Tinnitus and Sound predictability

Tinnitus, often described as ringing or buzzing in the ears, is a complex condition that affects millions worldwide. It is primarily diagnosed based on self-reported symptoms. However, it can also be a diagnosis of exclusion, as it may sometimes be caused by an underlying condition. In many cases, the exact cause remains elusive.

A comprehensive hearing (audiological) exam is crucial in assessing tinnitus. This typically includes Pure Tone Audiometry that evaluates hearing thresholds and identifies any hearing loss associated with tinnitus. It also helps describe the characteristics of tinnitus, such as loudness and pitch.

Different types of tinnitus sounds can provide clues about potential causes:

Clicking: May indicate muscle contractions in or around the ears

Pulsing, rushing, or humming: Could stem from vascular causes, such as high blood pressure

Low-pitched ringing: Might suggest ear canal blockages, Menière's disease, or otosclerosis

High-pitched ringing: Often associated with loud noise exposure, hearing loss, or certain medications

Continuous, high-pitched ringing in one ear: Could indicate acoustic neuroma

Additional diagnostic tools may include Lab tests - to check for anemia, thyroid problems, heart disease, or vitamin deficiencies and Imaging - CT scans or MRIs to identify structural abnormalities in the ear

A recent study from the Netherlands explored how tinnitus affects auditory processing, specifically focusing on sensory gating (SG) and predictability in sound perception.

Imaging: CT scans or MRIs of the ear can identify structural abnormalities.

Study Design:

Participants: 52 age-, education-, and sex-matched individuals with and without tinnitus

Task: Listening to paired-tone oddball sequences varying in pitch (standard vs. deviant) and timing (isochronous vs. random)

Measurement: 128-channel EEG recording

Analysis: Temporal spatial principal component analysis (tsPCA)

Both groups demonstrated sensory gating, suppressing responses to the second tone in a pair.

Deviant tones elicited larger amplitudes than standard tones in both groups.

Only participants without tinnitus showed an enhanced N100-like deviance response in the isochronous (predictable) timing condition compared to the random timing condition.

The study suggests that individuals with tinnitus may not benefit from temporal predictability in sound processing to the same extent as those without tinnitus. This indicates a potential deficit in temporal sensitivity in auditory processing for people with tinnitus.

Understanding tinnitus involves exploring its various manifestations, potential causes, and the underlying differences in auditory processing. While diagnosis primarily relies on self-reported symptoms, comprehensive audiological exams and additional tests can provide valuable insights. Recent research highlights the complex nature of tinnitus and its impact on sound perception, opening avenues for future studies and potential therapeutic approaches.

REFERENCE

Brinkmann P, Devos JVP, van der Eerden JHM, Smit JV, Janssen MLF, Kotz SA, Schwartze M. Parallel EEG assessment of different sound predictability levels in tinnitus. Hear Res. 2024 Jul 6;450:109073. doi: 10.1016/j.heares.2024.109073. Epub ahead of print. PMID: 38996530.

Genomic Therapy Restores Hearing in Children

Imagine a world where children born deaf can hear for the first time. This once far-fetched dream is becoming a reality thanks to a recent breakthrough in genomic therapy. A new study published in Nature Medicine reports promising results from an innovative gene therapy designed to treat autosomal recessive deafness 9 (DFNB9). 

DFNB9 is a genetic condition that leads to severe-to-complete hearing loss from birth or early childhood. It's caused by mutations in the OTOF gene, which encodes a crucial protein called otoferlin necessary for hearing. Without functional otoferlin, sound signals cannot be properly transmitted to the brain, resulting in deafness.

Researchers have been exploring gene therapy as a way to treat genetic disorders like DFNB9. In this approach, a healthy copy of the defective gene is delivered to the patient's cells using a viral vector. In previous studies, a single injection of an adeno-associated virus (AAV) carrying the human OTOF gene showed safety and some hearing improvement in one ear.

Building on this success, the researchers expanded their trial to test the therapy in both ears (binaural therapy) in children with DFNB9. Their latest paper presents interim results from this ongoing study.

Five children with DFNB9 who never received cochlear implants participated in the trial. Each received the gene therapy in both ears. The primary goals were to evaluate safety and to observe any improvements in hearing. Here’s what they found:

Safety: No serious adverse events or dose-limiting toxicities were reported. Out of 36 minor adverse events, the most common were increased lymphocyte counts and cholesterol levels, both manageable.

