Tinnitus is associated with increased extracellular matrix density in the auditory cortex of Mongolian gerbils.

Most scientists agree that subjective tinnitus is the pathological result of an interaction of damage to the peripheral auditory system and central neuroplastic adaptations. Here we investigate such tinnitus related adaptations in the primary auditory cortex (AC) 7 and 13 days after noise trauma induction of tinnitus by quantifying the density of the extracellular matrix (ECM) in the AC of Mongolian gerbils (Meriones unguiculatus). The ECM density has been shown to be relevant for neuroplastic processes and synaptic stability within the cortex. We utilized a mild monaural acoustic noise trauma in overall 22 gerbils to induce tinnitus and a sham exposure in 16 control (C) animals. Tinnitus was assessed by a behavioral response paradigm. Animals were separated for a presence (T) or absence (NT) of a tinnitus percept by a behavioral task. The ECM density 7 and 13 days after trauma was quantified using immunofluorescence luminance of Wisteria floribunda lectin-fluoresceine-5-isothiocyanate (WFA-FITC) on histological slices of the primary AC, relative to the non-auditory brainstem as a reference area. At both timepoints, we found that the WFA-FITC luminance of the AC of NT animals was not significantly different from that of C animals. However, we found a significant increase of luminance in T animals' ACs compared to NT or C animals' cortices. This effect was found exclusively on the AC side contralateral to the trauma ear. These results point to a hemisphere specific process of stabilization of synaptic connections in primary AC, which may be involved in the chronic manifestation of tinnitus.

Beyond the Buzz: Cortical and subcortical brain changes in patients with pulsatile tinnitus.

Pulsatile tinnitus (PT) can be a debilitating condition characterized by rhythmic, heartbeat-synchronous sounds, which can severely impact patients' quality of life. Understanding the neuroanatomical changes in PT patients may provide critical insights into the impacts of this condition. This study aimed to investigate potential differences in cortical and subcortical brain volume between adults with PT and age-matched controls (60 to 70 years of age). A retrospective, cross-sectional analysis of imaging and medical records was conducted, with data collected from January 2015 to December 2021. The study was conducted in a tertiary referral center with a specialized tinnitus clinic. A total of 135 adults diagnosed with PT and 135 age-matched controls were included. All participants were screened for PT and relevant medical history, with consecutive sampling used for selection. Cortical and subcortical brain volume differences between PT patients and controls were measured using Freesurfer. PT patients (n = 79, after exclusion of patients with inadequate imaging data) exhibited significant decreases in cortical thickness in the anterior cingulate and entorhinal cortex, and decreased volume in the left putamen, compared to age-matched controls (n = 135). PT patients also demonstrated significant increased volume in frontal and occipital lobe structures, the cerebellum, hippocampi, and ventral pallidum. In conclusion, our findings suggest that individuals with PT may have structural differences in brain regions related to auditory processing, and depression, which provides additional evidence of the psychiatric sequalae of PT. These findings demonstrate that there are neuroanatomical alterations in patients with PT, emphasizing the value in evaluating and treating this disease to prevent these neuroanatomical differences from developing.

Molecular mechanism of Rolupram reducing neuroinflammation in noise induced tinnitus mice through TLR4/NF kB/NLRP3 protein/caspase-1/IL-1 ß signaling pathway.

