Research Spotlight: Reversing Loudness Sensitivity by Inhibiting Nerve Activity in the Brain

Daniel Polley, PhD, director of the Eaton-Peabody Laboratories at Mass Eye and Ear, is the senior author of a paper published in Neuron, “Cortical PV interneurons regulate loudness perception and sustainably reverse loudness hypersensitivity.”

Q: How would you summarize your study for a lay audience?

Hyperacusis is a fairly common chronic hearing disorder in which moderately intense sounds are perceived as uncomfortably loud, or even painful. We observe loudness sensitivity in people with advanced age, neurodevelopmental disorders like autism and sensorineural hearing loss.

Our study discovered an approach for reversing hyperacusis by activating a type of inhibitory interneuron, or brain cell that helps calm overactive signals, found in the brain’s neocortex at a particular frequency (40-Hz, aka gamma stimulation). What was especially exciting was that a single, short bout of 40-Hz stimulation reversed hyperacusis for up to a week, even though the cochlea — the organ within the inner ear that’s crucial to hearing — was permanently damaged by noise exposure. Therefore, our research suggests that by intervening at the level of the cortex, we could perceptually cancel out a hearing condition caused by peripheral injury. 

Q: What question were you investigating?

We were interested in the distinction between sensation and perception. Sensation refers to how the nervous system converts physical energy in the world around us (e.g., sound pressure waves) into electrochemical messages (the language of the brain). Perception refers to how the brain’s electrochemical activity gives rise to how we consciously experience the world around us.

For people with hyperacusis, their perception of loudness is not proportionate to the sensory quantity of sound intensity. We wanted to understand why. But along the way, we also discovered a method to rebalance the sensory code for sound intensity and the perception of loudness, in effect re-establishing a normal relationship between sensation and perception.

Q: What methods or approach did you use?

Our study was performed in mice, which allowed us to monitor and manipulate the activity of specific cell types in the brain. The key discoveries in our study were focused on a type of inhibitory neurons called PV neurons (PVNs). We used a technique called optogenetics to turn PVNs on or off in a region of the cerebral cortex responsible for the perception of sound. We trained mice to behaviorally classify a sound as either soft or loud while we turned their PVNs on or off, and made recordings from neurons in the auditory centers of the cerebral cortex. We did this in mouse models with normal hearing and those with noise-induced hearing loss.   

Q: What did you find?

We found that PVNs acted like a volume knob on the perception of loudness. When we turned them down, all sounds became louder, and when we turned them up, all sounds became quieter. In mice with noise-induced damage of the cochlea, the PVNs were already turned down too low, so these mice heard sounds as too loud. We used optogenetics to turn the PVNs up in these mice and found that their hyperacusis instantly disappeared, but the effect only lasted as long as the optogenetic activation was on.

We wondered how we could make the volume knob adjustment “sticky” (i.e., turning it down and making it stay down). We found that activating the PVNs at 40-Hz for just a few minutes was enough to turn their volume knob down for up to a week. After 40-Hz activation of PVNs, the neural hyperactivity caused by noise-induced cochlear damage quieted down and the mice switched their perceptual classification of sounds from loud back to soft. 

Q: What are the implications?

It goes back to the distinction between sensation and perception. When we see patients who complain of hearing phantom sounds (tinnitus), difficulty suppressing the sound of other conversations in noisy restaurants (hidden hearing loss), or experiencing sounds as uncomfortably loud that don’t bother others (hyperacusis), they are describing their perception of sound, not their sensation. Even if these problems were caused by physical damage of their sensory organs, their lives would be immeasurably improved if we could eliminate the unwanted perception of these sounds.

The major insight from this paper is that the cerebral cortex is the seat of perception, not the cochlea. We can direct therapies at the seat of perception to fix perception, even when the physical damage of the cochlea is irreversible. Don’t get me wrong, fixing the cochlea would also do a lot of good. But that is very hard because the cochlea is one of the tiniest, most delicate, and most inaccessible organs in the body. Studies like ours can change the conversation around therapies for disorders of sound perception – widening the scope from just thinking about the peripheral injury to thinking about brain plasticity at the site where perception is generated. 

Q: What are the next steps?

Our study uses direct optogenetic activation of PVNs, which is not currently feasible to explore as a treatment in people with hyperacusis. However, 40-Hz gamma stimulation via sensory stimulation is an area that’s of major focus in the field right now for therapeutic research. Gamma stimulation is being tested in all kinds of circumstances for stroke and neurodegenerative diseases.

We are developing new kinds of therapeutic approaches that seek to leverage the endogenous plasticity pathways of the cortex to dampen the hyperactivity that directly causes perceptual disorders like tinnitus and sound sensitivity. Gamma stimulation is one piece of the puzzle that may allow these new types of therapies to work where prior efforts have had less success. We certainly have this in mind as we prepare for our upcoming clinical studies. 

Authorship: In addition to Polley, Mass General Brigham authors include Kameron K. Clayton, Bshara Awwad, Matthew McGill, Kamryn S. Stecyk, Caroline Kremer, Korey Sudana, Desislava Skerleva, Divya P. Narayanan, Jennifer Zhu, Kenneth E. Hancock, Sharon G. Kujawa, and Elliott D. Kozin.

Paper cited: Polley, D., et al. “Cortical PV interneurons regulate loudness perception and sustainably reverse loudness hypersensitivity.” Neuron. DOI: 10.1016/j.neuron.2025.10.017

Funding: These studies were supported by NIH grants (R01DC009836), (P50DC015857), (K08DC019128), (K99DC022957) and (F31DC018974) and research grants from the Nancy Lurie Marks Family Foundation, Centurion Foundation and the Mass General Neuroscience Transformative Scholar program.

Disclosures: Polley is a member of the Neuron scientific advisory board.

Related:  

Tune in to this episode of Down to a Science as Dr. Polley takes us inside the auditory system and explains what really happens when we hear.