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Advances in Optogenetic-based Auditory Implants

Kozin, Elliott D. MD; Lee, Daniel J. MD

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doi: 10.1097/01.HJ.0000499584.22815.e8
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Figure 1
Figure 1:
Cochlear Implant versus Auditory Brainstem Implant.The target of the multichannel cochlear implant (CI) electrode are the first order auditory neurons (spiral ganglion cells) in the cochlea. The CI electrode positioning takes advantage of the frequency-specific organization of the spiral-shaped cochlea. There are fundamental limits, however, in how many electrodes can be placed into the cochlea due to channel cross talk from overlapping electrical fields. The target of the auditory brainstem implant (ABI) electrode are the second order auditory neurons called the cochlear nucleus. With the close proximity of non-auditory nerves to the cochlear nucleus, off-target effects are common in ABI users due to electrical current spread. These side effects include facial twitching, dizziness, and pain (Adapted from Leblanc, 1999).

The cochlear implant (CI) is the most successful neuroprosthesis. The 2013 Lasker Award, given to pioneers of the CI, illustrates the profound success of the device and its substantial impact on society. CI technology has evolved from a rudimentary single channel implant in the mid-20th century to a multi-channel auditory neurostimulator that provides meaningful sound and speech perception to the majority of deaf users. A close analogue to the CI, the auditory brainstem implant (ABI) provides meaningful hearing perception to those who may not benefit from a CI due to anatomic constraints, such as neurofibromatosis 2 or cochlear nerve aplasia. Whereas the CI stimulates spiral ganglion neurons of the cochlea (first order auditory neurons), the ABI bypasses a damaged or absent cochlea and/or cochlear nerve to stimulate neurons of the cochlear nucleus in the brainstem (second order auditory neurons; Fig. 1; Sennaroglu. Otol Neurotol 2009;30[6]:708 Unlike most CI users who experience open set speech perception, the majority of ABI users have sound awareness that aids in lip reading.


Elliott D. Kozin, MD

In the last 50 years, over 300,000 people have received a CI, and over 1,000 have received an ABI (Semenov. Otolaryngol Clin North Am 2012;45[5]:959; NIH, 2016 But despite this widespread success, both the CI and ABI have significant limitations. Hearing outcomes of the CI and ABI are variable across similar patient cohorts (Semenov, 2012; Ray. Cochlear Implants Int 2006;7[1]:49 Colleti. Curr Opin Otolaryngol Head Neck Surg 2012;20[5]:353; Colleti. Laryngoscope 2005;115[11]:1974; Nevison. Ear Hear 2002;23[3]:170 CI and ABI users also have significant deficits in understanding speech in noisy environments and in music appreciation (Qian-Jie Fu. J Assoc Res Otolaryngol 2005;6[1]:9; Friesen. J Acoust Soc Am 2001;110[2]:1150; Van Deun. Ear Hear 2010;31[5]:702; Kohlberg. Laryngoscope 2014;124[3]:587 The limited and variable outcomes among CI and ABI patients are likely due to a common feature in all existing bionic devices: electrical current. Electrical stimulation results in current spread and channel crosstalk that may limit the performance of contemporary auditory implants (Boëx. J Acoust Soc Am 200;114:2049; Karg. Hear Res 2013;299:10; Qaz. Hear Res 2013;299:79 The degree of overlap among nerve fibers stimulated by adjacent CI or ABI electrodes degrades the quality of the implant's stimulus (Eisen. J Assoc Res Otolaryngol 2005;6[2]:160 ABI users in particular often have electrodes that cannot be used in the map due to off-target effects, resulting in facial nerve stimulation, pain, or dizziness primarily due to electrical current spread.


