A novel intraoperative continuous monitoring method combining dorsal cochlear nucleus action potentials monitoring with auditory nerve test system.

Highly accurate real-time cochlear nerve monitoring to preserve cochlear nerve function is essential for simultaneous cochlear implantation and ipsilateral vestibular schwannoma resection. In the present study, we developed a novel real-time monitoring system that combines dorsal cochlear nucleus action potential monitoring with intracochlear stimulating electrodes (Auditory Nerve Test System, ANTS). We used this system for a case with vestibular schwannoma resection via the translabyrinthine approach. The monitoring system developed in this study detected highly reliable evoked potentials from the cochlear nerve every two seconds continuously during tumor resection. Near-total tumor resection was achieved, and cochlear implantation was performed successfully after confirming the preservation of cochlear nerve function in a case. The patient's hearing was well compensated by cochlear implantation after surgery. Our novel method continuously achieved real-time monitoring of the cochlear nerve every two seconds during vestibular schwannoma resection. The usefulness of this monitoring system for simultaneous tumor resection and cochlear implantation was demonstrated in the present case. The system developed in this study is compatible with continuous facial nerve monitoring. This highly accurate and novel monitoring method will broaden the number of candidates for this type of surgery in the future.

Direct visualization of the murine dorsal cochlear nucleus for optogenetic stimulation of the auditory pathway.

Investigation into the use of virus-mediated gene transfer to arrest or reverse hearing loss has largely been relegated to the peripheral auditory system. Few studies have examined gene transfer to the central auditory system. The dorsal cochlear nucleus (DCN) of the brainstem, which contains second order neurons of the auditory pathway, is a potential site for gene transfer. In this protocol, a technique for direct and maximal exposure of the murine DCN via a posterior fossa approach is demonstrated. This approach allows for either acute or survival surgery. Following direct visualization of the DCN, a host of experiments are possible, including injection of opsins into the cochlear nucleus and subsequent stimulation by an optical fiber coupled to a blue light laser. Other neurophysiology experiments, such as electrical stimulation and neural injector tracings are also feasible. The level of visualization and the duration of stimulation achievable make this approach applicable to a wide range of experiments.

Behavioral determination of stimulus pair discrimination of auditory acoustic and electrical stimuli using a classical conditioning and heart-rate approach.

Acute animal preparations have been used in research prospectively investigating electrode designs and stimulation techniques for integration into neural auditory prostheses, such as auditory brainstem implants and auditory midbrain implants. While acute experiments can give initial insight to the effectiveness of the implant, testing the chronically implanted and awake animals provides the advantage of examining the psychophysical properties of the sensations induced using implanted devices. Several techniques such as reward-based operant conditioning, conditioned avoidance, or classical fear conditioning have been used to provide behavioral confirmation of detection of a relevant stimulus attribute. Selection of a technique involves balancing aspects including time efficiency (often poor in reward-based approaches), the ability to test a plurality of stimulus attributes simultaneously (limited in conditioned avoidance), and measure reliability of repeated stimuli (a potential constraint when physiological measures are employed). Here, a classical fear conditioning behavioral method is presented which may be used to simultaneously test both detection of a stimulus, and discrimination between two stimuli. Heart-rate is used as a measure of fear response, which reduces or eliminates the requirement for time-consuming video coding for freeze behaviour or other such measures (although such measures could be included to provide convergent evidence). Animals were conditioned using these techniques in three 2-hour conditioning sessions, each providing 48 stimulus trials. Subsequent 48-trial testing sessions were then used to test for detection of each stimulus in presented pairs, and test discrimination between the member stimuli of each pair. This behavioral method is presented in the context of its utilisation in auditory prosthetic research. The implantation of electrocardiogram telemetry devices is shown. Subsequent implantation of brain electrodes into the Cochlear Nucleus, guided by the monitoring of neural responses to acoustic stimuli, and the fixation of the electrode into place for chronic use is likewise shown.

In vivo validation of custom-designed silicon-based microelectrode arrays for long-term neural recording and stimulation.

