Four-Point Impedance: A Potential Biomarker for Residual Hearing After Cochlear Implantation.

INTRODUCTION: Preservation of residual hearing after cochlear implantation allows for electroacoustic stimulation, which leads to better music appreciation, noise localization, and speech comprehension in noisy environments. Real-time intraoperative electrocochleography (rt-ECochG) monitoring has shown promise in improving residual hearing rates. Four-point impedance (4PI) is being explored as a potential biomarker in cochlear implantation that has been associated with fibrotic tissue response, hearing loss, and dizziness. In this study, we explore whether monitoring both rt-ECochG intraoperatively and postoperative 4PI improves predictions of the preservation of residual hearing. METHODS: This was a prospective cohort study. Adults with residual acoustic hearing underwent cochlear implantation with intraoperative intracochlear electrocochleography (ECochG) monitoring. The surgeon responded to a drop in ECochG signal amplitude of greater than 30% by a standardized manipulation of the electrode with the aim of restoring the ECochG. At the end of the procedure, the ECochG signal was categorized as being maintained or having dropped more than 30%. 4PI was measured on 1 day, 1 week, and 1 and 3 months after cochlear implantation. Residual hearing was measured by routine pure-tone audiogram at 3 months postoperatively. The ECochG category and 4PI impedance values were entered as factors in a multiple linear regression predicting the protection of residual hearing. RESULTS: Twenty-six patients were recruited. Rt-ECochG significantly predicted residual hearing at 3 months (t test; mean difference, 37.7%; p = 0.002). Inclusion of both 1-day or 3-month 4PI in a multiple linear regression with rt-ECochG markedly improved upon correlations with residual hearing compared with the rt-ECochG-only model (rt-ECochG and 1-d 4PI model, R2 = 0.67; rt-ECochG and 3-mo 4PI model, R2 = 0.72; rt-ECochG-only model, R2 = 0.33). CONCLUSIONS: Both rt-ECochG and 4PI predict preservation of residual hearing after cochlear implantation. These findings suggest that the biological response of the cochlea to implantation, as reflected in 4PI, is an important determinant of residual hearing, independent of the acute effects on hearing during implant surgery seen with rt-ECochG. We speculate that 4PI relates to inflammation 1 day after implantation and fibrosis at 3 months.

The Effect of Electrode Position on Behavioral and Electrophysiologic Measurements in Perimodiolar Cochlear Implants.

BACKGROUND: The shape and position of cochlear implant electrodes could potentially influence speech perception, as this determines the proximity of implant electrodes to the spiral ganglion. However, the literature to date reveals no consistent association between speech perception and either the proximity of electrode to the medial cochlear wall or the depth of insertion. These relationships were explored in a group of implant recipients receiving the same precurved electrode. METHODS: This was a retrospective study of adults who underwent cochlear implantation with Cochlear Ltd.'s Slim Perimodiolar electrode at the Royal Victorian Eye and Ear Hospital between 2015 and 2018 (n = 52). Postoperative images were obtained using cone beam computed tomography (CBCT) and analyzed by multi-planar reconstruction to identify the position of the electrode contacts within the cochlea, including estimates of the proximity of the electrodes to the medial cochlear wall or modiolus and the angular depth of insertion. Consonant-vowel-consonant (CVC) monosyllabic phonemes were determined preoperatively, and at 3 and 12 months postoperatively. Electrically evoked compound action potential (ECAP) thresholds and impedance were measured from the implant array immediately after implantation. The relationships between electrode position and speech perception, electrode impedance, and ECAP threshold were an analyzed by Pearson correlation. RESULTS: Age had a negative impact on speech perception at 3 months but not 12 months. None of the electrode-wide measures of proximity between electrode contacts and the modiolus, nor measures of proximity to the medial cochlear wall, nor the angular depth of insertion of the most apical electrode correlated with speech perception. However, there was a moderate correlation between speech perception and the position of the most basal electrode contacts; poorer speech perception was associated with a greater distance to the modiolus. ECAP thresholds were inversely related to the distance between electrode contacts and the modiolus, but there was no clear association between this distance and impedance. CONCLUSIONS: Speech perception was significantly affected by the proximity of the most basal electrodes to the modiolus, suggesting that positioning of these electrodes may be important for optimizing speech perception. ECAP thresholds might provide an indication of this proximity, allowing for its optimization during surgery.

