Investigating The Safety Profile Of Body-Coupled Ultrasound For The Auditory System And Tissue Heating During Stimulation

Abstract

The use of ultrasound (US) for therapeutic purposes has increased in the past couple of decades with many exciting applications. US can non-invasively interact with tissue in the central nervous system (CNS) with high spatial and temporal precision, thus allowing for development of novel treatments for various disorders of the CNS. Two techniques include the ability of US to modulate neural activity and the ability to transiently open the blood-brain-barrier (BBB). Transiently opening the BBB allows localized delivery of therapeutic agents into the CNS that would not otherwise be able to achieve adequate concentrations for a therapeutic effect due to the restrictive nature of the BBB. Additionally, performing neuromodulation non-invasively with US provides the possibility for a lower risk treatment option over technologies such as deep brain stimulators or direct cortical electrical stimulation. When investigating US neuromodulation, the SONIC Lab discovered that body-coupled US readily activated the auditory system of a guinea pig through a peripheral, cochlear mechanism. This cochlear activation putatively occurs through vibrations of the cerebrospinal fluid which in turn vibrate the cochlear fluids through the cochlear aqueduct. With the rapid growth of these fields, safety studies and regulatory guidance have fallen behind. No groups have investigated the safety of stimulation for the auditory system but have begun to investigate tissue safety. Groups have typically used the Food and Drug Administration’s Guidance of Diagnostic Ultrasound to claim adequate safety, although actual parameter settings differ from diagnostic US. The current work investigated how published US neuromodulation and BBB opening parameters affect the auditory system. We show that many standard parameters in these two fields cause electrophysiological changes in the auditory system that are consistent with damage. We observed reductions in the amplitudes of waves of the auditory brainstem responses (ABR) in the guinea pig model as well as an increase in recorded thresholds of ABRs and electrocochleography. US center frequency appears to influence the overall extent of damage that occurs where lower frequencies (220 kHz) caused more damage than higher frequencies (520 kHz and 1 MHz). Additionally, we were interested in investigating the safety of chronic US stimulation for the hearing system. Other studies from the SONIC Lab show the ability to deliver complex auditory information using amplitude modulated US. Therefore, we tested various US stimuli with complex spectro-temporal properties in a chronic implant preparation and determined better stimuli design based on auditory system health. We report the need for informed stimulus design after observing larger safe dynamic ranges with amplitude modulated or ramped US stimuli and from choice of US carrier frequency. In addition to hearing affects, regulatory guidance has fallen behind on demonstrating thermal safety of stimulation with the variety of indications and parameters for developing therapeutic ultrasound techniques. Therefore, we developed a computational model to estimate the increase in temperature that a sonicated tissue would experience from US and designed a regulatory friendly and simple framework of implementation that can be more tailored to indication specific scenarios. This model provides a better estimate of safety from thermal effects of US than the standard thermal index used in diagnostic US with use of the t43 measure. We compare the computational results with experimental heating data. The model has been approved by the FDA during a pre-submission meeting for use with a novel therapeutic device to show device output safety clinical.