Information

Would tinnitus be explained by perpetually-bent/opened hairs in the cochlea?


When I look around for what causes tinnitus and the like, the usual response is "Well, loud sounds and hearing damage" but I feel like that's a little plain and I am curious about the underlying mechanism / explanation on a physiological level.

My previous understanding of how the ear works can be found in my previous question (with a terrific answer by AliceD).

So my question is this: Let's say a really loud, fierce sound occurs - the sort of thing that is said to cause tinnitus. This is equivalent to a really strong pressure wave approaching the eardrum. I imagine it would hit the eardrum, causing it to move violently / harshly, causing a similarly strong movement in the stapes, which is already providing something like a 20x pressure amplification to the cochlea.

So the stapes hammers hard on the oval window of the cochlea, causing a harsh pressure wave through the perilymph / endolymph, also causing the basilar membrane to move very harshly and violently. To me this would imply a fierce smashing/dragging of the hair cells against the tectorial membrane above, possibly causing sufficiently harsh wear-and-tear along the tops of the hair cells, leaving them bent or maybe even chopped, allowing their channels to remain perpetually open.

If these channels are always open, they're always accepting potassium, always creating the action potentials, always triggering the nerves underneath, which would mean the person is always hearing that particular tone all day, every day, 24/7.

Is this more or less what happens, or am I way off in my little thought experiment daydream here? Is this why tinnitus is difficult to cure, because it would require somehow rebuilding / closing up hair cells that are always open?


What you're describing would likely cause hearing loss, which could later result in tinnitus, but not by the mechanism you describe.

Hair cells transduce sound via remarkably fragile connections between stereocilia. The channels are closed until tension pulls the channels open (see Fettiplace 2011 for a review that covers pretty much all of sound transduction including a detailed description of the tip links and channels involved). Disconnection would result in the channels being perpetually closed, not perpetually open.

Anything like the trauma you describe would irreversibly damage the tip links and sound transmission would fail. There are mechanisms in the ear to prevent this sort of damage, but for sufficiently loud sounds the damage is not avoidable.

@AliceD has another excellent answer on tinnitus specifically here for more realistic mechanisms proposed for tinnitus: What is the mechanism behind tinnitus?. These are all centrally derived in some way. In short, the absence of proper input to the auditory processing parts of the brain results in compensation that induces an illusory perception. Similar sensations are experienced in other parts of the body as well, such as phantom limb.


Fettiplace, R. (2011). Hair cell transduction, tuning, and synaptic transmission in the mammalian cochlea. Comprehensive Physiology, 7(4), 1197-1227.


Tinnitus discovery could lead to new ways to stop the ringing

Neuroscientists at the University of California, Berkeley, are offering hope to the 10 percent of the population who suffer from tinnitus – a constant, often high-pitched ringing or buzzing in the ears that can be annoying and even maddening, and has no cure.

iStock photo

Their new findings, published online last week in the journalProceedings of the National Academy of Sciences, suggest several new approaches to treatment, including retraining the brain, and new avenues for developing drugs to suppress the ringing.

”This work is the most clearheaded documentation to this point of what’s actually happening in the brain’s cortex in ways that account for the ongoing genesis of sound,” said Michael Merzenich, professor emeritus of otolaryngology at UC San Francisco and inventor of the cochlear implant, who was not involved with the research. “As soon as I read the paper, I said, ‘Of course!’ It was immediately obvious that this is almost certainly the true way to think about it.”

Merzenich is also chief scientific officer at Posit Science, which develops software to retrain the brain, primarily to improve learning and memory but more recently to address problems like schizophrenia, Alzheimer’s Disease and tinnitus.

“Two million Americans are debilitated by tinnitus they can’t work, they can’t sleep. Its life destroying and a substantial cause of suicide,” he said. “These experiments have led us to rethink how we attack the tinnitus by our training strategies.”

Loud noises kill hair cells

According to coauthor Shaowen Bao, adjunct assistant professor in the Helen Wills Neuroscience Institute at UC Berkeley, tinnitus – pronounced TIN-it-tus or tin-NIGHT-us – is most commonly caused by hearing loss. Sustained loud noises, as from machinery or music, as well as some drugs can damage the hair cells in the inner ear that detect sounds. Because each hair cell is tuned to a different frequency, damaged or lost cells leave a gap in hearing, typically a specific frequency and anything higher in pitch.

Experiments in the past few years have shown that the ringing doesn’t originate in the inner ear, though, but rather in regions of the brain – including the auditory cortex – that receives input from the ear.

Bao’s experiments in rats with induced hearing loss explain why the neurons in the auditory cortex generate these phantom perceptions. They showed that neurons that have lost sensory input from the ear become more excitable and fire spontaneously, primarily because these nerves have “homeostatic” mechanisms to keep their overall firing rate constant no matter what.

“With the loss of hearing, you have phantom sounds,” said Bao, who himself has tinnitus. In this respect, tinnitus resembles phantom limb pain experienced by many amputees,

One treatment strategy, then, is to retrain patients so that these brain cells get new input, which should reduce spontaneous firing. This can be done by enhancing the response to frequencies near the lost frequencies. Experiments over the past 30 years, including important research by Merzenich, have shown that the brain is plastic enough to reorganize in this way when it loses sensory input. When a finger is amputated, for example, the region of the brain receiving input from that finger may start handling input from neighboring fingers.

Bao noted that retraining the ear has been tried before, but with limited success. Most such attempts have taken patients with some residual hearing and trained their ears to be more sensitive to the affected frequencies. This wouldn’t work for patients with profound hearing loss, however.

Most retraining is also based on the assumption that reorganization of the brain – that is, changing how frequencies “map” to regions of the auditory cortex – is a cause of the tinnitus. This is the opposite of Bao’s conclusion.

“We argue that reorganizing the cortical map should be the goal, so that the nerves get some input and stop their tinnitus activity,” he said. “You don’t want to leave these cells without sensory input.”

“We changed our (brain training) strategy from one where we completely avoided the tinnitus domain to one where we directly engage it and try to redifferentiate or reactivate it, and we seem to be seeing improvement,” Merzenich said.

Drugs can boost inhibitors

Another treatment strategy, Bao said, is to find or develop drugs that inhibit the spontaneous firing of the idle neurons in the auditory cortex. Hearing loss causes changes at junctions between nerve cells, the so-called synapses, that both excite and inhibit firing. His experiments showed that tinnitus is correlated with lower levels of the inhibitory neurotransmitter GABA (gamma-aminobutyric acid), but not with changes in the excitatory neurotransmitters.

