Transcutaneous vagus nerve stimulation modulates tinnitus-related beta- and gamma-band activity.

OBJECTIVES: The ability of a treatment method to interfere with tinnitus-related neural activity patterns, such as cortical gamma rhythms, has been suggested to indicate its potential in relieving tinnitus. Therapeutic modulation of gamma-band oscillations with vagus nerve stimulation has been recently reported in epileptic patients. The aim of this study was to investigate the effects of transcutaneous vagus nerve stimulation (tVNS) on neural oscillatory patterns. DESIGN: We calculated the power spectral density and synchrony of magnetoencephalography recordings during auditory stimulation in seven tinnitus patients and eight normal-hearing control subjects. Comparisons between subject groups were performed to reveal electrophysiological markers of tinnitus. tVNS-specific effects within each group were studied by comparing recording blocks with and without tVNS. We also investigated the correlation of each measure with individual ratings of tinnitus distress, as measured by the tinnitus handicap inventory questionnaire. RESULTS: Tinnitus patients differed from controls in the baseline condition (no tVNS applied), measured by both cortical oscillatory power and synchronization, particularly at beta and gamma frequencies. Importantly, we found tVNS-induced changes in synchrony, correlating strongly with tinnitus handicap inventory scores, at whole-head beta-band (r = -0.857, p = 0.007), whole-head gamma-band (r = -0.952, p = 0.0003), and frontal gamma-band (r = -0.952, p = 0.0003). CONCLUSIONS: We conclude that tVNS was successful in modulating tinnitus-related beta- and gamma-band activity and thus could have potential as a treatment method for tinnitus.

Prevention and Treatment of Life-Threatening COVID-19 May Be Possible with Oxygen Treatment.

Most SARS CoV-2 infections probably occur unnoticed or cause only cause a mild common cold that does not require medical intervention. A significant proportion of more severe cases is characterized by early neurological symptoms such as headache, fatigue, and impaired consciousness, including respiratory distress. These symptoms suggest hypoxia, specifically affecting the brain. The condition is best explained by primary replication of the virus in the nasal respiratory and/or the olfactory epithelia, followed by an invasion of the virus into the central nervous system, including the respiratory centers, either along a transneural route, through disruption of the blood-brain barrier, or both. In patients, presenting with early dyspnea, the primary goal of therapy should be the reversal of brain hypoxia as efficiently as possible. The first approach should be intermittent treatment with 100% oxygen using a tight oronasal mask or a hood. If this does not help within a few hours, an enclosure is needed to increase the ambient pressure. This management approach is well established in the hypoxia-related diseases in diving and aerospace medicine and preserves the patient's spontaneous breathing. Preliminary research evidence indicates that even a small elevation of the ambient pressure might be lifesaving. Other neurological symptoms, presenting particularly in long COVID-19, suggest imbalance of the autonomous nervous system, i.e., dysautonomia. These patients could benefit from vagal nerve stimulation.

Differential sensitivity of the inner ear sensory cell populations to forced cell cycle re-entry and p53 induction.

Previous studies have shown that the maintenance of post-mitotic state is critical for the life-long survival of the inner ear mechanosensory cells, the hair cells. A general concept is that differentiated, post-mitotic cells rapidly die following cell cycle re-entry. Here we have compared the response of postnatal cochlear (auditory) and utricular (balance) hair cells to forced cell cycle reactivation and p53 up-regulation. Forced S-phase entry was triggered through the human papillomavirus-16 E7 oncogene misexpression in explant cultures. It induced DNA damage and p53 induction in cochlear outer hair cells and these cells were rapidly lost, before entry into mitosis. The death was attenuated by p53 inactivation. In contrast, despite DNA damage and p53 induction, utricular hair cells showed longer term survival and a proportion of them progressed into mitosis. Consistently, pharmacological elevation of p53 levels by nutlin-3a led to a death-prone phenotype of cochlear outer hair cells, while other hair cell populations were death-resistant. These data have important clinical implications as they show the importance of p53 in sensory cells that are essential in hearing function.

