Evaluation of Subjective Tinnitus Severity and Distortion Product Otoacoustic Emissions and Extended High-Frequency Audiometry.

OBJECTIVE: Tinnitus is a multifactorial phenomenon with quality-of-life detriments for those affected by it. We aim to establish a relationship between subjective tinnitus severity with objective audiometric data in the extended high frequency (EHF) from 9 to 16 khz and with distortion product otoacoustic emissions (DPOAE). We hypothesize that severe subjective tinnitus as measured by the Tinnitus Handicap Inventory (THI) does not correlate with increased hearing thresholds in the EHF range. STUDY DESIGN: Prospective. SETTING: Single Tertiary Care Center. METHODS: Patients identified with tinnitus and normal hearing thresholds within standard frequency range (250-8000 Hz) were consented for participation. Those with underlying otologic disease, trauma, radiotherapy, or ototoxic drug use were excluded. The THI questionnaire was given to eligible patients and audiometric test results were collected. THI scores were categorized by severity groups. An n = 20 to 30 was determined to have an effect size of 0.7 with a significance level of P = .05. RESULTS: THI and audiometric data were collected for 38 patients and categorized into mild (n = 18, 47.4%), moderate (n = 8, 21.1%), slight (n = 7, 18.4%), and severe (n = 5, 13.2%) tinnitus severity groups. Mean THI score was 32.3 ± 19.6 with a statistically significant difference in scores by assigned THI severity group (P < .01). There were no significant differences or linear relationship among hearing thresholds in EHF range or DPOAE stratified by subjective tinnitus group (P = .49, r2 = 0.10) CONCLUSION: Subjective tinnitus severity is not predictive of audiometric outcomes. This finding can be used as a counseling tool to help tinnitus patients manage symptoms, expectations, and overall treatment outcomes.

Defining the role of T lymphocytes in the immunopathogenesis of neuromyelitis optica spectrum disorder.

Auto-reactive T cells are fundamental to many autoimmune processes, including neuromyelitis optica spectrum disorder (NMOSD). Several lines of evidence indicate that an antibody against aquaporin-4 (AQP4) is present in NMOSD patients. Further, this AQP4 antibody is pathogenic and can cause profound neurological damage. T cells are fundamental to many autoimmune processes, including NMOSD. Here we review work from animal models to discuss mechanisms by which auto-reactive T cells modulate the process by which antibodies cross the blood-brain barrier and orchestrate the local inflammatory milieu underlying NMOSD pathophysiology. We also examine clinical studies that document the presence of AQP4-specific T cells and the unique cytokine profile of NMOSD patients. This work encourages a renewed and broadened attention to the fundamental role of T cells in neuroautoimmune conditions which will hopefully lead to new therapies and better patients' outcomes.

Context-dependent memory following recurrent hypoglycaemia in non-diabetic rats is mediated via glucocorticoid signalling in the dorsal hippocampus.

AIMS/HYPOTHESIS: Recurrent hypoglycaemia is primarily caused by repeated over-administration of insulin to patients with diabetes. Although cognition is impaired during hypoglycaemia, restoration of euglycaemia after recurrent hypoglycaemia is associated with improved hippocampally mediated memory. Recurrent hypoglycaemia alters glucocorticoid secretion in response to hypoglycaemia; glucocorticoids are well established to regulate hippocampal processes, suggesting a possible mechanism for recurrent hypoglycaemia modulation of subsequent cognition. We tested the hypothesis that glucocorticoids within the dorsal hippocampus might mediate the impact of recurrent hypoglycaemia on hippocampal cognitive processes. METHODS: We characterised changes in the dorsal hippocampus at several time points to identify specific mechanisms affected by recurrent hypoglycaemia, using a well-validated 3 day model of recurrent hypoglycaemia either alone or with intrahippocampal delivery of glucocorticoid (mifepristone) and mineralocorticoid (spironolactone) receptor antagonists prior to each hypoglycaemic episode. RESULTS: Recurrent hypoglycaemia enhanced learning and also increased hippocampal expression of glucocorticoid receptors, serum/glucocorticoid-regulated kinase 1, cyclic AMP response element binding (CREB) phosphorylation, and plasma membrane levels of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) receptors. Both hippocampus-dependent memory enhancement and the molecular changes were reversed by glucocorticoid receptor antagonist treatment. CONCLUSIONS/INTERPRETATION: These results indicate that increased glucocorticoid signalling during recurrent hypoglycaemia produces several changes in the dorsal hippocampus that are conducive to enhanced hippocampus-dependent contextual learning. These changes appear to be adaptive, and in addition to supporting cognition may reduce damage otherwise caused by repeated exposure to severe hypoglycaemia.