He demonstrated that two drugs that increase the level of GABA eliminated tinnitus in rats. Unfortunately, these drugs have serious side effects and cannot be used in humans. He has applied for several grants to start screening drugs for their ability to enhance GABA receptor function, increase the synthesis of GABA, slow the re-uptake of GABA around nerve cells, or slow its enzymatic degradation.

“Our findings will guide the kind of research to find drugs that enhance inhibition on auditory cortical neurons,” Bao said. “There are a lot of things we can do to change GABA functions, some of which could potentially alleviate tinnitus with fewer side effects.”

Bao’s colleagues include post-doctoral fellow Sungchil Yang, who developed a new technique to measure tinnitus behaviors in rats with hearing loss, and research associates Banjamin D. Weiner and Li S. Zhang of the Wills Neuroscience Institute, and post-doc Sung-Jin Cho of UC Berkeley’s Department of Molecular and Cell Biology.

The research was supported by the American Tinnitus Association and the National Institutes of Health’s National Institute on Deafness and other Communicative Disorders.


Pitch-detection secrets of the inner ear revealed by research

The ability to discern pitch hinges on remarkable gradations in specialized cells within the inner ear. New research from the University of Virginia School of Medicine and the National Institute on Deafness and Communication Disorders has explained, for the first time, what controls these cells' development and patterning -- findings crucial to efforts to reverse hearing loss caused by age, loud sounds or other factors.

The researchers have been studying the development of these cells in chickens, which, like many creatures, have a remarkable capacity humans lack: the ability to regrow the sound-detecting cells after suffering hearing loss. Jeffrey T. Corwin, PhD, of UVA's Departments of Neuroscience and Cell Biology, noted that if both a human and a hen were to be exposed to a sound loud enough to destroy the ability to hear a certain pitch, the outcomes would be very different: "We would lose the ability to hear that sound for the rest of our lives. The bird also would lose the ability, but within 10 days, it would have its cells back -- they would hook back up to the nerves, and within a few weeks its hearing would be back and almost indistinguishable from before."

Understanding that process, then, may one day allow scientists to replicate it in humans. "Eventually therapies will come about from this regenerative approach, and these new discoveries will be a critical component," Corwin said.

Detecting Pitch

Pitch detection occurs within the cochlea, a small spiral structure within the inner ear. Inside the cochlea are specialized cells, known as hair cells, which are tuned to different sound pitches based, in part, on their locations along the cochlea's spiral and the number and the length of their stereocilia -- hair-like microscopic protrusions that give the cells their name. High-pitched sounds are detected by cells with shorter hair bundles, located closest to where sound enters the ear lower-pitched sounds are detected by cells with taller hair bundles located further in, and that pattern progresses through the several thousand hair cells that are essential for hearing. "When you hear different sounds, not every single hair cell in the cochlea is responding, only the ones that are sensitive to the specific sound frequencies," explained Benjamin R. Thiede, lead author of a paper outlining the new discovery.

Until now, scientists have not understood what orchestrates the formation of this critical pattern of individually distinct hair cells. The researchers, however, have solved that mystery, demonstrating that two specific molecules, Bmp7 and retinoic acid, guide cells to acquire location-specific attributes. Bmp7 starts the initial patterning process, and retinoic acid regulates how the cells' hair bundles grow to different lengths.

Thiede found evidence that there are different levels of retinoic acid activity along the length of the cochlea, so he tried adding more retinoic acid in cells grown in a lab dish and found that they produced longer hair bundles. Then he used a drug to block retinoic acid's activity and found that resulted in shorter bundles.

Thiede noted that when chickens regenerate damaged hair cells, the new cells develop with just the right characteristics for cells in those particular locations along the cochlea. "So the question is, are developmental signals like Bmp7 and retinoic acid involved in reestablishing the pattern of hair cells and restoring hearing to the regenerating cochlea?" he asked. "If we look at the mammalian system, which can't regenerate, are these signals lost? &hellip Does the mammal turn off these important signals once development is completed, so they're not reactivated for regeneration?"

That's a matter for further investigation, but it suggests a tantalizing path for developing new treatments.


Research Findings Reveal New Clues to Restoring Hearing

Scientists conducting a mouse study at Washington University School of Medicine? in St. Louis (WUSTL) have identified two signaling molecules that are required for the proper development of a part of the inner ear (cochlea), and for restoring hearing. Without both signals, the embryo does not produce enough of the cells that eventually make up the adult cochlea, resulting in a shortened cochlear duct and impaired hearing. The study, which was described in an online article in the April 27, 2015 edition of eLife, contributes to the understanding of inner ear development, a first step toward the goal of being able to recover lost hearing.

The study authors explain that the sensory hair cells of the cochlea or inner ear pick up sound vibrations and transmit those signals to the brain. Hearing loss occurs when these hair cells are damaged, most often by loud noise, some types of medications, and the aging process itself.

“To eventually be able to restore hearing, we would like to be able to regenerate the sensory hair cells of the cochlea,” said senior author David M. Ornitz, MD, PhD, the Alumni Endowed Professor of Developmental Biology at WUSTL. “If the inner ear in birds and fish is damaged, for example, cells in the inner ear are naturally turned back into progenitor cells that are capable of replacing the sensory cells. But mammals are more complex — with a better sense of hearing over a wider range of sounds. However, it is thought that in exchange for better hearing, we have lost the ability to regenerate sensory hair cells.”

A normal mouse cochlea shows a characteristic spiral shape. (Sung-Ho Huh, WUSTL)

According to an announcement from WUSTL, Ornitz and his colleagues showed in their study that proper inner ear development in mice depends on the presence of two signaling molecules called FGF9 and FGF20. Normal signaling of these molecules in the inner ear turns on at about day 11 of the mouse embryo’s typical 20-day development.

The study authors explain that over the next two to three days, these two molecules direct the progenitor cells to multiply. By embryonic day 14, the progenitor cells stop multiplying and begin to differentiate to become functional adult sensory cells. According to this and other studies, the cellular population that comprises the adult ear is largely complete at this point.

“In mammals, including mice and people, the number of sensory progenitor cells is fixed,” said first author Sung-Ho Huh, PhD, an instructor in developmental biology at WUSTL. “This number is determined by cell division or cell death in early stages of development. In mice, that’s between about embryonic days 11 and 14. Once that developmental window is closed, the number of cells you have is all you get. There is no compensating for low numbers.”