We developed and validated silicon-based neural probes for neural stimulating and recording in long-term implantation in the brain. The probes combine the deep reactive ion etching process and mechanical shaping of their tip region, yielding a mechanically sturdy shank with a sharpened tip to reduce insertion force into the brain and spinal cord, particularly, with multiple shanks in the same array. The arrays' insertion forces have been quantified in vitro. Five consecutive chronically-implanted devices were fully functional from 3 to 18 months. The microelectrode sites were electroplated with iridium oxide, and the charge injection capacity measurements were performed both in vitro and after implantation in the adult feline brain. The functionality of the chronic array was validated by stimulating in the cochlear nucleus and recording the evoked neuronal activity in the central nucleus of the inferior colliculus. The arrays' recording quality has also been quantified in vivo with neuronal spike activity recorded up to 566 days after implantation. Histopathology evaluation of neurons and astrocytes using immunohistochemical stains indicated minimal alterations of tissue architecture after chronic implantation.

In vivo analysis of the role of metabotropic glutamate receptors in the afferent regulation of chick cochlear nucleus neurons.

Cochlea removal results in the death of approximately 20-30% of neurons in the chick nucleus magnocellularis (NM). One early event in NM neuronal degradation is the disruption of their ribosomes. This can be visualized in the first few hours following cochlea removal using Y10B, an antibody that recognizes ribosomal RNA. Previous studies using a brain slice preparation suggest that maintenance of ribosomal integrity in NM neurons requires metabotropic glutamate receptor (mGluR) activation. Isolating the brain slice in vitro, however, may eliminate other potential sources of trophic support and only allows for evaluation of the early changes that occur in NM neurons following deafferentation. Consequently, it is not known if mGluR activation is truly required for the maintenance of NM neurons in the intact system. The current experiments evaluated the importance of mGluRs in vivo. The effects of short-term receptor blockade were assessed through Y10B labeling and the effects of long-term blockade were assessed through stereological counting of NM neurons in Nissl-stained tissue. mGluR antagonists or vehicle were administered intracerebroventricularly following unilateral cochlea removal. Vehicle-treated subjects replicated the previously reported effects of cochlea removal, showing lighter Y10B labeling and fewer Nissl-stained NM neurons on the deafened side of the brain. Blockade of mGluRs prevented the rapid activity-dependent difference in Y10B labeling, and in some cases, had the reverse effect, yielding lighter labeling of NM neurons on the intact side of the brain. Similarly, mGluR blockade over longer survival periods resulted in a reduction in number of cells on both intact and deafferented sides of the brain, and in some cases, yielded a reverse effect of fewer neurons on the intact side versus deafened side. These data are consistent with in vitro findings and suggest that mGluR activation plays a vital role in the afferent maintenance of NM neurons.

Brain stem responses evoked by stimulation of the mature cochlear nucleus with an auditory brain stem implant.

OBJECTIVES: The Nucleus auditory brain stem implant (ABI) has been used in the hearing rehabilitation of totally deaf individuals for whom a cochlear implant is not an option such as in the case of neurofibromatosis type 2 (NF2). Intraoperative electrically evoked auditory brain stem responses (EABRs) are recorded to assist in the placement of the electrode array over the dorsal and ventral cochlear nuclei in the lateral recess of the IVth ventricle of the brain stem. This study had four objectives: (1) to characterize EABRs evoked by stimulation with an ABI in adolescents and adults with NF2, (2) to evaluate how the EABR morphology relates to auditory sensations elicited from stimulation by an ABI, (3) to establish whether there is evidence of morphology changes in the EABR with site of stimulation by the ABI, and (4) to investigate how the threshold of the EABR relates to behavioral threshold and comfortably loud sensations measured at initial device activation. DESIGN: Intraoperative EABRs were recorded from 34 subjects with ABIs: 19 male and 15 female, mean age 27 yrs (range 12 to 52 yrs). ABI stimulation was applied at seven different sites using either wide bipolar stimulation across the array or in subsections of the array from medial to lateral and inferior to superior. The EABRs were analyzed with respect to morphology, peak latency, and changes in these characteristics with the site of stimulation. In a subset of eight subjects, additional narrow bipolar sites were stimulated to compare the intraoperative EABR threshold levels with the behavioral threshold (T) and comfortably loud (C) levels of stimulation required at initial device activation. RESULTS: EABRs were elicited from 91% of subjects. Morphology varied from one to four vertex-positive peaks with mean latencies of 0.76, 1.53, 2.51, and 3.64 msecs, respectively. The presence of an EABR from stimulation by electrodes across the whole array had a high predictive value for the presence of auditory electrodes at initial device activation. When examining subsections of the array, the absence of an EABR was a poor predictor for the absence of auditory electrodes. The morphology of the EABRs varied with site of stimulation in 16 cases, but there was no consistent pattern of change with stimulation site. There was a trend for more auditory electrodes to be present in stimulation sites that evoked EABRs with a higher number of peaks in the waveform. The EABR threshold was closer to the behavioral C level than the T level, but there was no overall correlation between the intraoperative EABR threshold level and the behavioral T and C levels. CONCLUSIONS: The presence of an intraoperative EABR corresponded well to the presence of auditory electrodes. The absence of an EABR from stimulating subsections of the array was not; however, a good indicator for the absence of auditory electrodes and the EABR from such stimulation would not be of assistance in identifying the nonauditory sections of the array to exclude in behavioral fitting of the device. The morphology of the EABR did not relate to site of stimulation. More peaks in the EABR was associated with a greater number of electrodes with auditory sensations, suggesting that correct positioning of the ABI activated more auditory subsystems within the cochlear nucleus. The intraoperative EABR thresholds did not correlate with the behavioral T and C levels and could not be used to assist in device fitting.