Tonsillar surface swab bacterial culture results differ from those of the tonsillar core in recurrent tonsillitis.

OBJECTIVES/HYPOTHESIS: We aimed to determine whether there was a difference between core and surface bacteriology of Finnish adults with recurrent or chronic tonsillitis to understand whether a surface swab is worthwhile and which bacteria are involved. STUDY DESIGN: Case series. METHODS: Uninflamed tonsillar surface swabs and core biopsies were taken prior to and during surgery, respectively, in 103 patients aged 16 to 66 years undergoing tonsillectomy for recurrent or chronic tonsillitis. The McNemar test was used to determine differences between the surface and core in the most prevalent bacterial species. RESULTS: Twenty-seven bacterial species were isolated in addition to normal flora and were more commonly found in the core (1.11 surface and 4.75 core bacteria isolated per patient). Viridans group streptococci were the most commonly detected bacteria, found in 88% of the patients, mainly in the core. The bacteria in general were mainly isolated from the core. Of the 10 most prevalent bacteria, only group C ß-hemolytic streptococci showed no difference between detection from core and surface swabs. Other bacteria found mainly in the core include Prevotella melaninogenica, Staphylococcus aureus, and fusobacteria. CONCLUSIONS: There is discord between the surface and core bacteria. A different population of bacteria exists in the core, especially anaerobic bacteria, suggesting that a core sample may be useful in evaluating recurrent and chronic tonsillitis. LEVEL OF EVIDENCE: 4 Laryngoscope, 2019.

Stress and Tinnitus; Transcutaneous Auricular Vagal Nerve Stimulation Attenuates Tinnitus-Triggered Stress Reaction.

INTRODUCTION: Tinnitus can become a strong stressor for some individuals, leading to imbalance of the autonomous nervous system with reduction of parasympathetic activity. It can manifest itself as sleep disturbances, anxiety and even depression. This condition can be reversed by bioelectrical vagal nerve stimulation (VNS). Conventional invasive VNS is an approved treatment for epilepsy and depression. Transcutaneous VNS (taVNS) stimulating the auricular branch of the vagus nerve has been shown to activate the vagal pathways similarly as an implanted VNS. Therefore, taVNS might also be a therapeutic alternative in health conditions such as tinnitus-related mental stress (TRMS). This retrospective study in 171 TRMS patients reports the clinical features, psychophysiological characteristics, and results of the heart rate variability (HRV) tests before and after test-taVNS. This study also reports the therapy outcomes of 113 TRMS patients treated with taVNS, in combination with standard tinnitus therapy. METHODS: Diagnostic tinnitus and hearing profiles were defined. To detect possible cardiac adverse effects, test-taVNS with heart rate monitoring as well as pre- and post-stimulation HRV tests were performed. Daily taVNS home therapy was prescribed thereafter. To assess therapeutic usefulness of taVNS, 1-year follow-up outcome was studied. Results of HRV tests were retrospectively analyzed and correlated to diagnostic data. RESULTS: The large majority of patients with TRMS suffer from associated symptoms such as sleep disturbances and anxiety. Baseline HRV data showed that more than three quarters of the 171 patients had increased sympathetic activity before test-taVNS. Test-taVNS shifted mean values of different HRV parameters toward increased parasympathetic activity in about 80% of patients. Test-taVNS did not cause any cardiac or other side effects. No significant adverse effects were reported in follow-up questionnaires. CONCLUSION: TRMS is an example of a stress condition in which patients may benefit from taVNS. As revealed by HRV, test-taVNS improved parasympathetic function, most efficiently in patients with a low starting HRV level. Our tinnitus treatment program, including taVNS, effectively alleviated tinnitus stress and handicap. For wider clinical use, there is a great need for more knowledge about the optimal methodology and parameters of taVNS.

