Interaural time difference sensitivity under binaural cochlear implant stimulation persists at high pulse rates up to 900 pps.

Spatial hearing remains one of the major challenges for bilateral cochlear implant (biCI) users, and early deaf patients in particular are often completely insensitive to interaural time differences (ITDs) delivered through biCIs. One popular hypothesis is that this may be due to a lack of early binaural experience. However, we have recently shown that neonatally deafened rats fitted with biCIs in adulthood quickly learn to discriminate ITDs as well as their normal hearing litter mates, and perform an order of magnitude better than human biCI users. Our unique behaving biCI rat model allows us to investigate other possible limiting factors of prosthetic binaural hearing, such as the effect of stimulus pulse rate and envelope shape. Previous work has indicated that ITD sensitivity may decline substantially at the high pulse rates often used in clinical practice. We therefore measured behavioral ITD thresholds in neonatally deafened, adult implanted biCI rats to pulse trains of 50, 300, 900 and 1800 pulses per second (pps), with either rectangular or Hanning window envelopes. Our rats exhibited very high sensitivity to ITDs at pulse rates up to 900 pps for both envelope shapes, similar to those in common clinical use. However, ITD sensitivity declined to near zero at 1800 pps, for both Hanning and rectangular windowed pulse trains. Current clinical cochlear implant (CI) processors are often set to pulse rates ≥ 900 pps, but ITD sensitivity in human CI listeners has been reported to decline sharply above ~ 300 pps. Our results suggest that the relatively poor ITD sensitivity seen at > 300 pps in human CI users may not reflect the hard upper limit of biCI ITD performance in the mammalian auditory pathway. Perhaps with training or better CI strategies good binaural hearing may be achievable at pulse rates high enough to allow good sampling of speech envelopes while delivering usable ITDs.

Standard cochlear implants as electrochemical sensors: Intracochlear oxygen measurements in vivo.

Cochlear implants are the most successful neural prostheses worldwide and routinely restore sensorineural hearing loss by direct electrical stimulation of the auditory nerve. Enhancing this standard implant by chemical sensor functionality opens up new possibilities, ranging from access to the biochemical microenvironment of the implanted electrode array to the long-term study of the electrode status. We developed an electrochemical method to turn the platinum stimulation microelectrodes of cochlear implants into electrochemical sensors. The electrodes showed excellent and stable chemical sensor properties, as demonstrated by in vitro characterizations with combined amperometric and active potentiometric dissolved oxygen and hydrogen peroxide measurements. Linear, stable and highly reproducible sensor responses within the relevant concentration ranges with negligible offset were shown. This approach was successfully applied in vivo in an animal model. Intracochlear oxygen dynamics in rats upon breathing pure oxygen were reproducibly and precisely measured in real-time from the perilymph. At the same time, correct implant placement and its functionality was verified by measurements of electrically evoked auditory brainstem responses with clearly distinguishable peaks. Acute measurements indicated no adverse influence of electrical stimulation on electrochemical measurements and vice versa. Our work is ground-breaking towards advanced implant functionality, future implant lifetime monitoring, and implant-life-long in situ investigation of electrode degradation in cochlear implant patients.

Sensitivity to interaural time differences in the inferior colliculus of cochlear implanted rats with or without hearing experience.

For deaf patients cochlear implants (CIs) can restore substantial amounts of functional hearing. However, binaural hearing, and in particular, the perception of interaural time differences (ITDs) with current CIs has been found to be notoriously poor, especially in the event of early hearing loss. One popular hypothesis for these deficits posits that a lack of early binaural experience may be a principal cause of poor ITD perception in pre-lingually deaf CI patients. This is supported by previous electrophysiological studies done in neonatally deafened, bilateral CI-stimulated animals showing reduced ITD sensitivity. However, we have recently demonstrated that neonatally deafened CI rats can quickly learn to discriminate microsecond ITDs under optimized stimulation conditions which suggests that the inability of human CI users to make use of ITDs is not due to lack of binaural hearing experience during development. In the study presented here, we characterized ITD sensitivity and tuning of inferior colliculus neurons under bilateral CI stimulation of neonatally deafened and hearing experienced rats. The hearing experienced rats were not deafened prior to implantation. Both cohorts were implanted bilaterally between postnatal days 64-77 and recorded immediately following surgery. Both groups showed comparably large proportions of ITD sensitive multi-units in the inferior colliculus (Deaf: 84.8%, Hearing: 82.5%), and the strength of ITD tuning, quantified as mutual information between response and stimulus ITD, was independent of hearing experience. However, the shapes of tuning curves differed substantially between both groups. We observed four main clusters of tuning curves - trough, contralateral, central, and ipsilateral tuning. Interestingly, over 90% of multi-units for hearing experienced rats showed predominantly contralateral tuning, whereas as many as 50% of multi-units in neonatally deafened rats were centrally tuned. However, when we computed neural d' scores to predict likely limits on performance in sound lateralization tasks, we did not find that these differences in tuning shapes predicted worse psychoacoustic performance for the neonatally deafened animals. We conclude that, at least in rats, substantial amounts of highly precise, "innate" ITD sensitivity can be found even after profound hearing loss throughout infancy. However, ITD tuning curve shapes appear to be strongly influenced by auditory experience although substantial lateralization encoding is present even in its absence.

