Insights Into Electrophysiological Metrics of Cochlear Health in Cochlear Implant Users Using a Computational Model.

PURPOSE: The hearing outcomes of cochlear implant users depend on the functional status of the electrode-neuron interface inside the cochlea. This can be assessed by measuring electrically evoked compound action potentials (eCAPs). Variations in cochlear neural health and survival are reflected in eCAP-based metrics. The difficulty in translating promising results from animal studies into clinical use has raised questions about to what degree eCAP-based metrics are influenced by non-neural factors. Here, we addressed these questions using a computational model. METHODS: A 2-D computational model was designed to simulate how electrical signals from the stimulating electrode reach the auditory nerve fibers distributed along the cochlea, evoking action potentials that can be recorded as compound responses at the recording electrodes. Effects of physiologically relevant variations in neural survival and in electrode-neuron and stimulating-recording electrode distances on eCAP amplitude growth functions (AGFs) were investigated. RESULTS: In line with existing literature, the predicted eCAP AGF slopes and the inter-phase gap (IPG) effects depended on the neural survival, but only when the IPG effect was calculated as the difference between the slopes of the two AGFs expressed in linear input-output scale. As expected, shallower eCAP AGF slopes were obtained for increased stimulating-recording electrode distance and larger eCAP thresholds for greater electrode-neuron distance. These non-neural factors had also minor interference on the predicted IPG effect. CONCLUSIONS: The model predictions demonstrate previously found dependencies of eCAP metrics on neural survival and non-neural aspects. The present findings confirm data from animal studies and provide insights into applying described metrics in clinical practice.

Direct Cochlear Recordings in Humans Show a Theta Rhythmic Modulation of Auditory Nerve Activity by Selective Attention.

The architecture of the efferent auditory system enables prioritization of strongly overlapping spatiotemporal cochlear activation patterns elicited by relevant and irrelevant inputs. So far, attempts at finding such attentional modulations of cochlear activity delivered indirect insights in humans or required direct recordings in animals. The extent to which spiral ganglion cells forming the human auditory nerve are sensitive to selective attention remains largely unknown. We investigated this question by testing the effects of attending to either the auditory or visual modality in human cochlear implant (CI) users (3 female, 13 male). Auditory nerve activity was directly recorded with standard CIs during a silent (anticipatory) cue-target interval. When attending the upcoming auditory input, ongoing auditory nerve activity within the theta range (5-8 Hz) was enhanced. Crucially, using the broadband signal (4-25 Hz), a classifier was even able to decode the attended modality from single-trial data. Follow-up analysis showed that the effect was not driven by a narrow frequency in particular. Using direct cochlear recordings from deaf individuals, our findings suggest that cochlear spiral ganglion cells are sensitive to top-down attentional modulations. Given the putatively broad hair-cell degeneration of these individuals, the effects are likely mediated by alternative efferent pathways compared with previous studies using otoacoustic emissions. Successful classification of single-trial data could additionally have a significant impact on future closed-loop CI developments that incorporate real-time optimization of CI parameters based on the current mental state of the user.SIGNIFICANCE STATEMENT The efferent auditory system in principle allows top-down modulation of auditory nerve activity; however, evidence for this is lacking in humans. Using cochlear recordings in participants performing an audiovisual attention task, we show that ongoing auditory nerve activity in the silent cue-target period is directly modulated by selective attention. Specifically, ongoing auditory nerve activity is enhanced within the theta range when attending upcoming auditory input. Furthermore, over a broader frequency range, the attended modality can be decoded from single-trial data. Demonstrating this direct top-down influence on auditory nerve activity substantially extends previous works that focus on outer hair cell activity. Generally, our work could promote the use of standard cochlear implant electrodes to study cognitive neuroscientific questions.

Comparison of automated and traditional ECAP recording approaches in clinical practice.