Figure 2
Figure 2:
Optogenetic versus Electrical Stimulation.Upper panel: optogenetic stimulation requires two steps: (1) Modification of neurons by introducing a gene into the cell (transfected neuron) that produces a light-sensitive protein called channelrhodopsin, and (2) exposure of the photosensitized neuron to light of the appropriate wavelength. The light photons result in a conformational change (change in the shape) of a non-selective cell membrane channel, allowing for the entry of positively-charged ions into the cell, and causing depolarization (excitation) of the neuron. Only neurons that express light-sensitive proteins will be stimulated while neighboring neurons remain quiet, resulting in more specific neuronal activity. Lower Panel: In contrast, the lower panels show that an implant based on electricity results in a current field that stimulates more broadly, resulting in less specificity. (Credit/Tiffany Otero, BS)

Light-based stimulation is an exciting new alternative to electrically-based implants that offers a theoretical advantage: light can be focused to target smaller areas while reducing the unintended consequence of current spread (Fu. J Acoust Soc Am 1998;104[6]:3586 The major type of light stimulation studied in the auditory system is “optogenetic” stimulation. Optogenetics refers to the combination of optics and genetics to control specific events within living cells, such as action potentials in neurons (Yizhar. Neuron 2011;71[1]:9 It requires the modification of neurons to make them photosensitive to a specific wavelength of light and is based on the expression of light-sensitive proteins, called opsins. One specific group of opsins, called channelrhodopsins, are light-gated ion channels found in blue-green algae and control movement in response to photons of light. Opsins are delivered to specific tissues using a viral vector or other approaches, which then may be used to control cellular events (such as turning on or off a neuron; Fig. 2). Upon exposure of the photosensitized neuron to a specific wavelength of light of appropriate brightness (or intensity), only cells that express the specific opsin will respond. This type of specific stimulation is in contrast to the nonspecific electric-based model (Fig. 2).

Daniel J. Lee, MD

Several landmark studies have recently demonstrated the feasibility of optogenetic stimulation of the auditory pathways in an animal model. In the first paper of its kind, Shimano et al. determined that an opsin called channelrhodopsin-2 (ChR2) could be expressed in the auditory brainstem and that appropriate wavelengths of blue light could activate these cochlear nucleus neurons in an in vivo rat model (Brain Res 2013;1511:138 Five weeks after the initial inoculation with the viral vector to introduce the gene that encodes for ChR2, expression of opsins was observed in all layers of the CN as well as in regions receiving projections from the injection site. Stable ChR2 expression levels were observed at the 18-month time point, which showed to be similar to the levels seen at five weeks after initial injection with the viral vector and ChR2 gene. Notably, no deleterious effects on hearing associated with the viral injections were observed based on sound-evoked auditory brainstem responses (ABR).

Figure 3
Figure 3:
Blue Light Stimulation of the Auditory Brainstem. In the left panel, the left cochlear nucleus is exposed surgically and a fiberoptic system is placed on the surface of the brainstem. Cells were photosensitized using a viral vector approach, resulting in expression of Channelrhodopsin-2 (ChR2) in cochlear nucleus neurons. Pulsed blue light of varying rates and intensities was delivered to the cochlear nucleus, resulting in multipeaked waveforms called optically-evoked auditory brainstem responses, or “oABRs” as shown in the right panel. These far-field auditory pathway responses resemble sound-evoked ABRs (Adapted from Hight. Hear Res 2015;322:235

Taking this initial approach one step further, Darrow et al., from our research group at the Massachusetts Eye and Ear, showed that higher auditory centers were activated as a result of stimulation of opsin-expressing cochlear nucleus neurons (Brain Res 2015;1599:44 Pulsed blue light delivered to the surface of the cochlear nucleus in mice injected with a viral vector with ChR2 four weeks prior demonstrated responses that resemble a sound-evoked ABR (Fig. 3). In addition, multiunit activity (firing of many neurons) was observed in the inferior colliculus (an upstream nucleus that receives signals from the cochlear nucleus), and the auditory cortex. From these results, Darrow et al. concluded that blue laser light activation of the photosensitized cochlear nucleus generates responses along the central auditory pathways, and provided the first evidence that a brainstem implant based on light was feasible. Control experiments that used laser light on the auditory brainstem of animals that did not express opsins failed to show any responses along the auditory pathways.