Noisy tinnitus is a common auditory system disease characterized by persistent tinnitus symptoms. The TLR4/NF - κ B/NLRP3 signaling pathway plays an important role in neuroinflammatory response. Select 6 control and 6 noise exposed mice for transcriptome sequencing analysis in the hippocampus, conduct high-throughput data analysis, identify differentially expressed genes, and screen for pathways. Auditory brainstem response (ABR) detection was performed to understand the hearing changes, and the modeling effect was evaluated using the GPIAS% inhibition experiment of auditory startle reflex. Morphological observation of the basement membrane was performed to determine whether the inner hair cells were damaged. Immunohistochemistry and immunofluorescence were used to determine the activation of microglia in the hippocampus of noise induced tinnitus mice. Finally, qPCR and Western Blot were used to detect the expression of TLR4, NF kB, NLRP3, caspase-1, and IL-1 ß in the hippocampus of each group of mice. Through high-throughput data analysis, it was found that there was no significant difference in the auditory threshold of the three groups of mice; After 2 h of exposure to 100 dB SPL noise, the GPIAS% of mice decreased significantly compared to before exposure, and membrane construction was successful. After 7 days, the GPIAS% of the drug intervention group increased. After noise exposure, mice developed tinnitus, and hippocampus neuroinflammation. Roflupram can inhibit neuroinflammation and improve tinnitus through the TLR4/NF kB/NLRP3/caspase-1/IL-1 ß signaling pathway.

Mendelian randomization analyses support causal relationships between tinnitus of different stages and severity and structural characteristics of specific brain regions.

This study aims to delineate the causal relationships between idiopathic tinnitus in different stages and severity and the morphological properties in specific brain regions. We utilized a two-sample bidirectional Mendelian randomization (MR) analysis to ascertain the causal effects of brain structural attributes on varying severities and stages of tinnitus. Our approach involved harnessing genetic variables derived from extensive genome-wide association studies as instrumental variables, centered mainly on pertinent single-nucleotide polymorphisms associated with tinnitus. Subsequently, we integrated this data with brain structural imaging inputs to facilitate the MR analysis. We also applied reverse MR analysis to pinpoint the critical brain regions implicated in the onset of tinnitus. Our analysis revealed a demonstrable causal relationship between tinnitus and brain structural alterations, including changes primarily within the auditory cortex and hub regions of the limbic system, as well as portions of the frontal-temporal-occipital circuit. We found that individuals exhibiting cortical thickness alterations in the bilateral peri-calcarine and right superior occipital gyrus might have previously experienced tinnitus. Changes in the cortical areas of the right rectus, left inferior frontal gyrus, and right pars-orbitalis appeared unrelated to tinnitus. Furthermore, moderate tinnitus patients showed more pronounced structural alterations. This study substantiates that tinnitus could instigate substantial structural alterations mainly within the auditory-limbic-frontal-visual system, while the reciprocal causality was not supported. Moreover, the data underscores that moderate, rather than severe, tinnitus precipitates the most significant structural changes. Morphological alterations in several specific brain areas either indicate a history of tinnitus or bear no relation to it.

Amygdala structural and functional reorganization as an indicator of affective dysfunction in patients with tinnitus.

The aim of this study was to systematically investigate structural and functional alterations in amygdala subregions using multimodal magnetic resonance imaging (MRI) in patients with tinnitus with or without affective dysfunction. Sixty patients with persistent tinnitus and 40 healthy controls (HCs) were recruited. Based on a questionnaire assessment, 26 and 34 patients were categorized into the tinnitus patients with affective dysfunction (TPAD) and tinnitus patients without affective dysfunction (TPWAD) groups, respectively. MRI-based measurements of gray matter volume, fractional anisotropy (FA), fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), degree centrality (DC), and functional connectivity (FC) were conducted within 14 amygdala subregions for intergroup comparisons. Associations between the MRI properties and clinical characteristics were estimated via partial correlation analyses. Compared with that of the HCs, the TPAD and TPWAD groups exhibited significant structural and functional changes, including white matter integrity (WMI), fALFF, ReHo, DC, and FC alterations, with more pronounced WMI changes in the TPAD group, predominantly within the left auxiliary basal or basomedial nucleus (AB/BM), right central nucleus, right lateral nuclei (dorsal portion), and left lateral nuclei (ventral portion containing basolateral portions). Moreover, the TPAD group exhibited decreased FC between the left AB/BM and left middle occipital gyrus and right superior frontal gyrus (SFG), left basal nucleus and right SFG, and right lateral nuclei (intermediate portion) and right SFG. In combination, these amygdalar alterations exhibited a sensitivity of 65.4% and specificity of 96.9% in predicting affective dysfunction in patients with tinnitus. Although similar structural and functional amygdala remodeling were observed in the TPAD and TPWAD groups, the changes were more pronounced in the TPAD group. These changes mainly involved alterations in functionality and white matter microstructure in various amygdala subregions; in combination, these changes could serve as an imaging-based predictor of emotional disorders in patients with tinnitus.

