To encourage research into Tinnitus (chronic ringing in the ears), Hyperacusis (hypersensitive for loud noises) and hearing loss (goes without saying) by the Baker Lab, I will regularly update this threade with information and research discoveries.

Tinnitus:

Tinnitus is the perception of sound within the human ear in the absence of corresponding external sound.

Tinnitus is not a disease, but a condition that can result from a wide range of underlying causes: neurological damage (multiple sclerosis), ear infections, oxidative stress,[1] foreign objects in the ear, nasal allergies that prevent (or induce) fluid drain, wax build-up and exposure to loud sounds. Withdrawal from benzodiazepines may cause tinnitus as well. In-ear earphones, whose sound enters directly into the ear canal without any opportunity to be deflected or absorbed elsewhere, are a common cause of tinnitus when volume is set beyond moderate levels.

Tinnitus is not a disease, but a condition that can result from a wide range of underlying causes: neurological damage (multiple sclerosis), ear infections, oxidative stress,[1] foreign objects in the ear, nasal allergies that prevent (or induce) fluid drain, wax build-up and exposure to loud sounds. Withdrawal from benzodiazepines may cause tinnitus as well. In-ear earphones, whose sound enters directly into the ear canal without any opportunity to be deflected or absorbed elsewhere, are a common cause of tinnitus when volume is set beyond moderate levels.

Tinnitus is common: about 20% of people between 55 and 65 years old report symptoms on a general health questionnaire, and 11.8% on more detailed tinnitus-specific questionnaires.

http://en.wikipedia.org/wiki/Tinnitus

Hyperacusis:

Hyperacusis is a health condition characterized by an over-sensitivity to certain frequency ranges of sound (a collapsed tolerance to usual environmental sound). A person with severe hyperacusis has difficulty tolerating everyday sounds, some of which may seem unpleasantly loud to that person but not to others.

Although severe hyperacusis is rare, a lesser form of hyperacusis affects musicians, making it difficult for them to play in the very loud environment of a rock band or orchestra which previously gave them no problems. It also makes attendance at loud discos or live events difficult for a portion of the population. Given that sound levels at such events usually exceed recommended safe levels of exposure, this is a problem which is probably showing up variations between people, which may be genetic, or the result of stress or ill-health, or it may be caused by abnormal response in the tensor tympani and stapedius muscles which function in the normal acoustic reflex response that protects the inner ear from loud sounds

40% of tinnitus patients complain of mild hyperacusis.

http://en.wikipedia.org/wiki/Hyperacusis

Proteins, genes and aspirin and their connection to Tinnitus

http://www.ata.org/sites/ata.org/files/pdf/Molecular_Basis_of_Salicylate_Induced_Tinnitus_Mazurek_Szczepek_Spring_10.pdf

How Hearing Occurs

People’s ability to hear is mediated by the sensory
hair cells in the inner ear and by the neurons in the
brain. Normally, auditory neurons get excited by a
signal coming from the sensory hair cells. This excitatory
signal is then forwarded from neuron to neuron,
and ends up in the auditory cortex, which analyzes
and perceives it as speech, music or other types of
sound. One of the central events, as the signal is
passed from one neuron to another, is the release of
neurotransmitters from the sender neuron and instant
engagement of the appropriate neurotransmitter
receptors on the recipient neuron. This event takes
place on a junction between the neurons, also known
as synapse. The neuronal synapses are not forever
fixed – they may change their strength. Neuroscience
refers to this change as synaptic plasticity, which
affects the quality of neuronal signals. In the auditory
system, it may be responsible for what and how we
hear. Consequently, it may be very likely that the
synaptic plasticity could be responsible for the
perception of tinnitus in the brain. This is why
recent trends in tinnitus research are to document
the presence and properties of neuronal plasticity
among auditory neurons.

Aspirin, Genes and Proteins

Aspirin, also referred to as salicylate, is an over-thecounter
drug that reduces fever and inflammation.
If overdosed, aspirin induces temporary tinnitus and
temporary hearing loss. The uniqueness of aspirin
is that unlike other ototoxic substances – it does not
Molecular Basis of Salicylate-Induced Tinnitus
damage the auditory tissues, it only changes their
performance. After a few hours, the body excretes
aspirin and the performance of the auditory system
recovers. A newly discovered property of aspirin is
its ability to regulate the expression of certain genes
and proteins. So far, investigators have studied the
influence of aspirin on the expression of genes and
proteins important in atherosclerosis and cancer.
The objective of the project funded by ATA was
to determine if aspirin can change the expression
of genes and proteins important for the synaptic
plasticity in the auditory system. As a model, we used
experimental animals (rats) treated with different
amounts of aspirin or with placebo. We tested the
hearing of the experimental animals at different
times after administering aspirin (or placebo) and
confirmed already-known properties of aspirin.
Next, our team dissected the auditory tissues
(cochlea, inferior colliculus and auditory cortex) and
examined them for gene and protein expression.
Finally, we compared the results from aspirin-treated
animals with those obtained from placebo-treated
animals and analyzed them using stringent
statistical methods.