Efficacy: Remarkably, all five children showed significant improvement in hearing. Before therapy, their average auditory brainstem response thresholds were greater than 95 dB, indicating profound hearing loss. After therapy, these thresholds improved dramatically. For example:

Patient 1: Improved to 58 dB and 63 dB in the right and left ears, respectively.

Patient 2: Improved to 75 dB and 85 dB.

Patients 3, 4, and 5 showed similar improvements.

Beyond these quantitative measures, qualitative improvements were equally striking. All five children gained the ability to perceive speech and locate sounds. Here are some inspiring individual stories:

Patient 1: An 11-year-old girl, deaf since birth, began responding to her name and recognizing sounds within weeks. By 13 weeks, she could speak simple syllables like "ba" (father) and "ma" (mother).

Patient 2: This child, who couldn’t hear at all initially, could turn to his grandparents' calls within six weeks and started saying words like "ayi" (aunt) and "bai" (bye) by 26 weeks.

Patient 3: Similarly, this patient began responding to his name within three weeks and could dance to music and say words like "baba" (father) and "yeye" (grandfather) by 26 weeks.

This study offers a glimmer of hope for the 430 million people worldwide who suffer from disabling hearing loss, including 34 million children. Approximately 26 million people have congenital hearing loss, with 60% of these cases due to genetic factors like DFNB9.

While these interim results are promising, the trial is ongoing, and longer follow-up is needed to confirm the therapy's long-term safety and efficacy. If successful, this gene therapy could revolutionize the treatment of genetic hearing loss, offering a new lease on life for countless individuals.

For more details, you can check the trial registration at the Chinese Clinical Trial Registry: ChiCTR2200063181.

REFERENCE

Wang, H., Chen, Y., Lv, J. et al. Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results. Nat Med (2024). https://doi.org/10.1038/s41591-024-03023-5

SARS-CoV-2 Lurking in the Middle Ear

From the common rhinovirus to infamous coronavirus, respiratory viruses can trigger a cascade of ear complications, including acute otitis media (AOM). This roster includes syncytial virus, rhinovirus, adenovirus, coronavirus, bocavirus, influenza virus, parainfluenza virus, enterovirus, human metapneumovirus and SARS-Cov2. Moreover, Otitis media can often manifest as the initial sign of COVID-19 and be associated with hearing loss. Otitis media secretory is one of the most common ear complications after infection with the Omicron strain of SARS-CoV-2 virus, and the significantly higher incidence is associated with middle ear viral infection. Middle ear effusion SARS-CoV-2 virus antigen test detected the virus, which survived longer in the middle ear effusion than in the nasal cavity. The middle ear effusion test can detect SARS-CoV-2 virus antigen and determine whether the organism contains virus residue. 

Recent findings have unveiled a potentially alarming revelation - individuals diagnosed with otitis media with effusion (OME) post-COVID-19 may harbor traces of the virus within their middle ear. In this study, a striking 12.0% of middle ear effusion samples tested positive for SARS-CoV-2, hinting at the possibility of viral persistence and recurrence.

The study examined 23 patients, ranging from 32 to 84 years of age, who presented with OME following Omicron infection. 91.3% of these patients showcased unilateral symptoms, with fluid accumulation observed in 88.0% of ears. The median duration from infection to middle ear effusion sampling was 21 days, showcasing the potential for prolonged viral presence in this concealed reservoir.

Adding to the intrigue is the elusive nature of OME itself. Characterized by fluid accumulation in the middle ear sans acute infection, OME has long puzzled experts in otolaryngology and audiology. While bacterial infections and immunological responses have been implicated, the precise mechanisms remain veiled in mystery.

REFERENCES

Chengzhou Han, Huifang Wang, Ying Wang, Chao Hang, Yangyang Wang, Xiangming Meng, The silent reservoir? SARS-CoV-2 detection in the middle ear effusion of patients with Otitis media with effusion after omicron infection, American Journal of Otolaryngology, 2024, 104229, ISSN 0196-0709, https://doi.org/10.1016/j.amjoto.2024.104229. 