Intra-cochlear Flushing Reduces Tissue Response to Cochlear Implantation.

INTRODUCTION: Intraoperative trauma leading to bleeding during cochlear implantation negatively impacts residual hearing of cochlear implant recipients. There are no clinical protocols for the removal of blood during implantation, to reduce the consequential effects such as inflammation and fibrosis which adversely affect cochlear health and residual hearing. This preclinical study investigated the implementation of an intra-cochlear flushing protocol for the removal of blood. METHODS: Three groups of guinea pigs were studied for 28 days after cochlear implantation; cochlear implant-only (control group); cochlear implant with blood injected into the cochlea (blood group); and cochlear implant, blood injection, and flushing of the blood from the cochlea intraoperatively (flush group). Auditory brainstem responses (ABRs) in addition to tissue response volumes were analyzed and compared between groups. RESULTS: After implantation, the blood group exhibited the highest ABR thresholds when compared to the control and flush group, particularly in the high frequencies. On the final day, the control and blood group had similar ABR thresholds across all frequencies tested, whereas the flush group had the lowest thresholds, significantly lower at 24 kHz than the blood and control group. Analysis of the tissue response showed the flush group had significantly lower tissue responses in the basal half of the array when compared with the blood and control group. CONCLUSIONS: Flushing intra-cochlear blood during surgery resulted in better auditory function and reduced subsequent fibrosis in the basal region of the cochlea. This finding prompts the implementation of a flushing protocol in clinical cochlear implantation. LEVEL OF EVIDENCE: N/A Laryngoscope, 134:1410-1416, 2024.

Electrocochleographic Patterns Predicting Increased Impedances and Hearing Loss after Cochlear Implantation.

OBJECTIVES: Different patterns of electrocochleographic responses along the electrode array after insertion of the cochlear implant electrode array have been described. However, the implications of these patterns remain unclear. Therefore, the aim of the study was to correlate different peri- and postoperative electrocochleographic patterns with four-point impedance measurements and preservation of residual hearing. DESIGN: Thirty-nine subjects with residual low-frequency hearing which were implanted with a slim-straight electrode array could prospectively be included. Intracochlear electrocochleographic recordings and four-point impedance measurements along the 22 electrodes of the array (EL, most apical EL22) were conducted immediately after complete insertion and 3 months after surgery. Hearing preservation was assessed after 3 months. RESULTS: In perioperative electrocochleographic recordings, 22 subjects (56%) showed the largest amplitude around the tip of the electrode array (apical-peak, AP, EL20 or EL22), whereas 17 subjects (44%) exhibited a maximum amplitude in more basal regions (mid-peak, MP, EL18 or lower). At 3 months, in six subjects with an AP pattern perioperatively, the location of the largest electrocochleographic response had shifted basally (apical-to-mid-peak, AP-MP). Latency was analyzed along the electrode array when this could be discerned. This was the case in 68 peri- and postoperative recordings (87% of all recordings, n = 78). The latency increased with increasing insertion depth in AP recordings (n = 38, median of EL with maximum latency shift = EL21). In MP recordings (n = 30), the maximum latency shift was detectable more basally (median EL12, p < 0.001). Four-point impedance measurements were available at both time points in 90% (n = 35) of all subjects. At the 3-month time point, recordings revealed lower impedances in the AP group (n = 15, mean = 222 Ω, SD = 63) than in the MP (n = 14, mean = 295 Ω, SD= 7 6) and AP-MP groups (n = 6, mean = 234 Ω, SD = 129; AP versus MP p = 0.026, AP versus AP-MP p = 0.023, MP versus AP-MP p > 0.999). The amplitudes of perioperative AP recordings showed a correlation with preoperative hearing thresholds ( r2 =0.351, p = 0.004). No such correlation was detectable in MP recordings ( r2 = 0.033, p = 0.484). Audiograms were available at both time points in 97% (n = 38) of all subjects. The mean postoperative hearing loss in the AP group was 13 dB (n = 16, SD = 9). A significantly larger hearing loss was detectable in the MP and AP-MP groups with 28 (n = 17, SD = 10) and 35 dB (n = 6, SD = 13), respectively (AP versus MP p = 0.002, AP versus AP-MP p = 0.002, MP versus AP-MP p = 0.926). CONCLUSION: MP and AP-MP response patterns of the electrocochleographic responses along the electrode array after cochlear implantation are correlated with higher four-point impedances and poorer postoperative hearing compared to AP response patterns. The higher impedances suggest that MP and AP-MP patterns are associated with increased intracochlear fibrosis.