The effect of tightened hearing protection regulations on military noise-induced tinnitus.

The objective of this study was to investigate the effect of tightened hearing protection regulations on tinnitus in the Finnish Defence Forces. The initial study group comprised 252 officers and non-commissioned officers (NCOs), of which 229 were included in the final study group. Subjective symptoms of tinnitus and audiometric test results for these officers and NCOs examined before retirement, from 1984 to 1986 (Period I), and 2003 to 2005 (Period II), were reviewed. Changes in tinnitus reports between the two time periods, during which regulations had been revised, were investigated. Prevalence of tinnitus showed a decline both in officers (from 68% to 63%) and in NCOs (from 76% to 72%) between the two study periods, in accordance with tightened hearing protection regulations. The Cox regression analysis showed a significantly decreased hazard ratio for constant or disturbing tinnitus for Period II. Tinnitus prevalence, especially constant or disturbing tinnitus, in the Finnish Defence Forces was diminished by tightened hearing protection regulations. Tinnitus might be more persistent than hearing loss and does not necessarily improve in direct relation to hearing loss after protective measures.

[Tinnitus]. / Tinnitus.

Tinnitus is a symptom caused by the dysfunction of the auditory system associated with hyperactive networks of the central auditory tract. Intimate relationship of the auditory tract with the limbic system may lead to a stress reaction with subsequent sleep disturbances, distress and depression. The target of tinnitus treatment shoud be the annoyance caused by tinnitus, not the sensation itself. Optimally, all tinnitus patients should be treated according to the TRT-principles including careful diagnostics, informational counceling and sound-based therapies. Some patients need sleep therapy as well as anti-depressive therapy.

FGFR1 is required for the development of the auditory sensory epithelium.

The mammalian auditory sensory epithelium, the organ of Corti, comprises the hair cells and supporting cells that are pivotal for hearing function. The origin and development of their precursors are poorly understood. Here we show that loss-of-function mutations in mouse fibroblast growth factor receptor 1 (Fgfr1) cause a dose-dependent disruption of the organ of Corti. Full inactivation of Fgfr1 in the inner ear epithelium by Foxg1-Cre-mediated deletion leads to an 85% reduction in the number of auditory hair cells. The primary cause appears to be reduced precursor cell proliferation in the early cochlear duct. Thus, during development, FGFR1 is required for the generation of the precursor pool, which gives rise to the auditory sensory epithelium. Our data also suggest that FGFR1 might have a distinct later role in intercellular signaling within the differentiating auditory sensory epithelium.

p19(Ink4d) and p21(Cip1) collaborate to maintain the postmitotic state of auditory hair cells, their codeletion leading to DNA damage and p53-mediated apoptosis.

Sensory hair cells of the auditory organ are generated during embryogenesis and remain postmitotic throughout life. Previous work has shown that inactivation of the cyclin-dependent kinase inhibitor (CKI) p19(Ink4d) leads to progressive hearing loss attributable to inappropriate DNA replication and subsequent apoptosis of hair cells. Here we show the synergistic action of another CKI, p21(Cip1), on cell cycle reactivation. The codeletion of p19(Ink4d) and p21(Cip1) triggered profuse S-phase entry of auditory hair cells during a restricted period in early postnatal life, leading to the transient appearance of supernumerary hair cells. In addition, we show that aberrant cell cycle reentry leads to activation of a DNA damage response pathway in these cells, followed by p53-mediated apoptosis. The majority of hair cells were absent in adult cochleas. These data, together with the demonstration of changing expression patterns of multiple CKIs in auditory hair cells during the stages of early postnatal maturation, show that the maintenance of the postmitotic state is an active, tissue-specific process, cooperatively regulated by several CKIs, and is critical for the lifelong survival of these sensory cells.

The effect of improved hearing protection regulations in the prevention of military noise-induced hearing loss.

