Gene therapy for hearing loss: Potential and limitations

Regenerating sensory hair cells, which produce electrical signals in response to vibrations within the inner ear, could form the basis for treating age- or trauma-related hearing loss. One way to do this could be with gene therapy that drives new sensory hair cells to grow.

Researchers at Emory University School of Medicine have shown that introducing a gene called Atoh1 into the cochleae of young mice can induce the formation of extra sensory hair cells.

Their results show the potential of a gene therapy approach, but also demonstrate its current limitations. The extra hair cells produce electrical signals like normal hair cells and connect with neurons. However, after the mice are two weeks old, which is before puberty, inducing Atoh1 has little effect. This suggests that an analogous treatment in adult humans would also not be effective by itself.

The findings were published May 9 in the Journal of Neuroscience.

"We've shown that hair cell regeneration is possible in principle," says Ping Chen, PhD, associate professor of cell biology at Emory University School of Medicine. "In this paper, we have identified which cells are capable of becoming hair cells under the influence of Atoh1, and we show that there are strong age-dependent limitations on the effects of Atoh1 by itself."

The first author of the paper, Michael Kelly, now a postdoctoral fellow at the National Institute on Deafness and Other Communication Disorders, was a graduate student in Emory's Neuroscience program.

Kelly and his coworkers engineered mice to turn on the Atoh1 gene in the inner ear in response to the antibiotic doxycycline. Previous experimenters had used a virus to introduce Atoh1 into the cochleae of animals. This approach resembles gene therapy, but has the disadvantage of being slightly different each time, Chen says. In contrast, the mice have the Atoh1 gene turned on in specific cells along the lining of the inner ear, called the cochlear epithelium, but only when fed doxycycline.

Young mice given doxycycline for two days had extra sensory hair cells, in parts of the cochlea where developing hair cells usually appear, and also additional locations (see accompanying image).

The extra hair cells could generate electrical signals, although those signals weren't as strong as mature hair cells. Also, the extra hair cells appeared to attract neuronal fibers, which suggests that those signals could connect to the rest of the nervous system.

"They can generate electrical signals, but we don't know if they can really function in the context of hearing." Chen says. "For that to happen, the hair cells' signals need to be coordinated and integrated."

Although doxycycline could turn on Atoh1 all over the surface of the cochlea, extra sensory hair cells did not appear everywhere. When they removed cochleae from the mice and grew them in culture dishes, her team was able to provoke even more hair cells to grow when they added a drug that inhibits the Notch pathway.

Manipulating the Notch pathway affects several aspects of embryonic development and in some contexts appears to cause cancer, so the approach needs to be refined further. Chen says that it may be possible to unlock the age-related limits on hair cell regeneration by supplying additional genes or drugs in combination with Atoh1, and the results with the Notch drug provide an example.

"Our future goals are to develop approaches to stimulate hair cell formation in older animals, and to examine functional recovery after Atoh1 induction," she says.

Source: Emory University [May 11, 2012]

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Hearing and Touch Have Common Genetic Basis

Vision and hearing are so crucial to our daily lives that any impairments usually become obvious to an affected person. Although a number of known genetic mutations can lead to hereditary defects in these senses, little is known about our sense of touch, where defects might be so subtle that they go unnoticed.

There are good reasons to suspect that hearing and touch might have a common genetic basis. Sound-sensing cells in the ear detect vibrations and transform them into electrical impulses. Likewise, nerves that lie just below the surface of the skin detect movement and changes in pressure, and generate impulses. The similarity suggests that the two systems might have a common evolutionary origin—they may depend on an overlapping set of molecules that transform motion into signals that can be transmitted along nerves to the brain [Credit: © Vladimir Voronin/ Fotolia]

People with good hearing also have a keen sense of touch; people with impaired hearing generally have an impaired sense of touch. Extensive data supporting this hypothesis was presented by Dr. Henning Frenzel and Professor Gary R. Lewin of the Max Delbruck Center for Molecular Medicine (MDC) Berlin-Buch, Germany. The two researchers showed that both senses -- hearing and touch -- have a common genetic basis. In patients with Usher syndrome, a hereditary form of deafness accompanied by impaired vision, the researchers discovered a gene mutation that is also causative for the patients' impaired touch sensitivity.