Clinical evaluation of expanded input dynamic range in Nucleus cochlear implants.

OBJECTIVE: The aim of this study was to investigate whether expanded instantaneous input dynamic ranges (IIDRs) in the Nucleus cochlear implant system benefit speech perception in the laboratory and listening in the real world. DESIGN: Until recently, Nucleus cochlear implants have used an IIDR of approximately 30 dB. In this study, an IIDR of 31 dB was compared with 46 dB and 56 dB in the SPEAR3 research processor with nine adult implant recipients. Subjects were given two, 2-wk blocks of take-home experience with each of the three IIDRs. A single IIDR setting was used in each trial period. During the take-home experience with the expanded IIDRs, subjects used two programs: a standard program (with clinically measured electrode dynamic ranges) and a program with adjusted thresholds (decreased T levels). After each block of take-home experience, speech perception testing was conducted for CNC words in quiet (at 45 dB and 55 dB SPL) and for CUNY sentences in the presence of multi-taker babble. RESULTS: On average, CNC word recognition at low presentation levels was significantly better with the 46 dB and 56 dB IIDRs, compared with the 31 dB IIDR; however, there was no significant difference between the 46 dB and 56 dB IIDR conditions. These benefits were greater for standard programs than for reduced T level programs. For CUNY sentences in babble, group results indicated no significant difference in performance across IIDR. The three IIDRs were rated similarly in real-life listening situations, and two of the subjects expressed tolerance problems with the expanded standard IIDRs. CONCLUSIONS: IIDRs of 46 and 56 dB provided benefit in accessing low-level speech without a decrement in sentence perception in babble. Most subjects accepted the standard, wider IIDR programs in everyday life. No significant differences were found between the 46 dB and 56 dB IIDR programs.

A model for auditory brain stem implants: bilateral surgical deafferentation of the cochlear nuclei in the macaque monkey.

