Minoo Lenarz

RORγt+ Innate Lymphoid Cells Acquire a Proinflammatory Program upon Engagement of the Activating Receptor NKp44

RORγt⁺ innate lymphoid cells (ILCs) are crucial players of innate immune responses and represent a major source of interleukin-22 (IL-22), which has an important role in mucosal homeostasis. The signals required by RORγt⁺ ILCs to express IL-22 and other cytokines have been elucidated only partially. Here we showed that RORγt⁺ ILCs can directly sense the environment by the engagement of the activating receptor NKp44. NKp44 triggering in RORγt⁺ ILCs selectively activated a coordinated proinflammatory program, including tumor necrosis factor (TNF), whereas cytokine stimulation preferentially induced IL-22 expression. However, combined engagement of NKp44 and cytokine receptors resulted in a strong synergistic effect. These data support the concept that NKp44⁺ RORγt⁺ ILCs can be activated without cytokines and are able to switch between IL-22 or TNF production, depending on the triggering stimulus.

Electrical stimulation of the midbrain for hearing restoration: Insight into the functional organization of the human central auditory system

The cochlear implant can restore speech perception in patients with sensorineural hearing loss. However, it is ineffective for those without an implantable cochlea or a functional auditory nerve. These patients can be implanted with the auditory brainstem implant (ABI), which stimulates the surface of the cochlear nucleus. Unfortunately, the ABI has achieved limited success in its main patient group [i.e., those with neurofibromatosis type 2 (NF2)] and requires a difficult surgical procedure. These limitations have motivated us to develop a new hearing prosthesis that stimulates the midbrain with a penetrating electrode array. We recently implanted three patients with the auditory midbrain implant (AMI), and it has proven to be safe with minimal movement over time. The AMI provides loudness, pitch, temporal, and directional cues, features that have shown to be important for speech perception and more complex sound processing. Thus far, all three patients obtain enhancements in lip reading capabilities and environmental awareness and some improvements in speech perception comparable with that of NF2 ABI patients. Considering that our midbrain target is more surgically exposable than the cochlear nucleus, this argues for the use of the AMI as an alternative to the ABI. Fortunately, we were able to stimulate different midbrain regions in our patients and investigate the functional organization of the human central auditory system. These findings provide some insight into how we may need to stimulate the midbrain to improve hearing performance with the AMI.

Auditory Midbrain Implant: A Review

The auditory midbrain implant (AMI) is a new hearing prosthesis designed for stimulation of the inferior colliculus in deaf patients who cannot sufficiently benefit from cochlear implants. The authors have begun clinical trials in which five patients have been implanted with a single shank AMI array (20 electrodes). The goal of this review is to summarize the development and research that has led to the translation of the AMI from a concept into the first patients. This study presents the rationale and design concept for the AMI as well a summary of the animal safety and feasibility studies that were required for clinical approval. The authors also present the initial surgical, psychophysical, and speech results from the first three implanted patients. Overall, the results have been encouraging in terms of the safety and functionality of the implant. All patients obtain improvements in hearing capabilities on a daily basis. However, performance varies dramatically across patients depending on the implant location within the midbrain with the best performer still not able to achieve open set speech perception without lip-reading cues. Stimulation of the auditory midbrain provides a wide range of level, spectral, and temporal cues, all of which are important for speech understanding, but they do not appear to sufficiently fuse together to enable open set speech perception with the currently used stimulation strategies. Finally, several issues and hypotheses for why current patients obtain limited speech perception along with several feasible solutions for improving AMI implementation are presented.

The auditory midbrain implant: Effects of electrode location

The auditory midbrain implant (AMI) is a new hearing prosthesis designed for stimulation of the inferior colliculus in patients who do not receive sufficient benefit from cochlear or brainstem prostheses. We have begun clinical trials in which three patients have been implanted with the AMI. Although the intended target was the central nucleus of the inferior colliculus (ICC), the electrode array was implanted into different locations across patients (i.e., ICC, dorsal cortex of inferior colliculus, lateral lemniscus). In this paper, we will summarize the effects of electrical stimulation of these different midbrain regions on various psychophysical properties and speech perception performance. The patient implanted within the intended target, the ICC, exhibited the greatest improvements in hearing performance. However, this patient has not yet achieved open-set speech perception to the performance level typically observed for cochlear implant patients, which we believe is partially due to the location of the array within the ICC. We will present findings from previous AMI studies in guinea pigs demonstrating the existence of spatially distinct functional output regions within the ICC and suggesting that further improvements in performance may be achieved by stimulating within a rostral-ventral region. Remaining questions include if a similar organization exists in the human ICC and if stimulation of its rostral-ventral region with currently available strategies (i.e., those designed for cochlear implants) can restore sufficient speech perception.

