.5
Once these technologies were incorporated, FUS research in the neurosciences increased dramatically, building on prior successes in treating nonneurological disorders such as uterine fibroids. Ultimately, the existing clinical MR-guided FUS (MRgFUS) devices were modified for the noninvasive application of focused exposures in the human brain. MRgFUS recently completed a clinical trial for the treatment of essential tremor (NCT01304758) and is currently being evaluated for Parkinson disease (NCT01772693, NCT02246374, NCT02263885), depression (NCT02348411), epilepsy (NCT02151175), neuropathic pain (NCT01699477), and acute brain injury (NCT02522429). The technology has numerous other potential therapeutic applications, including the treatment of stroke, obsessive compulsive disorder, Alzheimer disease, trigeminal neuralgia, and hydrocephalus (for a review, see Medel et al6). Neuro-oncology, in particular, is receiving renewed attention because MRgFUS provides new options for the targeted, noninvasive treatment of brain tumors, in contrast to more invasive thermal approaches that are emerging as viable treatment options.7,8 This article reviews the preclinical and clinical work exploring MRgFUS for generating cytotoxicity within tumor tissue, enhancing the delivery or activity of therapeutic agents, and modulating the tumor microenvironment to enhance immune recognition and clearance (Figure 1 and Table 1).