Functional Connectivity Alterations and Molecular Characterization of the Anterior Cingulate Cortex in Tinnitus Pathology without Hearing Loss.

Compared with individuals with hearing loss, tinnitus patients without hearing loss have more psychological or emotional problems. Tinnitus is closely associated to abnormal metabolism and function of the limbic system, a key brain region for emotion experience, but the underlying molecular mechanism remains unknown. Using whole-brain microvasculature dynamics imaging, the anterior cingulate cortex (ACC) is identified as a key brain region of limbic system involve in the onset of salicylate-induced tinnitus in mice. In the tinnitus group, there is enhanced purine metabolism, oxidative phosphorylation, and a distinct pattern of phosphorylation in glutamatergic synaptic pathway according to the metabolome profiles, quantitative proteomic, and phosphoproteomic data of mice ACC tissue. Electroencephalogram in tinnitus patients with normal hearing thresholds show that the functional connectivity between pregenual anterior cingulate cortex and the primary auditory cortex is significantly increased for high-gamma frequency band, which is positively correlated with the serum glutamate level. These findings indicate that ACC plays an important role in the pathophysiology of tinnitus by interacting with the primary auditory cortex and provide potential molecular targets in the ACC for tinnitus treatment.

Multimodal quantitative magnetic resonance imaging of the thalamus in tinnitus patients with different outcomes after sound therapy.

AIMS: This study systematically investigated structural and functional alterations in the thalamus and its subregions using multimodal magnetic resonance imaging (MRI) and examined its clinical relevance in tinnitus patients with different outcomes after sound therapy (narrowband noise). METHODS: In total, 60 patients with persistent tinnitus and 57 healthy controls (HCs) were recruited. Based on treatment efficacy, 28 patients were categorized into the effective group and 32 into the ineffective group. Five MRI measurements of the thalamus and its seven subregions, including gray matter volume, fractional anisotropy, fractional amplitude of low-frequency fluctuation, and functional connectivity (FC), were obtained for each participant and compared between the groups. RESULTS: Patients in both the groups exhibited widespread functional and diffusion abnormalities in the whole thalamus and several subregions, with more obvious changes observed in the effective group. All tinnitus patients had abnormal FC compared with the HCs; FC differences between the two patient groups were only observed in the striatal network, auditory-related cortex, and the core area of the limbic system. We combined the multimodal quantitative thalamic alterations and used it as an imaging indicator to evaluate prognosis before sound therapy and achieved a sensitivity of 71.9% and a specificity of 85.7%. CONCLUSION: Similar patterns of thalamic alterations were identified in tinnitus patients with different outcomes, with more obvious changes observed in the effective group. Our findings support the tinnitus generation hypothesis of frontostriatal gating system dysfunction. A combination of multimodal quantitative thalamic properties may be used as indicators to predict tinnitus prognosis before sound therapy.

Differences in Hearing, Balance, and Quality-of-Life Outcomes in Petroclival Versus Nonpetroclival Posterior Fossa Meningiomas.

