Can You Hear Me Now? How Neuroscience Is on a Quest to Repair Hearing Damage

A small rural hospital in KwaZulu-Natal (S. Africa) specializes in treatment of Tuberculosis (TB). Due to the living conditions and lack of proper drug administration, many of the patients escalate into multidrug-resistant (MDR) TB which so happens to be managed through highly-potent aminoglycosides. These injectable drugs also have a serious side effect resulting in loss of hearing if not properly managed, known as ototoxicity. Unfortunately, in November of 2015 the laptop that contained the software to manage the levels of ototoxicity in the TB patients was stolen and not replaced until March of 2016. Between that time frame not a single hearing test was administered. Due to the severity of their MDR TB, their choice was to either continue losing hearing or die. As a result, 123 patients suffered a complete loss of hearing. ¹ So, what is being done to help restore what was so wrongfully taken from them?

Even with proper monitoring, ototoxicity doesn’t always show symptoms until hearing loss has occurred. According to Dr. Gayla L. Poling, of the Mayo Clinic, “over 200 medications are reported to be potentially ototoxic” resulting in over nine million Americans that are currently exposed to the chemicals. The resulting exposure can lead to hearing loss, ringing in the ear (tinnitus), as well as balance disorders.² It’s important that we consider a few of the products that can cause this damage (full list): 

• Aspirin (acetylsalicylic acid) and Quinine 
• Loop diuretics - i.e. water pills 
• Aminoglycoside - i.e. neomycin, streptomycin, tobramycin 
• Anti-cancer drugs - i.e. Cisplatin and Carboplatin 
• Environmental Chemicals - i.e. mercury, lead, xylenes

Undamaged IHCs and OHCs B) Damaged IHCs and OHCs

Does this mean that you’ll wake up deaf after having a particularly late-night drinking Gin and Tonic’s followed up by a couple Aspirin? No. Most over-the-counter drugs are intended to be taken in moderation. However, consistent and high-doses over prolonged periods of time will have an effect. Dr. Marlan Hansen, of University of Iowa Hospitals and Clinics, notes that, “There’s a lot of people who [experience] sudden deafness, profound deafness, from taking significant doses of Vicodin over several months or years, and all of the sudden, one day – or within a day or two – they lose all hearing.” ³

 How are these chemicals actually “poisoning” our ears? It was determined that the loss of hearing was the result of damage to Inner Hair Cells (IHC) in the cochlea as vestibular areas of the inner ear.⁴ To better understand if it’s at all possible to restore those damaged cells, we first need to understand how the auditory system is interpreting and transmitting the sound received from the IHC’s into the brain.

In a study titled ”A Gata3–Mafb transcriptional network directs post-synaptic differentiation in synapses specialized for hearing” (Yu et al. 2013), they demonstrate that the transcription factor Mafb is the key player in formation of auditory ribbon synapses. These synapses specialize in “rapid transport” from hair cells to spiral ganglion neurons (SGNs). SGNs have shown to be the vehicle in which the representation of sound moves from the cochlea to the brain. ⁵ The findings point to potentially re-establishing connections with the IHC’s via stimulation of the Mafb. Given the relationship between Gata3 and Mafb as “key players in a transcriptional cascade,” what would the results look like if the methodology was applied to cochlear toxicity in hopes of reversing morphologic damage?

Schematic drawing of the innervation of hair cells. IHC: inner hair cell; OHCs: outer hair cells; AF: afferent fiber; EF: efferent fiber; LOC: lateral olivary complex; MOC: medial olivary complex.

Yu et al., like other similar studies, provided the needed insight to allow other research programs the opportunity to continue pushing the discussion. Toward the end of 2016, a new study was published, “Mammalian Cochlear Hair Cell Regeneration and Ribbon Synapse Reformation.” (Lu et al. 2016). The basis was to expand on what was learned with the Yu team to truly focus on regenerating IHC’s that were the direct result of ototoxicity. They discovered promising results for reinnervation of newly generated IHCs by encouraging regeneration of the ribbon synapses via signaling pathways/factors such as Gata3-mafb. However, they also discovered a limitation on capability to maintain and mature the newly formed IHCs - “we are still quite far from restoring the hearing function in the damaged inner ear. The maturation and survival of newly generated HCs are still challenging. Furthermore, the maturation of reinnervation of the regenerated HCs and the function of the reformed ribbon synapse remain open to question, such as the contact between stereocilium and tectorial membrane, reorganization of the innervation of afferent Type I and Type II spiral ganglion neuron, and the integral interplay of outer hair cell based cochlear amplification.” ⁶

How will all this help those 123 patients who are suffering because of ototoxicity? Sadly, right now it won’t, however, these are crucial steps to one day having the ability to repair and restore hearing. Loss of hearing is a debilitating disorder that can lead to confusion, frustration, social isolation and depression. Keeping your hearing “front of mind” as well as taking the proper preventative steps is the best approach. After a hearing test, your Audiologist can make a proper diagnosis and recommend aids, implants, or rehabilitation.

Support and funding are the most critical factors to enable continuing research in these fields.

Citation:

1. Singh, K. (2017, September 06). Over 100 TB patients go deaf because of negligence – DA. Retrieved October 18, 2017, from http://www.news24.com/SouthAfrica/News/over-100-tb-patients-go-deaf-because-of-negligence-da-20170906

2. Poling, G. L., Ph. D. (2016, February 6). The Five W’s of Ototoxicity Monitoring: Who, What, Where, When, & Why. Retrieved October 18, 2017, from https://www.mayo.edu/mayo-edu-docs/mayo-clinic-audiology-conference-documents/poling-handout.pdf

3. Schroeder, M. O. (2015, October 27). Silent Side Effect: Could Your Medication Cause Hearing Loss? Retrieved October 18, 2017, from https://health.usnews.com/health-news/patient-advice/articles/2015/10/27/silent-side-effect-could-your-medication-cause-hearing-loss

4. Haybach, P., RN, MS. (2015, December 28). Ototoxicity. Retrieved October 18, 2017, from http://vestibular.org/ototoxicity

5.  Yu, W., Appler, J. M., Kim, Y., Nishitani, A. M., Holt, J. R., & Goodrich, L. V. (2013). A Gata3–Mafb transcriptional network directs post-synaptic differentiation in synapses specialized for hearing. ELife, 2. doi:10.7554/elife.01341

6. Lu, X., Shu, Y., Tang, M., & Li, H. (2016). Mammalian Cochlear Hair Cell Regeneration and Ribbon Synapse Reformation. Neural Plasticity, 2016, 1-9. doi:10.1155/2016/2523458