It's been a long road in the history of those with hearing impairment—coming from being considered mentally inferior centuries ago to the use of the ear trumpet to refine hearing—but miles remain in the journey ahead.
What's next? Enter optogenetics.
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Shutterstock/Giovanni Cancemi, audiology, technology, cochlear implants.
Figure 1: (A) Sound pressure waves in the air (left) travel along the ear canal and are relayed via the ossicles into the intracochlear fluid, where they are decomposed in a frequency-dependent manner (center). A so-called traveling wave along the basilar membrane activates mechanosensitive hair cells (red) in the organ of Corti at the respective cochlear location and thereby starts the information flow in the auditory system via synaptic transmission to SGNs (yellow, right). The precise frequency-place mapping (tonotopy) is visualized through the color-coded basilar membrane (see color bar). (B, C) Acoustic signals are analyzed by an external processor, which extracts predominant frequencies and corresponding amplitudes of the signal. While frequencies are mapped to distinct stimulation sites (electrodes in the electrical CI or light emitters in the future optical CI) dependent on their tonotopic position, the signal amplitude determines stimulation intensity. SGNs around the tonotopic region that would be activated by hair cells for a given sound frequency in physiological hearing (A) are then directly activated with electric current (B) or light (C). Since light can be better confined in space than electric current, oCIs promise to activate the spiral ganglion with higher spatial precision (B vs. C, right). Reprinted with permission from EMBO Mol Med. 2020 Apr 7; 12(4): e11618. doi: 10.15252/emmm.201911618. Audiology, technology, cochlear implants.
According to Elliott Kozin, MD, a surgeon-scientist at Massachusetts Eye and Ear/Harvard Medical School, optogenetics uses both gene therapy and light-stimulation technologies to make cells sensitive to light and control cellular activity.
Kozin added that optogenetic technology is commonly used to control neurons and, in the case of the auditory pathway, spiral ganglion neurons may be genetically modified to make them sensitive to light and subsequently transmit signals to the brain—providing a promising way to improve the precision of bionic devices like cochlear implants (CIs).
“The technology is based on genes typically found in algae that ultimately allow them to detect and migrate towards light,” said Kozin. “These ‘light-sensing’ genes have been further refined such that they could be used in other species, such as mammals.”
According to Tobias Moser, MD, a professor of auditory neuroscience at the Institute for Neuroscience at the University Medical Center of Göttingen in Germany, “Optogenetics employs genetics to render cells light-sensitive and then optically controls cellular function.”
“Optogenetics is a technique that involves the genetic modification of neurons with light-sensitive ion channels (channelrhodopsins), enabling them to be activated with low-powered light in the visible spectrum,” noted Rachael Richardson, PhD, a senior research fellow at the Bionics Institute in Melbourne, Australia, and an associate professor in the medical bionics department at the University of Melbourne.
Richardson's optogenetics research team brings together expertise in cochlear implantation, gene therapy, and photonics to investigate the combination of optical and electrical stimulation to exploit the precision of optical stimulation and the efficiency of electrical stimulation.
With the traditional electrical stimulation in today's CIs, explained Richardson, there is an inherent spread of electrical current that radiates from the stimulating electrodes.
“Optical stimulation is a promising solution to this issue, as light can provide highly focused stimuli and is not limited by the same conductive spread as electrical current,” she said.
ADVANTAGES OF OPTICAL STIMULATION
“Optogenetic stimulation of the auditory nerve promises to overcome a major bottleneck of current CIs: poor spectral selectivity because light can be better confined in space than electrical current,” Moser explained. “We expect this to improve understanding speech in background noise and music appreciation.”
“Most medical devices stimulate cellular activity using electricity,” said Kozin, adding that that cardiac pacemakers, deep brain stimulators, and CIs all use electrical signals to drive cellular processes.
“While CIs are arguably the most successful neuroprosthesis, CI outcomes are still not perfect.”
Kozin pointed to studies revealing that individuals with CIs have decreased music appreciation and difficulty hearing in noisy environments.
“There are likely many causes of these types of suboptimal outcomes,” he explained, adding that one potential cause is non-specific current spread that is inherent to electrical stimulation. “In short, it is difficult to control how electricity stimulates cells. Proponents of emerging optogenetic technology argue that it may increase the ‘spatial resolution’—it may more finely control how, when, and where cells are stimulated.”
“Optical stimulation can be provided to non-modified neurons in the form of infrared or near-infrared light and result in the activation of auditory neurons with high spatial precision,” said Richardson.
While pointing out that some research suggests that infrared—or near-infrared stimulation—may not be effective in profoundly deaf individuals, Richardson sees many positives.
“Neural activation with the optogenetics technique uses up to 75 times less power compared to near-infrared light, making it much safer for the high stimulation rates used in the auditory system,” she said. “Compared to electrical stimulation, much higher precision of neural activation of channelrhodopsin-modified auditory neurons was demonstrated with optical stimuli, nearing that achieved with acoustic stimulation.”
Richardson's other major research focus is on protect and/or restore hearing. That focuses on employing gene therapy and nano-technology-inspired drug delivery techniques to introduce therapeutics into the cochlea for sensory cell regeneration or nerve survival and repair.
She added that these techniques have the potential to improve the outcomes achieved with cochlear implantation or even restore hearing by repopulating the damaged sensory region of the cochlea with new cells.
GLOBAL MINDS BEHIND OPTOGENETICS & AUDITORY RESEARCH
These are global concerns, with some of the best researchers in the world tackling the issues.