OBJECTIVE: To compare hearing, tinnitus, balance, and quality-of-life treatment outcomes of petroclival meningioma and nonpetroclival cerebellopontine angle meningioma cohorts. STUDY DESIGN: A retrospective cohort study of 60 patients with posterior fossa meningiomas, 25 petroclival and 35 nonpetroclival, who were treated at a single tertiary care center between 2000 and 2020. INTERVENTION: A survey battery that included the Hearing Effort of the Tumor Ear, Speech and Spatial Qualities of Hearing, Tinnitus Functional Index, Dizziness Handicap Inventory (DHI), and Short Form Health Survey. Petroclival and nonpetroclival cohorts were matched for tumor size and demographic features. MAIN OUTCOME MEASURES: Differences between groups in hearing, balance outcomes, and quality of life and patient factors that influence posttreatment quality of life. RESULTS: Petroclival meningioma patients reported poorer audiovestibular outcomes with a higher rate of deafness in the tumor ear (36.0% versus 8.6%, p = 0.032) and lower functional hearing by the Hearing Effort of the Tumor Ear, Speech and Spatial Qualities of Hearing (76.6 [6.1] versus 82.0 [4.4], p < 0.001). Current dizziness rate was higher (48.0% versus 23.5%, p = 0.05), with more severe dizziness by DHI (18.4 [4.8] versus 5.7 [2.2], p < 0.001). Both cohorts had similar high quality of life and low tinnitus severity indices. Quality-of-life Short Form Health Survey predictors were tumor size ( p = 0.012) and DHI ( p = 0.005) in multivariable analysis. CONCLUSIONS: Hearing and dizziness treatment outcomes of petroclival meningioma are poorer relative to other posterior fossa meningiomas. Despite audiovestibular outcome distinctions, the overall posttreatment quality of life was high for both petroclival and nonpetroclival meningioma.

Protective Effect of Resveratrol in an Experimental Model of Salicylate-Induced Tinnitus.

To date, the effect of resveratrol on tinnitus has not been reported. The attenuative effects of resveratrol (RSV) on a salicylate-induced tinnitus model were evaluated by in vitro and in vivo experiments. The gene expression of the activity-regulated cytoskeleton-associated protein (ARC), tumor necrosis factor-alpha (TNFα), and NMDA receptor subunit 2B (NR2B) in SH-SY5Y cells was examined using qPCR. Phosphorylated cAMP response element-binding protein (p-CREB), apoptosis markers, and reactive oxygen species (ROS) were evaluated by in vitro experiments. The in vivo experiment evaluated the gap-prepulse inhibition of the acoustic startle reflex (GPIAS) and auditory brainstem response (ABR) level. The NR2B expression in the auditory cortex (AC) was determined by immunohistochemistry. RSV significantly reduced the salicylate-induced expression of NR2B, ARC, and TNFα in neuronal cells; the GPIAS and ABR thresholds altered by salicylate in rats were recovered close to their normal range. RSV also reduced the salicylate-induced NR2B overexpression of the AC. These results confirmed that resveratrol exerted an attenuative effect on salicylate-induced tinnitus and may have a therapeutic potential.

Tinnitus Triggered by a Cerebellopontine Arachnoid Cyst in an Adolescent.

BACKGROUND Tinnitus can be a symptom of a wide range of disorders. The identification and treatment of the underlying condition is essential for management of tinnitus in children. Tinnitus can occur with medical conditions other than sensorineural hearing loss. Cerebellopontine arachnoid cysts are rare and can cause tinnitus and hearing loss in adults. Tinnitus caused by an arachnoid cyst has not been reported in an adolescent. We report clinical and radiological features of a teenager with bothersome tinnitus caused by an arachnoid cyst. CASE REPORT A 14-year-old girl with unilateral tinnitus for 10 months presented to the Pediatric Otolaryngology Clinic. The loudness and duration of tinnitus had progressed gradually. Turning the head to the right induced right otalgia and tinnitus. The patient denied hearing loss, vertigo, exposure to loud noise, feeling of fullness in ear, otorrhea, facial weakness, numbness, dysphagia, changes in smell or taste, and problems with the jaw or temporomandibular joint. The focused neurological examination and head and neck examination were within normal limits. The patient had normal hearing on audiometry. T1-weighted, T2-spin-echo, T2-FLAIR, and diffusion-weighted magnetic resonance imaging sequences were obtained, revealing a right cerebellopontine angle arachnoid cyst. After arachnoid cyst marsupialization, the patient's tinnitus and otalgia resolved. CONCLUSIONS This case highlights the importance of suspecting identifiable nonauditory system disorders as causes of tinnitus in children. Thorough analysis of clinical findings and timely use of imaging is critical to prevent delay in diagnosis and treatment of children with bothersome tinnitus caused by rare medical conditions.

