Direct evidence for synaptic density changes in tinnitus: 18F-SynVesT-1 PET reveals novel targets beyond metabolic changes.

Neurofeedback (NFB) is a relatively novel approach to the treatment of tinnitus, and prior studies have demonstrated that the increases in alpha activity rather than reduced delta power seem to drive these NFB-related improvements in tinnitus symptoms. The present study was therefore designed to explore whether the implementation of an alpha training protocol with a portable neurofeedback apparatus would achieve improvements in tinnitus patient symptoms. In this study, 38 tinnitus patients underwent NFB training while 18 were enrolled in a control group. The study was single-blinded such that only participants were not aware of their group assignments. Those in the NFB group underwent 15 NFB training sessions over 5 weeks, in addition to pre- and posttraining tests including the Tinnitus Handicap Inventory (THI), Tinnitus Handicap Questionnaire (THQ), visual analog scales (VAS), electroencephalography (EEG), and functional magnetic resonance imaging (fMRI). Our result find that when the THI, THQ, and VAS scores of patients in the two groups were assessed after a 5-week training period, these scores were unchanged in control patients whereas they had significantly improved in the NFB group patients. EEG analyses revealed that the alpha band was increased in the occipital lobe following NFB treatment, while fMRI indicated an increase in regional homogeneity (ReHo) in the right frontal lobe of patients in the NFB group after treatment that was negatively correlated with THI and VAS scores. The results of this analysis indicate that alpha NFB training can be effectively used to reduce tinnitus-related distress and sound perception in patients.

BackgroundsTinnitus is a meaningless sound signal perceived by the patients in the absence of auditory stimuli. Due to the complex etiology and unclear mechanism, specific therapies for tinnitus are still in the exploratory stage. In recent years, personalized and customized music therapy has been proposed as an effective method for tinnitus treatment. The aim of this study was to explore the efficacy of customized therapy with a well-designed follow-up system in the treatment of tinnitus through a large sample one arm study and to identify the relevant factors affecting the treatment outcome.MethodsThe study investigated a total of 615 patients with unilateral or bilateral chronic tinnitus who received personalized and customized music therapy for 3 months. A complete follow-up system was designed by the professionals. Questionnaires of Tinnitus Handicap Inventory (THI), Hospital Anxiety and Depression Scale (HADS) and Visual Analogue Scale (VAS) were used to evaluate the therapeutic effects and relevant factors affecting the efficacy of therapy.ResultsThe results showed a decreasing trend in THI and VAS scores after 3 months of therapy, with statistically significant differences between pre- and post-therapy time points (P < 0.001). All patients were divided into 5 groups according to THI scores, and the mean reduction score in catastrophic, severe, moderate, mild and slight group was 28, 19, 11, 5, 0 respectively. The proportion of tinnitus patients with anxiety was higher than that with depression (70.57% and 40.65%, respectively), and there were statistically significant differences between HADS-A/D scores pre- and post-therapy. Binary logistic regression showed that the baseline of THI, VAS scores, the duration of tinnitus and the state of anxiety prior to therapy were significant influencing factors of therapeutic efficacy.ConclusionsThe magnitude of reduction in THI scores after music therapy depended on the severity of the patients' tinnitus, the higher the initial THI scores, the greater the potential for improvement in tinnitus disorders. Music therapy also reduced the anxiety and depression levels of tinnitus patients. Therefore, personalized and customized music therapy with a comprehensive follow-up system may be an effective treatment option for chronic tinnitus patients.Graphical abstract

