Richard D. Rabbitt

Purpose Determine thresholds of vestibular compound action potentials (vCAPs) evoked by pulsed interaural bone-conducted vibration (BCV) and estimate synchronization tuning curves for sinusoidal BCV and stapes vibration (SV) in multiple mammalian species. Methods Thresholds were determined from previously reported vCAP data in response to vibration pulses with acceleration amplitudes ranging from ~ 0.0003 to 0.04 m s⁻² (~ 0.3–4 mG) and rise times from ~ 0.17 to 0.6 ms in guinea pigs of either sex. A simple two-degrees-of-freedom model was applied to estimate mechanical tuning curves underlying frequency-dependent synchronization. Results Stimulus-evoked vCAPs increased linearly with peak acceleration on a dB scale, and intercepted zero at a synchronization threshold of −54 dB (re: 1 m s⁻²). Combining the threshold with the model predicts a critical shear rate of − 34 dB (re: 1 rad s⁻¹) between otoconia and the sensory epithelium is sufficient to evoke synchronized action potentials. The interaural acceleration threshold required to reach the critical shear rate predicts a V-shaped tuning curve for sinusoidal BCV with thresholds near −55 dB (re: 1 m s⁻²) across species evaluated. The characteristic frequency (CF) was estimated as 210 Hz for humans, 286 Hz for sheep, 526 Hz for guinea pigs, 600 Hz for rats, and 688 Hz for mice. The threshold estimated for SV was − 50 dB (re: 1 m s⁻²) with relatively broad tuning extending approximately 1 kHz above the BCV CF. Conclusion Results are consistent with the hypothesis that synchronized action potentials in the utricular nerve are driven by the mechanical shear rate acting on sensory hair bundles.

Over the past two decades Biomedical Engineering has emerged as a major discipline that bridges societal needs of human health care with the development of novel technologies. Every medical institution is now equipped at varying degrees of sophistication with the ability to monitor human health in both non-invasive and invasive modes. The multiple scales at which human physiology can be interrogated provide a profound perspective on health and disease. We are at the nexus of creating “avatars” (herein defined as an extension of “digital twins”) of human patho/physiology to serve as paradigms for interrogation and potential intervention. Motivated by the emergence of these new capabilities, the IEEE Engineering in Medicine and Biology Society, the Departments of Biomedical Engineering at Johns Hopkins University and Bioengineering at University of California at San Diego sponsored an interdisciplinary workshop to define the grand challenges that face biomedical engineering and the mechanisms to address these challenges. The Workshop identified five grand challenges with cross-cutting themes and provided a roadmap for new technologies, identified new training needs, and defined the types of interdisciplinary teams needed for addressing these challenges. The themes presented in this paper include: 1) accumedicine through creation of avatars of cells, tissues, organs and whole human; 2) development of smart and responsive devices for human function augmentation; 3) exocortical technologies to understand brain function and treat neuropathologies; 4) the development of approaches to harness the human immune system for health and wellness; and 5) new strategies to engineer genomes and cells.

The biophysical and mechanical properties of outer hair cells (OHCs) vary systematically with location along the cochlear tonotopic map following monotopic rela

Amniotes evolved a unique calyceal postsynaptic terminal in the vestibular organs of the inner ear that underpins quantal and non-quantal transmission at the synapse of sensory hair cells and vestibular afferent neurons. The non-quantal component is of particular interest as it includes an ultrafast synaptic current thought to underlie the exquisite synchronization of action potentials in vestibular afferent fibres to dynamic stimuli such as sound and vibration. Here we demonstrate evidence that non-quantal transmission is responsible for short latency vestibular evoked potentials (vCAPs) in the guinea pig utricle. We first show that, unlike auditory nerve responses which are completely abolished, vCAPs are insensitive to local administration of the AMPA receptor agonist CNQX. Moreover, latency comparisons between presynaptic hair cell and postsynaptic neural responses reveal that the vCAP occurs without measurable synaptic delay. Finally, using a paired-pulse stimulus designed to deplete the readily releasable pool of synaptic vesicles in hair cells, we reveal that forward masking is lacking in vestibular responses, compared to the equivalent cochlear responses. Our data support the hypothesis that the fast component of non-quantal transmission at calyceal synapses is indefatigable and responsible for ultrafast responses of vestibular organs evoked by transient stimulation. Significance The mammalian vestibular system drives some of the fastest reflex pathways in the nervous system, ensuring stable gaze and postural control for locomotion on land. To achieve this, terrestrial amniotes evolved a large, unique calyx afferent terminal which completely envelopes one or more pre-synaptic vestibular hair cells, which transmits mechanosensory signals mediated by quantal and nonquantal (NQ) synaptic transmission. We present several lines of data in the guinea pig that reveal the pre-synaptic transmission of the most sensitive vestibular afferents are faster than their auditory nerve counterparts. Here, we present neurophysiological and pharmacological evidence that this vestibular speed advantage arises from ultrafast NQ electrical synaptic transmission from Type I hair cells to their calyx partners.