Altered Amplitude of Low-Frequency Fluctuations and Degree Centrality in Patients with Acute Subjective Tinnitus: A Resting-State Functional Magnetic Resonance Imaging Study.

BACKGROUND: The difference in spontaneous brain activity between acute subjective tinnitus patients (with or without hearing loss) and control participants was explored using the amplitude of low-frequency fluctuations and degree centrality methods through resting-state functional magnetic resonance imaging. The study aimed to provide an objective basis for clinical diagnosis and pathogenesis of patients with acute subjective tinnitus. METHODS: Fourteen acute subjective tinnitus (AST) patients with hearing loss (AST-HL), 6 AST patients with no hearing loss (AST-NHL), and 14 healthy controls (HCs) with age, sex, and education status matched were recruited for this study. Resting-state functional magnetic resonance imaging (fMRI) examinations were performed in a resting state and the amplitude of low-frequency fluctuations (ALFF) and degree centrality (DC) values of each group were acquired. Statistical analysis was performed to assess the ALFF and DC values of different brain areas of the participants (AST-HL and AST-NHL were compared with HCs, but AST-HL and AST-NHL were not). RESULTS: Patients with acute subjective tinnitus and hearing loss showed a significantly increased amplitude of low-frequency fluctuation values in the left middle temporal gyrus and bilateral frontal gyrus/marginal lobe/cingulate gyrus but a decreased amplitude of low-frequency fluctuations values in the bilateral superior temporal gyrus/anterior cerebellar lobe in comparison with healthy controls. The amplitude of low-frequency fluctuation values of patients with acute subjective tinnitus and hearing loss in the right posterior lobe of the cerebellum, bilateral temporal gyrus, bilateral lenticular nucleus, bilateral frontal gyrus, right inferior occipital gyrus, were higher, but were significantly lower in the bilateral anterior lobe of cerebellum/superior temporal gyrus and left posterior cerebellar lobe as compared with those of healthy controls. Degree centrality values in the healthy controls group were increased in the right superior marginal gyrus and decreased in the right thalamus in patients with acute subjective tinnitus and hearing loss, while patients with acute subjective tinnitus with no hearing loss presented significantly higher degree centrality values in the left frontal lobe and lower degree centrality values in the left center rear return. CONCLUSIONS: Aberrant amplitude of low-frequency fluctuations and values exist in various brain regions, indicating abnormal spontaneous brain activity in both acute subjective tinnitus and hearing loss and acute subjective tinnitus no hearing loss patients. The pathogenesis of acute subjective tinnitus may be related to abnormalities in both the auditory cortex and nonauditory cortex. These findings provide more evidence to help clarify the neuronal symptoms of acute subjective tinnitus patients.

Brain herniation (encephalocele) into arachnoid granulations: prevalence and association with pulsatile tinnitus and idiopathic intracranial hypertension.

PURPOSE: Brain herniation into arachnoid granulations (BHAG) of the dural venous sinuses is a recently described finding of uncertain etiology. The purpose of this study was to investigate the prevalence of BHAG in a cohort of patients with pulsatile tinnitus (PT) and to clarify the physiologic and clinical implications of these lesions. METHODS: The imaging and charts of consecutive PT patients were retrospectively reviewed. All patients were examined with MRI including pre- and post-contrast T1- and T2-weighted sequences. Images were reviewed separately by three blinded neuroradiologists to identify the presence of BHAG. Their location, signal intensity, size, presence of arachnoid granulation, and associated dural venous sinus stenosis were documented. Clinical records were further reviewed for idiopathic intracranial hypertension, history of prior lumbar puncture, and opening pressure. RESULTS: Two hundred sixty-two consecutive PT patients over a 4-year period met inclusion criteria. PT patients with BHAG were significantly more likely to have idiopathic intracranial hypertension than PT patients without BHAG (OR 4.2, CI 1.5-12, p = 0.006). Sixteen out of 262 (6%) patients were found to have 18 BHAG. Eleven out of 16 (69%) patients had unilateral temporal or occipital lobe herniations located in the transverse sinus or the transverse-sigmoid junction. Three out of 16 (19%) patients had unilateral cerebellar herniations and 2/16 (13%) patients had bilateral BHAG. CONCLUSION: In patients with PT, BHAG is a prevalent MRI finding that is strongly associated with the clinical diagnosis of IIH. The pathogenesis of BHAG remains uncertain, but recognition should prompt comprehensive evaluation for IIH.