CONCLUSION: Hearing protection regulations have improved the hearing test results of soldiers in the Finnish Defense Forces. OBJECTIVES: To investigate the effect of revised regulations regarding usage of hearing protectors of professional soldiers in the Finnish Defense Forces. SUBJECTS AND METHODS: The medical records of non-commissioned officers and officers examined at the Central Military Hospital ENT Department from 1984 to 1986 (Period I) and 2003 to 2005 (Period II) were reviewed. The study group comprised 252 persons. Changes in hearing between the two time periods, during which regulations were revised, were investigated. RESULTS: Hearing test results improved both in non-commissioned officers and in officers between the two study periods, in accordance with tightened hearing protection regulations. Improvement was found, especially in the high frequencies; however, the results were milder than expected, particularly in officers.

Nitrous oxide for applying local anesthesia in nasal operations: a randomized placebo-controlled single-blinded study.

CONCLUSIONS: In our study setting nitrous oxide (N(2)O) did not show any clinical benefit in discomfort experienced when applying local anesthesia for nasal operations. Further studies with longer inhalation times are needed to elucidate the role of N(2)O in application of local anesthesia in nasal surgery. OBJECTIVES: N(2)O inhalation reduces the discomfort experienced in various medical procedures. The objective of this study was to assess the suitability of N(2)O inhalation before application of local anesthesia for nasal procedures in outpatient surgery. PATIENTS AND METHODS: This was a prospective, randomized, single-blinded, placebo-controlled study at the Helsinki University Central Hospital, Finland. Ninety patients were randomly divided into three groups. Group A inhaled 10 breaths of 50% N(2)O/50% O(2) through a nasal mask with a Porter 2000 MXR scavenging system before application of local nasal anesthesia, group B inhaled room air through the same mask and group C received only local anesthesia. A visual analog scale was used to assess pain, nausea, and discomfort related to the application of nasal anesthesia. RESULTS: The N(2)O inhalation was easy to perform and well tolerated. The N(2)O inhalation before applying local anesthesia for nasal operations did not show any significant additional benefit in reducing pain or discomfort.

Attenuation of Positive Valence in Ratings of Affective Sounds by Tinnitus Patients.

Affective processing appears to be altered in tinnitus, and the condition is to a large extent characterized by the emotional reaction to the phantom sound. Psychophysiological models of tinnitus and supporting brain imaging studies have suggested a role for the limbic system in the emergence and maintenance of tinnitus. It is not clear whether the tinnitus-related changes in these systems are specific for tinnitus only, or whether they affect emotional processing more generally. In this study, we aimed to quantify possible deviations in affective processing in tinnitus patients by behavioral and physiological measures. Tinnitus patients rated the valence and arousal of sounds from the International Affective Digitized Sounds database. Sounds were chosen based on the normative valence ratings, that is, negative, neutral, or positive. The individual autonomic response was measured simultaneously with pupillometry. We found that the subjective ratings of the sounds by tinnitus patients differed significantly from the normative ratings. The difference was most pronounced for positive sounds, where sounds were rated lower on both valence and arousal scales. Negative and neutral sounds were rated differently only for arousal. Pupil measurements paralleled the behavioral results, showing a dampened response to positive sounds. Taken together, our findings suggest that affective processing is altered in tinnitus patients. The results are in line with earlier studies in depressed patients, which have provided evidence in favor of the so-called positive attenuation hypothesis of depression. Thus, the current results highlight the close link between tinnitus and depression.

Hearing disorder from music; a neglected dysfunction.