Zhang Y, Liu J, Yang F, He Y, Yan S, Bai Y, Zhang Z, Luan F. COVID-19-related secretory otitis media in the omicron era: a case series. Eur Arch Otorhinolaryngol. 2023 Oct;280(10):4697-4700. doi: 10.1007/s00405-023-08075-w. Epub 2023 Jun 21. PMID: 37341758.

Fan Y, Gao R, Shang Y, Tian X, Zhao Y, Chen X. Presence of SARS-CoV-2 in middle ear fluid and characterization of otitis media with effusion in patients with COVID-19. International Journal of Infectious Diseases. 2023 Nov 1;136:44-8.

Karimi-Galougahi M, Raad N, Ghorbani J, Mikaniki N, Haseli S. Otitis Media in COVID-19: A Case Series. Authorea Preprints. 2020 Jul 7.

Gene Therapy Rescues Childhood Deafness

Gene therapy, a revolutionary medical technique first conceptualized in the 1980s, has steadily advanced, offering new hope in treating various genetic disorders. This approach involves altering a person’s genetic makeup to combat diseases, representing a significant shift from traditional methods like drugs or surgery. 

Gene therapy faces challenges, including immune reactions, targeting errors, and the risk of new mutations. But in many cases benefits outweigh the risks.

A recent milestone in gene therapy has been its application in treating inherited hearing loss. The focus is on DFNB9, a form of deafness caused by mutations in the OTOF gene, responsible for producing otoferlin, a crucial protein in sound signal transmission. This leads to nonsyndromic Hearing Loss - a hearing loss that occurs with no other symptoms. A collaborative clinical trial between Chinese researchers and Mass Eye and Ear investigators has yielded remarkable results.

The trial involved six children with autosomal recessive deafness (DFNB9), all between one and seven years old. The gene therapy entailed injecting a functional OTOF gene using viral carriers into the inner ear. This process enabled the cells to produce otoferlin, thereby restoring hearing capabilities.

Over 26 weeks, five of the six children showed significant hearing improvements, with abilities ranging from understanding speech to verbalizing words, even holding phone conversations. 

This success paves the way for addressing other genetic forms of deafness involving genes like GJB2, MYO15A, TMC1, or SLC26A4. These genes play various roles in the inner ear's development and function, and researchers are diligently working to develop targeted gene therapies for these conditions.

Gene therapy, once a concept, is now transforming lives. As research continues, it holds the promise of curing not just deafness but a spectrum of genetic disorders, marking a new era in medical science.

REFERENCE

Qi J, Tan F, Zhang L, Lu L, Zhang S, Zhai Y, Lu Y, Qian X, Dong W, Zhou Y, Zhang Z, Yang X, Jiang L, Yu C, Liu J, Chen T, Wu L, Tan C, Sun S, Song H, Shu Y, Xu L, Gao X, Li H, Chai R. AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness. Adv Sci (Weinh). 2024 Jan 8:e2306788. doi: 10.1002/advs.202306788. Epub ahead of print. PMID: 38189623.

Music in the Streaming Age

In the grand tapestry of human evolution, our sense of hearing has played a pivotal role in our survival and cultural development. Over time, our hearing has evolved in response to environmental cues and the intricate dance of language and communication. This journey has left its imprint on the very structure of our inner ears and the regions of our brains responsible for language processing. 

As our societies grew in complexity, so did our music. It was evolving from simple and rhythmic, to intricate compositions of classical music and avant-garde, experimental, serialist, highly spatialized music. It was changing from danceable to complex and dissonant rhythms. Some complex music was very popular - such as psychedelic rock band Pink Floyd; other not so much - such as Karlheinz Stockhausen's compositions. Modern music was incorporating elements of many other genres - eg alternative rock: punk rock, heavy metal, and experimental music and even simpler Hip Hop: jazz, funk, and soul. The most popular music was not always simplest but was more accessible.

In the 2020s, the world of music experienced a seismic shift with the rise of streaming platforms like Spotify, Tencent, and Apple Music. The impact was profound, not only revitalizing the music industry's revenue but also redefining the very essence of music itself.