Distinct brain structural-functional network topological coupling explains different outcomes in tinnitus patients treated with sound therapy.

Topological properties, which serve as the core of the neural network, and their couplings can reflect different therapeutic effects in tinnitus patients. We hypothesized that tinnitus patients with different outcomes after sound therapy (narrowband noise) would have distinct brain network topological alterations. Diffusion tensor imaging and resting-state functional magnetic resonance imaging (fMRI) were prospectively performed in 60 patients with idiopathic tinnitus and 57 healthy controls (HCs). Graph-theoretical network analyses of structural connectivity (SC), functional connectivity (FC), and SC and FC coupling were performed. Associations between clinical performance and graph-theoretical features were also analyzed. Treatment was effective (effective group; EG) in 28 patients and ineffective (ineffective group; IG) in 32 patients. For FC, the patients in the EG showed higher local efficiency than patients in the IG. For SC, patients in both the EG and IG displayed lower normalized characteristic path length, characteristic path length, and global efficiency than the HCs. More importantly, patients in the IG had higher coupling than the HCs, whereas there was no difference in coupling between patients in the EG and HCs. Additionally, there were significant associations between the SC features and clinical performance in patients in the EG. Our findings demonstrate that tinnitus patients exhibited significant brain network topological alterations, especially in the structural brain network. More importantly, patients who demonstrated different curative effects showed distinct SC-FC topological coupling properties. SC-FC coupling could be an indicator that could be used to predict prognoses in patients with idiopathic tinnitus before sound therapy.

Topological features of limbic dysfunction in chronicity of tinnitus with intact hearing: New hypothesis for 'noise-cancellation' mechanism.

PURPOSE: The reorganization of the limbic regions extend to general cognitive network is believed to exist in the chronicity of tinnitus with particular 'hubs' contributing to a 'noise-cancellation' mechanism. To test this hypothesis, we investigated the topological brain network of tinnitus in different periods. METHODS: Resting-state functional magnetic resonance imaging were obtained from 32 patients with acute tinnitus, 41 patients with chronic tinnitus and 60 age- and gender- matched healthy controls (HC). The topological features of their brain networks were explored using graph theory analysis. RESULTS: Common small-world attributes were compared between the three groups, all showed a significantly increased values in Cp, Lp, λ (all p < 0.05). Significantly increased nodal centralities in the left superior frontal gyrus and the right precuneus, significantly decreased nodal centralities in the right inferior temporal gyrus were observed for acute tinnitus patients compared to HC. While for chronic tinnitus patients, there were significant increased nodal centralities in the left hippocampus, amygdala, and temporal pole, but decreased nodal centralities in the right inferior temporal gyrus. Additionally, significant higher nodal centralities were found in bilateral medial superior frontal gyrus for acute tinnitus patients compared to chronic tinnitus patients. Besides, alterations in rich-club organization were found in acute tinnitus patients and chronic tinnitus patients compared with HC, with increased functional connections among rich-club nodes and peripheral nodes in patients with tinnitus. CONCLUSIONS: Brain network topological properties altered across prefrontal-limbic-subcortical regions in tinnitus. The existed hubs in tinnitus might indicate an emotional and cognitive burden in 'noise-cancellation' mechanism.

Association between tinnitus and depressive symptoms in the South Korean population.

