Frequency-Following Responses in Sensorineural Hearing Loss: A Systematic Review.

PURPOSE: This systematic review aims to assess the impact of sensorineural hearing loss (SNHL) on various frequency-following response (FFR) parameters. METHODS: Following PRISMA guidelines, a systematic review was conducted using PubMed, Web of Science, and Scopus databases up to January 2023. Studies evaluating FFRs in patients with SNHL and normal hearing controls were included. RESULTS: Sixteen case-control studies were included, revealing variability in acquisition parameters. In the time domain, patients with SNHL exhibited prolonged latencies. The specific waves that were prolonged differed across studies. There was no consensus regarding wave amplitude in the time domain. In the frequency domain, focusing on studies that elicited FFRs with stimuli of 170 ms or longer, participants with SNHL displayed a significantly smaller fundamental frequency (F0). Results regarding changes in the temporal fine structure (TFS) were inconsistent. CONCLUSION: Patients with SNHL may require more time for processing (speech) stimuli, reflected in prolonged latencies. However, the exact timing of this delay remains unclear. Additionally, when presenting longer stimuli (≥ 170 ms), patients with SNHL show difficulties tracking the F0 of (speech) stimuli. No definite conclusions could be drawn on changes in wave amplitude in the time domain and the TFS in the frequency domain. Patient characteristics, acquisition parameters, and FFR outcome parameters differed greatly across studies. Future studies should be performed in larger and carefully matched subject groups, using longer stimuli presented at the same intensity in dB HL for both groups, or at a carefully determined maximum comfortable loudness level.

Health-Related Quality of Life in Subjective, Chronic Tinnitus Patients: A Scoping Review.

PURPOSE: This scoping review aims to assess whether the severity or distress of subjective tinnitus is negatively associated or correlated with the level of health-related quality of life (HRQoL). A second objective is to examine whether tinnitus patients score differently on HRQoL questionnaires in comparison to subjects without tinnitus and whether HRQoL differs between specific subgroups of tinnitus. METHODS: This scoping review adheres to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines (PRISMA guidelines): the statement and extension for scoping reviews (PRISMA-ScR). The following databases were consulted (on the 20th of October 2023): PubMed, Cochrane Library, Web of Science, and Scopus. The search string was composed of the terms tinnitus, HRQoL, and synonyms. A double-blinded screening for eligibility was performed, first on the title and abstract and subsequently on the full-text articles. Studies were considered eligible if they looked at HRQoL questionnaire results for adult patients (> 18 years) reporting chronic (> 3 months), subjective tinnitus as a primary complaint. RESULTS: In total, 37 studies with a total sample size of 33,900 participants were included in this scoping review, with some studies answering multiple study objectives. Seventeen studies demonstrated the presence of a significant negative correlation between tinnitus-related distress and HRQoL. Two studies indicated that HRQoL is mediated by tinnitus-related distress. Eighteen studies found that, in general, patients with tinnitus scored significantly lower on HRQoL questionnaires in comparison to subjects without tinnitus. Nineteen studies demonstrated that subgroups of patients with more severe tinnitus complaints or specific additional complaints scored worse on HRQoL questionnaires. CONCLUSION: Based on the current literature, chronic subjective tinnitus-related distress has a significant impact on health-related quality of life. In addition, subjects without tinnitus generally score significantly higher on HRQoL questionnaires than patients with tinnitus. The heterogeneity in outcome measures between studies precludes meta-analysis. Increased homogeneity in the choice of HRQoL questionnaires would make a comparison between studies possible, which would give valuable information on both a clinical and an economic level, guiding future tinnitus treatment. REGISTRATION: The protocol for the scoping review is registered at Open Science Framework: https://doi.org/10.17605/OSF.IO/F5S9C .

Validation of the acoustic change complex (ACC) prediction model to predict speech perception in noise in adult patients with hearing loss: a study protocol.