The absence of certain FGF signals during inner ear development results in a shortened cochlea and impaired hearing. (Sung-Ho Huh, WUSTL)

According to the new study, FGF9 and FGF20 send signals to their receptors, which are located in nearby cells that surround the developing sensory cells. Through signaling to these surrounding cells, FGF9 and FGF20 promote the growth of the sensory progenitor cells. This signaling activates a feedback loop that helps to direct proper development of the cochlea.

Ornitz and Huh report that future work is focused on identifying the molecules involved in the feedback mechanism.

“We have discovered that an FGF signal is instructive in forming the cochlea,” Ornitz said. “These FGF signals tell the surrounding tissue to make a factor — we don’t know yet what that factor is — but we know it regulates progenitor cell growth. And being able to grow progenitor cells, or instruct cells that can become progenitor cells to grow, is one key to restoring hearing.”

Photo credits: Sung-Ho Huh, Washington University School of Medicine in St. Louis


Tinnitus does not have a cure yet, but treatments that help many people cope better with the condition are available. Most doctors will offer a combination of the treatments below, depending on the severity of your tinnitus and the areas of your life it affects the most.

  • Hearing aids often are helpful for people who have hearing loss along with tinnitus. Using a hearing aid adjusted to carefully control outside sound levels may make it easier for you to hear. The better you hear, the less you may notice your tinnitus. Read the NIDCD fact sheet Hearing Aids for more information.
  • Counseling helps you learn how to live with your tinnitus. Most counseling programs have an educational component to help you understand what goes on in the brain to cause tinnitus. Some counseling programs also will help you change the way you think about and react to your tinnitus. You might learn some things to do on your own to make the noise less noticeable, to help you relax during the day, or to fall asleep at night.
  • Wearable sound generators are small electronic devices that fit in the ear and use a soft, pleasant sound to help mask the tinnitus. Some people want the masking sound to totally cover up their tinnitus, but most prefer a masking level that is just a bit louder than their tinnitus. The masking sound can be a soft “shhhhhhhhhhh,” random tones, or music.
  • Tabletop sound generators are used as an aid for relaxation or sleep. Placed near your bed, you can program a generator to play pleasant sounds such as waves, waterfalls, rain, or the sounds of a summer night. If your tinnitus is mild, this might be all you need to help you fall asleep.
  • Acoustic neural stimulation is a relatively new technique for people whose tinnitus is very loud or won’t go away. It uses a palm-sized device and headphones to deliver a broadband acoustic signal embedded in music. The treatment helps stimulate change in the neural circuits in the brain, which eventually desensitizes you to the tinnitus. The device has been shown to be effective in reducing or eliminating tinnitus in a significant number of study volunteers.
  • Cochlear implants are sometimes used in people who have tinnitus along with severe hearing loss. A cochlear implant bypasses the damaged portion of the inner ear and sends electrical signals that directly stimulate the auditory nerve. The device brings in outside sounds that help mask tinnitus and stimulate change in the neural circuits. Read the NIDCD fact sheet Cochlear Implants for more information.
  • Antidepressants and antianxiety drugs might be prescribed by your doctor to improve your mood and help you sleep.
  • Other medications may be available at drugstores and on the Internet as an alternative remedy for tinnitus, but none of these preparations has been proved effective in clinical trials.

Abbreviations

2-AG, 2-arachidonoylglycerol ABHD4, ABHD6, ABHD12, αβ-hydrolase domain 4,6,12 ACEA, arachidonyl-2'-chloroethylamide AEA, N-arachidonoylethanolamide (anandamide) BDNF, brain-derived nerve factor BNST, bed nucleus of the stria terminalis CBR CB1R CB2R, cannabinoid receptor, type 1, type 2 CBD, cannabidiol COX-2, cyclooxygenase type 2 CREB, cAMP response element binding protein DAG, diacylglycerol DAGL, DAG lipase DCN, dorsal cochlear nucleus DSE, Depolarization-induced suppression of excitation DSI, Depolarization-induced suppression of inhibition EC, endocannabinoid EMT, endocannabinoid membrane transporter ERK, Extracellular signal-Regulated Kinase FAAH, fatty acid amide hydrolase GDE1, glycerophosphodiesterase 1 GPCR, G-protein-coupled receptor HPA, hypothalamic-pituitary-adrenal MAGL, monoacylglycerol lipase NAPE, N-arachidoylphosphatidyletanolamine NAT, N-acyltransferase NR3C1, glucocorticoid receptor PHARC, Polyneuropathy, Hearing loss, Ataxia, Retinitis pigmentosa, and Cataracts PLA2, phospholipase A2 PLD, phospholipase D PPAR, Peroxisome proliferator-activated receptors PUFA, polyunsaturated fatty acids SPM, specialized pro-resolving mediators TRP, Transient receptor potential 㥉-THC, 㥉-tetrahydrocannabinol VCN, ventral cochlear nucleus.


ELI5: Why does tinnitus sometimes remain permanently?

In other words, why can't your ears always heal from hearing damage?

As a result of a number of rule breaking comments this thread has been locked.

Replies directly to OP must be written explanations or relevant follow-up questions. They may not be jokes, anecdotes, etc..

Neurophysiologist here, who, earlier in my life, spent over a decade studying the neurophysiology of tinnitus.

There is a lot of bad information here.

Tinnitus is the phantom perception of sound. This means that a person with tinnitus hears a sound (usually a ringing or a whistling sound) that cannot be heard by others. In a very small percentage of cases, a sound actually exists (usually a vascular anomaly, like an aneurysm, that causes blood to make a swishing or squirting sound) - this subgroup of people with tinnitus does not represent the majority of people with tinnitus.

In most cases there is no source for the sound that is perceived by the patient. The truth is that we don't know, exactly, what causes tinnitus.

What we do know, however, is that tinnitus can be caused by injury to the cochlea (the organ in the inner ear that houses the hair cells that detect vibrations in fluid that are transduced by your eardrum). Tinnitus can also be caused by injury to the auditory nerve, and by injuries (strokes, for example) to the brainstem, midbrain, and cortex.

We also know that tinnitus can be caused by exposure to noise and by certain drugs that damage the hair cells in the cochlea.

We also know that even when tinnitus is caused by injury to the cochlea (such as by trauma or by drugs that kill hair cells), you can remove the cochlea or cut the auditory nerve (that connects the cochlea to the brain) and the perception of tinnitus (in most people) still remains.

This fact tells us that, in most people with tinnitus, the generator(s) of tinnitus lie somewhere in the brain - even when the initial injury to the auditory system occurred in the inner ear (i.e. to hair cells in the cochlea).

Most people who study tinnitus believe that neural plasticity is involved in tinnitus. Neural plasticity is the ability of the brain to rewire itself in response to environmental stimuli and to injury. This ability is very useful - it enables, for example, the brain to recover some or all of its function after stoke.