BACKGROUND: Patients with extensive bilateral lesions of the auditory nerve have a profound and irreversible sensorineural hearing loss (SNHL), which can only be overcome with individually-fitted auditory brain stem implants that directly stimulate the cochlear nuclei. Despite the enormous potential of this increasingly applied treatment, the auditory performance of many implanted patients is limited, and the variability between cases hinders a complete understanding of the role played by the multiple parameters related to the efficacy of the implant. OBJECTIVES: To mimic the condition of patients who have bilateral lesions of the auditory nerve, we developed an experimental model of bilateral deafferentation of the cochlear nuclei by surgical transection of the cochlear nerves of adult primates. MATERIALS AND METHODS: We performed bilateral transection of the cochlear nerves of six adult, healthy, male captive-bred macaques (Macaca fascicularis). Before surgery, brain stem auditory evoked potentials were recorded. The histological material obtained from these animals was compared with similarly processed sections from seven macaques with intact cochlear nerves. The surgical technique, similar to that used in human neuro-otology, combined a labyrinthectomy and a neurectomy of the cochlear nerves, and caused deafness. We analyzed immunocytochemically the expression in cochlear nerve fibers of neurofilaments (SMI-32), and cytosolic calcium binding proteins calretinin, parvalbumin and calbindin, and also applied a histochemical reaction for acetylcholinesterase. RESULTS: None of the primates had any major complications due to the surgical procedure. The lesions produced massive anterograde degeneration of the cochlear nerves, evidenced by marked gliosis and by loss of both type I fibers (which in this species are immunoreactive for calretinin, parvalbumin and neurofilaments) and type II fibers (which are acetylcholinesterase positive). The model of surgical transection described herein causes extensive damage to the cochlear nerves while leaving the cochlea intact, thus mimicking the condition of patients with profound SNHL due to bilateral cochlear nerve degeneration. CONCLUSIONS: The phylogenetic proximity of primates to humans, and the paramount advantage of close anatomical and physiological similarities, allowed us to use the same surgical technique applied to human patients, and to perform a thorough evaluation of the consequences of neurectomy. Thus, bilateral surgical deafferentation of the macaque cochlear nuclei may constitute an advantageous model for study of auditory brain stem implants.

Migration of neural precursor cells derived from olfactory bulb in cochlear nucleus exposed to an augmented acoustic environment.

The regeneration of the auditory neural system remains a challenge in hearing restoration. Acoustic signals may induce a site-specific cell replacement in the auditory system. This hypothesis was tested with grafted implantation of neural precursor cells (NPCs) along the cochlear nucleus in the adult host followed by an augmented acoustic stimulation. NPCs were obtained from the olfactory bulbs at embryonic day 14-16 and were transplanted into the inside border of cochlear nucleus. The labeled cells survived at least 2 weeks, verified by Hoechst 33342 fluorescence, and by immunostaining for a neuronal marker. In some cases NPCs had migrated directionally to the root of the auditory nerve. This observation demonstrates the survival and migration of NPCs from the olfactory bulb (OB) along the adult auditory nerve in an augmented acoustic environment following implantation.

Auditory brainstem implants: surgical aspects.

Patients with neurofibromatosis type 2 often develop bilateral life-threatening vestibular schwannoma necessitating tumor removal, which results in deafness. We developed the auditory brainstem implant (ABI) in order to be able to electrically stimulate the cochlear nucleus complex in patients with bilateral cochlear nerve injury from bilateral schwannoma. After tumor removal, the electrode array of the ABI is inserted into the lateral recess of the fourth ventricle and placed over the surface of the ventral and dorsal cochlear nuclei. The ABI is designed to stimulate auditory neural structures within the cochlear nucleus in order to convey salient cues about the frequency, amplitude, and temporal characteristics of sounds. To date, more than 200 patients have received an ABI device at our institution. Recently, penetrating ABIs were introduced, and preliminary results of penetrating ABIs are discussed in this paper. The surgical anatomy of the nucleus and surgical placement of the ABI in patients with neurofibromatosis type 2 are described, and surgical considerations in this group of challenging patients are detailed.

Engraftment of embryonic stem cell-derived neurons into the cochlear modiolus.

This study aimed to evaluate the potential of embryonic stem cell-derived neural progenitors for use as transplants for the replacement of the auditory primary neurons, spiral ganglion neurons. Mouse embryonic stem cell-derived neural progenitors were implanted into the base of the cochlear modiolus of normal or deafened guinea pigs, which contains spiral ganglion neurons and cochlear nerve fibers. Histological analysis demonstrated the survival and neural differentiation of transplants in the cochlear modiolus and active neurite outgrowth of transplants toward host peripheral or central auditory systems. Functional assessments indicated the potential of transplanted embryonic stem cell-derived neural progenitors to elicit the functional recovery of damaged cochleae. These findings support the hypothesis that transplantation of embryonic stem cell-derived neural progenitors can contribute to the functional restoration of spiral ganglion neurons.

Neural response telemetry results with the nucleus 24 contour in a perimodiolar position.