BACKGROUND: Speech perception tests are essential to measure the functional use of hearing and to determine the effectiveness of hearing aids and implantable auditory devices. However, these language-based tests require active participation and are influenced by linguistic and neurocognitive skills limiting their use in patients with insufficient language proficiency, cognitive impairment, or in children. We recently developed a non-attentive and objective speech perception prediction model: the Acoustic Change Complex (ACC) prediction model. The ACC prediction model uses electroencephalography to measure alterations in cortical auditory activity caused by frequency changes. The aim is to validate this model in a large-scale external validation study in adult patients with varying degrees of sensorineural hearing loss (SNHL) to confirm the high predictive value of the ACC model and to assess its test-retest reliability. METHODS: A total of 80 participants, aged 18-65 years, will be enrolled in the study. The categories of severity of hearing loss will be used as a blocking factor to establish an equal distribution of patients with various degrees of sensorineural hearing loss. During the first visit, pure tone audiometry, speech in noise tests, a phoneme discrimination test, and the first ACC measurement will be performed. During the second visit (after 1-4 weeks), the same ACC measurement will be performed to assess the test-retest reliability. The acoustic change stimuli for ACC measurements consist of a reference tone with a base frequency of 1000, 2000, or 4000 Hz with a duration of 3000 ms, gliding to a 300-ms target tone with a frequency that is 12% higher than the base frequency. The primary outcome measures are (1) the level of agreement between the predicted speech reception threshold (SRT) and the behavioral SRT, and (2) the level of agreement between the SRT calculated by the first ACC measurement and the SRT of the second ACC measurement. Level of agreement will be assessed with Bland-Altman plots. DISCUSSION: Previous studies by our group have shown the high predictive value of the ACC model. The successful validation of this model as an effective and reliable biomarker of speech perception will directly benefit the general population, as it will increase the accuracy of hearing evaluations and improve access to adequate hearing rehabilitation.

Tinnitus suppression by means of cochlear implantation: does it affect cognition?

PURPOSE: Recent literature suggests that tinnitus can impact cognition, but results were varied due to a diversity in investigated aspects of cognition and utilized tests, as well as the possible influence of confounding factors. The purpose of this study was to assess the impact of tinnitus loudness on cognition by use of a within-subjects design in patients with a cochlear implant (CI). In this population, tinnitus loudness can be modulated by switching the CI on or off as CI is known to highly suppress tinnitus. METHODS: A total of 18 CI users completed two versions of the Repeatable Battery for Assessment of Neuropsychological Status for Hearing Impaired individuals (RBANS-H), once in unaided condition and once in best aided condition. Tinnitus suppression was defined as a difference in score on a visual-analogue scale (VAS) of at least one point out of ten between these two conditions. RESULTS: No significant differences in RBANS-H scores were found between the suppression and no suppression group, nor for the suppression group alone. No significant correlations between tinnitus loudness and RBANS-H were found, neither for the suppression group alone, nor for the group as a whole. CONCLUSION: The current study shows no significant effect of tinnitus loudness on cognition, which contradicts previous literature. This discrepancy could be explained by the use of a within-subjects design, which controls for confounding factors. Future research should include a larger and more diverse study sample to draw definitive conclusions on this topic.

Dual-site transcranial direct current stimulation to treat tinnitus: a randomized controlled trial.

Transcranial direct current stimulation (tDCS) has been proposed as a potential intervention for subjective tinnitus, but supporting evidence remains limited. We aimed to investigate the effect of anodal high-definition tDCS of the left temporal area and right dorsolateral prefrontal cortex on tinnitus severity. This double-blind randomized controlled trial included 77 patients (age range 18-79, 43 male) with chronic subjective tinnitus as their primary complaint. Thirty-eight subjects received six consecutive sessions of dual-site sequential high-definition-tDCS with electrodes positioned over the left temporal area and right dorsolateral prefrontal cortex. Both areas were stimulated for 15 min per session, with total stimulation time amounting to 30 min. Thirty-nine subjects received sham stimulation. The primary outcome measure was the change in tinnitus severity, as evaluated by the Tinnitus Functional Index, from baseline to a follow-up visit at 8 ± 2 weeks after treatment completion. Secondary outcomes included changes in perceived tinnitus loudness, as measured with a visual analogue scale and a tinnitus matching procedure, as well as scores on the Hospital Anxiety and Depression Scale, and the Hyperacusis Questionnaire. No differences in Tinnitus Functional Index change scores were identified between the active treatment and sham control groups (linear regression: P = 0.86). The Tinnitus Functional Index scores decreased significantly over time in both groups (P = 0.0012), indicating the presence of a considerable placebo effect. These change scores were significantly influenced by sex (linear regression: P = 0.037) and baseline symptoms of anxiety (linear regression: P = 0.049) in both groups. In general, Tinnitus Functional Index scores decreased more profoundly in males and in subjects with a higher degree of anxiety at baseline. None of the included secondary measures differed significantly between experimental arms. Our results suggest that dual-site sequential high-definition-tDCS of the left temporal area and right dorsolateral prefrontal cortex does not alleviate tinnitus severity. Interestingly, in our study population, fluctuations in tinnitus severity were influenced by gender and concurrent mental condition. It is therefore important to take these factors into account when conducting or planning randomized controlled trials in tinnitus populations.

