Gaussian Processes for Hearing Threshold Estimation Using Auditory Brainstem Responses.

The Auditory Brainstem Response (ABR) plays an important role in diagnosing and managing hearing loss, but can be challenging and time-consuming to measure. Test times are especially long when multiple ABR measurements are needed, e.g., when estimating hearing threshold at a range of frequencies. While many detection methods have been developed to reduce ABR test times, the majority were designed to detect the ABR at a single stimulus level and do not consider correlations in ABR waveforms across levels. These correlations hold valuable information, and can be exploited for more efficient hearing threshold estimation. This was achieved in the current work using a Gaussian Process (GP), i.e., a Bayesian approach for non-linear regression. The function to estimate with the GP was the ABR's amplitude across stimulus levels, from which hearing threshold was ultimately inferred. Active learning rules were also designed to automatically adjust the stimulus level and efficiently locate hearing threshold. Simulation results show test time reductions of up to  âˆ¼ 50% for the GP compared to a sequentially applied Hotelling's T2 test, which does not consider correlations across ABR waveforms. A case study was also included to briefly assess the GP approach in ABR data from an adult volunteer.

Evidence for a left ear bias in incidence of Meniere's disease.

OBJECTIVE: To explore a side of lesion differences in Meniere's disease (MD). DESIGN: A retrospective review (2019-2021) was conducted of patients with definite MD, as defined by 2015 Bárány Society diagnostic criteria. Testing information included pure tone audiometry, tympanometry, and extra-tympanic electrocochleography (ECochG). Normative ECochG data from healthy subjects determined the 95% cut-off value for clinical abnormality. STUDY SAMPLE: 107 patients with definite MD were included in the study and 40 healthy controls. RESULTS: The review identified 75 patients with unilateral MD and 32 patients with bilateral MD according to their clinical histories. 79% of unilateral cases were found to have MD on the L ear. 94% of bilateral MD cases had L ears more affected than R ears. Objective ECochG testing indicated a greater incidence of elevated SP/AP area curve and amplitude ratios in L ears. On binomial testing, all results indicate a highly significant bias of MD to the L side. CONCLUSIONS: Unilateral MD appears more common on the L side than the R, suggesting that the disease process underlying MD is not symmetrical. MD also appears more common in females than males. It appears that there is a physiological asymmetry in the progression/cause of MD.

Controlling test specificity for auditory evoked response detection using a frequency domain bootstrap.

BACKGROUND: Statistical detection methods are routinely used to automate auditory evoked response (AER) detection and assist clinicians with AER measurements. However, many of these methods are built around statistical assumptions that can be violated for AER data, potentially resulting in reduced or unpredictable test performances. This study explores a frequency domain bootstrap (FDB) and some FDB modifications to preserve test performance in serially correlated non-stationary data. METHOD: The FDB aims to generate many surrogate recordings, all with similar serial correlation as the original recording being analysed. Analysing the surrogates with the detection method then gives a distribution of values that can be used for inference. A potential limitation of the conventional FDB is the assumption of stationary data with a smooth power spectral density (PSD) function, which is addressed through two modifications. COMPARISONS WITH EXISTING METHODS: The FDB was compared to a conventional parametric approach and two modified FDB approaches that aim to account for heteroskedasticity and non-smooth PSD functions. Hotelling's T2(HT2) test applied to auditory brainstem responses was the test case. RESULTS: When using conventional HT2, false-positive rates deviated significantly from the nominal alpha-levels due to serial correlation. The false-positive rates of the modified FDB were consistently closer to the nominal alpha-levels, especially when data was strongly heteroskedastic or the underlying PSD function was not smooth due to e.g. power lines noise. CONCLUSION: The FDB and its modifications provide accurate, recording-dependent approximations of null distributions, and an improved control of false-positive rates relative to parametric inference for auditory brainstem response detection.

A fragmented sense of home: Reconfiguring therapeutic coastal encounters in Covid-19 times.