This study aimed to explore the effect of COVID-19 and the pandemic period on the tinnitus-related complaints of patients with chronic tinnitus. Ninety-six patients who were diagnosed with chronic tinnitus before the pandemic were enrolled in this study. Before the pandemic and in January 2022, all patients used the Visual Analog Scale (VAS) to assess tinnitus loudness, annoyance, and effect on everyday life, sleep, and concentration. Additionally, patients filled the Tinnitus Handicap Inventory (THI) and the Hyperacusis Questionnaire (HQ). In the entire cohort, tinnitus loudness, annoyance, and tinnitus-induced difficulties with concentration as well as THI and HQ scores increased significantly during the two pandemic years. Thirty-seven tinnitus patients contracted COVID-19 between March 2020 and January 2022. These patients were asked to list leading COVID-19 symptoms, changes in tinnitus complaints during and after the disease, and whether their hearing abilities were affected. Three patients in the COVID-19 group confirmed worsening their hearing abilities. There was no decrease in the tinnitus complaint during COVID-19, 24.3% of the infected patients reported exacerbation of tinnitus, and 75.7% said tinnitus remained the same. In the COVID-19-negative group, 13.5% reported tinnitus decrease during the pandemic, 57.6% said it remained the same, and 28.8% reported exacerbation of tinnitus. When split into infected and non-infected groups, a significant increase in tinnitus loudness, tinnitus effect on concentration, and THI scores were seen only in patients who contracted COVID-19, while hyperacusis worsened significantly (p < 0.05) only in COVID-19-negative tinnitus patients. Despite significant differences within the groups, there were no differences found between the groups. This study points to possible different effects of the infection with SARS-CoV-2 and the pandemic period on patients with chronic tinnitus. It also provides evidence for deterioration of preexisting tinnitus as a possible long-term effect of COVID-19.

BackgroundSynaptic loss, a key indicator of cognitive decline in neurodegenerative diseases, lacks a clinical biomarker, but emerging PET‐scan tracers targeting synaptic vesicle protein 2A (SV2A) show promise. The current understanding of regional changes in neurodegenerative disorders and the distribution of SV2A in the human brain is quite limited. This knowledge gap presents challenges when assessing the feasibility of using SV2A tracers in therapeutic applications. To assess the potential of SV2A tracers in diagnosis and therapy monitoring and enhance SV2A PET data interpretation, we quantified SV2A and synaptophysin (SYP) density in postmortem human brain tissue. We included subjects with different neurodegenerative conditions and healthy controls (CT) and mapped five susceptible regions.MethodHistological slides (8µm) of 28 cases (Table 1) underwent immunohistochemistry SV2A and synaptophysin. Slides were scanned using a calibrated Zeiss Axioscan. Synaptic density was quantified using the Zen software in 40 cortical ROIs (20 white &amp; 20 gray matter) per area/case. Values were normalized by white matter intensity. Moreover, we used frozen tissue from a subset of the same cases and areas to perform Western blot (WB) using the same antibodies against SV2A and (SYP), plus Beta‐actin. Intensity values were measured by using Image J software.ResultThe immunohistochemical analysis revealed decreased SV2A density across all diseases, exhibiting distinctive regional and disease‐specific patterns (Fig. 1). However, the correlation between SV2A and synaptophysin density was weak (Fig. 1). Western blot analysis similarity showed a distinctive reduction of SV2A with regional and disease‐specific patterns. The correlation with synaptophysin was moderate (Fig. 2).ConclusionIn conclusion, our findings demonstrate reduced SV2A density and protein levels in disease categories corresponding to specific regional vulnerabilities, corroborating SV2A as a reliable marker of brain tissue integrity. Nevertheless, the observed correlation between SV2A and synaptophysin changes was less robust than anticipated, prompting questioning into whether SV2A changes accurately reflect synaptophysin alterations. Additional studies comparing the utility of both markers in predicting clinical decline, metabolic shifts, and the progression of neurodegeneration are warranted.