The correlation between tinnitus-specific and quality of life questionnaires to assess the impact on the quality of life in tinnitus patients.

Introduction: Subjective tinnitus is often associated with a reduction in health-related quality of life (HRQoL). The HRQoL represents the impact of tinnitus on an individual's life by addressing the physical, social, and psychological domains of 1. A limited amount of studies has investigated the association between tinnitus and HRQoL questionnaires. The aim of this study was to examine the correlation between tinnitus-specific and HRQoL questionnaires in order to shorten fulfilling questionnaires, as it is often time-consuming. Material and method: Eighty-five patients with tinnitus as primary complaint completed five questionnaires, including one general, two tinnitus-specific, and two generic HRQoL questionnaires: Tinnitus Sample Case History Questionnaire (TSCHQ), Tinnitus Functional Index (TFI), Tinnitus Handicap Inventory (THI), short version of World Health Organization Quality of Life (WHOQOL-BREF), and the eight-item Short-Form (SF-8). Four simple linear regression models were used to analyze the relationship between the THI and TFI and the WHOQOL-BREF and SF-8. Results: A negative and strong correlation was found between the tinnitus questionnaires and the SF-8. More than half of the variability in the SF-8 scores could be explained by the TFI and THI, respectively 50.6 and 54.4% (all p < 0.001). A strong negative regression was also found between the WHOQOL-BREF and the THI and TFI with a decrease in the determination coefficient of approximately 10% compared with the SF-8. The weakest correlation (regression coefficient of 0.628, p < 0.001) was observed between the WHOQOL-BREF and the TFI, indicating that the WHOQOL-BREF mean score explained 39.4% of the TFI. When looking at the subdomain scores, a strong correlation was observed between the QoL subdomain of the TFI and a combination of the physical and psychological subdomain of the WHOQOL-BREF (r = -0.627, p < 0.001). Conclusion: The QoL subdomain of the TFI gives good information about the physical and psychological health. Thus, the TFI is suitable to assess both tinnitus severity and the HRQoL. The coefficients of determination of the WHOQOL-BREF were significantly lower compared to the SF-8, suggesting that the WHOQOL-BREF provides more specific information about HRQoL. If more specific information on HRQoL, such as "environment" and "social relationships", is required, it is recommended to use the WHOQOL-BREF.

Brainstem evoked auditory potentials in tinnitus: A best-evidence synthesis and meta-analysis.

Introduction: Accumulating evidence suggests a role of the brainstem in tinnitus generation and modulation. Several studies in chronic tinnitus patients have reported latency and amplitude changes of the different peaks of the auditory brainstem response, possibly reflecting neural changes or altered activity. The aim of the systematic review was to assess if alterations within the brainstem of chronic tinnitus patients are reflected in short- and middle-latency auditory evoked potentials (AEPs). Methods: A systematic review was performed and reported according to the PRISMA guidelines. Studies evaluating short- and middle-latency AEPs in tinnitus patients and controls were included. Two independent reviewers conducted the study selection, data extraction, and risk of bias assessment. Meta-analysis was performed using a multivariate meta-analytic model. Results: Twenty-seven cross-sectional studies were included. Multivariate meta-analysis revealed that in tinnitus patients with normal hearing, significantly longer latencies of auditory brainstem response (ABR) waves I (SMD = 0.66 ms, p < 0.001), III (SMD = 0.43 ms, p < 0.001), and V (SMD = 0.47 ms, p < 0.01) are present. The results regarding possible changes in middle-latency responses (MLRs) and frequency-following responses (FFRs) were inconclusive. Discussion: The discovered changes in short-latency AEPs reflect alterations at brainstem level in tinnitus patients. More specifically, the prolonged ABR latencies could possibly be explained by high frequency sensorineural hearing loss, or other modulating factors such as cochlear synaptopathy or somatosensory tinnitus generators. The question whether middle-latency AEP changes, representing subcortical level of the auditory pathway, are present in tinnitus still remains unanswered. Future studies should identify and correctly deal with confounding factors, such as age, gender and the presence of somatosensory tinnitus components. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021243687, PROSPERO [CRD42021243687].

Random Forest Classification to Predict Response to High-Definition Transcranial Direct Current Stimulation for Tinnitus Relief: A Preliminary Feasibility Study.