Exciting Results about Aspirin-Induced Changes

The outcome of the experiments was more than
exciting. Using quantitative molecular biology
methods, we found that of twenty-five genes studied,
the expression of seven was changed in the auditory
tissues of aspirin-treated animals. The changes were
dose- and time-dependent. This means that greater
amounts of aspirin induced bigger changes in gene
expression and that these changes were returning to
the baseline over time.
Even more interestingly, the addition of aspirin did
not generally affect the non-auditory tissues. This
implicates that aspirin preferentially targets the
auditory neurons. The identified genes encode
neurotransmitter receptors, some growth factors
and lastly, a handful of proteins responsible for
transport of neurotransmitters to the synapses.
Changed gene expression does not always mean
changed protein expression. This is why we conducted
further biochemical experiments. The results we
obtained in some cases confirmed to some extent,
and in other cases strongly verified, the tendency of
gene expression.

Next Steps

Thanks to ATA support, we demonstrated for the first
time that aspirin given to animals in amounts that
induce tinnitus, significantly affects the expression of
genes and proteins involved in the synaptic strength
in the auditory neurons. These results provide indirect
evidence for the new property of aspirin: activation
of synaptic plasticity in the auditory neurons. It is, of
course, an artificial system and one does not know if
this type of synaptic plasticity in the auditory neurons
is unique to aspirin or if it is found to be the universal
mechanism inducing tinnitus.
We need more studies to clarify these uncertainties
and to better characterize the changes in expression
of targeted genes on a single-cell level and their
involvement in the generation of tinnitus. It is very
likely that additional genes and proteins responsible
for the synaptic plasticity could also be affected.

Subsequent steps in research would be to screen
for mechanisms and substances able to reverse
the plastic changes in auditory neurons affected by
tinnitus and induced in various ways by substances
like aspirin. The hope is that somewhere between
the ear and auditory cortex, the tinnitus signal
becomes universal, and thus can be universally
treated. For more information, visit www.charite.de/
hno/tinnitus.
Birgit Mazurek, M.D., Ph.D., is an assistant professor
in the Department of Otorhinolaryngology at the
Charité University Hospital in Berlin, Germany.
She is a founder and head of the Tinnitus Center
in Berlin.
Agnieszka J. Szczepek, Ph.D., is an immunologist
and molecular biologist trained in Canada and the
United States. She is a senior scientist and manager
of the research laboratory at the Tinnitus Center at
Charité University Hospital.

New!

Researchers Identify Genetic Biomarker for Age-related Hearing Loss

http://www.hearingreview.com/insider/2012-11-08_08.asp

Researchers at the University of South Florida (USF), House Ear Institute, and the National Technical Institute for the Deaf at the Rochester Institute of Technology have identified a genetic biomarker for age-related hearing loss.

In a 9-year study, the research team was able to identify the first genetic biomarker for presbycusis. The genetic mutation carried by those who ultimately suffer from age-related hearing loss is linked to speech processing abilities in older people.

Their findings are published in the journal Hearing Research. The study was authored by USF College of Engineering professors Robert Frisina Jr and Robert Frisina Sr, the founders of the Global Center for Hearing & Speech Research, and David Eddins, a USF associate professor of communication sciences and disorders and chemical and biological engineering.

Working with the House Ear Institute in Los Angeles, the researchers discovered a gene that produces a key protein in the cochlea, called glutamate receptor metabotropic 7 (GRM7). The GRM7 protein is intimately involved in converting sound into the code of the nervous system, in the cochlea, which is then sent to the parts of the brain used for hearing and speech processing.

DNA analyses were conducted and completed at the University of Rochester Medical School and the Rochester Institute of Technology. Now having identified the gene, the researchers said people can be tested and take steps earlier in life, such as avoiding loud noises, wearing ear protection, and avoiding certain medicines known to damage hearing.

“This gene is the first genetic biomarker for human age related hearing loss, meaning if you had certain configurations of this gene, you would know that you are probably going to lose your hearing faster than someone who might have another configuration,” said Robert Frisina Jr.

