Tissue-Engineered Cochlear Fibrosis Model Links Complex Impedance to Fibrosis Formation for Cochlear Implant Patients.

Cochlear implants are a life-changing technology for those with severe sensorineural hearing loss, partially restoring hearing through direct electrical stimulation of the auditory nerve. However, they are known to elicit an immune response resulting in fibrotic tissue formation in the cochlea that is linked to residual hearing loss and suboptimal outcomes. Intracochlear fibrosis is difficult to track without postmortem histology, and no specific electrical marker for fibrosis exists. In this study, a tissue-engineered model of cochlear fibrosis is developed following implant placement to examine the electrical characteristics associated with fibrotic tissue formation around electrodes. The model is characterized using electrochemical impedance spectroscopy and an increase in the resistance and a decrease in capacitance of the tissue using a representative circuit are found. This result informs a new marker of fibrosis progression over time that is extractable from voltage waveform responses, which can be directly measured in cochlear implant patients. This marker is tested in a small sample size of recently implanted cochlear implant patients, showing a significant increase over two postoperative timepoints. Using this system, complex impedance is demonstrated as a marker of fibrosis progression that is directly measurable from cochlear implants to enable real-time tracking of fibrosis formation in patients, creating opportunities for earlier treatment intervention to improve cochlear implant efficacy.

Detection of Extracochlear Electrodes Using Stimulation-Current- Induced Non-Stimulating Electrode Voltage Recordings With Different Electrode Designs.

HYPOTHESIS: Stimulation-Current-Induced Non-Stimulating Electrode Voltage Recordings (SCINSEVs) can help detect extracochlear electrodes for a variety of Cochlear Implant (CI) devices. BACKGROUND: Extracochlear electrodes (EEs) occur in 9 to 13% of cochlear implantations and commonly go unnoticed without imaging. Electrodes on the electrode array located extracochlearly are associated with non-auditory stimulation and a decrease in speech outcomes. We have previously shown that SCINSEVs, with hardware and software from one manufacturer, could detect EEs. Here, we test the generalizability to other manufacturers. METHODS: Fresh-frozen human cadaveric heads were implanted with Cochlear Ltd. CI522 (CI-A) and MED-EL's FLEX24 (CI-B) electrodes. Contact impedances and SCIN- SEVs were measured, with Cochlear Ltd. research Custom Sound software (Transimpedance Matrix) and MED-EL's clinical MAESTRO (Impedance Field Telemetry), for full insertion and EEs in air, saline and soft tissue. An automated detection tool was optimized and tested for these implants. Intra-operative SCINSEVs with EEs were collected for clinical purposes for six patients. RESULTS: The pattern of SCINSEVs changed in the transition zone from intracochlear to extracochlear electrodes, even with low contact impedances on EEs. Automated detection in the cadaveric specimens, with two or more EEs in saline or soft tissue, showed a mean 91% sensitivity and specificity for CI-A and 100% sensitivity and specificity for CI-B. Quantification of EEs showed significant correlations of r  = 0.69 between estimated and actual EEs for CI-A and r = 0.76 for CI-B. CONCLUSION: The applicability of SCINSEVs to detect extra- cochlear electrodes could be expanded to other cochlear implant companies despite differences in electrode array design and measurement software.

3D printed biomimetic cochleae and machine learning co-modelling provides clinical informatics for cochlear implant patients.

Cochlear implants restore hearing in patients with severe to profound deafness by delivering electrical stimuli inside the cochlea. Understanding stimulus current spread, and how it correlates to patient-dependent factors, is hampered by the poor accessibility of the inner ear and by the lack of clinically-relevant in vitro, in vivo or in silico models. Here, we present 3D printing-neural network co-modelling for interpreting electric field imaging profiles of cochlear implant patients. With tuneable electro-anatomy, the 3D printed cochleae can replicate clinical scenarios of electric field imaging profiles at the off-stimuli positions. The co-modelling framework demonstrated autonomous and robust predictions of patient profiles or cochlear geometry, unfolded the electro-anatomical factors causing current spread, assisted on-demand printing for implant testing, and inferred patients' in vivo cochlear tissue resistivity (estimated mean = 6.6 kΩcm). We anticipate our framework will facilitate physical modelling and digital twin innovations for neuromodulation implants.

An Instrumented Cochlea Model for the Evaluation of Cochlear Implant Electrical Stimulus Spread.

Cochlear implants use electrical stimulation of the auditory nerve to restore the sensation of hearing to deaf people. Unfortunately, the stimulation current spreads extensively within the cochlea, resulting in "blurring" of the signal, and hearing that is far from normal. Current spread can be indirectly measured using the implant electrodes for both stimulating and sensing, but this provides incomplete information near the stimulating electrode due to electrode-electrolyte interface effects. Here, we present a 3D-printed "unwrapped" physical cochlea model with integrated sensing wires. We integrate resistors into the walls of the model to simulate current spread through the cochlear bony wall, and "tune" these resistances by calibration with an in-vivo electrical measurement from a cochlear implant patient. We then use this model to compare electrical current spread under different stimulation modes including monopolar, bipolar and tripolar configurations. Importantly, a trade-off is observed between stimulation amplitude and current focusing among different stimulation modes. By combining different stimulation modes and changing intracochlear current sinking configurations in the model, we explore this trade-off between stimulation amplitude and focusing further. These results will inform clinical strategies for use in delivering speech signals to cochlear implant patients.