Microsecond interaural time difference discrimination restored by cochlear implants after neonatal deafness.

Spatial hearing in cochlear implant (CI) patients remains a major challenge, with many early deaf users reported to have no measurable sensitivity to interaural time differences (ITDs). Deprivation of binaural experience during an early critical period is often hypothesized to be the cause of this shortcoming. However, we show that neonatally deafened (ND) rats provided with precisely synchronized CI stimulation in adulthood can be trained to lateralize ITDs with essentially normal behavioral thresholds near 50 µs. Furthermore, comparable ND rats show high physiological sensitivity to ITDs immediately after binaural implantation in adulthood. Our result that ND-CI rats achieved very good behavioral ITD thresholds, while prelingually deaf human CI patients often fail to develop a useful sensitivity to ITD raises urgent questions concerning the possibility that shortcomings in technology or treatment, rather than missing input during early development, may be behind the usually poor binaural outcomes for current CI patients.

Optimal Multichannel Artifact Prediction and Removal for Neural Stimulation and Brain Machine Interfaces.

Neural implants that deliver multi-site electrical stimulation to the nervous systems are no longer the last resort but routine treatment options for various neurological disorders. Multi-site electrical stimulation is also widely used to study nervous system function and neural circuit transformations. These technologies increasingly demand dynamic electrical stimulation and closed-loop feedback control for real-time assessment of neural function, which is technically challenging since stimulus-evoked artifacts overwhelm the small neural signals of interest. We report a novel and versatile artifact removal method that can be applied in a variety of settings, from single- to multi-site stimulation and recording and for current waveforms of arbitrary shape and size. The method capitalizes on linear electrical coupling between stimulating currents and recording artifacts, which allows us to estimate a multi-channel linear Wiener filter to predict and subsequently remove artifacts via subtraction. We confirm and verify the linearity assumption and demonstrate feasibility in a variety of recording modalities, including in vitro sciatic nerve stimulation, bilateral cochlear implant stimulation, and multi-channel stimulation and recording between the auditory midbrain and cortex. We demonstrate a vast enhancement in the recording quality with a typical artifact reduction of 25-40 dB. The method is efficient and can be scaled to arbitrary number of stimulus and recording sites, making it ideal for applications in large-scale arrays, closed-loop implants, and high-resolution multi-channel brain-machine interfaces.

Microsecond sensitivity to envelope interaural time differences in rats.

Currently, there is controversy around whether rats can use interaural time differences (ITDs) to localize sound. Here, naturalistic pulse train stimuli were used to evaluate the rat's sensitivity to onset and ongoing ITDs using a two-alternative forced choice sound lateralization task. Pulse rates between 50 Hz and 4.8 kHz with rectangular or Hanning windows were delivered with ITDs between ±175 µs over a near-field acoustic setup. Similar to other mammals, rats performed with 75% accuracy at ∼50 µs ITD, demonstrating that rats are highly sensitive to envelope ITDs.

Monaural Neonatal Deafness Induces Inhibition among Bilateral Auditory Networks under Binaural Activation.