Traditionally, music was a patient storyteller, often taking its time to build up to a climactic chorus or hook. Yet, the economics of streaming introduced a new imperative – capturing the listener's attention within the first 30 seconds. Enter the "Pop Overture," a clever technique where a song hints at its chorus within the initial moments, engaging the listener and encouraging them to stay for the full musical journey. 

To keep the dreaded "skip rate" at bay, artists began to craft shorter songs. Lengthy instrumental intros were swapped for immediate engagement, resulting in a significant reduction in the average duration of hit songs. In 2021, nearly two-thirds of chart-toppers clocked in at under three minutes, a departure from the days when a four-minute+ song was the norm.

As individual songs shrank, albums expanded. Streaming listeners, keen to maximize their musical experience, embraced longer albums. More songs equaled more income, with Taylor Swift's "Midnights" dominating the Hot 100 chart by offering an extensive musical journey. The average complexity of melodies had fallen over time, with two big drops in 1975 and 2000, as well as a smaller drop in 1996. The overriding pattern shows decreasing complexity and increasing note density in popular melodies over time, especially since 2000.

Streaming opened doors for genres that once struggled for visibility. Latin and K-Pop artists rose to prominence on Spotify's Global Top 100, fostering a rich tapestry of cross-genre collaborations. Remixes featuring artists from different backgrounds expanded a song's appeal and audience, exemplified by Justin Bieber's "Sorry (Latino Remix)" with J. Balvin.

While artistic creativity remains paramount, commercial considerations loom large. The streaming economy's dynamics, with its emphasis on plays, playlists, and recommendations, have compelled artists and labels to explore innovative strategies to maximize reach and revenue.

In this ever-evolving landscape of sound, music's essence has been reshaped by the streaming revolution. The emphasis on retaining listeners and optimizing plays has redefined how songs are crafted and albums are composed. With an emphasis on retaining listener engagement and maximizing plays, the industry has adapted to the evolving preferences and economics of the streaming era.

REFERENCES

Streaming is changing the sound of music(https://www.wsj.com/arts-culture/music/streaming-is-changing-the-sound-of-music-182dc907)

https://news.ycombinator.com/item?id=37531602

https://www.reddit.com/r/dataisbeautiful/comments/e5htxy/are_songs_getting_shorter_or_just_our_attention/

Hamilton, M., Pearce, M. Trajectories and revolutions in popular melody based on U.S. charts from 1950 to 2023. Sci Rep 14, 14749 (2024). https://doi.org/10.1038/s41598-024-64571-x

Acknowledgements: ChatGPT, Bard and Bing image creator

A Leap Towards Curing Genetic Deafness

In recent years, gene therapy has surfaced as a beacon of hope for those grappling with genetic hearing loss, showcasing promising results in neonatal mice. However, when it comes to adults, the complex structure of the cochlea, nestled within the temporal bone, has made treatment significantly more challenging. A recent study reported results that could change this narrative, opening new avenues in auditory research with the potential to revolutionize treatment for progressive genetic-mediated hearing loss in adults.

The crux of this breakthrough lies in the innovative method of gene delivery through the cerebrospinal fluid (CSF), a channel that has not been explored extensively in previous research. This study illuminates the lymphatic-like characteristics exhibited by the cochlear aqueduct in mice, indicating a pathway for the diffusion of gene therapy to the inner ear. Leveraging in vivo time-lapse magnetic resonance imaging, computed tomography, and optical fluorescence microscopy, the research team traced the journey of large-particle tracers from the CSF to the inner ear, demonstrating a viable route for targeted gene delivery.

By utilizing a single intracisternal injection of an adeno-associated virus carrying the Slc17A8 gene, known for encoding the vesicular glutamate transporter-3 (VGLUT3), the researchers successfully restored hearing in adult deaf mice. This restoration was achieved without any discernible ectopic expression in the brain or the liver, emphasizing the precision of this approach.

This pivotal study marks a significant stride in auditory research, presenting a feasible and innovative method to treat genetic deafness in adults, a segment that was previously considered hard to reach due to the risks associated with potential damage to inner ear structures. The CSF administration through the cochlear aqueducts emerges as a promising route, promising not just advancements in rodent studies but potentially paving the way for human applications.

In essence, this research might herald a new era where genetic deafness in adults could be treated more effectively and safely. As the world of medical science stands on the brink of this significant advancement, it brings renewed hope and anticipation for individuals affected by progressive genetic-mediated hearing loss, inching us closer to a future where hearing restoration is within reach for all.