OBJECTIVES: Transcranial direct current stimulation (tDCS) of the right dorsolateral prefrontal cortex has been hypothesized to reduce tinnitus severity by modifying cortical activity in brain regions associated with the perception of tinnitus. However, individual response to tDCS has proven to be variable. We investigated the feasibility of using random forest classification to predict the response to high-definition (HD) tDCS for tinnitus relief. DESIGN: A retrospective analysis was performed on a dataset consisting of 99 patients with subjective tinnitus receiving six consecutive sessions of HD-tDCS at the Antwerp University Hospital. A baseline assessment consisted of pure-tone audiometry and a set of questionnaires including the Tinnitus Functional Index (TFI), Hospital Anxiety and Depression Scale, and Edinburgh Handedness Inventory. Random forest classification was applied to predict, based on baseline questionnaire scores and hearing levels, whether each individual responded positively to the treatment (defined as a decrease of at least 13 points on the TFI). Further testing of the model was performed on an independent cohort of 32 patients obtained from the tinnitus center at the University of Regensburg. RESULTS: Twenty-four participants responded positively to the HD-tDCS treatment. The random forest classifier predicted treatment response with an accuracy of 85.71% (100% sensitivity, 81.48% specificity), significantly outperforming a more traditional logistic regression approach. Performance of the classifier on an independent cohort was slightly but not significantly above chance level (71.88% accuracy, 66.67% sensitivity, 73.08% specificity). Feature importance analyses revealed that baseline tinnitus severity, co-occurrence of depressive symptoms and handedness were the most important predictors of treatment response. Baseline TFI scores were significantly higher in responders than in nonresponders. CONCLUSIONS: The proposed random forest classifier predicted treatment response with a high accuracy, significantly outperforming a more traditional statistical approach. Machine learning methods to predict treatment response might ultimately be used in a clinical setting to guide targeted treatment recommendations for individual tinnitus patients.

The Rapid Screening for Somatosensory Tinnitus Tool: a Data-Driven Decision Tree Based on Specific Diagnostic Criteria.

BACKGROUND: Somatosensory or somatic tinnitus (ST) is a type of tinnitus where changes in somatosensory afference from the cervical spine or temporomandibular area alter the tinnitus perception. Very recently, the diagnostic value of a set of 16 diagnostic criteria for ST was determined. The next step in the development of easily applicable diagnostic criteria is to provide an uncomplicated model, based on the existing criteria, which can easily be used in clinical practice. OBJECTIVES: This study aims to construct an accurate decision tree, combining several diagnostic criteria, to optimize both sensitivity and specificity of ST diagnosis. DESIGN: An online survey was launched on the online forum Tinnitus Talk, managed by Tinnitus Hub in a convenience sample of participants with tinnitus. The survey included 42 questions, both on the presence of diagnostic criteria for ST and on other potentially influencing factors. A decision tree was constructed to classify participants with and without ST using the rpart package in R. Tree depth was optimized during a five-fold cross-validation. Finally, model performance was evaluated on a subset containing 20% of the original dataset. RESULTS: Data of 7981 participants were used to construct a decision tree for ST diagnosis. Four criteria were included in the final decision tree: 'Tinnitus and neck/jaw pain increase/decrease simultaneously', 'Tension in suboccipital muscles', 'Somatic modulation', and 'Bruxism'. The presented model has an accuracy of 82.2%, a sensitivity of 82.5%, and a specificity of 79%. Receiver operator characteristic curves demonstrated an area under the curve of 0.88. CONCLUSIONS: Based on a 42-item survey, a decision tree was created that was able to detect ST patients with high accuracy (82.2%) using only 4 questions. The RaSST is therefore expected to be easily implementable in clinical practice.

Cortical auditory evoked potentials, brain signal variability and cognition as biomarkers to detect the presence of chronic tinnitus.

The current limited understanding of tinnitus neurophysiology is one of the major obstacles in developing effective treatments for chronic tinnitus. As such, there is an urgent need for knowledge on underlying neural and/or neurobehavioral correlates that might function as potential biomarkers for tinnitus. We aimed to develop a model for the detection of tinnitus cases based on such potential biomarkers. In a first step, data from twenty patients suffering from chronic tinnitus, but no concurrent hearing loss or psychological complaints, were compared to data from twenty matched controls. Cortical auditory evoked potentials (CAEP) were elicited using a standard oddball paradigm. Source estimation and brain signal variability were analyzed to investigate putative differences between tinnitus patients and controls. Other examinations included standard audiometry, speech understanding in quiet and noisy conditions, and cognitive testing using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The P300 component, a response to unexpected but relevant stimuli, was significantly reduced in the tinnitus group. Source estimation revealed that the response of tinnitus patients was characterized by a decreased activity in temporal cortex, parahippocampus and insula. Brain signal variability on fine time scales was significantly higher in the tinnitus group, suggesting that tinnitus patients rely more strongly on local information processing. Furthermore, tinnitus was associated with a decreased cognitive performance, especially on tasks measuring delayed memory. In a second step, a logistic regression model was constructed based on CAEP activity, brain signal variability and RBANS scores. This model performed significantly above chance level when detecting tinnitus cases in an unseen dataset (accuracy of 75%, area under the ROC curve of 0.86). The successful classification between tinnitus cases and controls demonstrates the potential value of the proposed combination of biomarkers. Moreover, the identified associations between tinnitus, auditory evoked activity and cognitive performance point towards a significant contribution of top-down information processing in the perception of tinnitus.