The Frisinas launched their study of genetics’ role in hearing loss in hopes of identifying the cause of one of the most common forms of permanent hearing loss. Clinically, age-related hearing loss has been defined as a progressive loss of sensitivity to sound, starting at the high frequencies, inability to understand speech, the lengthening of the minimum discernible temporal gap in sounds, and a decrease in the ability to filter out background noise. Researchers now know the causes of presbycusis are likely a combination of multiple environmental and genetic factors.

The study involved 687 people who underwent three hours of extensive examination of their hearing capabilities, including genetic analyses and testing of speech processing.

It should be noted that while the variation had a negative impact for men, it did the opposite for women, who actually had better than average hearing in their elder years. That discovery supports a 2006 finding by the Frisina research group that the hormone aldosterone plays a role in hearing capabilities.

Link to the paper:
http://www.sciencedirect.com/science/article/pii/S0378595512002092

UCLA and Sound Pharmaceuticals Identify a Key Hearing Regeneration Protein in the Human Inner Ear

SEATTLE, Feb. 24, 2011 /PRNewswire/ -- In collaboration with scientists and clinicians from the University of California Los Angeles, scientists from Sound Pharmaceuticals have found p27Kip1 to be expressed in the adult and aged human inner ear including the auditory and vestibular sensory organs. In the adult human inner ear, the pattern of p27Kip1 expression was restricted to the nuclei of supporting cells in the organ of Corti, the sensory organ that controls hearing, and the utricle and cristae, two sensory organs that control balance. These findings are identical to what has been observed and reported in neonatal and adult rodents, further validating p27Kip1 as a key regeneration target in the deafened mammalian inner ear. The fact that p27Kip1 was expressed in the supporting cells of the aged human cochlea from patients over 80 years old suggests that p27Kip1 is still working to suppress proliferative regeneration throughout life and is an appropriate drug target to stimulate supporting cell and hair cell regeneration. These findings were presented at the 34th Annual Midwinter Meeting of the Association for Research in Otolaryngology held this week. This work was supported by the National Institute on Deafness and Other Communication Disorders and the Office of Naval Research.

SPI is developing a proprietary technology for regenerating cells within the inner ear of mammals as a means to restore auditory function to the hearing impaired or deaf. By inhibiting p27Kip1, a cyclin dependent kinase inhibitor or CKI, supporting cell and auditory hair cell regeneration is stimulated in adult mice and Guinea pigs that were previously exposed to intense noise or ototoxic drugs. This novel proliferative and regenerative ability is absent in adult mammals, resulting in permanent and often progressive sensorineural hearing loss, the most common communication disorder and neurologic disease. Current development is focused on the local injection of an inhibitor of p27Kip1 (a p27 siRNA) into the cochlea of deafened adult mammals five weeks after the establishment of permanent hearing loss. The ultimate goal of this novel CKI inhibition technology is to restore hearing to the severe or profoundly impaired.

Sound Pharmaceuticals, Inc. is a privately held biopharmaceutical company with a focus on developing the first drugs for hearing loss and brain injury. For more information please contact Jonathan Kil, MD, President and CEO, 206-634-2559 or visit www.soundpharma.com.

SOURCE Sound Pharmaceuticals, Inc.


RELATED LINKS
http://www.soundpharma.com
PR Newswire (http://s.tt/1rB6i)

Lidocaine is known to make tinnitus disappear for a short while. Read this paper for more information:

Objective evaluation of the effects of intravenous lidocaine on tinnitus

http://www.ncbi.nlm.nih.gov/pubmed/15574302

Researchers Find Molecule In Ear That Converts Sounds Into Brain Signals

Finding the exact genetic code that programs the ear’s machinery for responding to sound waves and converting them into electrical impulses in the inner ear has been something of a holy grail for the scientists who study the genetics of hearing and deafness.

A new study from The Scripps Research Institute (TSRI) has brought this search to fruition by identifying a critical component of the ear-to-brain conversation. This component is a protein called TMHS, a critical player in the ear’s so-called ‘mechanotransduction channels’. These channels convert the signals from mechanical sound waves into electrical impulses which are then transmitted to the nervous system.

The findings of this study were published recently in the journal Cell.

“Scientists have been trying for decades to identify the proteins that form mechanotransduction channels,” said Ulrich Mueller, a professor in the Department of Cell Biology and director of the Dorris Neuroscience Center at TSRI. The results suggest a promising new approach toward gene therapy.