OBJECTIVE: The purpose of the study was to analyze changes in neural response telemetry using the Cochlear Nucleus 24 Contour before and after stylet removal in a human model. STUDY DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS: Twelve patients (23-72 years old) undergoing cochlear implantation, using the Nucleus 24 Contour implant, secondary to congenital and age-related hearing loss. INTERVENTION: Cochlear implantation with Cochlear Nucleus 24 Contour implant. MAIN OUTCOME MEASURE: Neural response telemetry thresholds were recorded initially with the stylet in and then with the stylet out during the implant procedure. RESULTS: Stimulus levels to obtain neural response telemetry threshold after stylet removal were statistically lower after the stylet was removed. CONCLUSION: The Nucleus 24 Contour achieves a perimodiolar position once the stylet is removed, and this leads to reduction in the current required to elicit a threshold neural response telemetry response.

[Optimization of microsurgical operation technique to insert auditory brainstem implants, taking into account the results of a morphometric study]. / Morphometrische Studie zur Optimierung der Implantationstechnik zentraler Hörprothesen.

STATE OF THE ART: The surgical placement of auditory brainstem implants to stimulate the cochlear nuclear region in patients with acquired bilateral retrocochlear deafness allows limited restitution of hearing. However, there have been few studies on the topographical relations in the target region, particularly the floor of the IVth ventricle. TOPIC OF THE STUDY: Is it possible to obtain more precise anatomical data in order to improve the surgical approaches and techniques for the placement of auditory brainstem implants? AIMS. To obtain a more precise topo- anatomical orientation in the target region for microsurgical lateral and midline approaches or a stereotactic operative strategy. METHODS AND RESULTS: Landmarks for the placement of an auditory brainstem implant via the IVth ventricle were examined and measured in a series of formalin-fixed human brainstems ( n=28). These data, and knowledge of their variability, allow a more precise surgical lateral approach. It is essential to precisely localise the target region, as it can only be partly discerned under the microscope during an operation. For this reason, to date its precise localisation has been determined only electrophysiologically. CONCLUSION: Exact target localisation improves safety. From an anatomical point of view the midline approach gives the chance to enlarge the indication spectrum for an implant. The anatomical data obtained here could also be integrated into a stereotactic surgical strategy.

Alterations in calretinin immunostaining in the ferret superior olivary complex after cochlear ablation.

In this study, we used image analysis to assess changes in calretinin immunoreactivity in the lateral (LSO) and medial (MSO) superior olivary nuclei in ferrets 2 months after unilateral cochlear ablations at 30-40 days of age, soon after hearing onset. These two nuclei are the first significant sites of binaural convergence in the ascending auditory system, and both receive direct projections from the deafferented cochlear nucleus. Cochlear ablation results in a decrease in the overall level of calretinin immunostaining within the LSO ipsilaterally compared with the contralateral side and with control animals and within the MSO bilaterally compared with control ferrets. In addition, the level of calretinin immunostaining ipsilaterally within neurons in the LSO was significantly less in cochlear ablated than control animals. In contrast, there was no effect of cochlear ablation on the level of calretinin immunostaining within neurons either in the contralateral LSO or in the MSO. These results are consistent with a downregulation in calretinin within the neuropil of MSO bilaterally and LSO ipsilaterally, as well as a downregulation in calretinin within somata in the ipsilateral LSO as a result of unilateral cochlear ablation soon after hearing onset. Thus, cochlear-driven activity appears to affect calcium binding protein levels in both neuropil and neurons within the superior olivary complex.

Sending sound to the brain.

The cochlear implant, a microelectrode array that directly stimulates the auditory nerve, has greatly benefited many individuals with profound deafness. Deaf patients without an intact auditory nerve may be helped by the next generation of auditory prostheses: surface or penetrating auditory brainstem implants that bypass the auditory nerve and directly stimulate auditory processing centers in the brainstem.

Auditory deprivation modifies biological rhythms in the golden hamster.

To assess to what extent auditory sensory deprivation affects biological rhythmicity, sleep/wakefulness cycle and 24 h rhythm in locomotor activity were examined in golden hamsters after bilateral cochlear lesion. An increase in total sleep time as well as a decrease in wakefulness (W) were associated to an augmented number of W episodes, as well as of slow wave sleep (SWS) and paradoxical sleep (PS) episodes in deaf hamsters. The number of episodes of the three behavioural states and the percent duration of W and SWS increased significantly during the light phase of daily photoperiod only. Lower amplitudes of locomotor activity rhythm and a different phase angle as far as light off were found in deaf hamsters kept either under light-dark photoperiod or in constant darkness. Period of locomotor activity remained unchanged after cochlear lesions. The results indicate that auditory deprivation disturbs photic synchronization of rhythms with little effect on the clock timing mechanism itself.