Hyperacusis: demographic, audiological, and clinical characteristics of patients at the ENT department.

PURPOSE: To document whether patients with and without hyperacusis differ from each other on demographic, audiological, and clinical characteristics. METHODS: Based on the Hyperacusis Questionnaire's (HQ) cut-off (HQ > 28), a total of 2301 participants were divided into patients with and without hyperacusis. Demographic data, scores on self-reported questionnaires [Tinnitus Functional Index (TFI), Visual Analogue Scale of tinnitus loudness (VASloudness), Hospital Anxiety Depression Scale (HADS)], and audiological parameters were retrospectively analysed to determine differential factors between the two groups. RESULTS: In total, 10.9% of the patients was classified as hyperacusis patients (n = 251). They reported a significant, higher tinnitus severity (mean difference of 19 points on TFI) and mental distress (mean difference of 4 points on the HADS subscales) (p < 0.001) than patients without hyperacusis. Moreover, this group consisted of more women (45% % in hyperacusis group vs. 35% in non-hyperacusis group) and women scored significantly higher on the HQ (p < 0.001) and TFI (p < 0.01). CONCLUSION: Patients with hyperacusis have distinctive characteristics. The presence of hyperacusis in combination with tinnitus can indicate a higher need for psychoeducation. Patients that present themselves with hyperacusis without tinnitus complaints remain a minority, yet might be underdiagnosed. Hence, future studies should disentangle tinnitus from hyperacusis. In clinical practice, greater efforts are required to increase knowledge about hyperacusis as a primary or secondary complaint and to provide individualized treatment for these patients.

Long-term effects of a single psycho-educational session in chronic tinnitus patients.

PURPOSE: To evaluate the effects of a single psycho-educational session on tinnitus burden in chronic tinnitus patients. The session is organized at a tertiary referral center for otologic disorders at the University Hospital Antwerp as a group session (maximum of 10-15 patients a time) lasting for approximately 3-4 h. The session focusses on different aspects of tinnitus. METHODS: The current manuscript reports on 96 patients who completed the Tinnitus Functional Index (TFI), Visual Analogue Scale for mean loudness (VAS), Hyperacusis Questionnaire (HQ), and the Hospital Anxiety and Depression Scale (HADS) prior to treatment and at 6-month follow-up. The TFI was chosen as the primary outcome. Paired-samples T tests were performed to evaluate therapy effect at 6-month follow-up. In addition, a logistic regression model revealed baseline TFI/VAS scores and duration of tinnitus as contributing factors to a significant decrease of the TFI. RESULTS: The TFI total score showed a significant decrease (p < 0.001) at the 6-month follow-up time point. At follow-up, 75% of patients reported their tinnitus to be under control not requiring any additional treatment. The logistic regression model showed that patients with higher baseline TFI scores, lower baseline mean VAS loudness ratings, and shorter tinnitus duration were more likely to show clinically significant improvement on the TFI scale. CONCLUSIONS: Tinnitus Retraining Therapy or Cognitive Behavioural Therapy are effective, though very time-consuming and expensive treatments. A single psycho-educational group session was shown to be highly effective in decreasing the tinnitus burden, which increases feasibility and cost-effectiveness. TRIAL REGISTRATION: Not applicable as this is a retrospective reporting of tinnitus outcome in the daily clinical practice, not a clinical trial.

Somatosensory Tinnitus Diagnosis: Diagnostic Value of Existing Criteria.