OBJECTIVE: The traditional method of recording electrically evoked compound action potentials (ECAPs), as implemented in the MAESTRO clinical software (standard ART), requires manual adjustments during threshold determination through a specialist. The "FineGrain" research tool (FineGrain RT) uses a continuous stimulation paradigm combined with automatic ECAP threshold determination. The aim of this study was to compare the FineGrain RT with standard ART. DESIGN: ECAPs were recorded with standard ART and the FineGrain RT in paediatric cochlear implant recipients. Different stimulation rates were used for FineGrain ECAP recordings (40, 60, and 76 Hz). STUDY SAMPLE: Thirteen children (6 - 19 years) participated in this study - nine were bilaterally and four unilaterally implanted, resulting in a total of twenty-two implanted ears. RESULTS: ECAP threshold determination success rates were similar between the two approaches (92% and 89%) and ECAP thresholds correlated well (r: 0.94, p < 2.2e-16) with average ART thresholds being lower than FineGrain RT thresholds. FineGrain stimulation with different stimulation rates did not have a significant effect on ECAP thresholds but ECAP thresholds at medial and apical contacts were lower compared to basal contacts. CONCLUSIONS: TheFineGrain research approach is a reliable replacement for standard ART in clinical practice.

Comparison of a Traditional and Novel Evoked Compound Action Potentials Recording Approach and Evoked Auditory Brainstem Responses in Pediatric Cochlear Implants Users.

OBJECTIVES: Electrically evoked compound action potentials (eCAP) recordings are widely used in functional evaluation and fitting of cochlear implants (CI) in clinics. We compared the results from two eCAP recording approaches (StandardART and FineGrain, MED-EL, Austria). The FineGrain method is more advanced than the Auditory Nerve Response Telemetry (StandardART) method in terms of the stimulation and algorithm for the eCAP threshold detection. To understand the benefits of these alterations, we compared the two methods on a larger scale in pediatric CI users alongside evoked auditory brainstem responses (eABR). MATERIALS AND METHODS: We collected the eCAP recordings obtained with both methods from a population of pediatric subjects with CI, either intra- or post-operatively. The eABR recordings were only collected post-operatively. For comparability reasons, we used the same stimulation rate and similar amplitude levels for all three approaches. RESULTS: Our results demonstrate that, although the success rates are similar, the FineGrain method outperforms traditional StandardART in terms of robustness and measurement duration. The eCAP recordings in general outperform the eABR in terms of speed. CONCLUSION: We conclude that the eCAP recordings are the method of choice for measuring the auditory neural activity, and FineGrain outperforms StandardART. From the three investigated approaches, we conclude that FineGrain performed best and should be the first-choice method in pediatric patients.

Characterization of Cochlear, Vestibular and Cochlear-Vestibular Electrically Evoked Compound Action Potentials in Patients with a Vestibulo-Cochlear Implant.

The peripheral vestibular system is critical for the execution of activities of daily life as it provides movement and orientation information to motor and sensory systems. Patients with bilateral vestibular hypofunction experience a significant decrease in quality of life and have currently no viable treatment option. Vestibular implants could eventually restore vestibular function. Most vestibular implant prototypes to date are modified cochlear implants to fast-track development. These use various objective measurements, such as the electrically evoked compound action potential (eCAP), to supplement behavioral information. We investigated whether eCAPs could be recorded in patients with a vestibulo-cochlear implant. Specifically, eCAPs were successfully recorded for cochlear and vestibular setups, as well as for mixed cochlear-vestibular setups. Similarities and slight differences were found for the recordings of the three setups. These findings demonstrated the feasibility of eCAP recording with a vestibulo-cochlear implant. They could be used in the short term to reduce current spread and avoid activation of non-targeted neurons. More research is warranted to better understand the neural origin of vestibular eCAPs and to utilize them for clinical applications.

Assessing the Firing Properties of the Electrically Stimulated Auditory Nerve Using a Convolution Model.