REFERENCE

Mathiesen BK, Miyakoshi LM, Cederroth CR, Tserga E, Versteegh C, Bork PA, Hauglund NL, Gomolka RS, Mori Y, Edvall NK, Rouse S. Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice. Science Translational Medicine. 2023 Jun 28;15(702):eabq3916.

The Promise of Bimodal Neuromodulation

Tinnitus, often described as a persistent ringing or buzzing in the ears leading to distress and discomfort, affects more than 10% of the population worldwide. For years, finding an effective treatment for this phantom auditory condition has been a challenge. One promising approach is bimodal neuromodulation. 

Extensive animal studies demonstrated the ability of bimodal neuromodulation to induce neural plasticity in the auditory brain. 

The TENT-A1 clinical trial (clinicaltrials.gov: NCT02669069) conducted in 2020 involved 326 participants and demonstrated the safety and effectiveness of bimodal neuromodulation using the Lenire device. This therapy combined sound and tongue stimulation and significantly reduced tinnitus symptom severity scores in over 80% of participants during the 12-week treatment period, with effects lasting up to 12 months after treatment. The trial used three different parameter settings (PS1, PS2, and PS3) involving synchronized sound and tongue stimulation, short interstimulus delays, and lower-frequency tones, respectively, along with background wideband noise. TENT-A2, which was statistically powered to evaluate the necessity of wideband noise, found that it was not required for therapeutic benefit in arm 2 (absent in parameter settings). Furthermore, TENT-A2 completed in 2022 (clinicaltrials.gov: NCT03530306) explored the impact of adjusting sound and tongue stimulus parameters, demonstrating significant findings in both arms (PS1-PS4 and PS6-PS10). These results represent significant progress in tinnitus treatment.

The study found that these therapeutic effects were sustained up to 12 months after the treatment ended. This long-term relief is a promising development for tinnitus sufferers.

Tinnitus treatments can be categorized into three main groups based on a recent scoping review:

Medical Technology Therapies: This category includes therapies that involve the use of medical devices or technology to manage tinnitus. Notably, the study highlighted the effectiveness of stimulation therapies, although evidence-based guidelines did not strongly recommend them. Stimulation therapies encompass approaches such as tinnitus masking, which uses external sounds to reduce the perception of tinnitus, and acoustic therapies.

Behavioral/Habituation Therapies: These therapies focus on behavioral interventions to help individuals habituate to the perception of tinnitus. Common approaches mentioned in the review include counseling, tinnitus retraining therapy (TRT), cognitive-behavioral therapy (CBT), relaxation techniques, and attention diversion strategies.

Pharmacological, Herbal, Complementary, and Alternative Medicine Therapies: This category encompasses treatments involving medications, herbal remedies, complementary therapies, and alternative medicine. However, the review noted a lack of significant findings and strong recommendations for these interventions, indicating the need for further research in this area.

Tinnitus research has predominantly focused on stimulation therapies and acoustic therapies. However. digital therapies, including internet-based interventions, are more cost-effective and are gaining traction in the treatment and management of tinnitus. They are showing promise in improving the effectiveness of interventions, particularly cognitive-behavioral therapy (CBT). They have the potential to improve patient outcomes and provide accessible options for individuals with tinnitus. However, their integration into healthcare systems requires careful consideration and the accumulation of strong evidence to support their effectiveness and long-term benefits.

REFERENCES

Conlon B, Hamilton C, Meade E, Leong SL, O Connor C, Langguth B, Vanneste S, Hall DA, Hughes S, Lim HH. Different bimodal neuromodulation settings reduce tinnitus symptoms in a large randomized trial. Sci Rep. 2022 Jun 30;12(1):10845. doi: 10.1038/s41598-022-13875-x. Erratum in: Sci Rep. 2023 Jul 10;13(1):11152. PMID: 35773272; PMCID: PMC9246951.

Chhaya, V., Patel, D., Shethia, F. et al. Current Therapeutic Trends for Tinnitus Cure and Control: A Scoping Review. Indian J Otolaryngol Head Neck Surg (2023). https://doi.org/10.1007/s12070-023-03910-2