Four-Point Impedance Changes After Cochlear Implantation for Lateral Wall and Perimodiolar Implants.

OBJECTIVE: Monitor four-point impedance in cochlear implant recipients over time and determine if implant type, surgical approach, and electrode positioning affected impedance measurements. STUDY DESIGN: Prospective observational. SETTING: Hospital. PATIENTS: Adult cochlear implant recipients implanted with a perimodiolar or lateral wall cochlear implant. MAIN OUTCOME MEASURES: Mean values for four-point impedances were calculated for all electrode contacts at perioperative and 3 months after surgery. Linear mixed models were applied to the impedance data to compare between implant types and time points. The angular insertion depth and electrode position relative to the medial and lateral wall, commonly termed the Intracochlear Position Index (ICPI), were collected and compared with impedance measurements. RESULTS: Perioperatively, the four-point impedance was similar between implant types, with perimodiolar implants having marginally higher impedance values in the basal region. At 3 months after surgery, impedances significantly increased in the basal half of the electrode array for both implants, with higher impedance values for CI532 implants. There were no significant differences in insertion angle depth between implant types. The ICPI values for the seven most basal electrodes were similar for both implants; however, CI532 arrays were significantly more medially placed along the remaining apical portion of the array, which is expected. ICPI values did not correlate with impedance measurements for either implant. CONCLUSIONS: Four-point impedance increases at 3 months after surgery may reflect fibrous tissue formation after cochlear implantation. The higher impedance values in perimodiolar implants may reflect a more extensive fibrosis formation as a result of surgical approaches used, requiring drilling of the cochlea bone.

Four-point Impedance Changes in the Early Post-Operative Period After Cochlear Implantation.

OBJECTIVE: Monitoring four-point impedance changes after cochlear implantation with comparison to conventional impedance measurements. Four-point impedance provides information regarding the bulk biological environment surrounding the electrode array, which is not discernible with conventional impedances. STUDY DESIGN: Prospective observational. SETTING: Hospital. PATIENTS: Adult cochlear implant recipients with no measurable hearing before implantation and implanted with a perimodiolar cochlear implant. MAIN OUTCOME MEASURES: Mean values for four-point and common ground impedances were calculated for all electrode contacts at intra-operative, 1 day, 1 week, 4 to 6 weeks, and 3 months post implantation. Linear mixed models were applied to the impedance data to compare between impedances and time points. Furthermore, patients were divided into groups dependent on the normalized change in four-point impedance from intra-operative to 1 day post-operative. The normalized change was then calculated for all other time points and compared across the two groups. RESULTS: Significant increases in four-point impedance occurred 1 day and 3 months after surgery, particularly in the basal half of the array. Four-point impedance at 1 day was highly predictive of four-point impedance at 3 months. Four-point impedance at the other time points showed marginal or no increases from intra-operative. Patients with an average increase higher than 10% in four-point impedance from intra-operative to 1 day, had significantly higher values at 3 months ( p = 0.012). These patterns were not observed in common ground impedance. CONCLUSION: This is the first study to report increases in four-point impedance within 24 hours of cochlear implantation. The increases at 1 day and 3 months align with the natural timeline of an acute and chronic inflammatory responses.

