Ariel Edward Hight

Hearing the light: neural and perceptual encoding of optogenetic stimulation in the central auditory pathway

Optogenetics provides a means to dissect the organization and function of neural circuits. Optogenetics also offers the translational promise of restoring sensation, enabling movement or supplanting abnormal activity patterns in pathological brain circuits. However, the inherent sluggishness of evoked photocurrents in conventional channelrhodopsins has hampered the development of optoprostheses that adequately mimic the rate and timing of natural spike patterning. Here, we explore the feasibility and limitations of a central auditory optoprosthesis by photoactivating mouse auditory midbrain neurons that either express channelrhodopsin-2 (ChR2) or Chronos, a channelrhodopsin with ultra-fast channel kinetics. Chronos-mediated spike fidelity surpassed ChR2 and natural acoustic stimulation to support a superior code for the detection and discrimination of rapid pulse trains. Interestingly, this midbrain coding advantage did not translate to a perceptual advantage, as behavioral detection of midbrain activation was equivalent with both opsins. Auditory cortex recordings revealed that the precisely synchronized midbrain responses had been converted to a simplified rate code that was indistinguishable between opsins and less robust overall than acoustic stimulation. These findings demonstrate the temporal coding benefits that can be realized with next-generation channelrhodopsins, but also highlight the challenge of inducing variegated patterns of forebrain spiking activity that support adaptive perception and behavior.

Auditory brainstem implant candidacy in the United States in children 0–17 years old

OBJECTIVES The auditory brainstem implant (ABI) is an option for hearing rehabilitation in profoundly deaf patients ineligible for cochlear implantation. Over the past decade, surgeons have begun implanting ABIs in pediatric patients who are unable to receive cochlear implants due to congenital or acquired malformations of the inner ear. No study has examined the potential population-level demand for ABIs in the United States (US). Herein, we aim to quantify the potential need for pediatric ABIs. METHODS A systematic literature review was conducted to identify studies detailing the rates of congenital cochlear and/or cochlear nerve (CN) anomalies. Absolute indications for ABI include bilateral cochlea or CN aplasia (Group A), and relative indications for ABI include bilateral cochlea or CN hypoplasia (Group B). Data was subsequently correlated to the US Census Bureau, the National Health Interview Survey, and the Gallaudet Research Institute to provide an estimation of pediatric ABI candidates. RESULTS Eleven studies documented rates of bilateral findings. Bilateral cochlea aplasia was identified in 0-8.7% of patients and bilateral CN aplasia in 0-4.8% of patients (Group A). Bilateral cochlea hypoplasia was identified in 0-8.7% of patients and bilateral CN hypoplasia in 0-5.4% of patients (Group B). Using population-level sensorineural hearing loss data, we roughly estimate 2.1% of potential implant candidates meet absolute indications for an ABI in the United States. CONCLUSION Congenital cochlear and cochlear nerve anomalies are exceedingly rare. This study provides the first preliminary estimate of cochlea and CN aplasia/hypoplasia at the population level albeit with limitations based on available data. These data suggest the need for dedicated ABI centers to focus expertise and management.

A biophysical model examining the role of low-voltage-activated potassium currents in shaping the responses of vestibular ganglion neurons

The vestibular nerve is characterized by two broad groups of neurons that differ in the timing of their interspike intervals; some fire at highly regular intervals, whereas others fire at highly irregular intervals. Heterogeneity in ion channel properties has been proposed as shaping these firing patterns (Highstein SM, Politoff AL. Brain Res 150: 182-187, 1978; Smith CE, Goldberg JM. Biol Cybern 54: 41-51, 1986). Kalluri et al. (J Neurophysiol 104: 2034-2051, 2010) proposed that regularity is controlled by the density of low-voltage-activated potassium currents (IKL). To examine the impact of IKL on spike timing regularity, we implemented a single-compartment model with three conductances known to be present in the vestibular ganglion: transient sodium (gNa), low-voltage-activated potassium (gKL), and high-voltage-activated potassium (gKH). Consistent with in vitro observations, removing gKL depolarized resting potential, increased input resistance and membrane time constant, and converted current step-evoked firing patterns from transient (1 spike at current onset) to sustained (many spikes). Modeled neurons were driven with a time-varying synaptic conductance that captured the random arrival times and amplitudes of glutamate-driven synaptic events. In the presence of gKL, spiking occurred only in response to large events with fast onsets. Models without gKL exhibited greater integration by responding to the superposition of rapidly arriving events. Three synaptic conductance were modeled, each with different kinetics to represent a variety of different synaptic processes. In response to all three types of synaptic conductance, models containing gKL produced spike trains with irregular interspike intervals. Only models lacking gKL when driven by rapidly arriving small excitatory postsynaptic currents were capable of generating regular spiking.

Medical and bioethical considerations in elective cochlear implant array removal

Objective Cochlear explantation for purely elective (e.g. psychological and emotional) reasons is not well studied. Herein, we aim to provide data and expert commentary about elective cochlear implant (CI) removal that may help to guide clinical decision-making and formulate guidelines related to CI explantation. Data sources We address these objectives via three approaches: case report of a patient who desired elective CI removal; review of literature and expert discussion by surgeon, audiologist, bioethicist, CI user and member of Deaf community. Review methods A systematic review using three scientific online databases was performed. Included articles addressed the benefits and/or complications of cochlear implantation in young children, CI explantation with or without revision surgery and the ethical debate between the medical and Deaf communities on cochlear implantation and explantation. Conclusions The medical and audiological perspectives identify a host of risks related to implant removal without reimplantation, including risk from surgery, general anaesthesia, cochlear ossification and poor audiometric outcomes. The member of the deaf community and bioethicist argue that physicians need to guide the principles of beneficence, non-maleficence and patient autonomy. Taken together, patient desires should be seen as paramount, if the patient is otherwise fit for surgery and well informed. Implications for practice Similar to the case of device implantation, device explantation should be a multidisciplinary and collaborative decision with the patient and the family’s desires at the centre. While every case is different, we offer a CI explantation discussion to assist in clinical decision-making, patient counselling and education.