The electrically evoked compound action potential (eCAP) is a routinely performed measure of the auditory nerve in cochlear implant users. Using a convolution model of the eCAP, additional information about the neural firing properties can be obtained, which may provide relevant information about the health of the auditory nerve. In this study, guinea pigs with various degrees of nerve degeneration were used to directly relate firing properties to nerve histology. The same convolution model was applied on human eCAPs to examine similarities and ultimately to examine its clinical applicability. For most eCAPs, the estimated nerve firing probability was bimodal and could be parameterised by two Gaussian distributions with an average latency difference of 0.4 ms. The ratio of the scaling factors of the late and early component increased with neural degeneration in the guinea pig. This ratio decreased with stimulation intensity in humans. The latency of the early component decreased with neural degeneration in the guinea pig. Indirectly, this was observed in humans as well, assuming that the cochlear base exhibits more neural degeneration than the apex. Differences between guinea pigs and humans were observed, among other parameters, in the width of the early component: very robust in guinea pig, and dependent on stimulation intensity and cochlear region in humans. We conclude that the deconvolution of the eCAP is a valuable addition to existing analyses, in particular as it reveals two separate firing components in the auditory nerve.

Noninvasive detection of lung cancer by analysis of exhaled breath.

BACKGROUND: Lung cancer is one of the leading causes of death in Europe and the western world. At present, diagnosis of lung cancer very often happens late in the course of the disease since inexpensive, non-invasive and sufficiently sensitive and specific screening methods are not available. Even though the CT diagnostic methods are good, it must be assured that "screening benefit outweighs risk, across all individuals screened, not only those with lung cancer". An early non-invasive diagnosis of lung cancer would improve prognosis and enlarge treatment options. Analysis of exhaled breath would be an ideal diagnostic method, since it is non-invasive and totally painless. METHODS: Exhaled breath and inhaled room air samples were analyzed using proton transfer reaction mass spectrometry (PTR-MS) and solid phase microextraction with subsequent gas chromatography mass spectrometry (SPME-GCMS). For the PTR-MS measurements, 220 lung cancer patients and 441 healthy volunteers were recruited. For the GCMS measurements, we collected samples from 65 lung cancer patients and 31 healthy volunteers. Lung cancer patients were in different disease stages and under treatment with different regimes. Mixed expiratory and indoor air samples were collected in Tedlar bags, and either analyzed directly by PTR-MS or transferred to glass vials and analyzed by gas chromatography mass spectrometry (GCMS). Only those measurements of compounds were considered, which showed at least a 15% higher concentration in exhaled breath than in indoor air. Compounds related to smoking behavior such as acetonitrile and benzene were not used to differentiate between lung cancer patients and healthy volunteers. RESULTS: Isoprene, acetone and methanol are compounds appearing in everybody's exhaled breath. These three main compounds of exhaled breath show slightly lower concentrations in lung cancer patients as compared to healthy volunteers (p < 0.01 for isoprene and acetone, p = 0.011 for methanol; PTR-MS measurements). A comparison of the GCMS-results of 65 lung cancer patients with those of 31 healthy volunteers revealed differences in concentration for more than 50 compounds. Sensitivity for detection of lung cancer patients based on presence of (one of) 4 different compounds not arising in exhaled breath of healthy volunteers was 52% with a specificity of 100%. Using 15 (or 21) different compounds for distinction, sensitivity was 71% (80%) with a specificity of 100%. Potential marker compounds are alcohols, aldehydes, ketones and hydrocarbons. CONCLUSION: GCMS-SPME is a relatively insensitive method. Hence compounds not appearing in exhaled breath of healthy volunteers may be below the limit of detection (LOD). PTR-MS, on the other hand, does not need preconcentration and gives much more reliable quantitative results then GCMS-SPME. The shortcoming of PTR-MS is that it cannot identify compounds with certainty. Hence SPME-GCMS and PTR-MS complement each other, each method having its particular advantages and disadvantages. Exhaled breath analysis is promising to become a future non-invasive lung cancer screening method. In order to proceed towards this goal, precise identification of compounds observed in exhaled breath of lung cancer patients is necessary. Comparison with compounds released from lung cancer cell cultures, and additional information on exhaled breath composition in other cancer forms will be important.

Breath isoprene--aspects of normal physiology related to age, gender and cholesterol profile as determined in a proton transfer reaction mass spectrometry study.