Behavioral studies are critical to determine whether animals that “hear the light” respond meaningfully as they do to sound-driven tasks. To this end, Guo et al., also from the Massachusetts Eye and Ear, developed a mouse model of a central auditory implant using opsins and a chronically implanted optical fiber in the region of the inferior colliculus (Sci Rep 2015;5:10319 These mice were then trained to avoid a foot shock when they heard either sound or when exposed to light stimulation of the photosensitized inferior colliculus. Indeed, these mice behaved similarly when exposed to sound or to light and provided the first evidence that optical responses were perceptually relevant in a model of an optical central auditory implant. In this regard, the mice closely approximated an auditory midbrain implant based on light stimulation (Lenarz. Otol Neurotol 2006;27[6]:838; Lim. Hear Res 2015;322:212; Samii. Otol Neurotol 2007;28[1]:31


The cochlea has been a more challenging target for optogenetic approaches. Decades of research have attempted to optimize gene therapy to the peripheral auditory system for regeneration of hearing (Chien. Ear Hear 2015;36[1]:1; Kelly. Otolaryngol Clin North Am 2015;48[6]:1149 Translational models of optogenetics in the auditory periphery have trailed behind those of the central auditory system. Majority of published studies and abstracts that focused on optogenetic cochlear stimulation have utilized transgenic mouse models. While transgenic mouse lines provide cell-specific and consistent opsin expression, they are not readily translatable to humans.

In one published study on the feasibility of optogenetics in the cochlea, Hernandez et al. utilized a ChR2 transgenic mouse line (J Clin Invest 2014;124[3]:1114 This mouse line expresses ChR2 in cochlear spiral ganglion neurons but not in hair cells. Blue light stimulation of the photosensitized cochlea resulted in optically-evoked ABRs (oABRs) as well as corresponding firing of neurons in the inferior colliculus. Hernandez also demonstrated successful cochlear light stimulation of a mouse model of human nonsyndromic deafness. These mice have a point mutation of the otoferlin gene and demonstrate a defect of neurotransmitter release from cochlear inner hair cells, resulting in hearing loss. Hernandez et al. created a special transgenic mouse that was both deaf and expressed ChR2 to photosensitize the spiral ganglion neurons in the deaf cochlea. Transcochlear LED stimulation elicited optically-evoked ABRs in these mice. The authors concluded that optogenetic stimulation of the cochlea can activate the auditory pathways in mouse models of human deafness.


Optogenetics has revolutionized neuroscience research in the last decade, affording unprecedented control of cellular events with millisecond precision. CI research has led the field of neuroprosthetics, but its limitations, especially those of the ABI, suggest that a new approach to these neuroprostheses is warranted. While existing studies largely demonstrate proof of concept of the use of optogenetics to stimulate the auditory system, many questions remain. Some of the major hurdles to incorporate optogenetic technology are the demonstration that optogenetics provides better spatial selectivity compared to electrical stimulation, and the delivery of opsins to auditory neurons in humans.

The optogenetic promise of tissue-specificity resulting in increased number of independent channels is still largely theoretical. To address whether optogenetic-based implants may be as good or better than electrically-based implants, optical hardware needs to be substantially refined. While it is feasible to fit several traditional electrodes into an array suitable for the tiny cochlea of a mouse, this is not feasible with optrode technology based on LEDs. Indeed, to do a true comparison, light-based optrodes will need to fit within the size constraints of the auditory system. Much of this type of hardware has yet to be optimized for use in the cochlea or brainstem.

Targeted and robust opsin delivery and expression on auditory neurons will also be pivotal in developing a successful optogenetic implant. Unlike the electrically-based CI or ABI, optical auditory implants necessitate tissue modification and gene delivery, and these approaches have yet to be demonstrated in humans. While there are ongoing clinical trials for viral gene therapy of the cochlea, this research is far from standard of care. As safe and efficient gene transfer (both viral and non-viral) of the peripheral and central auditory system develops in animal models and in human clinical trials, so too will the feasibility of an optogenetic-based auditory implant.

Optogenetic stimulation of the cochlear nucleus using channelrhodopsin-2 evokes activity in the central auditory pathways.

Darrow KN, Slama MC, Kozin ED, et al.

Brain Res.2015 Mar 2;1599:44-56.

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

Guo W, Hight AE, Chen JX, et al.

Sci Rep.2015 May 22;5:10319.

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