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1.  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.
doi:10.1007/s10162-006-0056-5
PMCID: PMC2504634  PMID: 17075701
auditory prosthesis; inferior colliculus; auditory cortex; electrical stimulation; NF2; deep brain stimulation
2.  Effects of Pulse Phase Duration and Location of Stimulation Within the Inferior Colliculus on Auditory Cortical Evoked Potentials in a Guinea Pig Model 
The auditory midbrain implant (AMI), which consists of a single shank array designed for stimulation within the central nucleus of the inferior colliculus (ICC), has been developed for deaf patients who cannot benefit from a cochlear implant. Currently, performance levels in clinical trials for the AMI are far from those achieved by the cochlear implant and vary dramatically across patients, in part due to stimulation location effects. As an initial step towards improving the AMI, we investigated how stimulation of different regions along the isofrequency domain of the ICC as well as varying pulse phase durations and levels affected auditory cortical activity in anesthetized guinea pigs. This study was motivated by the need to determine in which region to implant the single shank array within a three-dimensional ICC structure and what stimulus parameters to use in patients. Our findings indicate that complex and unfavorable cortical activation properties are elicited by stimulation of caudal–dorsal ICC regions with the AMI array. Our results also confirm the existence of different functional regions along the isofrequency domain of the ICC (i.e., a caudal–dorsal and a rostral–ventral region), which has been traditionally unclassified. Based on our study as well as previous animal and human AMI findings, we may need to deliver more complex stimuli than currently used in the AMI patients to effectively activate the caudal ICC or ensure that the single shank AMI is only implanted into a rostral–ventral ICC region in future patients.
doi:10.1007/s10162-010-0229-0
PMCID: PMC2975884  PMID: 20717834
auditory midbrain implant; auditory brainstem implant; cochlear implant; deep brain stimulation; auditory cortex; auditory thalamus
3.  Benefits and detriments of unilateral cochlear implant use on bilateral auditory development in children who are deaf 
We have explored both the benefits and detriments of providing electrical input through a cochlear implant in one ear to the auditory system of young children. A cochlear implant delivers electrical pulses to stimulate the auditory nerve, providing children who are deaf with access to sound. The goals of implantation are to restrict reorganization of the deprived immature auditory brain and promote development of hearing and spoken language. It is clear that limiting the duration of deprivation is a key factor. Additional considerations are the onset, etiology, and use of residual hearing as each of these can have unique effects on auditory development in the pre-implant period. New findings show that many children receiving unilateral cochlear implants are developing mature-like brainstem and thalamo-cortical responses to sound with long term use despite these sources of variability; however, there remain considerable abnormalities in cortical function. The most apparent, determined by implanting the other ear and measuring responses to acute stimulation, is a loss of normal cortical response from the deprived ear. Recent data reveal that this can be avoided in children by early implantation of both ears simultaneously or with limited delay. We conclude that auditory development requires input early in development and from both ears.
doi:10.3389/fpsyg.2013.00719
PMCID: PMC3797443  PMID: 24137143
deafness; cochlear implantation; unilateral hearing; auditory brainstem responses; auditory evoked cortical potentials; auditory development; plasticity; binaural hearing
4.  Spatial Selectivity to Intracochlear Electrical Stimulation in the Inferior Colliculus is Degraded Following Long-Term Deafness in Cats 
Journal of neurophysiology  2007;98(5):2588-2603.
Selective neural activation is an important factor for achieving functional independence of channels in a multichannel cochlear implant. In an animal model of electrical hearing in prelingually deaf adults this study examined the effects of deafness duration on response thresholds and spatial selectivity of intracochlear electrical stimulation (i.e., spatial tuning and dynamic range) in the central auditory system. Electrically evoked auditory brainstem response (EABR) thresholds and neural response thresholds in the external (ICX) and central (ICC) nuclei of the inferior colliculus were estimated in cats after varying durations of neonatally induced deafness: 1) in animals deafened <1.5 yr (short-deafened, SDU cats) with a mean spiral ganglion cell (SGC) density of ∼45% of normal and 2) in animals deafened >2.5 yr (long-deafened, LD cats) with severe cochlear pathology (mean SGC density <7% of normal). LD animals were subdivided into unstimulated cats and those that received chronic intracochlear electrical stimulation via a feline cochlear implant. Acutely deafened, implanted adult cats served as controls. Threshold distributions were analyzed across IC depth to determine the cochleotopic organization, the spread of excitation and the dynamic range of neural responses.
Independent of their stimulation history, LD animals had significantly higher EABR and ICC thresholds than SDU and control animals. In addition, the spatial extent of electrical excitation was significantly broader and the dynamic range significantly reduced in LD animals. Despite the prolonged durations of deafness the fundamental cochleotopic organization was maintained in both the ICX and the ICC of LD animals. There was no difference between SDU and control cats in any of the response properties tested.