BACKGROUND: This study was performed to clarify variations in breath isoprene concentrations with age, gender, body mass index (BMI) and total serum cholesterol. Our cohort consisted of 205 adult volunteers of different smoking background without health complaints. Total cholesterol in blood serum was measured in 79 of these volunteers. METHODS: Mixed expiratory exhaled breath was sampled using Tedlar bags. Concentrations of isoprene were then determined using proton transfer reaction-mass spectrometry. RESULTS: Isoprene concentrations ranged from 5.8 to 274.9 ppb, with an overall geometric mean (GM) of 99.3 ppb. There was no statistically significant difference in mean isoprene in breath between males and females (GM 105.4 and 95.5 ppb, respectively). Ageing led to a decrease in concentration in men, with an estimated slope of the regression line for log-transformed isoprene concentrations of -0.0049, but did not influence isoprene levels in women. We did not observe any significant correlation between isoprene breath content and cholesterol level in blood, even after adjusting for the possible influence of age. Similarly, no correlation was found between isoprene levels and BMI. CONCLUSIONS: Isoprene concentrations in exhaled breath showed gender-specific correlations with respect to age. Further investigations are necessary to clarify the relation between isoprene concentrations in exhaled breath and cholesterol levels and synthesis rates in blood.

Compounds enhanced in a mass spectrometric profile of smokers' exhaled breath versus non-smokers as determined in a pilot study using PTR-MS.

A pilot study has been carried out to define typical characteristics of the trace gas compounds in exhaled breath of non-smokers and smokers to assist interpretation of breath analysis data from patients who smoke with respiratory diseases and lung cancer. Exhaled breath was analyzed using proton transfer reaction-mass spectrometry (PTR-MS) for 370 volunteers (81 smokers, 210 non-smokers, 79 ex-smokers). Volatile organic compounds corresponding to product ions at seven mass-to-charge ratios (m/z 28, 42, 69, 79, 93, 97, 123) in the PTR-MS spectra differentiated between smokers and non-smokers. The Youden index (= maximum of sensitivity + specificity - 1, YI) as a measure for differentiation between smokers and non-smokers was YI = 0.43 for ions at the m/z values 28 (tentatively identified as HCN), YI = 0.75 for m/z = 42 (tentatively identified as acetonitrile) and YI = 0.53 for m/z = 79 (tentatively identified as benzene). No statistically significant difference between smokers and non-smokers was observed for the product ions at m/z = 31 and 33 (compounds tentatively identified as formaldehyde and methanol). When interpreting the exhaled breath of lung cancer or COPD patients, who often smoke, compounds appearing at the above-mentioned seven mass-to-charge ratios should be considered with appropriate care to avoid misdiagnosis. Validation studies in larger numbers of patients with more precise delineation of their smoking behavior and using additional analytical techniques such as GC/MS and SIFT-MS should be carried out.

Variability issues in determining the concentration of isoprene in human breath by PTR-MS.

This paper deals with variability issues connected with the proton transfer reaction-mass spectrometry (PTR-MS) measurements of isoprene concentration. We focus on isoprene as an abundant and widely studied compound in human breath. The variability caused by the measurement process is described by the within-sample distribution. Thus, based on the formula for computing isoprene concentration that reflects the principle of the PTR-MS, a theoretical model for the within-sample distribution of isoprene concentration is suggested. This model, which assumes that the distribution is proportional to a quotient of two independent Poisson-distributed random variables, is then confronted with empirical distributions obtained from 17 breath samples collected from a healthy individual within a month. (In each sample, isoprene concentration was determined 97 times.) The empirical within-sample distributions are also compared to normal and log-normal distributions. While those seem to be satisfactory approximations, the theoretical model is found suitable only in 10 out of 17 breath samples. We also comment on the stability of samples during the measurement process in the PTR-MS instrument and, for the sake of comparison, determine the within-sample and the within-subject variability of isoprene concentrations in our data. The respective geometric standard deviations are 1.01 and 1.29.