A growing body of research suggests positive links between coastal proximity, interaction, human health and wellbeing. In 2020, following the onset of the Covid-19 pandemic, many people in the UK could not engage in their usual coastal practices due to a national lockdown and associated restrictions, including government bans in entering the sea. This paper shares findings from an exploratory study examining how these restrictions shaped the recreational coastal practices, perceptions and emotions of residents in the case study region of Devon, South West England. In-depth semi-structured interviews were conducted with a purposive sample of 12 residents, with varying domestic and employment circumstances in the pandemic. We foreground three key themes identified through an inductive thematic analysis of the interviews: feeling 'at home' with the sea, experiencing a fragmented sense of home with Covid-19, and reconfiguring the coast as a therapeutic landscape. While important to understand the links between coastal proximity, health and wellbeing, we highlight the value of gaining more nuanced insights into the emotional, social, material and temporal dynamics that can re-shape the therapeutic potential of coastal encounter in the largely unprecedented situation of a global pandemic.

An exploration of vestibular function pre and post unilateral cochlear implantation.

Objectives: To examine the effects of unilateral cochlear implantation on the balance system for adult patients with bilateral severe to profound sensory neural hearing loss. Methods: 7 CI candidates. The function of the sacculus, utricle, and three semi-circular canals (SCCs) was assessed separately using air conduction cervical vestibular evoked myogenic potentials (VEMP), vibration ocular VEMP and the video head impulse test (vHIT) respectively on each side, pre- and post-operatively. Results: The Otoliths appear more affected by implantation than SCCs. In 3 of 7 cases VEMP was affected by implantation. In 2 cases this was associated with short-term dizziness. Discussion: Differential assessment of vestibular end organ function may elucidate how cochlear implantation affects the vestibular system. As many CI candidates have some vestibular function, pre-implant vestibular assessment may help to inform which side of implantation may best preserve that function if other audiology and surgical considerations are equal. Post-implant assessment with VEMP may help to predict short-term dizziness. More work with a larger sample will be needed to make the case for routine clinical assessment. Conclusions: There is potential benefit of conducting multimodal vestibularassessment pre and post cochlear implantation. The otoliths appear more affected by implantation than the SCC.

A group sequential test for ABR detection.

Objective: To detect the auditory brainstem response (ABR) automatically using an innovative sequentially applied Hotelling's T 2 test, with the overall goal of optimising test time whilst controlling the false-positive rate (FPR). Design: The stage-wise critical decision boundaries for accepting or rejecting the null hypothesis were found using a new approach called the Convolutional Group Sequential Test (CGST). Specificity, sensitivity, and test time were evaluated using simulations and subject recorded data. Study sample: Data consists of click-evoked ABR threshold series from 12 normal hearing adults, and recordings of EEG background activity from 17 normal hearing adults. Results: Reductions in mean test time of up to 40-45% were observed for the sequential test, relative to a conventional "single shot" test where the statistical test is applied to the data just once. To obtain these results, it will occasionally be necessary to run the test to a higher number of stimuli, i.e. the maximum test time needs to be increased. Conclusions: The CGST can be used to control the specificity of a sequentially applied ABR detection method. Doing so can reduce test time, relative to the "single shot" test, when considered across a cohort of test subjects.

Measuring depth of anaesthesia using changes in directional connectivity: a comparison with auditory middle latency response and estimated bispectral index during propofol anaesthesia.

General anaesthesia is associated with changes in connectivity between different regions of the brain, the assessment of which has the potential to provide a novel marker of anaesthetic effect. We propose an index that quantifies the strength and direction of information flow in electroencephalographic signals collected across the scalp, assess its performance in discriminating 'wakefulness' from 'anaesthesia', and compare it with estimated bispectral index and the auditory middle latency response. We used a step-wise slow induction of anaesthesia in 10 patients to assess graded changes in electroencephalographic directional connectivity at propofol effect-site concentrations of 2 µg.ml-1 , 3 µg.ml-1 and 4 µg.ml-1 . For each stable effect-site concentration, connectivity was estimated from multichannel electroencephalograms using directed coherence, together with middle latency response and estimated bispectral index. We used a linear support vector machine classifier to compare the performance of the different electroencephalographic features in discriminating wakefulness from anaesthesia. We found a significant reduction in the strength of long-range connectivity (interelectrode distance > 10 cm) (p < 0.008), and a reversal of information flow from markedly postero-frontal to fronto-posterior (p < 0.006) between wakefulness and a propofol effect-site concentration of 2 µg.ml-1 . This then remained relatively constant as effect-site concentration increased, consistent with a step change in directed coherence with anaesthesia. This contrasted with the gradual change with increasing anaesthetic dose observed for estimated bispectral index and middle latency response. Directed coherence performed best in discriminating wakefulness from anaesthesia with an accuracy of 95%, indicating the potential of this new method (on its own or combined with others) for monitoring adequacy of anaesthesia.