Automatic analysis of cochlear response using electrocochleography signals during cochlear implant surgery.

Cochlear implants (CIs) provide an opportunity for the hearing impaired to perceive sound through electrical stimulation of the hearing (cochlear) nerve. However, there is a high risk of losing a patient's natural hearing during CI surgery, which has been shown to reduce speech perception in noisy environments as well as music appreciation. This is a major barrier to the adoption of CIs by the hearing impaired. Electrocochleography (ECochG) has been used to detect intra-operative trauma that may lead to loss of natural hearing. There is early evidence that ECochG can enable early intervention to save natural hearing of the patient. However, detection of trauma by observing changes in the ECochG response is typically carried out by a human expert. Here, we discuss a method of automating the analysis of cochlear responses during CI surgery. We establish, using historical patient data, that the proposed method is highly accurate (∼94% and ∼95% for sensitivity and specificity respectively) when compared to a human expert. The automation of real-time cochlear response analysis is expected to improve the scalability of ECochG and improve patient safety.

The Effect of Different Round Window Sealants on Cochlear Mechanics Over Time.

BACKGROUND: This project investigated the effects of round window membrane (RWM) sealants after surgical incision, with a focus on audiological thresholds, ossicular mechanics, and the impact upon cochlear function and pathology. METHODS: Twenty-eight guinea pigs were randomly allocated to one of three sealant groups (muscle, n = 7; fascia, n = 7, Tisseel, n = 8) or an unsealed control group (n = 6). Preoperative hearing was measured using auditory brainstem responses (ABRs). The ossicular chain and RWM were exposed surgically, and Laser Doppler Vibrometry (LDV) measurements were obtained from the long process of the incus. The RWM was incised then sealed (or left unsealed) according to group. ABR testing and LDV measurements were repeated 4 and 12 weeks after surgery. At 12 weeks all cochleae were harvested. RESULTS: ABR thresholds deteriorated over time in all groups. Overall, group was not statistically significant (p = 0.064). There was no significant effect by group on LDV measurements (p = 0.798). Histopathological analyses of the RWM showed that the fascia group had more extensive fibrosis than other groups (Independent-Samples Median Test, p = 0.001). However, there were minimal differences in the outer hair cell counts between the different intervention groups. CONCLUSIONS: All the interventions appeared to be safe while none affected the cochlear mechanics or hearing thresholds in a statistically significant manner.

Real Time Monitoring During Cochlear Implantation: Increasing the Accuracy of Predicting Residual Hearing Outcomes.

OBJECTIVES: Real-time electrocochleography (rt-ECochG) is a method to detect intracochlear potential changes during cochlear implantation (CI). Steep amplitude drops of the cochlear microphonic (CM) signal (so called "ECochG events") have been correlated with worse residual hearing outcomes. However, the sensitivity and specificity of monitoring CM amplitude on its own are too low to use it as a biomarker. The aim of this article was to establish if additional signal components would help to better predict postoperative hearing outcomes. DESIGN AND SETTING: Single-center, prospective cohort study at a tertiary referral hospital. PARTICIPANTS AND INTERVENTIONS: Between 2017 and 2020, we included 73 adult patients receiving a lateral wall cochlear implant electrode. During electrode insertion, rt-ECochG measurements were performed. MAIN OUTCOMES: We calculated a multiple regression analysis for patients with one ECochG event. The dependant variable was the relative acoustic hearing result 4 weeks after surgery. Independent variables were CM latency, a ratio of the auditory nerve neurophonic to the CM (the ANN/CM index) as well as CM signal recovery. RESULTS: The change of the ANN/CM index linearly correlated with acoustic hearing outcomes 4 weeks after surgery. Adding this factor led to a statistically significant increase in the variance accounted for by the regression model. CONCLUSIONS: When monitoring the implantation process with rt-ECochG, prediction of postoperative hearing thresholds is improved by addition of the ANN/CM index to a model that includes CM amplitude fluctuation.