In this study, we aimed to examine the association between tinnitus and depressive symptoms in middle-aged and elderly South Korean population. The participants were selected from among those who participated in the 2014, 2016, and 2018 Korea National Health and Nutrition Examination Surveys. The incidence and severity of tinnitus was assessed using a self-reported questionnaire, while depressive symptoms were evaluated using self-reported Patient Health Questionnaire-9. Multiple logistic regression was performed to examine the association between tinnitus and depressive symptoms. Overall, 10 979 (4821 men and 6158 women) participants were enrolled in the study. Regardless of sex, individuals who reported having tinnitus were more likely to have depressive symptoms than those without tinnitus (men: odds ratio 1.53, 95% confidence interval 1.01-2.32; women: odds ratio 1.78, 95% confidence interval 1.35-2.35). In severe cases of tinnitus, women were more likely to have depressive symptoms (odds ratio 7.18, 95% confidence interval 3.71-13.87) compared to men. This study revealed a significant association between tinnitus and depressive symptoms among the middle-aged and elderly South Korean population.

Migraine and Cochlear Symptoms.

Migraine is one of the most common and highest burdens of disease. As a primary cerebral dysfunction illness, migraine might exhibit other system-related symptoms, including vestibular and cochlear symptoms. With the publication of the diagnostic criteria of vestibular migraine, the link between migraine and vestibular symptoms became clear. However, the relationship between migraine and cochlear symptoms is far from straightforward. Therefore, we focus on the correlation between migraine and deafness, sudden sensorineural hearing loss, acute tinnitus, and chronic tinnitus to better understand the relationship between migraine and cochlear symptoms.

The role of vitamin D in subjective tinnitus-A case-control study.

Regarding the high prevalence of vitamin D (25(OH)D) deficiency in the population and its possible association with ear diseases, we aimed to investigate the 25(OH)Dserum level in patients with subjective, nonpulsating tinnitus and its effect on tinnitus severity. The study included 201 tinnitus patients and 99 controls. Patient clinical information, including tinnitus characteristics and severity according to Tinnitus Handicap Inventory (THI), loudness assessed by Visual Analogue Scale (VAS), audiometry, and the blood level of vitamin D, was recorded. The level of 25(OH)D in tinnitus patients was significantly decreased compared with the controls (19.86 ± 7.53 and 27.43 ± 8.85 ng/ml, respectively; P value < 0.0001). More patients in the tinnitus group were deficient in vitamin D, compared with the controls (50.7% vs. 22.2% respectively, p < 0.0001). Tinnitus patients with a lower serum level of 25(OH)D (≤15 ng/dl) were significantly younger, had a higher degree of tinnitus severity measured with THI and VAS scales, had higher triglyceride and TSH levels, and a lower HDL level compared with individuals who had higher 25(OH)D level (>15 ng/dl). There was a strong correlation between the 25(OH)D level and THI. Our findings suggest that a large proportion of tinnitus patients suffers from vitamin D deficiency and that the vitamin D level correlates with tinnitus impact. We recommend a vitamin D assessment for all tinnitus patients.

Evidence of Tinnitus Development Due to Stress: An Experimental Study in Rats.