A true minimally invasive approach for cochlear implantation: high accuracy in cranial base navigation through flat-panel-based volume computed tomography.

Objective: High-precision intraoperative navigation using high-resolution flat-panel volume computed tomography makes feasible the possibility of minimally invasive cochlear implant surgery, including cochleostomy. Conventional cochlear implant surgery is typically performed via mastoidectomy with facial recess to identify and avoid damage to vital anatomic landmarks. To accomplish this procedure via a minimally invasive approach-without performing mastoidectomy-in a precise fashion, image-guided technology is necessary. With such an approach, surgical time and expertise may be reduced, and hearing preservation may be improved. Interventions: Flat-panel volume computed tomography was used to scan 4 human temporal bones. A drilling channel was planned preoperatively from the mastoid surface to the round window niche, providing a margin of safety to all functional important structures (e.g., facial nerve, chorda tympani, incus). Main Outcome Measures: Postoperatively, computed tomographic imaging and conventional surgical exploration of the drilled route to the cochlea were performed. Results: All 4 specimens showed a cochleostomy located at the scala tympani anterior inferior to the round window. The chorda tympani was damaged in 1 specimen-this was preoperatively planned as a narrow facial recess was encountered. Conclusion: Using flat-panel volume computed tomography for image-guided surgical navigation, we were able to perform minimally invasive cochlear implant surgery defined as a narrow, single-channel mastoidotomy with cochleostomy. Although this finding is preliminary, it is technologically achievable.

Demagnetization of Cochlear Implants and Temperature Changes in 3.0T MRI Environment

Objective To investigate the level of demagnetization of the magnets and temperature changes in cochlear implants (Cis) in a 3.0 tesla (3.0T) MRI. Study Design Experimental. Subjects and Methods Demagnetization and remagnetization measurements were done on magnets for different types of CIs. Temperature of different body and electrode sides was measured in the MRI environment. Results Demagnetization of the magnets of the CI is dependent on the angle between the magnetic field of the CI magnet and the MRI. When this angle was greater than 80 degrees, relevant demagnetization occurred and sufficient remagnetization was not possible with the 3.0T MRI magnet. Maximum temperature rise was 0.5°C. Conclusions Patients carrying CIs with non-removable magnets should not enter a 3.0T MRI device in a routine clinical setup. Under special conditions (angle between the two magnets less than 80 degrees) imaging in a 3.0T MRI may be possible without harming the patient or the implant.

Effects of phase duration and pulse rate on loudness and pitch percepts in the first auditory midbrain implant patients: Comparison to cochlear implant and auditory brainstem implant results

The auditory midbrain implant (AMI), which is designed for stimulation of the inferior colliculus (IC), is now in clinical trials. The AMI consists of a single shank array (20 contacts) and uses a stimulation strategy originally designed for cochlear implants since it is already approved for human use and we do not yet know how to optimally activate the auditory midbrain. The goal of this study was to investigate the effects of different pulse rates and phase durations on loudness and pitch percepts because these parameters are required to implement the AMI stimulation strategy. Although each patient was implanted into a different region (i.e. lateral lemniscus, central nucleus of IC, dorsal cortex of IC), they generally exhibited similar threshold versus phase duration, threshold versus pulse rate, and pitch versus pulse rate curves. In particular, stimulation with 100 mus/phase, 250 pulse per second (pps) pulse trains achieved an optimal balance among safety, energy, and current threshold requirements while avoiding rate pitch effects. However, we observed large differences across patients in loudness adaptation to continuous pulse stimulation over long time scales. One patient (implanted in dorsal cortex of IC) even experienced complete loudness decay and elevation of thresholds with daily stimulation. Comparing these results with those of cochlear implant and auditory brainstem implant patients, it appears that stimulation of higher order neurons exhibits less and even no loudness summation for higher rate stimuli and greater current leakage for longer phase durations than that of cochlear neurons. The fact that all midbrain regions we stimulated, which includes three distinctly different nuclei, exhibited similar loudness summation effects (i.e. none for pulse rates above 250 pps) suggests a possible shift in some coding properties that is affected more by which stage along the auditory pathway rather than the types of neurons are being stimulated. However, loudness adaptation occurs at multiple stages from the cochlea up to the midbrain.