Using Interleaved Stimulation to Measure the Size and Selectivity of the Sustained Phase-Locked Neural Response to Cochlear Implant Stimulation.

We measured the sustained neural response to electrical stimulation by a cochlear implant (CI). To do so, we interleaved two stimuli with frequencies F1 and F2 Hz and recorded a neural distortion response (NDR) at F2-F1 Hz. We show that, because any one time point contains only the F1 or F2 stimulus, the instantaneous nonlinearities typical of electrical artefact should not produce distortion at this frequency. However, if the stimulus is smoothed, such as by charge integration at the nerve membrane, subsequent (neural) nonlinearities can produce a component at F2-F1 Hz. We stimulated a single CI electrode with interleaved sinusoids or interleaved amplitude-modulated pulse trains such that F2 = 1.5F1, and found no evidence for an NDR when F2-F1 was between 90 and 120 Hz. However, interleaved amplitude-modulated pulse trains with F2-F1~40 Hz revealed a substantial NDR with a group delay of about 45 ms, consistent with a thalamic and/or cortical response. The NDR could be measured even from recording electrodes adjacent to the implant and at the highest pulse rates (> 4000 pps) used clinically. We then measured the selectivity of this sustained response by presenting F1 and F2 to different electrodes and at different between-electrode distances. This revealed a broad tuning that, we argue, reflects the overlap between the excitation elicited by the two electrodes. Our results also provide a glimpse of the neural nonlinearity in the auditory system, unaffected by the biomechanical cochlear nonlinearities that accompany acoustic stimulation. Several potential clinical applications of our findings are discussed.

Detection of Extracochlear Electrodes in Cochlear Implants with Electric Field Imaging/Transimpedance Measurements: A Human Cadaver Study.

OBJECTIVES: Extracochlear electrodes in cochlear implants (CI), defined as individual electrodes on the electrode array located outside of the cochlea, are not a rare phenomenon. The presence of extracochlear electrodes frequently goes unnoticed and could result in them being assigned stimulation frequencies that are either not delivered to, or stimulating neurons that overlap with intracochlear electrodes, potentially reducing performance. The current gold-standard for detection of extracochlear electrodes is computed tomography (CT), which is time-intensive, costly and involves radiation. It is hypothesized that a collection of Stimulation-Current-Induced Non-Stimulating Electrode Voltage recordings (SCINSEVs), commonly referred to as "transimpedance measurements (TIMs)" or electric field imaging (EFI), could be utilized to detect extracochlear electrodes even when contact impedances are low. An automated analysis tool is introduced for detection and quantification of extracochlear electrodes. DESIGN: Eight fresh-frozen human cadaveric heads were implanted with the Advanced Bionics HiRes90K with a HiFocus 1J lateral-wall electrode. The cochlea was flushed with 1.0% saline through the lateral semicircular canal. Contact impedances and SCINSEVs were recorded for complete insertion and for 1 to 5 extracochlear electrodes. Measured conditions included: air in the middle ear (to simulate electrodes situated in the middle ear), 1.0% saline in the middle ear (to simulate intraoperative conditions with saline or blood in the middle ear), and soft tissue (temporal muscle) wrapped around the extracochlear electrodes (to simulate postoperative soft-tissue encapsulation of the electrodes). Intraoperative SCINSEVs from patients were collected, for clinical purposes during slow insertion of the electrode array, as well as from a patient postoperatively with known extracochlear electrodes. RESULTS: Full insertion of the cochlear implant in the fresh-frozen human cadaveric heads with a flushed cochlea resulted in contact impedances in the range of 6.06 ± 2.99 kΩ (mean ± 2SD). Contact impedances were high when the extracochlear electrodes were located in air, but remained similar to intracochlear contact impedances when in saline or soft tissue. SCINSEVs showed a change in shape for the extracochlear electrodes in air, saline, and soft tissue. The automated analysis tool showed a specificity and sensitivity of 100% for detection of two or more extracochlear electrodes in saline and soft tissue. The quantification of two or more extracochlear electrodes was correct for 84% and 81% of the saline and soft tissue measurements, respectively. CONCLUSIONS: Our analysis of SCINSEVs (specifically the EFIs from this manufacturer) shows good potential as a detection tool for extracochlear electrodes, even when contact impedances remain similar to intracochlear values. SCINSEVs could potentially replace CT in the initial screening for extracochlear electrodes. Detecting migration of the electrode array during the final stages of surgery could potentially prevent re-insertion surgery for some CI users. The automated detection tool could assist in detection and quantification of two or more extracochlear electrodes.