Worldwide, almost 500 million people are hearing impaired, making hearing loss the most common sensory impairment among humans. For people with single-sided deafness (SSD), cochlear implants (CIs) can be enormously beneficial by providing binaural information. However, binaural benefits in CI users have been only incompletely realized. Overcoming these limitations requires a better knowledge of how neuronal circuits adapt to SSD and how unilateral CI stimulation can compensate a deaf ear. We investigated effects of neonatal SSD on auditory brainstem circuitry using acoustic (AS), electric (ES), or acoustic stimulation on one ear and electric stimulation on the other ear (AS + ES). The molecular marker Fos was used to investigate changes in interneuronal communication due to SSD. To induce SSD, neonatal rats obtained a unilateral intracochlear injection of neomycin. In adulthood, rats were acutely stimulated by AS, ES, or AS + ES. AS and ES were applied correspondingly in terms of intracochlear stimulation side and intensity resulting in bilaterally comparable Fos expression in hearing rats. In contrast, SSD rats showed a loss of tonotopic order along the deafened pathway, indicated by a massive increase and spread of Fos expressing neurons. We report three major results: First, AS of the hearing ear of SSD rats resulted in bilateral activation of neurons in the cochlear nucleus (CN). Second, ES of the deaf ear did not activate contralateral CN. Third, AS + ES of SSD rats resulted in bilateral reduced Fos expression in the auditory brainstem compared to monaural stimulations. These findings indicate changes in inhibitory interactions among neuronal networks as a result of monaural deafness.

Astrocyte Hypertrophy and Microglia Activation in the Rat Auditory Midbrain Is Induced by Electrical Intracochlear Stimulation.

Neuron-glia interactions contribute to tissue homeostasis and functional plasticity in the mammalian brain, but it remains unclear how this is achieved. The potential of central auditory brain tissue for stimulation-dependent cellular remodeling was studied in hearing-experienced and neonatally deafened rats. At adulthood, both groups received an intracochlear electrode into the left cochlea and were continuously stimulated for 1 or 7 days after waking up from anesthesia. Normal hearing and deafness were assessed by auditory brainstem responses (ABRs). The effectiveness of stimulation was verified by electrically evoked ABRs as well as immunocytochemistry and in situ hybridization for the immediate early gene product Fos on sections through the auditory midbrain containing the inferior colliculus (IC). Whereas hearing-experienced animals showed a tonotopically restricted Fos response in the IC contralateral to electrical intracochlear stimulation, Fos-positive neurons were found almost throughout the contralateral IC in deaf animals. In deaf rats, the Fos response was accompanied by a massive increase of GFAP indicating astrocytic hypertrophy, and a local activation of microglial cells identified by IBA1. These glia responses led to a noticeable increase of neuron-glia approximations. Moreover, staining for the GABA synthetizing enzymes GAD65 and GAD67 rose significantly in neuronal cell bodies and presynaptic boutons in the contralateral IC of deaf rats. Activation of neurons and glial cells and tissue re-composition were in no case accompanied by cell death as would have been apparent by a Tunel reaction. These findings suggest that growth and activity of glial cells is crucial for the local adjustment of neuronal inhibition to neuronal excitation.

Induction of single-sided deafness in the newborn rat and its consequence for cochlear nucleus volume development.

Aim of this study was to induce a single-sided deafness (SSD) in rats before hearing onset. Rats were operated at postnatal day 10 by approaching the tympanic cavity along a retroauricular path without manipulating ossicles or tympanic membrane. The ototoxic aminoglycoside neomycin was injected intracochlearly through the round window membrane on one side. When the animals have reached young adult stages, their hearing threshold was determined by their auditory brainstem response (ABR). Monaural deafening was considered successful when the hearing threshold was at least 95 dB above the threshold of the normal hearing ear. Growing up with one non-functional ear, rats developed a striking anatomical asymmetry of their cochlear nuclei (CN). The CN from age-matched normal hearing brains and from both sides of single-sided deaf brains were cut into series of frontal sections and their volumes calculated. No difference was detected between the volume of the normal hearing CN and the contralateral CN in SSD rats. By contrast, growth retardation was found for the ventral CN on the deaf side to result in a volume of only 57% compared to the normal hearing side. Marginal growth retardation was also observed for the dorsal CN on the deaf side. Thus, loss of sensory activation leads mainly, but not exclusively, to a reduction of tissue volume in the ventral CN of the deaf side, leaving the contralateral side apparently unaffected.

Gap43 transcription modulation in the adult brain depends on sensory activity and synaptic cooperation.