We think that some neurological disorders are caused when injury or environmental stimuli (like noise exposure) result in the activation of neural plasticity, resulting in one or more circuits in the auditory system to become altered - and this altered function results in the perception of sound when no sound exists.

For example, we have shown that chronic exposure to noise results in a change in the balance between excitatory and inhibitory neurotransmitters in certain parts of the auditory cortex and midbrain. This change in the balance of inhibition and excitation results in a net increase in excitation - with both theoretical and experimental evidence that this change can result in the phantom perception of sound.

TLDR: The cause(s) of tinnitus in most patients is unknown, but strong experimental and clinical evidence points to neural plasticity in the brain being the reason for the phantom perception of sound.


So What Causes The Ringing?

When the outer hair cells put energy back into the vibration, it’s called positive feedback or “saturation feedback”. The process is meant to amplify very quiet sounds more so than loud ones. Most of the time, it works great and you go on with your life, not noticing anything out of the ordinary. However, biological systems aren’t always flawless. Occasionally, the amplification level of one or more outer hair cells will go awry and as a result, the whole system will erupt into spontaneous oscillation.

When this occurs, it becomes audible to us (we hear it). We perceive it as a ringing in the ear, or “sudden-onset ringing tinnitus”. As with most of our biological systems, there are quite a few homestatic control mechanisms (negative feedback loops) which exist to correct the problem and get rid of the unpleasant oscillation. Nerves whose job it is to tell the auditory nerve and/or hair cells to cut it out. It takes roughly 30 seconds for this mechanism to begin to do its thing and send the required messages which suppress the ringing. After the message is sent and received, the tinnitus percept begins to fade away. You can tell when this reaction has taken place as its often accompanied by a slight reduction in hearing sensitivity (like background or ambient noise we hear suddenly getting quieter), followed by a feeling of fullness in the ear. It usually takes about a minute for this process to fully complete.

Our ears are walking a tightrope in high winds. While want our ear’s gain turned up high to maximize our hearing, we also don’t want the spontaneous oscillations that come with the increased sensitivity. If you stop and think about it, it’s amazing that our regulatory mechanisms work well enough that ringing doesn’t happen more often. The human body is more amazing than we give it credit for.

Why Is Your Hearing Less When Yawning?

Your ear muscles emit a quiet, low-frequency sound when they contract. When you yawn, your muscles around the middle ear are contracting (specifically, the tensor veli palatini). This causes a dull roar from the muscle contraction and is also responsible clicking or popping sounds you may hear from your Eustachian tubes opening.

When the Eustachian tubes open, the pressure around them goes down. This lowering of pressure not only causes the rumbling or subtle roaring noises to lessen, but all of your hearing is temporarily decreased until the yawn is over and the Eustachian tubes close.

Other interesting facts:

  • Under ideal acoustic circumstances (in a soundproof room having an ambient noise level of 17 dB or less), slight tinnitus is present in 80 to 90% of all adults.
  • Fish don’t have ears, but they can “hear” pressure changes in water through ridges on their body.
  • Your hearing doesn’t “turn off” in your sleep, your brain just tunes out or “ignores” any incoming sounds.
  • One-third of adults over the age of 65 suffers from some hearing loss however, more than half of those who suffer from hearing loss are under age 65.
  • Your ears contain over 25,000 inner & outer hair cells.

Jan Schnupp, Israel Nelken and Andrew King (2011). Auditory Neuroscience.
Peng, AW. Salles, FT. Pan, B. Ricci, AJ. “Integrating the biophysical and molecular mechanisms of auditory hair cell mechanotransduction“.
Nicolas-Puel C, Faulconbridge RL, Guitton M, Puel JL, Mondain M, Uziel A. “Characteristics of tinnitus and etiology of associated hearing loss: a study of 123 patients”. The international tinnitus journal 8 (1): 37–44
Daniel Schacter, Daniel Gilbert, Daniel Wegner (2011). “Sensation and Perception”. In Charles Linsmeiser. Psychology. Worth Publishers. p. 158-159.
Simmons R, Stocking C, (2009). “Head, Neck, and Eye Movements That Modulate Tinnitus“. Seminars in hearing 29: 360–371.
Manley GA, Popper AN, Fay RR (2004). Evolution of the Vertebrate Auditory System. New York: Springer-Verlag. ISBN 0-387-21093-8.


Tinnitus discovery could lead to new ways to stop the ringing

Neuroscientists at the University of California, Berkeley, are offering hope to the 10 percent of the population who suffer from tinnitus – a constant, often high-pitched ringing or buzzing in the ears that can be annoying and even maddening, and has no cure.

Their new findings, published online last week in the journal Proceedings of the National Academy of Sciences, suggest several new approaches to treatment, including retraining the brain, and new avenues for developing drugs to suppress the ringing.

”This work is the most clearheaded documentation to this point of what’s actually happening in the brain’s cortex in ways that account for the ongoing genesis of sound,” said Michael Merzenich, professor emeritus of otolaryngology at UC San Francisco and inventor of the cochlear implant, who was not involved with the research. “As soon as I read the paper, I said, ‘Of course!’ It was immediately obvious that this is almost certainly the true way to think about it.”

Merzenich is also chief scientific officer at Posit Science, which develops software to retrain the brain, primarily to improve learning and memory but more recently to address problems like schizophrenia, Alzheimer’s Disease and tinnitus.

“Two million Americans are debilitated by tinnitus they can’t work, they can’t sleep. Its life destroying and a substantial cause of suicide,” he said. “These experiments have led us to rethink how we attack the tinnitus by our training strategies.”

Loud noises kill hair cells

According to coauthor Shaowen Bao, adjunct assistant professor in the Helen Wills Neuroscience Institute at UC Berkeley, tinnitus – pronounced TIN-it-tus or tin-NIGHT-us – is most commonly caused by hearing loss. Sustained loud noises, as from machinery or music, as well as some drugs can damage the hair cells in the inner ear that detect sounds. Because each hair cell is tuned to a different frequency, damaged or lost cells leave a gap in hearing, typically a specific frequency and anything higher in pitch.

Experiments in the past few years have shown that the ringing doesn’t originate in the inner ear, though, but rather in regions of the brain – including the auditory cortex – that receives input from the ear.

Bao’s experiments in rats with induced hearing loss explain why the neurons in the auditory cortex generate these phantom perceptions. They showed that neurons that have lost sensory input from the ear become more excitable and fire spontaneously, primarily because these nerves have “homeostatic” mechanisms to keep their overall firing rate constant no matter what.