Tinnitus therapy using tailor-made notched music delivered via a smartphone application and Ginko combined treatment: A pilot study

To determine the level of disability in patients suffering from tinnitus using the Tinnitus Handicap Inventory (THI) score, to evaluate the changes in otoacoustic emissions in a patient with tinnitus and evaluate the co-relation of the Tinnitus Handicap Inventory score with the Otoacoustic emission result This is an observational study done over a period of 6months, in which patients aged more than 18years who presented to the ENT OPD of our institute with complaints of tinnitus were considered for inclusion in the study. Patients with primary tinnitus, who consented to be part of the study were assessed for handicap caused by tinnitus using the Tinnitus Handicap Inventory (THI) score. All patients were subjected to Pure Tone Audiometry (PTA) and Screening OAE to look for the "Pass" or "Refer" in the OAE result. The THI score was compared with the OAE results to look for any correlation. 52 patients with tinnitus were evaluated in this study. In patients with OAE "Pass", the average THI score was 14.55, while in patients with OAE "Refer", the average THI score was 26.13. The higher THI score among tinnitus patients with OAE result "refer" was evaluated using a sample t test, which showed a p value of 0.001, indicating a high statistical significance. So, a strong positive correlation exists between tinnitus severity as determined by the THI score and the OAE outcome. This study showed a strong positive correlation between the Tinnitus Handicap Inventory (THI) Score and OHC dysfunction (assessed using OAE). The possibility of OHC being the site of primary pathology leading to tinnitus cannot be ruled out. Further research using a more objective measure of tinnitus, like tinnitus frequency and intensity matching with OHC function, would establish a stronger association between tinnitus and OHC function.

Objective Tinnitus retraining therapy (TRT) has been widely used in tinnitus management. However, its efficacy is often assessed through subjective methods. Here, we aimed to assess potential neural changes following TRT using mismatch negativity (MMN). Design Chronic tinnitus (>6 months) patients participated in a six-month TRT program. We collected tinnitus psychoacoustic features and gathered the tinnitus handicap inventory (THI) before and after TRT. We also used a multi-featured paradigm, including frequency, intensity, duration, location and silent gap deviants, to elicit MMN response before and after TRT. Data were analyzed retrospectively. Study sample The study involved 26 chronic tinnitus patients. Results Post-TRT measurements showed that MMN amplitudes significantly increased for all deviant conditions (p ≤ .03). However, we did not find a significant difference in MMN latencies for all deviant conditions (p ≥ .13). The THI scores of the patients significantly decreased following the TRT program (p < 0.001). Our results reveal improved subjective tinnitus perception following the TRT program. Conclusion These findings indicate that TRT might be a viable alternative in tinnitus management. The greater MMN amplitudes and improved subjective tinnitus perception raise the possibility that MMN can be a useful tool in tinnitus research and tinnitus patient follow-up.

Tinnitus is a common complaint among patients visiting an ENT clinic. It can cause severe annoyance and distress to some patients. Many treatment modalities are available for the management of tinnitus, with different degrees of effectiveness. This article is protected by copyright. All rights reserved.

Analysis of Differential Expression of Synaptic Vesicle Protein 2A in the Adult Rat Brain

Conclusion: The factors of tinnitus loudness and Tinnitus Handicap Inventory (THI) score in tinnitus patients have the potential to relate to therapeutic results of tinnitus retraining therapy (TRT). Objectives: To confirm what factors in tinnitus influence the results of TRT. Patients and methods: Twelve factors were investigated in 53 patients with tinnitus, examining the relationship between these factors and the results of TRT. A THI score was determined before and 6 months after TRT introduction (pre- and post-TRT). Moreover, the change of THI score from pre- to post-TRT (ΔTHI) was referred to as the therapeutic effect of TRT. Based on the 12 factors, subjects were respectively divided into two groups, comparing Δ THI between groups. Results: Two groups of greater tinnitus loudness and higher THI score showed significant increases in ΔTHI, indicating that two factors of tinnitus loudness and THI score were related to the therapeutic effect of TRT.