Introduction: Calyx bearing vestibular afferent neurons innervating type I hair cells in the striolar region of the utricle are exquisitely sensitive to auditory-frequency air conducted sound (ACS) and bone conducted vibration (BCV). Here, we present experimental data and a mathematical model of utricular mechanics and vestibular compound action potential generation (vCAP) in response to clinically relevant levels of ACS and BCV. Vibration of the otoconial layer relative to the sensory epithelium was simulated using a Newtonian two-degree-of-freedom spring-mass-damper system, action potential timing was simulated using an empirical model, and vCAPs were simulated by convolving responses of the population of sensitive neurons with an empirical extracellular voltage kernel. The model was validated by comparison to macular vibration and vCAPs recorded in the guinea pig, in vivo.Results: Transient stimuli evoked short-latency vCAPs that scaled in magnitude and timing with hair bundle mechanical shear rate for both ACS and BCV. For pulse BCV stimuli with durations 0.9 ms the magnitude increased in proportion to temporal bone jerk. Once validated using ACS and BCV data, the model was applied to predict blast-induced hair bundle shear, with results predicting acute mechanical damage to bundles immediately upon exposure.Discussion: Results demonstrate the switch from linear acceleration to linear jerk as the adequate stimulus arises entirely from mechanical factors controlling the dynamics of sensory hair bundle deflection. The model describes the switch in terms of the mechanical natural frequencies of vibration, which vary between species based on morphology and mechanical factors.

The present work examines the hypothesis that cochlear outer hair cell (OHC) properties vary in precise proportions along the tonotopic map to optimize electromechanical power conversion. We tested this hypothesis using a very simple model of a single isolated OHC driving a mechanical load. Results identify three non-dimensional ratios that are predicted to optimize power conversion: the ratio of the resistive-capacitive (RC) corner to the characteristic frequency (CF), the ratio of nonlinear to linear capacitance and the ratio of OHC stiffness to cochlear load stiffness. Optimum efficiency requires all three ratios to be universal constants, independent of CF and species. The same ratios are cardinal control parameters that maximize power output by positioning the OHC operating point on the edge of a dynamic instability. Results support the hypothesis that OHC properties evolved to optimize electro-mechanical power conversion. Identification of the RC corner frequency as a control parameter reveals a powerful mechanism used by medial olivocochlear efferent system to control OHC power output. Results indicate the upper-frequency limit of OHC power output is not constrained by the speed of the motor itself but instead is probably limited by the size of the nucleus and membrane surface area available for ion-channel expression.

Ménière’s disease (MD) is a debilitating disorder with unclear pathophysiology whose diagnosis often relies on clinical judgment rather than objective testing. To complicate matters further, a dissociation has emerged between two vestibular function tests commonly used in patients with MD to examine the same end-organ (the semicircular canals): the caloric test and video head impulse testing (vHIT). Caloric responses are often abnormal, while vHIT results remain normal. Explaining this dissociation could reveal novel insights into MD pathophysiology. Here, we conduct a histopathological study using temporal bone specimens (N = 58, 21 MD-affected ears and 37 age-matched controls) and their clinical testing data to examine current hypotheses aimed at this dissociation. We find otolith membrane herniation into the horizontal semicircular canal in 69% of MD ears, with 90% of these ears demonstrating a diminished caloric response. No ears with a normal response had this herniation. Moreover, we evaluated the semicircular canals for endolymphatic hydrops, which had been hypothesized to contribute to the dissociation, and found no evidence of duct dilation/hydrops. We did, however, note a potentially novel morphologic finding—smaller bony labyrinth cross-sectional diameters/areas in some MD ear canals compared to controls, suggesting relative size of the membranous duct to the bony canal rather than absolute size may be of importance. Taken together, this study refines hypotheses on the vestibular test dissociation in MD, holding diagnostic implications and expanding our understanding of the mechanisms underlying this enigmatic disease.