Intrahippocampal administration of a domain antibody that binds aggregated amyloid-ß reverses cognitive deficits produced by diet-induced obesity.

BACKGROUND: The prevalence of high fat diets (HFD), diet-induced obesity (DIO) and Type 2 diabetes continues to increase, associated with cognitive impairment in both humans and rodent models. Mechanisms transducing these impairments remain largely unknown: one possibility is that a common mechanism may be involved in the cognitive impairment seen in obese and/or diabetic states and in dementia, specifically Alzheimer's disease (AD). DIO is well established as a risk factor for development of AD. Oligomeric amyloid-ß (Aß) is neurotoxic, and we showed that intrahippocampal oligomeric Aß produces cognitive and metabolic dysfunction similar to that seen in DIO or diabetes. Moreover, animal models of DIO show elevated brain Aß, a hallmark of AD, suggesting that this may be one source of cognitive impairment in both conditions. METHODS: Intrahippocampal administration of a novel anti-Aß domain antibody for aggregated Aß, or a control domain antibody, to control or HFD-induced DIO rats. Spatial learning measured in a conditioned contextual fear (CCF) task after domain antibody treatment; postmortem, hippocampal NMDAR and AMPAR were measured. RESULTS: DIO caused impairment in CCF, and this impairment was eliminated by intrahippocampal administration of the active domain antibody. Measurement of hippocampal proteins suggests that DIO causes dysregulation of hippocampal AMPA receptors, which is also reversed by acute domain antibody administration. CONCLUSIONS: Our findings support the concept that oligomeric Aß within the hippocampus of DIO animals may not only be a risk factor for development of AD but may also cause cognitive impairment before the development of dementia. GENERAL SIGNIFICANCE AND INTEREST: Our work integrates the engineering of domain antibodies with conformational- and sequence-specificity for oligomeric amyloid beta with a clinically relevant model of diet-induced obesity in order to demonstrate not only the pervasive effects of obesity on several aspects of brain biochemistry and behavior, but also the bioengineering of a successful treatment against the long-term detrimental effects of a pre-diabetic state on the brain. We show for the first time that cognitive impairment linked to obesity and/or insulin resistance may be due to early accumulation of oligomeric beta-amyloid in the brain, and hence may represent a pre-Alzheimer's state.

Intratympanic steroids for idiopathic sudden sensorineural hearing loss.

OBJECTIVES: We undertook to evaluate the effectiveness of intratympanic (IT) steroid injections for treating idiopathic sudden sensorineural hearing loss (ISSHL) by performing a retrospective case series study in a private otology practice. METHODS: A total of 21 eligible patients with ISSHL were included. We defined ISSHL as a hearing loss of 20 dB or more at at least 3 consecutive audiometric frequencies that develops within 72 hours or less and cannot be attributed to any commonly identifiable cause of sudden hearing loss. Three IT injections of 0.4 mL of 62.5 mg/mL methylprednisolone solution were administered 1 week apart. The end point for the study was a clinically significant change in audiometric values, with a positive response determined to be a 10-dB or greater improvement in the 4-tone pure tone average and/ or a 15% or greater improvement in the word discrimination score. Audiometric data were recorded just before therapy and 1 week after the last IT treatment. The potentially confounding variables recorded included age, sex, "prompt treatment" (defined as treatment within 14 days from onset), concurrent or prior treatment with oral steroids, and severity of hearing loss. RESULTS: The overall response rate to the IT steroid protocol was 67% (14 of 21 patients), with a 95% confidence interval of 43% to 85%. Backward stepwise logistic regression identified "prompt treatment" as the only variable that significantly affected the outcome. The response rate of the "prompt treatment" cohort was 91% (10 of 11 patients), with a 95% confidence interval of 59% to 100%. CONCLUSIONS: These findings support the use of IT steroids as an early intervention in the treatment of ISSHL.