The team was able to place functional TMHS into the sensory cells for sound perception in newborn deaf mice. This laboratory experiment allowed the researchers to restore the function of these cells.

“In some forms of human deafness, there may be a way to stick these genes back in and fix the cells after birth,” said Mueller.

Previous studies have found specific genetic forms of this protein in people with common inherited forms of deafness. This new discovery would also seem to suggest the first explanation for how these genetic variations affect hearing loss.

Receptor cells deep in the ear collect vibrations and convert them into electrical signals and are the physical basis for hearing and mechanotransduction. These signals run along nerve fibers to areas in the brain where they are interpreted as sound. This basic mechanism evolved early in the history of life on Earth, and structures nearly identical to the modern human inner ear have been found in the fossilized remains of dinosaurs that died out 120 million years ago. Almost all mammals today share the basic inner ear structure.

Mechanical vibration waves travel from a sound source to hit the outer ear, propagate down the ear canal into the middle ear and strike the eardrum. A delicate set of bones is moved by the vibrating eardrum, communicating the vibrations to a fluid-filled spiral in the inner ear known as the cochlea. The moving bones compress a membrane on one side of the cochlea, causing the fluid inside to move.

Specialized hair cells inside the cochlea have symmetric arrays of extensions known as stereocilia protruding out from their surface. The moving fluid inside the cochlea causes the stereocilia to move, which in turn causes proteins known as ion channels to open. Sensory neurons surrounding the hair cells monitor the opening of the channels. When those neurons sense some threshold level of stimulation, they fire off communicating electrical signals to the auditory cortex of the brain.

Hearing involves many structures and is such a complex process that there are hundreds and hundreds of underlying genes involved. There are many ways it can be disrupted as well.

Long before birth, hair cells form in the inner ear. Humans are born with a finite number of these hair cells, as they do not regenerate themselves throughout life. Many, if not most, forms of deafness are associated with defects and loss of these hair cells. Genetic forms of deafness emerge when those hair cells are unable to transduce sound waves into electrical signals.

Scientists have identified dozens of genes linked to hearing loss over the years. Some of these genes have been identified from genetic studies involving deaf people and some from studies with mice, which have inner ear structures remarkably similar to humans.

A clear picture of how these genes interact to form the biological basis of hearing has been missing, however. Though scientists have known that many of these genes are involved in deafness, they haven’t been able to account for the various forms of hearing loss. However, the picture is becoming clearer since the discovery of TMHS, which plays a role in a molecular complex called the ‘tip link’.

Several years ago, it was discovered that the tip link caps the stereocilia protruding out of hair cells. The tip links connect neighboring stereocilia at the top, bundling them together. When they are missing, the hair cells become splayed apart.

The tip links do more than maintain the structure of these bundles, however, they also house the machinery crucial for hearing – the proteins that physically receive the force of a sound wave and transduce it into electrical impulses by regulating the activity of ion channels. Mueller’s lab previously identified the molecules that form the tip links. But the ion channels and the molecules that connect the tip links to the channels remained elusive. Mueller says that scientists have been searching for the exact identity of the proteins responsible for this process for years.

The new study reveals that TMHS is one of the lynchpins of this process. TMHS is a subunit of the protein-based ion channel that directly binds it to the tip link. If the TMHS protein is missing, hair cells that are otherwise completely normal lose their ability to send electrical signals.

Mueller’s team demonstrated this using a lab technique that emulates hearing with cells in the test tube. Sounds are imitated by vibrations that are deflected off the cells, and the cells can be probed to see if they can transduce the vibrations into electrical signals. What these tests showed is that with TMHS, this ability to transduce disappears.

This, say the researchers, is a crucial puzzle piece in understanding the genetic basis of hearing and hearing loss.

“We can now start to understand how organisms convert mechanical signals to electrical signals, which are the language of the brain,” concluded Mueller.

http://www.redorbit.com/news/health/1112744250/molecule-converts-sound-into-brain-signals-120712/

U-M tinnitus discovery opens door to possible new treatment avenues

http://www.uofmhealth.org/news/archive/201312/u-m-tinnitus-discovery-opens-door-possible-new-treatment

ANN ARBOR, Mich. — For tens of millions of Americans, there’s no such thing as the sound of silence. Instead, even in a quiet room, they hear a constant ringing, buzzing, hissing, humming or other noise in their ears that isn’t real. Called tinnitus, it can be debilitating and life-altering.
tinnitussm.jpg
Tinnitus illustration
Tens of millions of Americans "hear" ringing, buzzing or humming in their ears -- an annoying and sometimes disabling condition known as tinnitus.