PET technology has produced many radiopharmaceuticals that target specific brain proteins and other measures of brain function. Recently, a new approach has emerged to image synaptic density by targeting the synaptic vesicle protein 2A (SV2A), an integral glycoprotein in the membrane of synaptic vesicles and widely distributed throughout the brain. Multiple SV2A ligands have been developed and translated to human use. The most successful of these to date is 11C-UCB-J, because of its high uptake, moderate metabolism, and effective quantification with a 1-tissue-compartment model. Further, since SV2A is the target of the antiepileptic drug levetiracetam, human blocking studies have characterized specific binding and potential reference regions. Regional brain SV2A levels were shown to correlate with those of synaptophysin, another commonly used marker of synaptic density, providing the basis for SV2A PET imaging to have broad utility across neuropathologic diseases. In this review, we highlight the development of SV2A tracers and the evaluation of quantification methods, including compartment modeling and simple tissue ratios. Mouse and rat models of neurodegenerative diseases have been studied with small-animal PET, providing validation by comparison to direct tissue measures. Next, we review human PET imaging results in multiple neurodegenerative disorders. Studies on Parkinson disease and Alzheimer disease have progressed most rapidly at multiple centers, with generally consistent results of patterns of SV2A or synaptic loss. In Alzheimer disease, the synaptic loss patterns differ from those of amyloid, tau, and 18F-FDG, although intertracer and interregional correlations have been found. Smaller studies have been reported in other disorders, including Lewy body dementia, frontotemporal dementia, Huntington disease, progressive supranuclear palsy, and corticobasal degeneration. In conclusion, PET imaging of SV2A has rapidly developed, and qualified radioligands are available. PET studies on humans indicate that SV2A loss might be specific to disease-associated brain regions and consistent with synaptic density loss. The recent availability of new 18F tracers, 18F-SynVesT-1 and 18F-SynVesT-2, will substantially broaden the application of SV2A PET. Future studies are needed in larger patient cohorts to establish the clinical value of SV2A PET and its potential for diagnosis and progression monitoring of neurodegenerative diseases, as well as efficacy assessment of disease-modifying therapies.

The objectives of this study were to characterize the features of tinnitus in patients with profound sensorineural hearing loss and to evaluate the effect of cochlear implantation (CI) on their tinnitus. Medical records were reviewed for 35 patients who underwent CI, and completed tinnitus questionnaire between March 2003 and August 2011. Of them, 22 had tinnitus prior to CI (62.9 %) and the tinnitus group was older than the non-tinnitus group (47.5 ± 15.1 vs. 28.9 ± 15.2). The mean tinnitus handicap inventory (THI) score of the tinnitus group was 50.5 ± 28.7 before surgery, and the mean THI score and visual analogue scale (VAS) scores for loudness, annoyance, effect on life, and awareness decreased significantly after CI, with a mean follow-up period of 10.7 months. Tinnitus was completely eliminated in ten patients (45.5 %) and THI scores decreased in all patients. In a correlation analysis of the decrease in THI scores, preoperative VAS scores for loudness, awareness, effect on life, and annoyance, as well as preoperative THI scores, were highly correlated with the degree of decrease in THI scores postoperatively. The auditory performance of patients older than 40 years did not differ from that of younger patients, but their tinnitus was more improved after CI. In conclusion, tinnitus is a common complaint in patients with cochlear implants, and is more prevalent in elderly implantees. In the present study, CI improved tinnitus in all patients, although the most severe cases had the greatest benefit.