The examination was preceded by various studies, including studies with healthy identical and non-identical human twins. In total, the researchers assessed sensory function in 518 volunteers.

In all vertebrates, and consequently also in humans, hearing and touch represent two distinct sensory systems that both rely on the transformation of mechanical force into electrical signals. When we hear, sound waves trigger vibrations that stimulate the hair-like nerve endings in the cochlea in the inner ear. These then transform the mechanical stimuli into electrical signals, which are transmitted to the brain via the auditory nerve. When we touch something a similar process takes place: The mechanical stimulus -- sliding the fingers over a rough or smooth surface, the perception of vibrations -- is taken up via sensors in the skin, converted into an electrical stimulus and transmitted to the brain.

Twin study with 100 pairs of twins

In recent years about 70 genes have been identified in humans, mutations in which trigger hearing loss or deafness. "Surprisingly, no genes have been found that negatively influence the sense of touch," Professor Lewin said. To see whether the sense of touch also has a hereditary component, the researchers first studied 100 pairs of twins -- 66 pairs of monozygotic twins and 34 dizygotic pairs of twins. Monozygotic twins are genetically completely identical; dizygotic twins are genetically identical to 50 percent. The tests showed that the touch sensitivity of the subjects was determined to more than 50 percent by genes. Furthermore, hearing and touch tests showed that there is a correlation between the sense of hearing and touch.

The researchers therefore suspected that genes that influence the sense of hearing may also have an influence on the sense of touch. In a next step, they recruited test subjects at a school in Berlin for students with hearing impairments. There they assessed the touch sensitivity in a cohort of 39 young people who suffered from severe congenital hearing impairment. The researchers compared these findings with the data from their twin study and discovered that not all of the young people with hearing loss had impaired tactile acuity. "Strikingly, however, many of these young people did indeed have poor tactile acuity," Professor Lewin explained.

The researchers decided it would take too much time to analyze which of the approximately 70 genes that adversely affect the sense of hearing may also negatively affect the sense of touch. Therefore, the researchers focused specifically on patients with the Usher syndrome, a hereditary form of hearing impairment, in which the patients progressively become blind. Usher syndrome patients have varying degrees of hearing impairment, and the disease is genetically very well studied. There are nine known Usher genes carrying mutations which cause the disease.

The researchers examined one cohort of patients in a special consultation at the Charite -- Universitatsmedizin Berlin for Usher patients from all over Germany. A second cohort was recruited at the university hospital La Fe in Valencia, Spain. The studies revealed that not all patients with Usher-syndrome have poor tactile acuity and touch sensitivity. The researchers showed that only patients with Usher syndrome who have a mutation in the gene USH2A have poor touch sensitivity. This mutation is also responsible for the impaired hearing of 19 patients. The 29 Usher-syndrome patients in whom the mutation could not be detected had a normal sense of touch. The researchers thus demonstrated that there is a common genetic basis for the sense of hearing and touch. They suspect that even more genes will be discovered in the future that influence both mechanosensory traits.

Women hear better than men and have a finer sense of touch

The researchers discovered another interesting detail during their five-year study. "When women complain that their men are not really listening to them, there is some truth in that," Professor Lewin said. "The studies with a total of 518 individuals including 295 women have actually shown that women hear better and they also have a finer sense of touch than men; in short woman hear and feel more than men!"

Source: Helmholtz Association of German Research Centres [May 01, 2012]

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Scientists decode how the brain hears words

US scientists said Wednesday they have found a way to decode how the brain hears words, in what researchers described as a major step toward one day helping people communicate after paralysis or stroke. 