“With the loss of hearing, you have phantom sounds,” said Bao, who himself has tinnitus. In this respect, tinnitus resembles phantom limb pain experienced by many amputees,

One treatment strategy, then, is to retrain patients so that these brain cells get new input, which should reduce spontaneous firing. This can be done by enhancing the response to frequencies near the lost frequencies. Experiments over the past 30 years, including important research by Merzenich, have shown that the brain is plastic enough to reorganize in this way when it loses sensory input. When a finger is amputated, for example, the region of the brain receiving input from that finger may start handling input from neighboring fingers.

Bao noted that retraining the ear has been tried before, but with limited success. Most such attempts have taken patients with some residual hearing and trained their ears to be more sensitive to the affected frequencies. This wouldn’t work for patients with profound hearing loss, however.

Most retraining is also based on the assumption that reorganization of the brain – that is, changing how frequencies “map” to regions of the auditory cortex – is a cause of the tinnitus. This is the opposite of Bao’s conclusion.

“We argue that reorganizing the cortical map should be the goal, so that the nerves get some input and stop their tinnitus activity,” he said. “You don’t want to leave these cells without sensory input.”

“We changed our (brain training) strategy from one where we completely avoided the tinnitus domain to one where we directly engage it and try to redifferentiate or reactivate it, and we seem to be seeing improvement,” Merzenich said.

Drugs can boost inhibitors

Another treatment strategy, Bao said, is to find or develop drugs that inhibit the spontaneous firing of the idle neurons in the auditory cortex. Hearing loss causes changes at junctions between nerve cells, the so-called synapses, that both excite and inhibit firing. His experiments showed that tinnitus is correlated with lower levels of the inhibitory neurotransmitter GABA (gamma-aminobutyric acid), but not with changes in the excitatory neurotransmitters.

He demonstrated that two drugs that increase the level of GABA eliminated tinnitus in rats. Unfortunately, these drugs have serious side effects and cannot be used in humans. He has applied for several grants to start screening drugs for their ability to enhance GABA receptor function, increase the synthesis of GABA, slow the re-uptake of GABA around nerve cells, or slow its enzymatic degradation.

“Our findings will guide the kind of research to find drugs that enhance inhibition on auditory cortical neurons,” Bao said. “There are a lot of things we can do to change GABA functions, some of which could potentially alleviate tinnitus with fewer side effects.”

Bao’s colleagues include post-doctoral fellow Sungchil Yang, who developed a new technique to measure tinnitus behaviors in rats with hearing loss, and research associates Banjamin D. Weiner and Li S. Zhang of the Wills Neuroscience Institute, and post-doc Sung-Jin Cho of UC Berkeley’s Department of Molecular and Cell Biology.

The research was supported by the American Tinnitus Association and the National Institutes of Health’s National Institute on Deafness and other Communicative Disorders.


Stimulation Strategies for Tinnitus Suppression in a Neuron Model

Tinnitus is a debilitating perception of sound in the absence of external auditory stimuli. It may have either a central or a peripheral origin in the cochlea. Experimental studies evidenced that an electrical stimulation of peripheral auditory fibers may alleviate symptoms but the underlying mechanisms are still unknown. In this work, a stochastic neuron model is used, that mimics an auditory fiber affected by tinnitus, to check the effects, in terms of firing reduction, of different kinds of electric stimulations, i.e., continuous wave signals and white Gaussian noise. Results show that both white Gaussian noise and continuous waves at tens of kHz induce a neuronal firing reduction however, for the same amplitude of fluctuations, Gaussian noise is more efficient than continuous waves. When contemporary applied, signal and noise exhibit a cooperative effect in retrieving neuronal firing to physiological values. These results are a proof of concept that a combination of signal and noise could be delivered through cochlear prosthesis for tinnitus suppression.

1. Introduction

Tinnitus is a debilitating perception of sound in the absence of external auditory stimuli that affects more than 10% of the world population [1–3] and tends to increase with the age [2, 3].

The origin of this debilitating disorder may be central or peripheral i.e., it can originate in the cochlea, in the primary hearing cortex or in any other point of the auditory pathway [4].

Based on frequency and permanence of sound perception, tinnitus is classified in continuous low frequency tinnitus (CLFT) for frequencies below 100 Hz, continuous high frequency tinnitus (CHFT) for frequencies above 3 kHz, and transient spontaneous tinnitus (TST) [5]. Several studies [6, 7] confirm that the CHFT is the most widespread tinnitus typology, generally associated with a reduction of cochlear functionality at high frequency, due to a damage of the basal section of the cochlea. In the tonotopic organization of sound perception [8], the cochlea basal section encodes for high frequency stimuli, above 3 kHz.

This close association between tinnitus and hearing loss suggests that, in many cases, it is due to an impairment of the outer hair cells (OHC) of the cochlear basal section that, in turn, induces a pathologic state of depolarization of the inner hair cells (IHC) [9].

In 1995 Le Page [9] proposed a cochlear model to explain tinnitus origin. The OHCs determine the hair deflection of the IHCs that, in turn, depolarize the acoustic fibers. In physiologic conditions, in the absence of an external stimulus, the OHCs fix the operating point on the IHC transfer function (acoustic neuron depolarization versus IHC hair deflection) to a position that brain recognizes as absence of sound. When the OHCs are damaged, the control input to the IHCs gets lost with a consequent shift of the operating IHC point and a permanent firing rate of the acoustic fiber interpreted by the brain as a real acoustic pattern [9].

This modification of the nerve fiber firing pattern due to OHC impairment was experimentally observed in different animal models [10–13].

Several experimental studies [14–16] revealed that an electric stimulation of the cochlea, delivered through cochlear prosthesis or transtympanic electrode, could alleviate tinnitus perception in a significant percentage of treated patients. McKerrow and colleagues [14] used continuous wave (CW) high frequency signals (2-6 MHz) superposed to a Gaussian white noise (GWN), whereas other authors used pulse trains with repetition frequency up to 5 kHz [15, 17]. Recently, Tyler and colleagues [18] efficiently used pulsed modulated signals delivered to the Vagus nerve on human volunteers.

However, the electric signals delivered in stimulation, in terms of type (CW, pulse train, white noise), frequency content, amplitude, and modulation, were empirically chosen and their mechanisms of action on the auditory fibers were not defined.

Moving from a recent study by the authors [19] showing an inhibitory effect of an electric exogenous stimulation on a hyperexcited neuronal network model, it was hypothesized that an electric stimulation may interfere with the neuron firing pattern of a pathologically polarized acoustic neuron by reducing its firing rate to the physiologic one.