BACKGROUND: Tinnitus can be influenced by changes in somatosensory afference from the cervical spine or temporomandibular area, then called somatosensory or somatic tinnitus (ST). In 2018, a new set of diagnostic criteria for ST was agreed upon by a large group of ST experts. Currently, however, it still requires extensive and specific expertise to diagnose ST correctly. The next step in the development of easily applicable diagnostic criteria is to assess the diagnostic value of each individual criterion. OBJECTIVES: The aim of this study was, therefore, to further investigate the diagnostic value of these criteria, validate them empirically, and identify their sensitivity and specificity. METHODS: An online survey, questioning the presence of 12 diagnostic criteria for ST in a convenience sample of participants with tinnitus, was launched on the online forum Tinnitus Talk, managed by Tinnitus Hub. Participants were divided into three groups: a group with no somatic influence, a group with some somatic influence and a group with large somatic influence on their tinnitus. Chi-square tests were used to calculate differences between these groups. Afterward, sensitivity, specificity, positive and negative likelihood ratios (LR), and pre- and posttest probabilities were calculated for each ST diagnostic criterion. For this analysis, all patients with some and large somatic influence were compared as one group to the group with no somatic influence. RESULTS: In total, 8221 participants filled out the online survey. As expected, the diagnostic criteria for ST are more prevalent in the groups with somatic influence, but the criterium of tinnitus modulation also often occurs in the group with no somatic influence. The simultaneous onset or increase and decrease of both tinnitus and pain complaints have the highest positive LR (6.29 and 10.72, respectively), next to the influence of certain postures on the tinnitus (+LR: 6.04). To rule out ST, the absence of neck pain or tension in the neck extensor muscles are most suited, as they decrease the posttest probability to 18% and 19%, respectively. CONCLUSION: The simultaneous onset or increase and decrease of tinnitus and neck or jaw pain and the influence of certain postures are most suited to use as a single criterion for identifying patients with a somatic influence on their tinnitus. On the other hand, the absence of neck pain or tension in the neck extensor muscles is valid criterion to rule out a somatic influence. Additional analysis is needed to identify clusters of symptoms and criteria to further aid ST diagnosis.

Cortical Auditory Evoked Potentials in Cognitive Impairment and Their Relevance to Hearing Loss: A Systematic Review Highlighting the Evidence Gap.

Background: Alzheimer's disease (AD) is the most prevalent cause of dementia which affects a growing number of people worldwide. Early identification of people at risk to develop AD should be prioritized. Hearing loss is considered an independent potentially modifiable risk factor for accelerated cognitive decline and dementia in older adults. The main outcome of interest of this review is the alteration of Cortical Auditory Evoked Potential (CAEP) morphology in an AD or mild cognitive impairment (MCI) population with and without hearing loss. Methods: Two investigators independently and systematically searched publications regarding auditory processing on a cortical level in people with cognitive impairment (MCI or AD) with and without hearing loss. Only articles which mentioned at least one auditory elicited event-related potential (ERP) component and that were written in English or Dutch were included. Animal studies were excluded. No restrictions were imposed regarding publication date. The reference list of potential sources were screened for additional articles. Results: This systematic review found no eligible articles that met all inclusion criteria. Therefore, no results were included, resulting in an empty systematic review. Conclusion: In general, dysfunction - being either from cognitive or auditory origin - reduces CAEP amplitudes and prolongs latencies. Therefore, CAEPs may be a prognostic indicator in the early stages of cognitive decline. However, it remains unclear which CAEP component alteration is due to cognitive impairment, and which is due to hearing loss (or even both). In addition, vestibular dysfunction - associated with hearing loss, cognitive impairment and AD - may also alter CAEP responses. Further CAEP studies are warranted, integrating cognitive, hearing, and vestibular evaluations.

Uncovering a 'sensitive window' of multisensory and motor neuroplasticity in the cerebrum and cerebellum of male and female starlings.

Traditionally, research unraveling seasonal neuroplasticity in songbirds has focused on the male song control system and testosterone. We longitudinally monitored the song behavior and neuroplasticity in male and female starlings during multiple photoperiods using Diffusion Tensor and Fixel-Based techniques. These exploratory data-driven whole-brain methods resulted in a population-based tractogram confirming microstructural sexual dimorphisms in the song control system. Furthermore, male brains showed hemispheric asymmetries in the pallium, whereas females had higher interhemispheric connectivity, which could not be attributed to brain size differences. Only females with large brains sing but differ from males in their song behavior by showing involvement of the hippocampus. Both sexes experienced multisensory neuroplasticity in the song control, auditory and visual system, and cerebellum, mainly during the photosensitive period. This period with low gonadal hormone levels might represent a 'sensitive window' during which different sensory and motor systems in the cerebrum and cerebellum can be seasonally re-shaped in both sexes.

Systematic review and meta-analysis of late auditory evoked potentials as a candidate biomarker in the assessment of tinnitus.