Auditory midbrain implant: a combined approach for vestibular schwannoma surgery and device implantation.

Hypothesis: The lateral suboccipital approach is a well-established route for safe removal of vestibular schwannomas in neurofibromatosis Type 2 (NF2) patients. The goal of this study was to assess if this approach can be extended to a lateral supracerebellar infratentorial approach to enable insertion of an auditory midbrain implant (AMI) penetrating array along the tonotopic gradient of the inferior colliculus central nucleus (ICC). Background: The AMI is a new auditory prosthesis designed for penetrating stimulation of the ICC in patients with neural deafness. The initial candidates are NF2 patients who, because of the growth and/or surgical removal of bilateral acoustic neuromas, develop neural deafness and are unable to benefit from cochlear implants. The ideal surgical approach in NF2 patients must first enable safe removal of vestibular schwannomas and then provide sufficient exposure of the midbrain for AMI implantation. Methods: This study was performed on formalin-fixed and fresh cadaver specimens. Computed tomography scan and magnetic resonance imaging were used to study the heads of the specimens and for surgical navigation. Results: The lateral suboccipital craniotomy enabled sufficient exposure of the cerebellopontine angle and internal auditory canal for tumor removal. It could then be extended to a lateral supracerebellar infratentorial approach that provided good exposure of the dorsolateral aspect of the tentorial hiatus and mesencephalon for implantation of the AMI along the tonotopic gradient of the ICC. This approach did not endanger the trochlear nerve or any major midline venous structures in the quadrigeminal cistern. Conclusion: This modified lateral suboccipital approach ensures safe removal of large vestibular schwannomas and provides sufficient exposure of the inferior colliculus for ideal AMI implantation.

Artifacts caused by cochlear implants with non-removable magnets in 3T MRI: phantom and cadaveric studies.

The aim of this study was to evaluate artifacts produced by cochlear implants (CI) during 3.0 Tesla (T) magnetic resonance imaging of the brain using different sequences on phantom and cadaveric specimens. A phantom and three cadaveric specimens with CIs were imaged using a 3.0 T clinical scanner. Artifacts were analyzed quantitatively and according to the sequence used. Different brain regions were evaluated for image distortion and limitation of diagnostic significance. In cadaver studies, all sequences generated signal-void areas around the implant. In T2-weighted sequences, additional periodic shadowing was discovered. Anatomical structures of the brain on the contralateral side of the CI were for the most part undistorted. At 3T, artifacts around CIs with non-removable magnets compromise image quality of the nearby brain regions and diagnosis of brain lesions is limited. In the contralateral hemisphere, diagnostic accuracy is only marginally limited.

Electrophysiological Validation of a Human Prototype Auditory Midbrain Implant in a Guinea Pig Model

The auditory midbrain implant (AMI) is a new treatment for hearing restoration in patients with neural deafness or surgically inaccessible cochleae who cannot benefit from cochlear implants (CI). This includes neurofibromatosis type II (NF2) patients who, due to development and/or removal of vestibular schwannomas, usually experience complete damage of their auditory nerves. Although the auditory brainstem implant (ABI) provides sound awareness and aids lip-reading capabilities for these NF2 patients, it generally only achieves hearing performance levels comparable with a single-channel CI. In collaboration with Cochlear Ltd. (Lane Cove, Australia), we developed a human prototype AMI, which is designed for electrical stimulation along the well-defined tonotopic gradient of the inferior colliculus central nucleus (ICC). Considering that better speech perception and hearing performance has been correlated with a greater number of discriminable frequency channels of information available, the ability of the AMI to effectively activate discrete frequency regions within the ICC may enable better hearing performance than achieved by the ABI. Therefore, the goal of this study was to investigate if our AMI array could achieve low-threshold, frequency-specific activation within the ICC, and whether the levels for ICC activation via AMI stimulation were within safe limits for human application. We electrically stimulated different frequency regions within the ICC via the AMI array and recorded the corresponding neural activity in the primary auditory cortex (A1) using a multisite silicon probe in ketamine-anesthetized guinea pigs. Based on our results, AMI stimulation achieves lower thresholds and more localized, frequency-specific activation than CI stimulation. Furthermore, AMI stimulation achieves cortical activation with current levels that are within safe limits for central nervous system stimulation. This study confirms that our AMI design is sufficient for ensuring safe and effective activation of the ICC, and warrants further studies to translate the AMI into clinical application.