Angular Electrode Insertion Depth and Speech Perception in Adults With a Cochlear Implant: A Systematic Review.

OBJECTIVE: By discussing the design, findings, strengths, and weaknesses of available studies investigating the influence of angular insertion depth on speech perception, we intend to summarize the current status of evidence; and using evidence based conclusions, possibly contribute to the determination of the optimal cochlear implant (CI) electrode position. DATA SOURCES: Our search strategy yielded 10,877 papers. PubMed, Ovid EMBASE, Web of Science, and the Cochrane Library were searched up to June 1, 2018. Both keywords and free-text terms, related to patient population, predictive factor, and outcome measurements were used. There were no restrictions in languages or year of publication. STUDY SELECTION: Seven articles were included in this systematic review. Articles eligible for inclusion: (a) investigated cochlear implantation of any CI system in adults with post-lingual onset of deafness and normal cochlear anatomy; (b) investigated the relationship between angular insertion depth and speech perception; (c) measured angular insertion depth on imaging; and (d) measured speech perception at, or beyond 1-year post-activation. DATA EXTRACTION AND SYNTHESIS: In included studies; quality was judged low-to-moderate and risk of bias, evaluated using a Quality-in-Prognostic-Studies-tool (QUIPS), was high. Included studies were too heterogeneous to perform meta-analyses, therefore, effect estimates of the individual studies are presented. Six out of seven included studies found no effect of angular insertion depth on speech perception. CONCLUSION: All included studies are characterized by methodological flaws, and therefore, evidence-based conclusions regarding the influence of angular insertion depth cannot be drawn to date.

Atypical Endometrial Polyps and Concurrent Endometrial Cancer: A Systematic Review.

OBJECTIVE: To estimate the risk of concurrent endometrial cancer in nonpolypoid endometrium when atypia was diagnosed within an endometrial polyp. DATA SOURCES: MEDLINE, EMBASE, Web of Science, and ClinicalTrials.gov were searched for studies published between 1990 and January 2015 in which 1) women with atypical hyperplastic endometrial polyps underwent a consecutive hysterectomy; or 2) the natural behavior of endometrium with concurrent atypical endometrial polyps was evaluated. METHODS OF STUDY SELECTION: Studies were selected when at least one patient within each study was initially diagnosed with an atypical endometrial polyp for which follow-up pathology was available. RESULTS: Broad searches yielded 2,922 authentic citations, 307 met criteria for full-text evaluation, and 10 met inclusion criteria. Two authors independently reviewed articles and consensus was reached. The final selection included eight retrospective studies reporting on concurrent endometrial cancer in case of atypical endometrial polyps and two follow-up studies on patients conserving their uterus after hysteroscopic resection of atypical endometrial polyps. In total, 127 patients were included with an initial diagnosis of atypical endometrial hyperplasia within polyps. Meta-analysis showed a pooled risk estimate of 5.6% (95% confidence interval [CI] 0.2-17.6%) on concurrent endometrial cancer after resection of an atypical endometrial polyp. CONCLUSION: The pooled risk estimate of 5.6% (95% CI 0.2-17.6%) on endometrial cancer when atypia is found within an endometrial polyp differs from the well-established risk of nonpolypoid atypical endometrial hyperplasia on endometrial cancer of up to 42%. This risk of endometrial cancer is important in the process of shared decision-making regarding follow-up and further treatment.

MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia.

The outcome for pediatric acute lymphoblastic leukemia (ALL) patients who relapse is dismal. A hallmark of relapsed disease is acquired resistance to multiple chemotherapeutic agents, particularly glucocorticoids. In this study, we performed a genome-scale short hairpin RNA screen to identify mediators of prednisolone sensitivity in ALL cell lines. The incorporation of these data with an integrated analysis of relapse-specific genetic and epigenetic changes allowed us to identify the mitogen-activated protein kinase (MAPK) pathway as a mediator of prednisolone resistance in pediatric ALL. We show that knockdown of the specific MAPK pathway members MEK2 and MEK4 increased sensitivity to prednisolone through distinct mechanisms. MEK4 knockdown increased sensitivity specifically to prednisolone by increasing the levels of the glucocorticoid receptor. MEK2 knockdown increased sensitivity to all chemotherapy agents tested by increasing the levels of p53. Furthermore, we demonstrate that inhibition of MEK1/2 with trametinib increased sensitivity of ALL cells and primary samples to chemotherapy in vitro and in vivo. To confirm a role for MAPK signaling in patients with relapsed ALL, we measured the activation of the MEK1/2 target ERK in matched diagnosis-relapse primary samples and observed increased phosphorylated ERK levels at relapse. Furthermore, relapse samples have an enhanced response to MEK inhibition compared to matched diagnosis samples in xenograft models. Together, our data indicate that inhibition of the MAPK pathway increases chemosensitivity to glucocorticoids and possibly other agents and that the MAPK pathway is an attractive target for prevention and/or treatment of relapsed disease.