Subjective tinnitus, the perception of sound in the absence of any sound source, is routinely assessed using questionnaires. The subjective nature of these tools hampers objective evaluation of tinnitus presence, severity and treatment effects. Late auditory evoked potentials (LAEPs) might be considered as a potential biomarker for assessing tinnitus complaints. Using a multivariate meta-analytic model including data from twenty-one studies, we determined the LAEP components differing systematically between tinnitus patients and controls. Results from this model indicate that amplitude of the P300 component is lower in tinnitus patients (standardized mean difference (SMD) = -0.83, p < 0.01), while latency of this component is abnormally prolonged in this population (SMD = 0.97, p < 0.01). No other investigated LAEP components were found to differ between tinnitus and non-tinnitus subjects. Additional sensitivity analyses regarding differences in experimental conditions confirmed the robustness of these results. Differences in age and hearing levels between the two experimental groups might have a considerable impact on LAEP outcomes and should be carefully considered in future studies. Although we established consistent differences in the P300 component between tinnitus patients and controls, we could not identify any evidence that this component might covary with tinnitus severity. We conclude that out of several commonly assessed LAEP components, only the P300 can be considered as a potential biomarker for subjective tinnitus, although more research is needed to determine its relationship with subjective tinnitus measures. Future trials investigating experimental tinnitus therapies should consider including P300 measurements in the evaluation of treatment effect.

Bimodal Therapy for Chronic Subjective Tinnitus: A Randomized Controlled Trial of EMDR and TRT Versus CBT and TRT.

INTRODUCTION: To date, guidelines recommend the use of a stepped care approach to treat tinnitus. The current clinical management of tinnitus frequently consists of audiologic interventions and tinnitus retraining therapy (TRT) or cognitive behavioral therapy (CBT). Due to the high heterogeneity of the tinnitus population and comorbidity of tinnitus with insomnia, anxiety, and depression, these interventions may not be sufficient for every patient. The current study aims to determine whether a bimodal therapy for chronic, subjective tinnitus consisting of the combination of TRT and eye movement desensitization reprocessing (EMDR) results in a clinically significant different efficacy in comparison with the prevailing bimodal TRT and CBT therapy. METHODS: Patients were randomized in two treatment groups. The experimental group received the bimodal therapy TRT/EMDR and the active control group received the bimodal therapy TRT/CBT. Evaluations took place at baseline (T0), at the end of the treatment (T1), and 3 months after therapy (T2). The tinnitus functional index (TFI) was used as primary outcome measurement. Secondary outcome measurements were the visual analog scale of tinnitus loudness (VASLoudness), tinnitus questionnaire (TQ), hospital anxiety and depression scale (HADS), hyperacusis questionnaire (HQ), global perceived effect (GPE), and psychoacoustic measurements. FINDINGS: The TFI showed clinically significant improvement in both bimodal therapies (mean decrease 15.1 in TRT/CBT; p < 0.001 vs. 16.2 in TRT/EMDR; p < 0.001). The total score on the TQ, HADS, HQ, and VASLoudness all demonstrated significant decrease after treatment and follow-up (p < 0.001) in the experimental and the active control group. GPE-measurements revealed that more than 80% (i.e., 84% in TRT/CBT vs. 80% in TRT/EMDR) of the patients experienced substantial improvement of tinnitus at follow up. Treatment outcome remained stable after 3 month follow-up and no adverse events were observed. CONCLUSION: Both psychotherapeutic protocols result in a clinically significant improvement for patients with chronic subjective tinnitus. No significant different efficacy was found for the TRT/EMDR treatment compared to the combination of TRT and CBT. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03114878. April 14, 2017.

Sex Differences in the Response to Different Tinnitus Treatment.