Toward a Better Understanding of Electrocochleography: Analysis of Real-Time Recordings.

OBJECTIVES: Real-time electrocochleography (ECochG) has been used as a monitoring tool during cochlear implantation (CI), whereby, amplitude drops have been correlated with postoperative acoustic hearing results. However, no consensus has been reached as to how a single event of an amplitude drop should be characterized. The aim of this study was to identify ECochG events that predict loss of hearing 1 month after surgery. DESIGN: Fifty-five patients were included in this prospective cohort study. Real-time ECochG measurements were performed during CI electrode insertion. Single ECochG events were characterized according to their amplitude loss and slope steepness. RESULTS: Using receiver operating characteristic analyses, the most efficient cut-off criterion for a relative hearing loss of 25% was an amplitude loss of 61% at a fixed slope steepness of 0.2 µV/sec. Three-quarters of our population had at least one such event during implantation. Most events occurred shortly before full insertion. With increasing number of events, median residual hearing thresholds deteriorated for all frequencies. Larger amplitude drops trended toward worse hearing preservation. Signal recovery after an ECochG event could not be correlated to acoustic hearing outcomes. CONCLUSIONS: Our data suggest that amplitude drops exceeding 61% of the ongoing signal at a slope steepness of 0.2 µV/sec are correlated with worse acoustic hearing preservation. Clearly defined ECochG events have the potential to guide surgeons during CI in the future. This is essential if a fully automated data analysis is to be employed or benchmarking undertaken.

Four-point impedance as a biomarker for bleeding during cochlear implantation.

Cochlear implantation has successfully restored the perception of hearing for nearly 200 thousand profoundly deaf adults and children. More recently, implant candidature has expanded to include those with considerable natural hearing which, when preserved, provides an improved hearing experience in noisy environments. But more than half of these patients lose this natural hearing soon after implantation. To reduce this burden, biosensing technologies are emerging that provide feedback on the quality of surgery. Here we report clinical findings on a new intra-operative measurement of electrical impedance (4-point impedance) which, when elevated, is associated with high rates of post-operative hearing loss and vestibular dysfunction. In vivo and in vitro data presented suggest that elevated 4-point impedance is likely due to the presence of blood within the cochlea rather than its geometry. Four-point impedance is a new marker for the detection of cochlear injury causing bleeding, that may be incorporated into intraoperative monitoring protocols during CI surgery.

On-line stable isotope gas exchange reveals an inducible but leaky carbon concentrating mechanism in Nannochloropsis salina.

Carbon concentrating mechanisms (CCMs) are common among microalgae, but their regulation and even existence in some of the most promising biofuel production strains is poorly understood. This is partly because screening for new strains does not commonly include assessment of CCM function or regulation despite its fundamental role in primary carbon metabolism. In addition, the inducible nature of many microalgal CCMs means that environmental conditions should be considered when assessing CCM function and its potential impact on biofuels. In this study, we address the effect of environmental conditions by combining novel, high frequency, on-line (13)CO2 gas exchange screen with microscope-based lipid characterization to assess CCM function in Nannochloropsis salina and its interaction with lipid production. Regulation of CCM function was explored by changing the concentration of CO2 provided to continuous cultures in airlift bioreactors where cell density was kept constant across conditions by controlling the rate of media supply. Our isotopic gas exchange results were consistent with N. salina having an inducible "pump-leak" style CCM similar to that of Nannochloropsis gaditana. Though cells grew faster at high CO2 and had higher rates of net CO2 uptake, we did not observe significant differences in lipid content between conditions. Since the rate of CO2 supply was much higher for the high CO2 conditions, we calculated that growing cells bubbled with low CO2 is about 40 % more efficient for carbon capture than bubbling with high CO2. We attribute this higher efficiency to the activity of a CCM under low CO2 conditions.