CONCLUSION: Music-induced acute acoustic trauma is not inevitably linked to hearing dysfunction as validated by conventional pure tone audiometry. Tinnitus is often in combination with hyperacusis. Our results point at 'silent hearing loss' as the underlying pathology, having afferent nerve terminal damage rather than hair cell loss as the structural correlate. OBJECTIVES: Exposure to loud music is one of the most common causes of acute acoustic trauma, which adolescents and teenagers experience by voluntary exposure to loud music of sound levels up to 110 dB(A). METHODS: The clinical and psychophysical data of 104 consecutive patients with music-induced hearing disorder (MIHD) were analyzed to construct individual hearing and tinnitus profiles. In all cases, tinnitus was the presenting symptom. RESULTS: Hearing abilities were normal in about two-thirds of the tinnitus patients. Tinnitus was experienced most often as a high-frequency tone (83%). The Tinnitus Handicap Inventory (THI) scores ranged from 0 to 94 with an average score of 43.1. Visual analog scales (VAS) were used to assess tinnitus loudness (average 42.4) and annoyance (average 54.2), and tinnitus awareness was estimated (average 60.3). All VAS values correlated strongly with the THI. Hyperacusis was present in 65% and 71% of the patients reported sleeping disorders.

Occupational noise-induced hearing loss reports and tinnitus in Finland.

CONCLUSION: In occupational noise-induced hearing loss (NIHL) reports, many tinnitus sufferers probably remain undetected and untreated at present. Attention should be focused on tinnitus, as well as threshold shifts resulting from NIHL. OBJECTIVES: Occupational NIHL is frequent among workers in industrialized countries and it is one of the greatest occupational health hazards. Hearing conservation programs have led to a reduction in the numbers of severe occupational NIHL. Our objectives were to analyze the severity of occupational NIHL reported in Finland, identify risk occupations, and investigate the occurrence of tinnitus among the reported cases. MATERIALS AND METHODS: We examined the records of 857 NIHL cases with an identifiable disability category of the total 858 NIHL cases reported in 2000. We sent tinnitus questionnaires to 366 of these NIHL cases. RESULTS: The degree of speech-frequency hearing loss was generally low, and a mention of tinnitus was reported in only 34 cases (4.0%). However, 88.7% of the patients actually had unreported tinnitus.

Non-invasive vagus nerve stimulation reduces sympathetic preponderance in patients with tinnitus.

CONCLUSION: Transcutaneous vagal nerve stimulation (tVNS) might offer a targeted, patient-friendly, and low-cost therapeutic tool for tinnitus patients with sympathovagal imbalance. OBJECTIVES: Conventionally, VNS has been performed to treat severe epilepsy and depression with an electrode implanted to the cervical trunk of vagus nerve. This study investigated the acute effects of tVNS on autonomic nervous system (ANS) imbalance, which often occurs in patients with tinnitus-triggered stress. METHODS: This study retrospectively analysed records of 97 patients who had undergone ANS function testing by heart rate variability (HRV) measurement immediately before and after a 15-60 min tVNS stimulation. RESULTS: The pre-treatment HRV recording showed sympathetic preponderance/reduced parasympathetic activity in about three quarters (73%) of patients. Active tVNS significantly increased variability of R-R intervals in 75% of patients and HRV age was decreased in 70% of patients. Either the variability of R-R intervals was increased or the HRV age decreased in 90% of the patients. These results indicate that tVNS can induce a shift in ANS function from sympathetic preponderance towards parasympathetic predominance. tVNS caused no major morbidity, and heart rate monitoring during the tVNS treatment showed no cardiac or circulatory effects (e.g. bradycardia) in any of the patients.

c-Jun N-Terminal Phosphorylation: Biomarker for Cellular Stress Rather than Cell Death in the Injured Cochlea.