These findings suggest that long-term auditory deprivation results in a significant and possibly irreversible degradation of response thresholds and spatial selectivity to intracochlear electrical stimulation in the auditory midbrain. Similar changes likely contribute to the poor speech discrimination performance observed in prelingually deaf adult human cochlear implant users implanted after long durations of deafness.
doi:10.1152/jn.00011.2007
PMCID: PMC2430866  PMID: 17855592
cochlear implant; spatial selectivity; inferior colliculus; long-term deafness; thresholds
5.  Synaptic Plasticity after Chemical Deafening and Electrical Stimulation of the Auditory Nerve in Cats 
The Journal of comparative neurology  2010;518(7):1046-1063.
The effects of deafness on brain structure and function have been studied using animal models of congenital deafness that include surgical ablation of the organ of Corti, acoustic trauma, ototoxic drugs, and hereditary deafness. This report describes the morphologic plasticity of auditory nerve synapses in response to ototoxic deafening and chronic electrical stimulation of the auditory nerve. Normal kittens were deafened by neonatal administration of neomycin that eliminated auditory receptor cells. Some of these cats were raised deaf, whereas others were chronically implanted with cochlear electrodes at two months of age and electrically stimulated for up to 12 months. The large endings of the auditory nerve, endbulbs of Held, were studied because they hold a key position in the timing pathway for sound localization, are readily identifiable, and exhibit deafness-associated abnormalities. Compared to normal hearing cats, synapses of ototoxically deafened cats displayed expanded postsynaptic densities, a decrease in synaptic vesicle (SV) density, and a reduction in the somatic size of spherical bushy cells (SBCs). When compared to normal hearing cats, endbulbs of ototoxically deafened cats that received cochlear stimulation expressed postsynaptic densities (PSDs) that were statistically identical in size, showed a 32.8% reduction in SV density, and whose target SBCs had a 25.5% reduction in soma area. These results demonstrate that electrical stimulation via a cochlear implant in chemically-deafened cats preserves PSD size but not other aspects of synapse morphology. The results further suggest that the effects of ototoxic deafness are not identical to those of hereditary deafness.
doi:10.1002/cne.22262
PMCID: PMC2935524  PMID: 20127807
cochlear implant; deafness; electrical stimulation; endbulb of Held; ototoxicity
6.  Challenges for stem cells to functionally repair the damaged auditory nerve 
Introduction
In the auditory system, a specialised subset of sensory neurons are responsible for correctly relaying precise pitch and temporal cues to the brain. In individuals with severe-to-profound sensorineural hearing impairment these sensory auditory neurons can be directly stimulated by a cochlear implant, which restores sound input to the brainstem after the loss of hair cells. This neural prosthesis therefore depends on a residual population of functional neurons in order to function effectively.
Areas covered
In severe cases of sensorineural hearing loss where the numbers of auditory neurons are significantly depleted, the benefits derived from a cochlear implant may be minimal. One way in which to restore function to the auditory nerve is to replace these lost neurons using differentiated stem cells, thus re-establishing the neural circuit required for cochlear implant function. Such a therapy relies on producing an appropriate population of electrophysiologically functional neurons from stem cells, and on these cells integrating and reconnecting in an appropriate manner in the deaf cochlea.
Expert opinion
Here we review progress in the field to date, including some of the key functional features that stem cell-derived neurons would need to possess and how these might be enhanced using electrical stimulation from a cochlear implant.
doi:10.1517/14712598.2013.728583
PMCID: PMC3543850  PMID: 23094991
7.  Laser Stimulation of Single Auditory Nerve Fibers 
The Laryngoscope  2010;120(10):2071-2082.
Objectives/Hypothesis
One limitation with cochlear implants is the difficulty stimulating spatially discrete spiral ganglion cell groups because of electrode interactions. Multipolar electrodes have improved on this some, but also at the cost of much higher device power consumption. Recently, it has been shown that spatially selective stimulation of the auditory nerve is possible with a mid-infrared laser aimed at the spiral ganglion via the round window. However, these neurons must be driven at adequate rates for optical radiation to be useful in cochlear implants. We herein use single-fiber recordings to characterize the responses of auditory neurons to optical radiation.
Study Design
In vivo study using normal-hearing adult gerbils.
Methods
Two diode lasers were used for stimulation of the auditory nerve. They operated between 1.844 μm and 1.873 μm, with pulse durations of 35 μs to 1,000 μs, and at repetition rates up to 1,000 pulses per second (pps). The laser outputs were coupled to a 200-μm-diameter optical fiber placed against the round window membrane and oriented toward the spiral ganglion. The auditory nerve was exposed through a craniotomy, and recordings were taken from single fibers during acoustic and laser stimulation.
Results
Action potentials occurred 2.5 ms to 4.0 ms after the laser pulse. The latency jitter was up to 3 ms. Maximum rates of discharge averaged 97 ± 52.5 action potentials per second. The neurons did not strictly respond to the laser at stimulation rates over 100 pps.
Conclusions
Auditory neurons can be stimulated by a laser beam passing through the round window membrane and driven at rates sufficient for useful auditory information. Optical stimulation and electrical stimulation have different characteristics; which could be selectively exploited in future cochlear implants.