Tinnitus is considered a neurological disorder affecting both auditory and nonauditory networks. This study aimed to investigate the structural brain covariance network in tinnitus patients and analyze its altered topological properties. Fifty three primary tinnitus patients and 67 age- and sex-matched healthy controls (HCs) were included. Gray matter volume (GMV) of each participant was extracted using voxel-based morphometry, a group-level structural covariance network (SCN) was constructed based on the GMV of each participant, and graph theoretic analyses were performed using graph analysis toolbox (GAT). The differences in the topological properties of SCN between both groups were compared and analyzed. Both groups exhibited small-world attributes. Compared with HCs, tinnitus patients had significantly higher characteristic path length, lambda, transitivity, and assortativity (p < 0.05), and significantly lower global efficiency (p < 0.05). Tinnitus patients had higher clustering coefficient and reduced gamma and modularity, but neither was remarkable. The hubs in tinnitus network focused on the temporal lobe. In addition, the tinnitus network was found to be reduced in robustness to targeted attacks compared with HCs. Besides, a significant negative correlation between Tinnitus Handicap Inventory (THI) score and GMV in the left angular gyrus (r = -0.283, p = 0.040) as well as left superior temporal pole (r = -0.282, p = 0.041) were identified. Tinnitus patients showed reduced small-world properties, altered hub nodes, and reduced ability to respond to targeted attacks in brain network. The GMV in the left angular gyrus and left superior temporal pole showed significant negative correlation with tinnitus distress (THI score), indicating potential therapeutic target.

Background and Objectives Tinnitus retraining therapy (TRT) is a well-known effective method for tinnitus management by retraining the brain to achieve habituation of tinnitus. The mobile device based TRT can let both clinicians and patients be free from time and space limitations and secure cost-effectiveness. The study aimed to investigate whether the mobile-based TRT is inferior or not to the conventional TRT in treatment outcomes for chronic subjective tinnitus.Subjects and Method A prospective randomized controlled trial was conducted in a single tertiary hospital. Adult patients with chronic subjective tinnitus were enrolled. Pure tone audiometry, State-Trait Anxiety Inventory [(STAI), axis1 and axis2], Beck Depression Inventory, Pittsburgh Sleep Quality Index, and a survey for TRT were evaluated. Tinnitus Handicap Inventory (THI), Visual Analog Scale (VAS) of tinnitus, and Tnnitogram were compared at the start, then at one month and three months of the treatment. The mobile group was subdivided into the treatment effective group and the refractory group. Demographics, baseline tinnitus severity, and therapy compliance were comparatively analyzed.Results A total of 19 patients for the mobile-based TRT and 21 patients for the conventional TRT were enrolled. THI scores and Tinnitus scores using VAS were significantly reduced in the mobile group after the treatment. Furthermore, THI and STAI were significantly more improved in the conventional group than in the mobile-based TRT at one and three months of the treatment. Also, the effective group of the mobile device based TRT was statistically younger than the refractory group and had a higher understanding of the treatment method.Conclusion The mobile-based TRT could improve THI and VAS scores of tinnitus at one and three months of treatment. However, the conventional TRT showed better outcome than the Mobile-based TRT with respect to THI scores. The mobile-based TRT can be one of different potential options that clinicians can apply to tinnitus patients who cannot follow the conventional TRT or limited candidate. Further improvement of the mobile device based TRT would be needed.

Tinnitus patients have higher risk of developing anxiety-depressive disorders and decreased quality of life. The reasons why selected patients are able to cope with chronic tinnitus, whereas it represents a disabling symptom for others remain under discussion. the objective of the study was to determine the tinnitus-related degree of distress along with the prevalence of anxiety-depression disorders in a sample of eighty patients referring for chronic tinnitus at the Department of Otolaryngology of Catholic University of Rome from March to September 2015. We administered to all patients the Italian versions of Tinnitus Handicap Inventory (THI) and Hospital Anxiety and Depression Scale (HADS). Furthermore we investigated the correlation among patient's discomfort, severity of hearing loss and age. Average THI score was 40.85, meaning moderate degree of discomfort; 57.5% of the patients showed HADS scores consistent with high risk of psychiatric comorbidities. A significant linear correlation between THI and HADS scores was demonstrated. We suggest that patients with severe tinnitus-related distress are routinely invited to accomplish psychometric questionnaires, to assess the possibility of a neuropsychiatric evaluation and/or specific pharmacological planning. At this purpose we recommend the administration of HADS, as a reliable and quick instrument.