Prevention of auditory hair cell death offers therapeutic potential to rescue hearing. Pharmacological blockade of JNK/c-Jun signaling attenuates injury-induced hair cell loss, but with unsolved mechanisms. We have characterized the c-Jun stress response in the mouse cochlea challenged with acoustic overstimulation and ototoxins, by studying the dynamics of c-Jun N-terminal phosphorylation. It occurred acutely in glial-like supporting cells, inner hair cells, and the cells of the cochlear ion trafficking route, and was rapidly downregulated after exposures. Notably, death-prone outer hair cells lacked c-Jun phosphorylation. As phosphorylation was triggered also by nontraumatic noise levels and none of the cells showing this activation were lost, c-Jun phosphorylation is a biomarker for cochlear stress rather than an indicator of a death-prone fate of hair cells. Preconditioning with a mild noise exposure before a stronger traumatizing noise exposure attenuated the cochlear c-Jun stress response, suggesting that the known protective effect of sound preconditioning on hearing is linked to suppression of c-Jun activation. Finally, mice with mutations in the c-Jun N-terminal phosphoacceptor sites showed partial, but significant, hair cell protection. These data identify the c-Jun stress response as a paracrine mechanism that mediates outer hair cell death.

Induction of CD69 expression and Th1 cytokines release from human peripheral blood lymphocytes after in vitro stimulation with Alloiococcus otitidis and three middle ear pathogens.

Alloiococcus otitidis is a recently discovered pathogen of otitis media. However, only a limited number of studies are available about the pathogenic and immunological role of A. otitidis. The aim of this study was to investigate the activation and the cytokine production of human peripheral blood lymphocytes at the early immune response after stimulation with A. otitidis. After stimulation of whole human peripheral blood lymphocytes for 18 h with whole killed A. otitidis or the three major middle ear pathogens (Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis), the expression of CD69 and the production of cytokines were analyzed. The expression of CD69 on T cells and B cells was dose-dependently enhanced after stimulation with A. otitidis. The release of interleukin (IL)-12 was induced after stimulation with A. otitidis, whereas the release of IL-4 was not induced after stimulation with A. otitidis. In addition, the release of interferon (IFN)-gamma was induced after stimulation with A. otitidis. Although the release of IFN-gamma started within 18 h after stimulation with A. otitidis, intracellular production of IFN-gamma was not observed in either CD4+ T cells or CD8+ T cells within 18 h upon stimulation. The patterns of CD69 expression and T helper-type 1 (Th1)-promoting cytokines production were similarly shown when human peripheral blood lymphocytes were stimulated with the other three major pathogens. Our results suggest that A. otitidis has sufficient immunogenic potential to modulate a host immune response, like the other three major middle ear pathogens, and also suggest that the immunogenicity of A. otitidis is very similar, at the early immune response, to that of the three major middle ear pathogens.

Blockade of c-Jun N-terminal kinase pathway attenuates gentamicin-induced cochlear and vestibular hair cell death.

The ototoxic action of aminoglycoside antibiotics leading to the loss of hair cells of the inner ear is well documented. However, the molecular mechanisms are poorly defined. We have previously shown that in neomycin-exposed organotypic cultures of the cochlea, the c-Jun N-terminal kinase (JNK) pathway--associated with stress, injury and apoptosis--is activated in hair cells and leads to their death. We have also shown that hair cell death can be attenuated by CEP-1347, an inhibitor of JNK signalling [Pirvola et al., J. Neurosci. 20 (2000) 43-50]. In the present study, we demonstrate that gentamicin-induced ototoxicity leads to JNK activation and apoptosis in the inner ear hair cells in vivo. We also show that systemic administration of CEP-1347 attenuates gentamicin-induced decrease of auditory sensitivity and cochlear hair cell damage. In addition, CEP-1347 treatment reduces the extent of hair cell loss in the ampullary cristae after gentamicin intoxication. Particularly, the inner hair cells of the cochlea and type I hair cells of the vestibular organs are protected. We have previously shown that also acoustic overstimulation leads to apoptosis of cochlear hair cells and that CEP-1347 can attenuate noise-induced sensory cell loss. These results suggest that activation of the JNK cascade may be a common molecular outcome of cellular stress in the inner ear sensory epithelia, and that attenuation of the lesion can be provided by inhibiting JNK activation.