“I am an auditory neuroscientist and otologist having the great privilege to collaborate with a multidisciplinary team of scientists located in Göttingen, Chemnitz, and Freiburg,” noted Moser. “Developing optogenetic hearing restoration is a massive task and I am glad that, in addition to our program, there are several labs worldwide that work on various aspects of the optical cochlear implant.”
Including Richardson, Moser named other leaders in the field—such as Drs. Werner Hemmert, Daniel Lee, Stephanie Lacour, and Andrew Wise—who are working at keeping optogenetics at the cutting edge.
But they are not alone.
“Next to optogenetics, Dr. Claus Peter Richter has been pioneering infrared stimulation of the cochlea in an effort of direct photonic activation of the auditory nerve,” said Moser, who identified some of the breakthroughs that are required prior to running the clinical trial: (1) efficient, stable, and safe gene therapy; (2) efficient, stable, and safe multichannel optical stimulation; (3) further physiological and psychophysical evidence for superior performance of optogenetic coding of sound frequency and intensity information as well as acceptable time coding in comparison to electrical coding; and (4) development of multichannel optical cochlear implant system with independent stimulation channels and efficient coding strategy compatible with a day-long battery lifetime.
MAKING OPTICAL COCHLEAR IMPLANTS A REALITY
Kozin's expertise tells him that the prospects of optogenetics are exciting.
“However, clinically-focused optogenetic technology is still in its infancy,” Kozin noted. “More research, funding support, and industry partners are needed to foster its clinical translation.”
Moser agrees: “Prior to potential clinical translation, major efforts are required both for advancing the light-gated ion channels, gene therapy of spiral ganglion neurons as well as for developing the optical CI as a medical device.”
Drawing a blueprint for the future of this technology, Kozin outlined two main areas of innovation need to be tackled to make an optogenetic cochlear implant a reality: “The first area of innovation that is needed is thw development of a device itself that can encode and deliver optical stimulation. In standard CIs, sound information is encoded and delivered via electrodes in a cochlear array.”
In an optogenetic device, Kozin explained, programming will be needed to code optical stimulation and the array will have optrodes to stimulate the inner ear.
“The second area of innovation relates to ‘programing’ cells to become sensitive to light, which requires improvements in safe and effective gene therapy,” he added. “And other considerations include a small form factor and low power requirements.”
RECENT ADVANCES & CHALLENGES
As has been the case in many fields of technology, there are ongoing recent developments, including LED-based CIs.
Richardson explains that the goal of her research team is to determine whether light stimulation alone or in combination with electrical stimulation can significantly improve the precision of nerve activation in the cochlea and whether this will result in a meaningful difference to the way people hear sound.
With electrical stimulation, the current spreads out from the platinum stimulating electrodes and activates a broad area of the cochlea (shown by the colored neurons in Fig. 1). If two electrodes were to be simultaneously stimulated, there would be regions of channel interaction where the neurons are receiving stimuli from multiple sources. This makes it very difficult to deliver any of the temporal fine structure of the acoustic signal to the cochlea that would be required to improve pitch and music perception for cochlear implant recipients.
Hybrid stimulation is the combination of electrical and optical stimuli where one or both of these stimuli are presented at sub-threshold levels. For example, sub-threshold focused light is used to raise the excitability of a small area of the cochlea and at the same time sub-threshold or very low levels of electrical current is used to activate the neurons. This means that there is much less current spread and allows independent channel of information to be delivered to the neural population.
Richardson was encouraged by the development of flexible, multichannel devices will be required for clinical translation of optogenetic techniques, alongside safe and effective methods to modify auditory neurons to express channelrhodopsins.
Recent developments in multichannel light-emitting devices are providing sufficient light in testing for neural stimulation in mice and gerbils.
“Unlike forward-emitting optical fibers, these devices direct the light towards the modiolus to efficiently activate opsin-expressing neurons in rodents,” she said. “Lifetime reliability, thermal load, and potential phototoxicity are among the challenges and potential issues to be addressed before clinical application.
“Many challenges remain before the clinical implementation of optical stimulation. The power requirements for optogenetic-based optical stimulation are 5-10 fold higher than electrical-only stimulation.”
Richardson explained that, for a battery-powered device, the power usage must be kept as low as possible to enable at least a full day of use.
She pointed at temporal fidelity, important for pitch perception in the auditory system, which may be impacted by the relatively slow channel closing kinetics of channelrhodopsin. “For neurons expressing ChR2, the maximum following rate is approximately 70 Hz. Ultrafast opsins such as Chronos improve maximum following rates to 200 Hz, but fall short of the stimulation rates commonly used in the auditory system (500 Hz).”
As for solutions, one could be to combine optical and electrical stimuli in such a way as to exploit the spatial precision of optical stimulation and the power-efficiency and temporal fidelity of electrical stimulation.
Said Richardson: “In preliminary studies in vitro and in mice, it was demonstrated that the integration of electrical stimulation with optogenetic stimulation significantly and safely improved the spatial precision and temporal fidelity of neural activation that was not possible with either modality alone.”
Richardson added that combined stimuli, also called hybrid stimulation, may also enable a safer clinical transition to optical stimulation, as electrical-only stimulation can be used as a failsafe option should anything affect the optogenetic stimulation pathway.
“An increase in precision of neural activation has the potential to increase the number of independent channels in a cochlear implant,” she said. “Such an increase in independent stimulating channels, e.g., by an order of magnitude, could allow the fine structure of the stimulus to be delivered, thereby greatly improving perception. Application of optogenetics and optical stimulation to the auditory system, therefore, has the potential to provide a transformative hearing experience for cochlear implant recipients.”
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