Objective measures for detecting the auditory brainstem response: comparisons of specificity, sensitivity and detection time.

OBJECTIVE: To evaluate and compare the specificity, sensitivity and detection time of various time-domain and multi-band frequency domain methods when detecting the auditory brainstem response (ABR). DESIGN: Simulations and subject recorded data were used to assess and compare the performance of the Hotelling's T2 test (applied in either time or frequency domain), two versions of the modified q-sample uniform scores test and both the Fsp and Fmp, which were evaluated using both conventional F-distributions with assumed degrees of freedom and a bootstrap approach. STUDY SAMPLE: Data consisted of click-evoked ABRs and recordings of EEG background activity from 12 to 17 normal hearing adults, respectively. RESULTS: An overall advantage in sensitivity and detection time was demonstrated for the Hotelling's T2 test. The false-positive rates (FPRs) of the Fsp and Fmp were also closer to the nominal alpha-level when evaluating statistical significance using the bootstrap approach, as opposed to using conventional F-distributions. The FPRs of the remaining methods were slightly higher than expected. CONCLUSIONS: In this work, Hotelling's T2 outperformed the alternative methods for automatically detecting ABRs. Its promise as a sensitive and efficient detection method should now be tested in a larger clinical study.

Directional connectivity in the EEG is able to discriminate wakefulness from NREM sleep.

A reliable measure of consciousness is of great interest for various clinical applications including sleep studies and the assessment of depth of anaesthesia. A number of measures of consciousness based on the EEG have been proposed in the literature and tested in studies of dreamless sleep, general anaesthesia and disorders of consciousness. However, reliability has remained a persistent challenge. Despite considerable theoretical and experimental effort, the neural mechanisms underlying consciousness remain unclear, but connectivity between brain regions is thought to be disrupted, impairing information flow. OBJECTIVE: The objective of the current work was to assess directional connectivity between brain regions using directed coherence and propose and assess an index that robustly reflects changes associated with non-REM sleep. APPROACH: We tested the performance on polysomnographic recordings from ten healthy subjects and compared directed coherence (and derived features) with more established measures calculated from EEG spectra. We compared the performance of the different indexes to discriminate the level of consciousness at group and individual level. MAIN RESULTS: At a group level all EEG measures could significantly discriminate NREM sleep from waking, but there was considerable individual variation. Across all individuals, normalized power, the strength of long-range connections and the direction of functional links strongly correlate with NREM sleep stages over the experimental timeline. At an individual level, of the EEG measures considered, the direction of functional links constitutes the most reliable index of the level of consciousness, highly correlating with the individual experimental time-line of sleep in all subjects. SIGNIFICANCE: Directed coherence provides a promising new means of assessing level of consciousness, firmly based on current physiological understanding of consciousness.

Is there a role for radiotherapy in the primary management of primary central nervous system lymphoma? A single-centre case series.