Now, University of Michigan Medical School researchers report new scientific findings that help explain what is going on inside these unquiet brains.

The discovery reveals an important new target for treating the condition. Already, the U-M team has a patent pending and device in development based on the approach.

The critical findings are published online in the prestigious Journal of Neuroscience. Though the work was done in animals, it provides a science-based, novel approach to treating tinnitus in humans.

Susan Shore, Ph.D., the senior author of the paper, explains that her team has confirmed that a process called stimulus-timing dependent multisensory plasticity is altered in animals with tinnitus – and that this plasticity is “exquisitely sensitive” to the timing of signals coming in to a key area of the brain.
Susan Shore, Ph.D.

Susan Shore, Ph.D., U-M Kresge Hearing Research Institute

That area, called the dorsal cochlear nucleus, is the first station for signals arriving in the brain from the ear via the auditory nerve. But it’s also a center where “multitasking” neurons integrate other sensory signals, such as touch, together with the hearing information.

Shore, who leads a lab in U-M’s Kresge Hearing Research Institute, is a Professor of Otolaryngology and Molecular and Integrative Physiology at the U-M Medical School, and also Professor of Biomedical Engineering, which spans the Medical School and College of Engineering.

She explains that in tinnitus, some of the input to the brain from the ear’s cochlea is reduced, while signals from the somatosensory nerves of the face and neck, related to touch, are excessively amplified.

“It’s as if the signals are compensating for the lost auditory input, but they overcompensate and end up making everything noisy,” says Shore.

The new findings illuminate the relationship between tinnitus, hearing loss and sensory input and help explain why many tinnitus sufferers can change the volume and pitch of their tinnitus’s sound by clenching their jaw, or moving their head and neck.

But it’s not just the combination of loud noise and overactive somatosensory signals that are involved in tinnitus, the researchers report.

It’s the precise timing of these signals in relation to one another that prompt the changes in the nervous system’s plasticity mechanisms, which may lead to the symptoms known to tinnitus sufferers.

Shore and her colleagues, including former U-M biomedical engineering graduate student and first author Seth Koehler, Ph.D., hope their findings will eventually help many of the 50 million people in the United States and millions more worldwide who have the condition, according to the American Tinnitus Association. They hope to bring science-based approaches to the treatment of a condition for which there is no cure – and for which many unproven would-be therapies exist.

Tinnitus especially affects baby boomers, who, as they reach an age at which hearing tends to diminish, increasingly experience tinnitus. The condition most commonly occurs with hearing loss, but can also follow head and neck trauma, such as after an auto accident, or dental work.

Loud noises and blast forces experienced by members of the military in war zones also can trigger the condition. Tinnitus is a top cause of disability among members and veterans of the armed forces.

Researchers still don’t understand what protective factors might keep some people from developing tinnitus, while others exposed to the same conditions experience tinnitus.

In this study, only half of the animals receiving a noise-overexposure developed tinnitus. This is similarly the case with humans -- not everyone with hearing damage ends up with tinnitus. An important finding in the new paper is that animals that did not get tinnitus showed fewer changes in their multisensory plasticity than those with evidence of tinnitus. In other words, their neurons were not hyperactive.

Shore is now working with other students and postdoctoral fellows to develop a device that uses the new knowledge about the importance of signal timing to alleviate tinnitus. The device will combine sound and electrical stimulation of the face and neck in order to return to normal the neural activity in the auditory pathway.

“If we get the timing right, we believe we can decrease the firing rates of neurons at the tinnitus frequency, and target those with hyperactivity,” says Shore. She and her colleagues are also working to develop pharmacological manipulations that could enhance stimulus timed plasticity by changing specific molecular targets.

But, she notes, any treatment will likely have to be customized to each patient, and delivered on a regular basis. And some patients may be more likely to derive benefit than others.

Funding: The research was supported by National Institutes of Health grants DC004825 and P30 DC05188. Shore’s device project is funded by the Coulter Translational Research Partnership, which is supported by the Wallace H. Coulter Foundation and the University of Michigan.

Reference: The Journal of Neuroscience, December 11, 2013 • 33(50):19647–19656

As one who has tinnitus, I will find this interesting. My case comes, I believe, from long exposure to high noise levels (long motorcycle rides over days at a time). Fortunately, I find it easy to live with, in that unless I stop to think about it, I don't notice it, though it is always present. I have noticed that head position can cause it to increase - if I am reading in a lying down position with my head propped on a pillow, it noticeably increases.

Anyway, I'll be reading!