Aim of this work is to verify such a hypothesis and to study the efficacy of a combination of signal and noise in tinnitus inhibition, using a simple model of a hyperexcited auditory fiber.

In a biomedical perspective, the final aim is to deliver this stimulation to the auditory nerve using cochlear prosthesis to suppress tinnitus in patients with acoustic impairment.

2. Models and Methods

2.1. Neuron Model

To describe the single Ranvier node of an auditory fiber, a stochastic Hodgkin-Huxley (HH) model was used [20–22]. In this model, the neuronal membrane patch is represented by an electrical equivalent, in which the balance of the currents per unit area is given by

where is the unit area capacitance that takes into account the dielectric properties of the membrane phospholipidic bilayer, is the transmembrane potential, gNa, gK, gl are sodium, potassium and leakage conductances per unit area, respectively, and ENa, EK, El are the reversal potentials of the corresponding current densities. Finally, I0 is the bias current density that controls the transition between the resting state and the firing activity of the neuron [23]. For the deterministic HH model at 6.3°C, the threshold value above which the neuron starts its firing activity is equal to 6.3 μA/cm 2 [23].

Despite the model limitation concerning the operating temperature equal to 6.3°C, it is simple, very well characterized in terms of neuronal response as a function of model parameters, and the most used in different applications, with more than 10000 citations in the Scopus database [24], so that it can be considered as a golden standard when a new hypothesis has to be tested. Moreover, the possibility of including channel gating stochasticity allowed us to realistically model channel noise which is particularly relevant in the auditory fibers, due to their small size [25, 26].

To account for the random gating of sodium and potassium channels, the ionic current densities

and were calculated using a channel-state-tracking algorithm [27, 28] where Markov chains [27, 29] modeled independent gating particles belonging to each ionic channel.

The magnitude of fluctuations in current densities (channel noise) depends on the number of ionic channels and, thus, for fixed channel densities (

=18 channels/μm 2 ), on the area of the considered membrane patch. Specifically, channel noise is inversely proportional to the square root of the number of ionic channels in the membrane patch [21, 30]. Acoustic fibers are characterized by small Ranvier nodes, whose size may vary from 2.2 [25] to 15.7 μm 2 [26] and thus by high levels of intrinsic channel noise. In this work, three patch areas were considered: 2.2, 11.0, and 15.7 μm 2 , corresponding to the maximum, the minimum, and an intermediate fiber size.

Besides Na, K, and leakage current densities, I0 represents here the background level of stimulation coming from the OHCs. This current density determines the firing rate of the neuron, i.e., the operating point on the IHC transfer function.

To simulate different states of pathologic neuron depolarization, I0 was set to a value close to the threshold: 6 μA/cm 2 and to suprathreshold values: 7 and 10 μA/cm 2 [23]. Conversely, physiological spontaneous firing of the auditory fiber was modeled by using a subthreshold bias current density I0 equal to 2 μA/cm 2 . With respect to this physiological condition, the other conditions increased the background firing activity from 30 to 80%, as suggested by experimental recordings in animals with induced tinnitus [12, 13].

In this paper, for each patch area, four bias currents densities were used: 2, 6, 7, and 10 μA/cm 2 . The first value was used to model a healthy acoustic fiber the other ones modeled paroxysmal excitation underlying tinnitus.

The model was run in the C++ environment using the forward Euler integration method with time step 10 μs.

In principle, the HH model extends its validity up to frequencies that short-circuit the membrane capacitance. According to [31], this occurs above the beta relaxation frequency of the cell membrane, at about 100 MHz. Moreover, the ionic channel modeling using Markov chains [32] is valid if the sampling time is much longer than the channel protein transition time (order of ps) [33]. The used time step of 10 μs imposes a practical limitation of 50 kHz to the maximum frequencies that can be studied with the model. This is well below the theoretical frequency limitations of the model previously discussed.

For each studied condition, 300 independent runs of the model, 1 s in duration, were considered. The number of runs was approximately the number of afferent fibers contemporary stimulated by a single electrode of the cochlear prosthesis this number was calculated by considering the size of the electrode (0.3 mm), the diameter of a IHC (≈10 μm), and the number of auditory fibers (≈10) contacting a single IHC.

2.2. Stimulation

The exogenous stimulation was introduced in the model as an additional voltage over the membrane potential [34–36]. In terms of equivalent HH electric circuit, the electric stimulus was represented as a voltage generator in series with the membrane capacitor and the ionic conductances per unit area [37–40].

The applied electric stimulation was either a CW or a zero-mean GWN or a combination of both.

It should be noticed that the CW is a deterministic signal completely characterized by amplitude (A) and frequency (f), whereas the GWN, being a stochastic process, is described by its statistic moments, namely, average value, variance (

), and autocorrelation function.

The GWN had zero-mean value, flat spectrum, and variance values: =3, 25, 100 mV 2 . The variance can be associated with the average power that the process dissipates on a 1 Ω resistance. The CW signal was chosen to have amplitude values: A=1.73, 5, 10 mV, equal to the standard deviations ( ) of the considered GWN processes, where was taken as a measure of the amplitude of noise fluctuations. The CW frequencies were chosen to be equal to 25, 35, 50 kHz because they are above the upper perception threshold of human hearing (20 kHz). Due to the time step of 10 μs chosen for the model solution, 50 kHz is the maximum frequency allowed for an input signal. For the same reason, even the GWN spectrum is practically limited to that upper frequency.

After separately studying the two kinds of stimulation, all combinations of the CW signals and the GWN were applied to the model to check possible cooperative effects.

2.3. Quantification of Firing Reduction

As already mentioned in Introduction, a pathologic acoustic fiber exhibits a spontaneous firing rate higher than that of a healthy neuron [12, 13]. The mean firing rate, i.e., the number of spikes per second, is due to the operating point fixed by the OHC and to the endogenous noise related to the number of ionic channels. To quantify the level of firing inhibition, and thus of tinnitus suppression, induced by the electric stimulation, it is necessary to introduce a sensitive technique.

In this work, the inactivation function (IA) was defined as follows:

where =0 A=0 f=0 I0=6 is the number of spikes per second of a pathologic neuron (I0=6 μA/cm 2 ) in the absence of exogenous electric stimulation ( =0 mV A=0 mV f=0 Hz) A≠0 f≠0 I0=6 ) is the number of spikes per second of a pathologic neuron during the exogenous electric stimulation ( mV A 0 mV f 0 Hz) = A=0 f=0 I0= is the number of spikes per second of a healthy neuron (I0=2 μA/cm 2 ) in the absence of exogenous electric stimulation ( =0 mV A=0 mV f=0 Hz).