AIMS: In recent years, the optimum primary management of primary central nervous system lymphoma (PCNSL) has evolved from combined modality chemoradiotherapy to chemotherapy alone. We describe a single-centre case series of PCNSL with a view to assessing the role of radiotherapy in primary disease management. MATERIALS AND METHODS: West of Scotland PCNSL cases between 2001 and 2010 were identified by neuropathology. Observational data were collected retrospectively from case notes and electronic systems. RESULTS: Forty-nine patients fulfilled the eligibility criteria. The median age was 61 years. Chemotherapy with a view to consolidation radiotherapy on completion was delivered to 61% (n = 30). Regimens varied, but were generally methotrexate-based. Chemotherapy was discontinued prematurely in 80% (n = 24) due to progressive disease (n = 12), intolerable toxicity (n = 7) or death (n = 4). In all patients who progressed or did not tolerate chemotherapy, treatment was changed to immediate salvage radiotherapy; modal irradiation was 40 Gy. Radiotherapy alone was delivered to those not suitable for chemotherapy (18%, n = 9) and best supportive care to those with poor performance status (18%, n = 9). The overall median survival was 8 months. In those receiving single modality radiotherapy or chemotherapy, the median survival was 5 and 8 months, respectively. For those completing chemoradiotherapy in its entirety, 3 year survival was 100%; in groups receiving salvage radiotherapy despite progressive disease or chemotherapy toxicity, moderate survival was maintained with immediate radiotherapy with 3 year survival rates of 33 and 60%, respectively. CONCLUSIONS: Although chemotherapy alone remains the optimal treatment of PCNSL, out with clinical trials only a minority of patients complete chemotherapy due to toxicity and disease progression; in such patients, immediate salvage radiotherapy provides an effective and safe alternative with maintenance of good outcomes.

Auditory evoked potentials for monitoring during anaesthesia: a study of data quality.

UNLABELLED: The auditory evoked potential termed the middle latency response (MLR) has been suggested as an indicator of adequacy of anaesthesia during surgery. However, the response is small and must be extracted from high levels of background noise. A key consideration in using the MLR for clinical monitoring is whether data quality is sufficient to detect small changes. The aim of this study was to investigate the quality of the MLR recorded during anaesthesia, as a rigorous analysis of data quality is lacking in many studies. MLR recordings from patients sedated in intensive care after cardiac surgery were compared to recordings from a reference group of young volunteers with normal hearing. Data quality was measured with the F(sp) parameter. A bootstrap analysis was used to measure statistical response presence and to detect within-subject changes during clinical anaesthesia. Noise levels were high in the normative group probably due to myogenic and EEG activity. With 5 Hz click stimulation, MLR presence in the normative group was below 30%. Response presence improved using stimulation paradigms with chirps or maximum length sequences and reached 100% with a combination of maximum length sequences and chirps. F(sp) values generally improved during anaesthesia as noise levels reduced and MLR presence was 100% for MLS click stimulation. Changes in the MLR amplitude with propofol infusion rate were small. Some within-subject changes in MLR amplitude were detected using the bootstrap analysis, but 100% detection was not possible. CONCLUSION: Obtaining good quality MLR data in awake subjects is challenging. Data quality improves during clinical anaesthesia and with advanced stimulation methods, but reliable detection of changes in the MLR for clinical monitoring remains a challenge.

Effects of eye position on the vestibular evoked myogenic potential.

CONCLUSION: The position of a subject's eyes during vestibular evoked myogenic potential (VEMP) recording significantly alters the magnitude of the response. This change is largely due to an alteration in the tonicity of the sternocleidomastoid muscle (SCM) caused by variations in the position of the eye. However, even if electromyographic (EMG) normalization is conducted effects of eye position remain. OBJECTIVE: To determine if eye position has a significant effect on the magnitude of the VEMP. SUBJECTS AND METHODS: VEMPs were collected from 32 ears measured on 16 healthy subjects. The recordings were made unilaterally using the head turn method. The acoustic stimuli were 500 Hz air-conduction short tone bursts. VEMPs were measured in three recording conditions: (i) eyes in the same direction as head turn, (ii) eyes straight ahead, (iii) eyes in the opposite direction to head turn. RESULTS: All 32 ears tested showed a VEMP response with eyes in all three positions. Repeated measures analysis of variance (RM-ANOVA) verified an overall significant effect of eye position (p<0.001). Post hoc paired t tests revealed statistically significant differences between the eyes opposite and the other two conditions (p<0.001). Normalization of the VEMP magnitude using pre-stimulus EMG reduced the effect; however, some variability remained.

Recording the middle latency response of the auditory evoked potential as a measure of depth of anaesthesia. A technical note.

The middle latency response of the auditory evoked potential may be useful as an indicator of the hypnotic state during anaesthesia. However, it is difficult to record in some circumstances. This communication provides some suggestions and guidance for those not familiar with the technique.

Role of the cystine-knot motif at the C-terminus of rat mucin protein Muc2 in dimer formation and secretion.