The retrosigmoid approach for auditory brainstem implantation.

OBJECTIVE: To describe our experience with the retrosigmoid-transmeatal (RS-TM) approach in auditory brainstem implantation (ABI) as well as the anatomosurgical guidelines for this route. STUDY DESIGN: Retrospective case review. SETTING: Ear, Nose, and Throat Department of the University of Verona. PATIENTS: Five patients with neurofibromatosis type 2 (NF2) were operated on for vestibular schwannoma removal with ABI implantation from April 1997 to June 1999. The patients were four men and one woman, whose ages ranged from 22 to 37 years. The tumor sizes ranged from 12 to 30 mm. The records of a total of 179 patients operated on for vestibular schwannoma (VS) removal via the RS-TM approach from January 1990 to June 1999 were also evaluated. Their ages ranged from 18 to 88 years (average 54 years). The tumor sizes ranged from 4 to 50 mm. Five patients had a solitary VS in the only hearing ear. INTERVENTION: The classic RS-TM approach was used in all patients. After tumor excision, for ABI implantation, the landmarks (seventh, eighth, and ninth cranial nerves, choroid plexus) for the foramen of Luschka were carefully identified. The choroid plexus was then partially removed, and the tela choroidea was divided and bent back. The floor of the lateral recess of the fourth ventricle and the convolution of the dorsal cochlear nucleus became visible. The electrode array was then inserted into the lateral recess and correctly positioned with the aid of electrically evoked auditory brainstem responses (EABRs). MAIN OUTCOME MEASURES: Intraoperative EABR and postoperative speech perception evaluation. RESULTS: Auditory sensations were induced in all patients with various numbers of electrodes. Different pitch sensations could be identified with different electrode stimulation. CONCLUSIONS: In the authors' experience, the RS-TM approach is the route of choice for patients who are candidates for ABI when there is a chance of hearing preservation during surgery. If auditory function is lost during surgery, anatomical preservation of the cochlear nerve may allow hearing restoration with a cochlear implant. Direct intraoperative recording of cochlear nerve action potentials (CNAPs) and round window electrical stimulation are mandatory for these purposes. In addition, decompression of the intrameatal portion of the vestibular schwannoma and planned partial tumor resection with hearing preservation are also possible with the RS-TM approach.

Experimental study following inactive implantation of an auditory brain stem implant in nonhuman primates.

We report changes in the cochlear nuclei (CNs) after 3 months of bilateral auditory deafferentation and simultaneous unilateral implantation of a dummy auditory brain stem implant (ABI) in 6 nonhuman primates (Macaca fascicularis). These specimens were compared to CNs of 9 controls and 7 bilaterally deafferented animals without implantation. The ABI array consists of 3 platinum electrodes mounted on a silicone pad with the back side covered with Dacron. No migration of the ABI was observed. All deafferented animals showed astrocytic reorganization in the CNs. Histologic changes consisted of superficial reactions around the implant, with formation of fibrillar bundles of fusiform cells, and the presence of giant cells close to the Dacron. Other findings were related to surgical trauma. The dummy ABI did not itself provoke serious adverse reactions in the CNs. Our observations support the possibility of ABI reimplantation surgery.

Stimulation of the cochlear nucleus with multichannel auditory brainstem implants and long-term results: Freiburg patients.

Since 1992 18 patients with bilateral retrocochlear deafness have been provided with a multichannel auditory brainstem implant (ABI). The surgical procedure implies tumour removal and ABI implantation in one stage. Most implantations were via the translabyrinthine approach. The long-term follow-up varied between nine and 80 months. In one case auditory perception could not be achieved and in a second case post-operative stimulation was not possible as the subject died due to lung emboli. In all the other cases auditory perception was achieved and only two subjects became non-users during the follow-up period. The presented long-term results suggest that deaf neurofibromatosis type 2 patients regain acoustic contact with the environment, enlarge their communication skills and improve their quality of life by using a multichannel auditory brainstem prosthesis.