This quantity furnishes the percentage of firing reduction obtained using the stimulation in the pathologic neuron with respect to the difference, in terms of firing activity, between a pathologic and a physiologic neuron. The inactivation function will be 0% if the stimulation does not change the number of spikes of pathologic neuron and 100% if the neuron activity is turned back to the physiologic one. In this latter case, tinnitus is considered completely suppressed. Inactivation could be also higher than 100% if the firing activity is reduced below the physiologic condition or negative if the effect of electric stimulation is excitatory instead of inhibitory.

3. Results

3.1. Spontaneous Firing

The used stochastic neuron model exhibits a firing activity, quantified by the mean firing rate (spikes per second), that increases with the bias current density I0 injected in the model, as shown in Table 1. Even in subthreshold conditions (see second column of Table 1) a not null firing rate is observed, due to the energy injected into the system by channel noise, that increases as the Ranvier node area becomes smaller (Table 1).

The neuron firing rate is due to the contemporary presence of channel noise and bias current density the first one is determined by the typical sizes of the acoustic Ranvier nodes, the second one accounts for the operating point set by the OHC on the IHC transfer function, according to [9].

As shown in Table 1, for the same patch area, the three bias current densities, used to mimic the neuron with tinnitus (pathologic condition), increase the firing activity with respect to the physiologic condition, here modeled using the subthreshold bias current density I0=2 μA/cm 2 . These increases range from 21% (I0=6 μA/cm 2 ) to 35% (I0=10 μA/cm 2 ), for the 2.2 μm 2 patch area, from 25% (I0=6 μA/cm 2 ) to 40% (I0=10 μA/cm 2 ), for the 11.0 μm 2 patch area, and from 35% (I0=6 μA/cm 2 ) to 57% (I0=10 μA/cm 2 ), for the 15.7 μm 2 patch area (Table 1). This shows that when channel noise decreases, in correspondence of larger patch areas, bias current densities assume a stronger influence on neuron firing.

The increased firing activity obtained by using the close to threshold and the suprathreshold current densities reported in Table 1 agrees with the experimental recordings on animals with induced tinnitus, reporting an increase from 35 to 83% [12, 13].

In the next sections, it will be examined the efficacy of different exogenous electric stimulations (see Section 2.2) in reducing the firing activity of pathologic neurons down to physiologic conditions.

3.2. Effect of Different Electric Stimulations

The effects of a GWN on the mean firing rate of the neuron model, in each operating condition, have been quantified by the inactivation function IA, defined in Section 2.3, and summarized in Figure 1. For each pathologic condition, Figure 1 shows inactivation versus patch area for three standard deviations of noise fluctuations: 1.73 mV (panel (a)), 5 mV (panel (b)), and 10 mV (panel (c)).

For the lowest (Figure 1(a)), the inactivation does not exceed 2% and, in some cases, assumes negative values, indicating an increase of the mean firing frequency instead of a reduction. For of 5 mV (Figure 1(b)) it is possible to observe higher inactivation values that increase with the patch area and decrease with the bias current density, reaching a value of about 10% for patch size 15.7 μm 2 and bias current density 6 μA/cm 2 . However, such values are too low to induce considerable tinnitus alleviation. Further increasing up to 10 mV (Figure 1(c)), the inactivation could become considerable, reaching 53% for the highest patch area and the smallest bias current density. However, the inactivation is just some percent points for the smallest patch area, where the endogenous channel noise dominates on the exogenous stimulation in determining the neuron firing rate.

Therefore, a standard deviation of 10 mV is necessary for the GWN to induce an inactivation from 26 to 53% in acoustic fibers whose Ranvier nodes are larger than 11 μm 2 .

However, a broadband stimulation with a quite high power, related to the variance of noise fluctuations, may in principle induce unwanted acoustic perceptions coming from neighboring healthy hear cells.

Thus, it is worth evaluating the effect of using a stimulation with comparable amplitude of noise at a single frequency (CW) above 20 kHz, the upper perception limit of the human hearing. In fact, this stimulation cannot be directly interpreted as a sound by the human auditory system.

Figure 2(a) shows the inactivation versus the bias current density for the larger patch area (best case) and an applied CW at 25 kHz and amplitude equal to 1.73, 5, or 10 mV. As discussed in Section 2.2, these amplitudes have been chosen to have the same standard deviation of the used GWNs.

Even in this case, the signal with 1.73 mV of amplitude is not efficient in inhibiting firing and that of 5 mV inactivates the neuron up to 10%. The effect becomes considerable for the 10 mV signal, when the inactivation is equal to 18% for I0=10 μA/cm 2 and reaches a maximum of 35% for I0=6 μA/cm 2 . As already noticed for the GWN stimulation, the inactivation decreases with the bias current density, i.e., with the background firing activity of the pathologic neuron.

To evaluate the sensitivity to different stimulation frequencies, also 35 and 50 kHz CW signals have been considered. Figure 2(b) shows the inactivation induced by 25 kHz, 35 kHz and 50 kHz CW signals with the amplitude set to 10 mV.

It is worth noticing that the CW is almost ineffective at 50 kHz, being the inactivation always less than 20%, whereas 25 kHz and 35 kHz signals behave in a similar way, with a slightly better performance of the 25 kHz CW. This evidences a frequency sensitivity of the neuron already observed also in a lower frequency range (50-500 Hz) [41, 42].

Results of simulations show that the GWN, having the standard deviation equal to the sinusoidal amplitude, is always more efficient than the 25 kHz CW in inducing firing reduction. Figure 3 compares the inactivations induced by these two exogenous stimulations in the best case (I0=6 μA/cm 2 patch area=15.7 μm 2 ). Although the inactivation values are very similar when both the noise standard deviation ( ) and the signal amplitude (A) are equal to 1.73 and 5 mV, for =10 mV the inactivation induced by GWN is 52% versus 35% obtained by using the 25 kHz CW signal with the same amplitude. In fact, while the CW inactivation trend versus the amplitude (purple line in Figure 3) is accurately approximated (R=0.99976) by a quadratic curve with the second-order coefficient equal to 0.35, in the case of GWN (orange line in Figure 3), the quadratic function which best fits the inactivation trend (R=0.99964) has a second-order coefficient equal to 0.64.

assume the same values I0=6 μA/cm 2 patch area=15.7 μm 2 .

To obtain 100 % inactivation, too high amplitude values for the CW signal would be necessary conversely GWN has the disadvantage of having a spectrum segment in the auditory frequency band.