These images courtesy of the Center for Vital Longevity, The University of Texas at Dallas, show positron emission tomography scans of the brains of healthy adults showing low (L) and high (R) levels of beta-amyloid protein. US scientists said Wednesday they have found a way to decode how the brain hears words [Credit: AFP]

By placing electrodes on the brains of research subjects and then having them listen to conversations, scientists were able to analyze the sound frequencies registered and figure out which words they were hearing. 

"We were focused on how the brain processes the sounds of speech," researcher Brian Pasley of the Helen Wills Neuroscience Institute at the University of California Berkeley told AFP. 

"Most of the information in speech is between one to 8,000 hertz. Essentially the brain analyzes those different sound frequencies in somewhat separate locations." 

By tracking how and where the brain registered sounds in the temporal lobe -- the center of the auditory system -- scientists were able to map out the words and then recreate them as heard by the brain. 

"When a particular brain site is being activated, we know that roughly corresponds to some sound frequency that the patient is actually listening to," Pasley said. 

"So we could map that out to an extent that would allow us to use that brain activity to resynthesize the sound from the frequencies we were guessing." 

One word the researchers mapped was "structure." The high-frequency "s" sound showed up as a certain pattern in the brain, while the lower harmonics of the "u" sound appeared as a different pattern. 

"There is to some extent a correspondence between these features of sound and the brain activity that they cause," and putting together the physical registry in the brain helped rebuild the words, Pasley explained. 

The work builds on previous research in ferrets, in which scientists read to the animals and recorded their brain activity. 

They were able to decode which words the creatures heard even though the ferrets themselves didn't understand the words. 

The next step for researchers is to figure out just how similar the process of hearing sounds may be to the process of imagining words and sounds. 

That information could one day help scientists determine what people want to say when they cannot physically speak. 

Some previous research has suggested there may be similarities, but much more work needs to be done, Pasley said. 

"This is huge for patients who have damage to their speech mechanisms because of a stroke or Lou Gehrig's disease and can't speak," co-author Robert Knight, a UC Berkeley professor of psychology and neuroscience, said in a statement. 

"If you could eventually reconstruct imagined conversations from brain activity, thousands of people could benefit." 

Participating researchers came from the University of Maryland, UC Berkeley and Johns Hopkins University in Baltimore, Maryland. 

The study appears in the January 31 edition of the open access journal PLoS Biology. 

Author: Kerry Sheridan | Source: AFP [February 01, 2012]

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Music training has biological impact on aging process

Age-related delays in neural timing are not inevitable and can be avoided or offset with musical training, according to a new study from Northwestern University. The study is the first to provide biological evidence that lifelong musical experience has an impact on the aging process. 

Measuring the automatic brain responses of younger and older musicians and non-musicians to speech sounds, researchers in the Auditory Neuroscience Laboratory discovered that older musicians had a distinct neural timing advantage. 

"The older musicians not only outperformed their older non-musician counterparts, they encoded the sound stimuli as quickly and accurately as the younger non-musicians," said Northwestern neuroscientist Nina Kraus. "This reinforces the idea that how we actively experience sound over the course of our lives has a profound effect on how our nervous system functions." 

Kraus, professor of communication sciences in the School of Communication and professor of neurobiology and physiology in the Weinberg College of Arts and Sciences, is co-author of "Musical experience offsets age-related delays in neural timing" published online in the journal Neurobiology of Aging. 

"These are very interesting and important findings," said Don Caspary, a nationally known researcher on age-related hearing loss at Southern Illinois University School of Medicine. "They support the idea that the brain can be trained to overcome, in part, some age-related hearing loss." 

"The new Northwestern data, with recent animal data from Michael Merzenich and his colleagues at University of California, San Francisco, strongly suggest that intensive training even late in life could improve speech processing in older adults and, as a result, improve their ability to communicate in complex, noisy acoustic environments," Caspary added. 