Brain development and learning is accompanied by morphological and molecular changes in neurons. The growth associated protein 43 (Gap43), indicator of neurite elongation and synapse formation, is highly expressed during early stages of development. Upon maturation of the brain, Gap43 is down-regulated by most neurons with the exception of subdivisions such as the CA3 region of hippocampus, the lateral superior olive (LSO) and the central inferior colliculus (CIC). Little is known about the regulation of this mRNA in adult brains. We found that the expression of Gap43 mRNA in specific neurons can be modulated by changing sensory activity of the adult brain. Using the central auditory system of rats as a model, Gap43 protein and mRNA levels were determined in LSO and CIC of hearing-experienced rats unilaterally or bilaterally deafened or unilaterally stimulated by a cochlear implant (CI). Our data indicate that Gap43 is a marker useful beyond monitoring neuronal growth and synaptogenesis, reflecting also specific patterns of synaptic activities on specific neurons. Thus, unilateral loss of input to an adult auditory system directly causes asymmetrical expression of Gap43 mRNA between LSOs or CICs on both sides of the brainstem. This consequence can be prevented by simple-patterned stimulation of a dysfunctional ear by way of a CI. We suggest that as a function of input balance and activity pattern, Gap43 mRNA expression changes as cells associate converging afferent signals.

The impact of hearing experience on signal integration in the auditory brainstem: a c-Fos study of the rat.

In this study we investigated the pattern of c-Fos expression in anteroventral (AVCN) and dorsal cochlear nucleus (DCN) and central inferior colliculus (CIC) following electrical intracochlear stimulation (EIS) of anesthetized adult rats that were neonatally deafened. The animals never experienced acoustic sensations as their hair cells were destroyed by daily kanamycin injections between postnatal days 10 to 20, resulting in a rise of hearing threshold by about 90 dB. Unilateral EIS was applied through a cochlear implant inserted into the medial turn of the left cochlea and lasted for 45 or 73 min, 2, 3:15, or 5h. Following EIS at 50Hz, a high number of c-Fos positive nuclei were observed showing only marginal tonotopic order in ipsilateral AVCN, in DCN bilaterally, and in contralateral CIC. Quantifying the number of c-Fos positive nuclei in ipsilateral AVCN, we found a steady increase with stimulation time. By contrast, the population of neurons expressing c-Fos in DCN and CIC revealed a transient maximum at 73 min. A direct comparison with our previous study (Rosskothen-Kuhl, N., Illing, R.-B., 2010. Nonlinear development of the populations of neurons expressing c-Fos under sustained electrical intracochlear stimulation in the rat auditory brainstem. Brain Res. 1347, 33-41) reveals that absence of hearing experience has far-reaching consequences for the interneuronal communication within networks of the auditory brainstem. When hearing fails, EIS entails expression of c-Fos in populations of neurons that are much larger than normally, essentially disregard tonotopic order, and lack much of spatio-temporal variations seen in hearing-experienced rats.

Nonlinear development of the populations of neurons expressing c-Fos under sustained electrical intracochlear stimulation in the rat auditory brainstem.

The immediate-early-gene c-fos is among the first genes to be expressed following sensory-invoked neuronal activity. Its gene product c-Fos forms the limiting monomer of the heterodimeric activator protein-1 transcription factor that triggers various genes involved in neuroplastic remodeling. This study investigated the pattern of c-Fos expression in anteroventral (AVCN) and dorsal cochlear nucleus (DCN) and central inferior colliculus (CIC) after 45 min, 73 min, 2 h, 3:15 h and 5 h of unilateral electrical intracochlear stimulation (EIS) at 50 Hz in anaesthetized rats. Following EIS, tonotopic c-Fos expression was observed for each stimulation time in ipsilateral AVCN, DCN bilaterally, and contralateral CIC. By counting c-Fos positive nuclei, we discovered temporal non-linearities in the size of the respective population of c-Fos expressing neurons. In all regions investigated, the populations significantly increased from 73 min to 2 h but decreased towards 3:15 h. In AVCN, the number rose again by 5 h of EIS. Remarkably, the same was noted for neurons with large nuclei in deep DCN. In both regions, the population of responsive neurons shifted spatially: In central AVCN, the density of c-Fos positive cells increased significantly from 2 to 5h with medial and lateral regions remaining unchanged. In DCN, the density of large c-Fos positive nuclei fell in the upper and rose in the deep layers from 45 min to 5h of EIS. In conclusion, spatiotemporally varying recruitments of neuronal subpopulations into cellular networks responding to specific patterns of sensory activity take place in the auditory brainstem.