INTRODUCTION: Tinnitus is a complex symptom requiring a thorough multidisciplinary assessment to construct an individual's tinnitus profile. The Antwerp University Hospital hosts a tertiary tinnitus clinic providing intensive, multidisciplinary tinnitus care in the form of combinational psychological treatment with either Tinnitus Retraining Therapy (TRT)/Cognitive Behavioral Therapy (CBT) or TRT/eye movement desensitization and reprocessing therapy (EMDR), high-definition transcranial direct current stimulation (HD-tDCS), and physical therapy treatment (in cases of somatic influence of the neck or the temporomandibular area). Several factors may contribute to therapy effect of which the role of gender has recently gained more interest. As such, the current manuscript explores gender differences in the outcome of different tinnitus treatments. METHODS: Data on treatment outcome of four distinct tinnitus treatments (1. HD-tDCS; 2. orofacial physical therapy; 3. combination TRT + CBT; and 4. combination TRT + EMDR) were pooled and compared. Treatment outcome was assessed via the Tinnitus Functional Index (TFI). Participants completed the TFI at baseline, immediately after treatment and after 9 weeks (±3 weeks) follow-up. To explore the effect of gender on different treatment outcomes, a linear mixed model was designed including Time point, Gender, and Therapy Group as fixed factors as well as all interactions between these factors. RESULTS: TFI scores improved significantly over time regardless of therapy group (p < 0.0001). A mean TFI decrease of at least 13 points was obtained by all participants except by those in the HD-tDCS. Significant interactions between Gender and Time point were identified in all groups except for the TRT +EMDR group. Female subjects improved more extensively than males in the HD-tDCS (p = 0.0009) and orofacial therapy group (p = 0.0299). Contrarily, in the TRT +CBT group, male participants showed a significant improvement whereas the mean TFI scores of female subjects remained on baseline levels (p = 0.0138). CONCLUSION: Our data suggest that male and female tinnitus patients seem to react differently to different therapy options. We strongly encourage further prospective studies to discern the relevance of gender in therapy outcome.

PIEZO1 activation delays erythroid differentiation of normal and hereditary xerocytosis-derived human progenitor cells.

Hereditary xerocytosis is a dominantly inherited red cell membrane disorder caused in most cases by gain-of-function mutations in PIEZO1, encoding a mechanosensitive ion channel that translates a mechanic stimulus into calcium influx. We found that PIEZO1 was expressed early in erythroid progenitor cells, and investigated whether it could be involved in erythropoiesis, besides having a role in the homeostasis of mature red cell hydration. In UT7 cells, chemical PIEZO1 activation using YODA1 repressed glycophorin A expression by 75%. This effect was PIEZO1-dependent since it was reverted using specific short hairpin-RNA knockdown. The effect of PIEZO1 activation was confirmed in human primary progenitor cells, maintaining cells at an immature stage for longer and modifying the transcriptional balance in favor of genes associated with early erythropoiesis, as shown by a high GATA2/GATA1 ratio and decreased α/ß-globin expression. The cell proliferation rate was also reduced, with accumulation of cells in G0/G1 of the cell cycle. The PIEZO1-mediated effect on UT7 cells required calcium-dependent activation of the NFAT and ERK1/2 pathways. In primary erythroid cells, PIEZO1 activation synergized with erythropoietin to activate STAT5 and ERK, indicating that it may modulate signaling pathways downstream of erythropoietin receptor activation. Finally, we studied the in-vitro erythroid differentiation of primary cells obtained from 14 PIEZO1-mutated patients, from 11 families, carrying ten different mutations. We observed a delay in erythroid differentiation in all cases, ranging from mild (n=3) to marked (n=8). Overall, these data demonstrate a role for PIEZO1 during erythropoiesis, since activation of PIEZO1 - both chemically and through activating mutations - delays erythroid maturation, providing new insights into the pathophysiology of hereditary xerocytosis.

In vivo online monitoring of testosterone-induced neuroplasticity in a female songbird.

Adult neuroplasticity in the song control system of seasonal songbirds is largely driven by photoperiod-induced increases in testosterone. Prior studies of the relationships between testosterone, song performance and neuroplasticity used invasive techniques, which prevent analyzing the dynamic changes over time and often focus on pre-defined regions-of-interest instead of examining the entire brain. Here, we combined (i) in vivo diffusion tensor imaging (DTI) to assess structural neuroplasticity with (ii) repeated monitoring of song and (iii) measures of plasma testosterone concentrations in thirteen female photosensitive starlings (Sturnus vulgaris) who received a testosterone implant for 3 weeks. We observed fast (days) and slower (weeks) effects of testosterone on song behavior and structural neuroplasticity and determined how these effects correlate on a within-subject level, which suggested separate contributions of the song motor and anterior forebrain pathways in the development of song performance. Specifically, the increase in testosterone correlated with a rapid increase of song rate and RA volume, and with changes in Area X microstructure. After implant removal, these variables rapidly reverted to baseline levels. In contrast, the more gradual improvement of song quality was positively correlated with the fractional anisotropy values (DTI metric sensitive to white matter changes) of the HVC-RA tract and of the lamina mesopallialis, which contains fibers connecting the song control nuclei. Thus, we confirmed many of the previously reported testosterone-induced effects, like the increase in song control nuclei volume, but identified for the first time a more global picture of the spatio-temporal changes in brain plasticity.