The light intensity under which cells are grown controls the type of peripheral light-harvesting complexes that are assembled in a purple photosynthetic bacterium.

The differing composition of LH2 (peripheral light-harvesting) complexes present in Rhodopseudomonas palustris 2.1.6 have been investigated when cells are grown under progressively decreasing light intensity. Detailed analysis of their absorption spectra reveals that there must be more than two types of LH2 complexes present. Purified HL (high-light) and LL (low-light) LH2 complexes have mixed apoprotein compositions. The HL complexes contain PucAB(a) and PucAB(b) apoproteins. The LL complexes contain PucAB(a), PucAB(d) and PucB(b)-only apoproteins. This mixed apoprotein composition can explain their resonance Raman spectra. Crystallographic studies and molecular sieve chromatography suggest that both the HL and the LL complexes are nonameric. Furthermore, the electron-density maps do not support the existence of an additional Bchl (bacteriochlorophyll) molecule; rather the density is attributed to the N-termini of the α-polypeptide.

Kinetics and energetics of electron transfer in reaction centers of the photosynthetic bacterium Roseiflexus castenholzii.

The kinetics and thermodynamics of the photochemical reactions of the purified reaction center (RC)-cytochrome (Cyt) complex from the chlorosome-lacking, filamentous anoxygenic phototroph, Roseiflexus castenholzii are presented. The RC consists of L- and M-polypeptides containing three bacteriochlorophyll (BChl), three bacteriopheophytin (BPh) and two quinones (Q(A) and Q(B)), and the Cyt is a tetraheme subunit. Two of the BChls form a dimer P that is the primary electron donor. At 285K, the lifetimes of the excited singlet state, P*, and the charge-separated state P(+)H(A)(-) (where H(A) is the photoactive BPh) were found to be 3.2±0.3 ps and 200±20 ps, respectively. Overall charge separation P*→→ P(+)Q(A)(-) occurred with ≥90% yield at 285K. At 77K, the P* lifetime was somewhat shorter and the P(+)H(A)(-) lifetime was essentially unchanged. Poteniometric titrations gave a P(865)/P(865)(+) midpoint potential of +390mV vs. SHE. For the tetraheme Cyt two distinct midpoint potentials of +85 and +265mV were measured, likely reflecting a pair of low-potential hemes and a pair of high-potential hemes, respectively. The time course of electron transfer from reduced Cyt to P(+) suggests an arrangement where the highest potential heme is not located immediately adjacent to P. Comparisons of these and other properties of isolated Roseiflexus castenholzii RCs to those from its close relative Chloroflexus aurantiacus and to RCs from the purple bacteria are made.

Pigment organization in the photosynthetic apparatus of Roseiflexus castenholzii.

The light-harvesting-reaction center (LHRC) complex from the chlorosome-lacking filamentous anoxygenic phototroph (FAP), Roseiflexus castenholzii (R. castenholzii) was purified and characterized for overall pigment organization. The LHRC is a single complex that is comprised of light harvesting (LH) and reaction center (RC) polypeptides as well as an attached c-type cytochrome. The dominant carotenoid found in the LHRC is keto-gamma-carotene, which transfers excitation to the long wavelength antenna band with 35% efficiency. Linear dichroism and fluorescence polarization measurements indicate that the long wavelength antenna pigments absorbing around 880 nm are perpendicular to the membrane plane, with the corresponding Q(y) transition dipoles in the plane of the membrane. The antenna pigments absorbing around 800 nm, as well as the bound carotenoid, are oriented at a large angle with respect to the membrane. The antenna pigments spectroscopically resemble the well-studied LH2 complex from purple bacteria, however the close association with the RC makes the light harvesting component of this complex functionally more like LH1.