DNA constructs based on the 534-amino-acid C-terminus of rat mucin protein Muc2 (RMC), were transfected into COS cells and the resultant (35)S-labelled dimers and monomers were detected by SDS/PAGE of immunoprecipitates. The cystine-knot construct, encoding the C-terminal 115 amino acids, appeared in cell lysates as a 45 kDa dimer, but was not secreted. A construct, devoid of the cystine knot, failed to form dimers. Site-specific mutagenesis within the cystine knot was performed on a conserved unpaired cysteine (designated Cys-X), which has been implicated in some cystine-knot-containing growth factors as being important for intermolecular disulphide-bond formation. Dimerization of RMC was effectively abolished. Each cysteine (Cys-1-Cys-6) comprising the three intramolecular disulphide bonds of the cystine knot was then mutated. Dimer formation was impaired in each case, although much less so for the Cys-3 mutant than the others. Abnormal high-molecular-mass, disulphide-dependent aggregates formed with mutations Cys-1, Cys-2, Cys-4 and Cys-5(,) and were poorly secreted. It is concluded that the intact cystine-knot domain is essential for dimerization of the C-terminal domain of rat Muc2, and that residue Cys-X in the knot plays a key role. The structural integrity of the cystine knot, maintained by intramolecular bonds Cys-1-Cys-4, Cys-2-Cys-5 and Cys-3-Cys-6, also appears to be important for dimerization, probably by allowing correct positioning of the unpaired Cys-X residue for stable intermolecular cystine-bond formation.

The feasibility of maximum length sequences to reduce acquisition time of the middle latency response.

Maximum length sequences (MLS) have been used to improve the signal-to-noise ratio (SNR) of otoacoustic emissions [Thornton, J. Acoust. Soc. Am. 94, 132-136 (1993)] and the auditory brainstem response [Thornton and Slaven, Br. J. Audiol. 27, 205-210 (1993)]. By implication, a shorter recording time would be required to give equal signal-to-noise ratio (SNR). This study aimed to establish whether it is also possible to improve the SNR of the auditory-evoked potential termed the middle latency response (MLR) using maximum length sequences (MLS). Recordings of 180 s each were made using a conventional recording rate and MLS rates of 42, 89, and 185 clicks/s. Three different stimulus intensities were used in the range 30 to 70 dB nHL. The rate of 89 clicks/s was found to produce most improvement in SNR for both the Na-Pa region of the MLR and the Na-Pb region. This improvement in SNR using MLS implies that an MLS rate of 89 clicks/s would produce a fourfold reduction in recording time for equal SNR over conventional recording for the Pa-Nb region of the MLR at a stimulus intensity of 70 dB nHL. The latency of the Nb wave was found to reduce significantly using MLS. An MLR could not be recorded from every subject in this study, but more subjects had an identifiable response for MLS than for conventional recordings. Use of MLS to record the MLR appears to offer the potential for reduction in test time and better wave identification.

The cationic C-terminus of rat Muc2 facilitates dimer formation post translationally and is subsequently removed by furin.

Earlier immunolocalization experiments showed that the extreme cationic C-terminus of the rat intestinal mucin Muc2 (RMC) was present at the base of intestinal goblet cells in the vicinity of ER and golgi compartments, but was not found with the rest of the mucin in apical storage granules. This prompted us to investigate the possibility that an early proteolytic cleavage reaction occurs post-translationally. A plasmid pRMC, encoding the C-terminal 534 amino acids of the mucin, was expressed in COS-7 cells and was shown to undergo cleavage at an R-T-R-R sequence located within the C-terminal 14 amino acids. Cleavage did not occur with the construct RMCfH, a furin site-mutated (A-T-A-A) counterpart of pRMCH (poly His6 tagged RMC). Addition of a furin inhibitor to COS-7 cell incubations also prevented cleavage of RMC and RMCH products. 35S pulse-chase kinetic experiments revealed that a truncated mutant lacking the C-terminal 14 amino acids (pRMCDeltaCT) forms faulty (doublet) dimers in the ER. These were not secreted as efficiently as the normal dimer of wild-type (pRMC) constructs. Thus the cationic C-terminus of rMuc2 apppears to facilitate the correct formation of normal Muc2 domain dimers.