OBJECTIVES/HYPOTHESIS: Tinnitus can develop due to, or be aggravated by, stress in a rat model. To investigate stress as a possible causal factor in the development of tinnitus, we designed an animal study that included tinnitus behavior and excitatory/inhibitory neurotransmitter expression after noise exposure as well as restraint stress. STUDY DESIGN: An experimental animal study. METHODS: Wistar rats were grouped according to single or double exposure to noise and restraint stress. The noise exposure (NE) group was subjected to 110 dB sound pressure level (SPL) of 16 kHz narrow-band noise (NBN) for 1 hour, and the restraint stress (RS) group was restrained for 1 hour with or without noise exposure. Gap prepulse inhibition of the acoustic startle (GPIAS) reflex was measured at an NBN of 16 kHz to investigate tinnitus development. Various immunohistopathologic and molecular biologic studies were undertaken to evaluate possible mechanisms of tinnitus development after noise and/or restraint stress. RESULTS: The RS-only group showed a reduced GPIAS response, which is a reliable sign of tinnitus development. In the double-stimulus groups, more tinnitus-development signs of reduced GPIAS responses were observed. The expression of γ-aminobutyric acid A receptor α1 (GABAAR α1) in the hippocampus decreased in the NE│RS group. Increased N-methyl-d-aspartate receptor1 intensities in the NE│RS group and decreased GABAAR α1 intensities in the RS and NE│RS groups were observed in the CA3 region of the hippocampus. CONCLUSIONS: Tinnitus appeared to develop after stress alone in this animal study. An imbalance in excitatory and inhibitory neurotransmitters in the hippocampus may be related to the development of tinnitus after acute NE and/or stress. LEVEL OF EVIDENCE: NA Laryngoscope, 131:2332-2340, 2021.

Role of microRNA­375­3p­mediated regulation in tinnitus development.

Changes in the dorsal cochlear nucleus (DCN) following exposure to noise play an important role in the development of tinnitus. As the development of several diseases is known to be associated with microRNAs (miRNAs/miRs), the aim of the present study was to identify the miRNAs that may be implicated in pathogenic changes in the DCN, resulting in tinnitus. A previously developed tinnitus animal model was used for this study. The study consisted of four stages, including identification of candidate miRNAs involved in tinnitus development using miRNA microarray analysis, validation of miRNA expression using reverse transcription­quantitative PCR (RT­qPCR), evaluation of the effects of candidate miRNA overexpression on tinnitus development through injection of a candidate miRNA mimic or mimic negative control, and target prediction of candidate miRNAs using mRNA microarray analysis and western blotting. The miRNA microarray and RT­qPCR analyses revealed that miR­375­3p expression was significantly reduced in the tinnitus group compared with that in the non­tinnitus group. Additionally, miR­375­3p overexpression via injection of miR­375­3p mimic reduced the proportion of animals with persistent tinnitus. Based on mRNA microarray and western blot analyses, connective tissue growth factor (CTGF) was identified as a potential target for miR­375­3p. Thus, it was inferred that CTGF downregulation by miR­375­3p may weaken with the decrease in miRNA expression, and the increased pro­apoptotic activity of CTGF may result in more severe neuronal damage, contributing to tinnitus development. These findings are expected to contribute significantly to the development of a novel therapeutic approach to tinnitus, thereby bringing about a significant breakthrough in the treatment of this potentially debilitating condition.

Cortical and subcortical gray matter changes in patients with chronic tinnitus sustaining after vestibular schwannoma surgery.

Tinnitus is attributed to partial sensory deafferentation resulting in a central maladaptive neuroplasticity. Unfortunately, the agent of deafferentation is usually unknown or irreversible. In patients with unilateral vestibular schwannoma (VS), however, the auditory nerve is affected by a benign tumor. Hence, removal of the tumor can cease the tinnitus. In turn, sustaining complaints after surgery indicate cortical neuroplasticity. The present study is a cross sectional study which aims to track cortical structural changes by surface-based morphometry in 46 VS patients with sustained (i.e. centralized) or ceased (i.e. peripheral) tinnitus after surgery. A volumetric analysis of cortical and subcortical gray matter (GM) anatomy was performed on preoperative high-resolution MRI and related to the presence of hearing impairment, pre- and/or postoperative tinnitus. Patients with sustained (i.e. chronic) tinnitus showed an increased GM volume of the bilateral caudate nucleus, the contralateral superior colliculus, the middle frontal and middle temporal gyrus, the fusiform gyrus as well as the ipsilateral pars orbitalis when compared to those patients in whom tinnitus ceased postoperatively. Chronic tinnitus in VS patients is associated with characteristic structural changes in frontal, temporal and subcortical areas. Notably, a significant GM change of the caudate nucleus was detected providing further support for the striatal gaiting model of tinnitus.