Influence of trainee participation on operative times for adult and pediatric cochlear implantation

Abstract Objective Few studies have examined operative times for cochlear implantation (CI) using multivariable linear regression analyses to identify predictors of case length. Herein, we assess whether trainee participation, among other factors, influences operating room (OR) times. Methods We retrospectively reviewed total OR and procedural times for isolated unilateral implants over a 5-year period (2009–2013) in children and adults. Total operating and procedural times were compared. Multivariable linear regression analyses were used to identify predictors of procedural time. Results We identified a total of 455 unilateral CI procedures (n = 35 pediatric, n = 420 adult). Mean total OR time was 193.6 minutes (SD = 58.9 minutes) and mean procedural time was 147.1 minutes (SD = 56.2). The presence of trainees was associated with a significant difference in procedure time: 149.9 minutes (SD = 54.9) with trainees versus 136.6 minutes (SD = 59.9) without trainees, P = 0.0375. Trainee involvement did not significantly increase total OR time: 196.3 minutes (SD = 56.9) with trainees versus 183.8 minutes (SD = 65.0) without trainees, P = 0.0653. Surgeon identity was also associated with differences in procedural time (P < 0.001). Patient age, gender, American Society of Anesthesiologists classification, and pediatric designation had no significant impact on length of case. Conclusions Major predictors of longer procedural OR times for CI are surgeon identity and trainee participation. Few published data exist on length of CI in an academic setting using multivariable linear regression analyses. Our data may be instructive for comparative analyses and have implications for operative planning and surgical education.

Generation of a Novel Transgenic ChR2 Mouse to Investigate Cochlear Implant Model Based on Optogenetics

Objectives: Optogenetics is a powerful new tool to use for the auditory system and involves the introduction of a light-sensitive protein into neurons. This exciting approach may help to increase spatial resolution of auditory implants that are limited due to electrical current spread and to improve outcomes. Herein, we describe: (1) generation of a novel transgenic mouse expressing channelrhodopsin-2 (ChR2+) in spiral ganglion cells (SGC), (2) auditory responses to optical stimulation of the cochlea in our ChR2+ transgenic mouse. Methods: A left cochleostomy was performed and the right inferior colliculus (IC) was exposed via craniotomy in adult ChR2+ mice. Optically evoked auditory brainstem responses (oABRs) and IC multi-unit recordings were conducted in response to optical stimulation via a blue-light laser fiber (473nm wavelength) placed into the cochleostomy. The expression of ChR2 in cochlea was histologically identified under confocal microscope. Results: ChR2 expression was observed in the soma, the peripheral and central axons of almost all SGCs in 1 to 7- month-old ChR2+ mice. A single 1-ms blue light pulse can evoke oABRs with peak magnitudes up to 10uV and latencies short as 2 ms. Evoked multi-unit activity (~180 spikes/second) in the IC was substantially synchronized (0.9 synchronization index) to a 28-Hz light pulse train applied in cochlea. Conclusions: We generated and characterized a novel ChR2 transgenic mouse line that is sensitive to light-based stimulation in the peripheral auditory system. Our study may demonstrate the feasibility of using optogenetic technology as the basis for new neuronal stimulation paradigm for cochlear implants.

Community network for deaf scientists

We are a community of scientists who have personally experienced the barriers imposed by hearing loss described by G. Buckley et al. in their Letter “Building community for deaf scientists” (20 January, p. [255][1]). They propose an institutional hub for deaf and hard-of-hearing (D/HH) trainees

Histologic Analysis of Chronos in an Optogenetic-Based Auditory Brainstem Implant Model

Objectives: Optogenetics affords the potential for improved spatial resolution compared with electric stimulation in future auditory neuroprostheses. No histologic studies have yet examined the virally-mediated gene transfer of Chronos, a new opsin, to the murine cochlear nucleus (CN). Herein, we aim to (1) identify CN regions and neurons receptive to gene transfer of Chronos and (2) describe the morphology of putative cell types that express Chronos. Methods: CBA/CaJ mice underwent CN-targeted injection of Chronos. The Chronos construct consisted of an adeno-associated viral vector (AA2/8), CAG promoter, and a fluorescent marker. Following a 4-week incubation period, mice were sacrificed and intravascularly fixed with paraformaldehyde, and brains were extracted, sucrose cryoprotected, and cryostatically sectioned. Sections of 35-µm thickness were co-labeled with neuron-specific markers microtubule associated protein-2 and anti-tubulin, beta III isoform and DAPI-fluoromounted. Sections of 60-µm thickness were DAPI-fluoromounted, and confocal microscopy revealed cellular morphologies. Results: Opsin-linked fluorescence demonstrates Chronos expression throughout the dorsal CN with contiguous extension routinely into the ventral CN and variably into the auditory nerve and inferior cerebellar peduncle. Chronos localizes to neuronal-specific and nonneuronal populations. Confocal microscopy suggests involvement of a wide array of CN cell types, including morphologies consistent with pyramidal cells and giant cells. Conclusions: Our histologic analyses confirm widespread infection of multiple neuronal populations throughout the CN. This work sets the stage for correlation with ongoing neurophysiology experiments. Future work with CN-specific promoters to target neuronal subpopulations may further improve clinical potential for an optogenetics-based auditory neuroprosthesis.