For these reasons, it would be useful to combine in a suitable way these two kinds of stimulation.

3.3. Effects of Combined Stimulation

The question arises on what happens if monochromatic and white stimulations are combined.

Results of the combined stimulation have been compared to the superposition of the effects induced by the two stimulations applied individually. Figure 4 shows a comparison of inactivation obtained by combining the two kinds of stimulation IA(CW+GWN) with the sum of the inactivations obtained by using the two single stimulations IA(CW)+IA(GWN), in the best case: CW at 25 kHz with amplitude 10 mV, and GWN with =10 mV.

=10 mV (solid lines), compared with the superposition of the inactivations induced by the two stimulations applied individually (dashed lines).

As evident from Figure 4, except for the lowest patch area and I0=6 μA/cm 2 , IA(CW+GWN) is always higher than IA(CW)+IA(GWN) and, for I0=6 μA/cm 2 and patch area 15.7 μm 2 , it reaches 100%. This means that the firing rate of the stimulated neuron is reduced to physiologic conditions.

These results, due to the nonlinear neuronal behavior, show a cooperative effect of the applied signal and noise that can be usefully exploited in applications. So, a good stimulation solution could be a combination of CW and GWN to maximize tinnitus suppression while reducing possible side effects.

4. Discussion

Results of this work furnish a proof of concept that a suitable exogenous electrical stimulation, consisting of a high frequency (25-35 kHz) CW and/or Gaussian noise, can alleviate tinnitus through a mechanism of firing inhibition. This finding is coherent with studies on human volunteers, where the electrical stimulation was delivered to the cochlea [14–16], and suggests a possible interaction mechanism based on the reduction of the pathologic firing rate to the spontaneous activity of a healthy auditory fiber.

To simulate the single Ranvier node of an auditory fiber, a stochastic HH neuron model was used, since it is well characterized and considered as a reference model in the literature for a lot of different applications with more than 10000 citations in the Scopus database [24]. The authors themselves already used it to study neuronal encoding [37, 38, 42, 43] and to explain the analgesic effect of the Complex Neuroelectromagnetic Pulse [44] by means of a silencing mechanism [19].

A limitation of the used model is that, even if a temperature correction factor is used [45], it cannot work at the mammalian temperature of 37°C. In the HH model, a temperature increase causes the threshold current density to shift towards higher values, and the firing rate to change depending on the patch size [45]. So, different operating conditions, in terms of bias current densities, would mimic healthy and pathologic neuronal activities. Similar mechanisms of relative firing reduction are expected to occur for a suitable combination of signal and noise since the model anyway presents two attraction basins for firing ad resting states and the exogenous stimulation can push the system from one state to the other. However, since the temperature adjustment in neuronal models is still an open question, here it was preferred to use the well-assessed reference temperature for the HH model.

Due to the generality of the used model and the high number of degrees of freedom, a complete evaluation of the uncertainty budget is not practicable but, besides the temperature, the other main variables that may influence results are examined in the following.

An aspect that could contribute to the uncertainty of results is that, for frequencies above 10 kHz, the membrane capacitance per unit area (

) is not constant, differently from what was assumed in our model. In fact, the permittivity of the cell membrane decreases with frequency due to the relaxation of the alpha polarization phenomenon [46]. Nevertheless, our simplification is largely acceptable since the frequency dependence of was shown to have a negligible effect on the stimulation threshold of a HH model (median = 1.4%) [47].

Other model parameters that induce a great variability of results are the bias current density I0 and the patch area. When applying a combination of the CW (f=25 kHz, A=10 mV) and the GWN ( =10 mV) to the neuronal patch of 15.7 μm 2 , the inactivation ranges from 54% (I0=10 μA/cm 2 ) to 100% (I0=6 μA/cm 2 ). Conversely, for I0=6 μA/cm 2 , the inactivation passes from 28% to 100% if the patch size increases from 2.2 to 15.7 μm 2 . Such variations could explain the great variability of results on human volunteers [16] that could be attributed to the individual variability of auditory fiber size (patch area in the model) and tinnitus severity (bias current density in the model).

This study suggests a plausible mechanism of tinnitus suppression using exogenous electrical excitation and is a first step towards the characterization of kind and parameters of stimulation that maximize the efficacy while reducing possible short-term or long-term side effects, such as unwanted sound perception or adaptation.

To control side effects, charge-balanced signals should be used and the induced currents should not exceed typical currents used in cochlear prostheses. A recent dosimetric study [48] revealed that a typical cochlear implant delivered, at the location of the afferent fibers of the auditory nerve, a peak voltage of several tens of mVs, higher than the signal amplitudes used in this work (≤ 10 mV). This suggests that the stimulation signals used in this work are plausible to be released from cochlear implants without severe side effects, even though it will be necessary to conduct a careful risk analysis to assess the safety of the proposed technique.

5. Conclusions

A stochastic HH neuron model was used to evaluate the efficacy of different electric stimulation strategies in tinnitus suppression. The used stimulations were CW signals at different frequencies in the range of tens of kHz and GWN.

Results of simulations show that both a CW and a white noise, applied individually to the neuron model, may induce a firing inhibition. The inactivation level is shown to depend on many parameters, such as patch area, bias current density, CW frequency and amplitude, and noise standard deviation. The more the background activity is low (larger patch size and lower bias currents), the more the inactivation is high. Considerable inactivation values are obtained by using either CW at 25 or 35 kHz or GWN with 10 mV of standard deviation, but GWN is shown to be more efficient than CW (IA=53% versus IA=35% in the best condition) for a comparable amplitude of fluctuations.

Moreover, the inactivation induced by a combination of signal and noise is almost always higher than the sum of the inactivations induced by the two stimulations applied individually and it reaches 100% for the lowest I0 and the highest patch area.

These results are a proof of concept that signal and noise act on the neuron in a cooperative way and could be suitably delivered in combination through cochlear prosthesis to alleviate tinnitus while reducing possible side effects due to a broadband stimulation.

Future works will concern the validation of the presented results on a mammalian neuronal model at 37°C, such as the Spatially Extended Nonlinear Node (SENN) [49] and the McIntyre-Richardson-Grill (MRG) [50] models and the identification of a colored stimulating noise suitably filtered considering the typical frequency selectivity of the used model.

Disclosure

This work was partially performed within the context of the European COST EMF-MED Action BM1309. Preliminary results were presented at the Joint Annual Meeting of the Bioelectromagnetics Society and the European BioElectromagnetics Association, Ghent, Belgium, 2016.

Conflicts of Interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Copyright

Copyright © 2018 Alessandra Paffi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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