Previous studies from Kraus' Auditory Neuroscience Laboratory suggest that musical training also offset losses in memory and difficulties hearing speech in noise -- two common complaints of older adults. The lab has been extensively studying the effects of musical experience on brain plasticity across the life span in normal and clinical populations, and in educational settings. 

However, Kraus warns that the current study's findings were not pervasive and do not demonstrate that musician's have a neural timing advantage in every neural response to sound. "Instead, this study showed that musical experience selectively affected the timing of sound elements that are important in distinguishing one consonant from another." 

The automatic neural responses to speech sounds delivered to 87 normal-hearing, native English-speaking adults were measured as they watched a captioned video. "Musician" participants began musical training before age 9 and engaged consistently in musical activities through their lives, while "non-musicians" had three years or less of musical training.  

Source: Northwestern University [January 30, 2012]

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Even unconsciously, sound helps us see

“Imagine you are playing ping-pong with a friend. Your friend makes a serve. Information about where and when the ball hit the table is provided by both vision and hearing. Scientists have believed that each of the senses produces an estimate relevant for the task (in this example, about the location or time of the ball’s impact) and then these votes get combined subconsciously according to rules that take into account which sense is more reliable. And this is how the senses interact in how we perceive the world. However, our findings show that the senses of hearing and vision can also interact at a more basic level, before they each even produce an estimate,” says Ladan Shams, a UCLA professor of psychology, and the senior author of a new study appearing in the December issue of Psychological Science, a journal published by the Association for Psychological Science. 

[Credit: Oscar Burriel/Science Photo Library]

“If we think of the perceptual system as a democracy where each sense is like a person casting a vote and all votes are counted (albeit with different weights) to reach a decision, what our study shows is that the voters talk to one another and influence one another even before each casts a vote.” 

“The senses affect each other in many ways,” says cognitive neuroscientist Robyn Kim. There are connections between the auditory and visual portions of the brain and at the cognitive level. When the information from one sense is ambiguous, another sense can step in and clarify or ratify the perception. Now, for the first time, Kim, Megan Peters, and Ladan Shams, working at the University of California Los Angeles, have shown behavioral evidence that this interplay happens in the earliest workings of perception—not just before that logical decision-making stage, but before the pre-conscious combination of sensory information. 

To demonstrate that one sense can affect another even before perception, the researchers showed 63 participants a bunch of dots on a screen, in two phases with a pause between them. In one phase, the dots moved around at random; in the other, some proportion moved together from right to left. The participants had to indicate in which phase the dots moved together horizontally. In experiment 1, the subjects were divided into three groups. While they looked at the dots, one group heard sound moving in the same direction as the right-to-left dots, and stationary sound in the random phase. A second group heard the same right-to-left sound in both phases. The third group heard the identical sound in both phases, but it moved in the opposite direction of the dots. In the second and third conditions, because the sound was exactly the same in both phases, it added no cognitively useful information about which phase had the leftward-moving dots. In experiment 2, each participant experienced trials in all three conditions. 

The results: All did best under the first condition—when the sound moved only in the leftward-motion phase. The opposite-moving sound neither enhanced nor worsened the visual perception. But surprisingly, the uninformative sound—the one that traveled leftward both with the leftward-moving dots and also when the dots moved randomly—helped people correctly perceive when the dots were moving from one side to the other. Hearing enhanced seeing, even though the added sense couldn’t help them make the choice. 

The study, says Kim, should add to our appreciation of the complexity of our senses. “Most of us understand that smell affects taste. But people tend to think that what they see is what they see and what they hear is what they hear.” The findings of this study offer “further evidence that, even at a non-conscious level, visual and auditory processes are not so straightforward,” she says. “Perception is actually a very complex thing affected by many factors.” 

“This study shows that at least in regards to perception of moving objects, hearing and sight are deeply intertwined, to the degree that even when sound is completely irrelevant to the task, it still influences the way we see the world,” Shams says. 

Source: Association for Psychological Science [December 01, 2011]

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