The present work examines the hypothesis that cochlear outer hair cell (OHC) length, membrane properties, and mechano-electrical transduction (MET) current vary in precise proportions along the cochlear tonotopic map to optimize electro-mechanical power conversion at each characteristic frequency (CF). We tested this hypothesis in a minimal model of OHC electro-mechanics that accounts for OHC biophysical properties as well as the cochlear mechanical load. Results identify three nondimensional ratios that maximize power conversion: the ratio of the resistive-capacitive (RC) corner frequency to CF, the ratio of nonlinear to linear capacitance, and the ratio of OHC stiffness to cochlear load stiffness. Optimum efficiency requires all three ratios to be universal constants quantitatively related to each other, independent of CF and species. From a dynamical systems perspective, the same three ratios are cardinal control parameters that combine to maximize power output by poising the OHC to operate on the edge of a dynamic instability, the critical point. Results support the hypothesis that OHC properties in extant species evolved to optimize electro-mechanical power conversion. Identification of the RC corner frequency as a dynamical control parameter that sets the critical point reveals a powerful mechanism used by medial olivocochlear efferent system to exert control over OHC stability and power output. Results further suggest the upper frequency limit of mammalian hearing is not constrained by the RC corner frequency or the speed of the motor, but instead is likely limited by the size of the nucleus and membrane surface area available for protein expression. Significance Statement Results provide strong evidence that evolutionary development of OHCs was driven by pressure to enhance electro-mechanical power conversion. Efficient power conversion requires specific OHCs properties that simultaneously match the cochlear load and poise the cell at the critical point. Results identify a parametric blueprint for optimum OHC design, which we posit applies across species and CFs. The blueprint reveals biophysical principles used by OHCs to amplify vibration across the entire bandwidth of mammalian hearing, including frequencies far exceeding what might be expected based on the low pass features of the membrane-motor complex measured in isolation. When applied to short OHCs of the odontocete cetaceans for example, the blueprint predicts peak power output at frequencies exceeding 100 kHz.

To examine mechanisms responsible for vestibular afferent sensitivity to transient air conducted sounds (ACS) and inter-aural bone conducted vibration (BCV), we performed simultaneous measurements of stimulus-evoked vestibular compound action potentials (vCAPs), utricular macula or stapes velocity, and Vestibular Microphonics (VMs) in the anaesthetized guinea pig. For short duration punctate stimuli (<1ms), the vCAP increases magnitude in close proportion to macular velocity and temporal bone (ear-bar) acceleration, rather than other kinematic variables. For longer duration stimuli, the vCAP magnitude switches from acceleration sensitive to linear jerk sensitive. vCAP input-output (IO) functions suggest primary afferent response generation has the same origins for both BCV and ACS, with similar macular velocity thresholds and IO functions for both stimuli. Frequency tuning curves evoked by tone-burst stimuli also show the vCAP increases magnitude in proportion to macular velocity, while in contrast, the VM increases magnitude in proportion to macular displacement across the entire frequency bandwidth tested. The subset of vestibular afferent neurons responsible for synchronized firing and vCAPs make calyceal synaptic contacts with type I hair cells in the striolar region of the epithelium and have irregularly spaced inter-spike intervals at rest. Present results provide new insight into mechanical and neural mechanisms underlying synchronized action potentials in these sensitive afferents, with clinical relevance for understanding the activation and tuning of neurons responsible for driving rapid compensatory reflex responses. Significant statement: Calyx-bearing afferents in the utricle have the remarkable ability to fire an action potential at a precise time following the onset of a transient stimulus and provide temporal information required for compensatory vestibular reflex circuits, but specifically how transient high-frequency stimuli lead to mechanical activation of hair cells and neural responses is poorly understood. Here, we dissect the relative contributions of mechanics, hair cell transduction, and action potential generation on short-latency responses to transient stimuli. Results provide a framework for the interpretation of synchronized vestibular afferent responses, with relevance to understanding origins of myogenic reflex responses commonly used in the clinic to assay vestibular function, and vestibular short latency potentials commonly used for vestibular phenotyping in rodents.