Level of Evidence
Not applicable.
doi:10.1002/lary.21102
PMCID: PMC3411104  PMID: 20830761
Cochlear implant; neuroprosthesis; optical stimulation; spatial selectivity; spiral ganglion cell
8.  Neural representation in the auditory midbrain of the envelope of vocalizations based on a peripheral ear model 
The auditory midbrain implant (AMI) consists of a single shank array (20 sites) for stimulation along the tonotopic axis of the central nucleus of the inferior colliculus (ICC) and has been safely implanted in deaf patients who cannot benefit from a cochlear implant (CI). The AMI improves lip-reading abilities and environmental awareness in the implanted patients. However, the AMI cannot achieve the high levels of speech perception possible with the CI. It appears the AMI can transmit sufficient spectral cues but with limited temporal cues required for speech understanding. Currently, the AMI uses a CI-based strategy, which was originally designed to stimulate each frequency region along the cochlea with amplitude-modulated pulse trains matching the envelope of the bandpass-filtered sound components. However, it is unclear if this type of stimulation with only a single site within each frequency lamina of the ICC can elicit sufficient temporal cues for speech perception. At least speech understanding in quiet is still possible with envelope cues as low as 50 Hz. Therefore, we investigated how ICC neurons follow the bandpass-filtered envelope structure of natural stimuli in ketamine-anesthetized guinea pigs. We identified a subset of ICC neurons that could closely follow the envelope structure (up to ß100 Hz) of a diverse set of species-specific calls, which was revealed by using a peripheral ear model to estimate the true bandpass-filtered envelopes observed by the brain. Although previous studies have suggested a complex neural transformation from the auditory nerve to the ICC, our data suggest that the brain maintains a robust temporal code in a subset of ICC neurons matching the envelope structure of natural stimuli. Clinically, these findings suggest that a CI-based strategy may still be effective for the AMI if the appropriate neurons are entrained to the envelope of the acoustic stimulus and can transmit sufficient temporal cues to higher centers.
doi:10.3389/fncir.2013.00166
PMCID: PMC3800787  PMID: 24155694
auditory brainstem implant; cochlear implant; envelope; inferior colliculus; model; phase locking; speech; temporal code
9.  Using Evoked Potentials to Match Interaural Electrode Pairs with Bilateral Cochlear Implants 
Bilateral cochlear implantation seeks to restore the advantages of binaural hearing to the profoundly deaf by providing binaural cues normally important for accurate sound localization and speech reception in noise. Psychophysical observations suggest that a key issue for the implementation of a successful binaural prosthesis is the ability to match the cochlear positions of stimulation channels in each ear. We used a cat model of bilateral cochlear implants with eight-electrode arrays implanted in each cochlea to develop and test a noninvasive method based on evoked potentials for matching interaural electrodes. The arrays allowed the cochlear location of stimulation to be independently varied in each ear. The binaural interaction component (BIC) of the electrically evoked auditory brainstem response (EABR) was used as an assay of binaural processing. BIC amplitude peaked for interaural electrode pairs at the same relative cochlear position and dropped with increasing cochlear separation in either direction. To test the hypothesis that BIC amplitude peaks when electrodes from the two sides activate maximally overlapping neural populations, we measured multiunit neural activity along the tonotopic gradient of the inferior colliculus (IC) with 16-channel recording probes and determined the spatial pattern of IC activation for each stimulating electrode. We found that the interaural electrode pairings that produced the best aligned IC activation patterns were also those that yielded maximum BIC amplitude. These results suggest that EABR measurements may provide a method for assigning frequency–channel mappings in bilateral implant recipients, such as pediatric patients, for which psychophysical measures of pitch ranking or binaural fusion are unavailable.
doi:10.1007/s10162-006-0069-0
PMCID: PMC1907379  PMID: 17225976
binaural hearing; electric stimulation; neural prosthesis; cochlear implant; inferior colliculus
10.  Using Evoked Potentials to Match Interaural Electrode Pairs with Bilateral Cochlear Implants 
Bilateral cochlear implantation seeks to restore the advantages of binaural hearing to the profoundly deaf by providing binaural cues normally important for accurate sound localization and speech reception in noise. Psychophysical observations suggest that a key issue for the implementation of a successful binaural prosthesis is the ability to match the cochlear positions of stimulation channels in each ear. We used a cat model of bilateral cochlear implants with eight-electrode arrays implanted in each cochlea to develop and test a noninvasive method based on evoked potentials for matching interaural electrodes. The arrays allowed the cochlear location of stimulation to be independently varied in each ear. The binaural interaction component (BIC) of the electrically evoked auditory brainstem response (EABR) was used as an assay of binaural processing. BIC amplitude peaked for interaural electrode pairs at the same relative cochlear position and dropped with increasing cochlear separation in either direction. To test the hypothesis that BIC amplitude peaks when electrodes from the two sides activate maximally overlapping neural populations, we measured multiunit neural activity along the tonotopic gradient of the inferior colliculus (IC) with 16-channel recording probes and determined the spatial pattern of IC activation for each stimulating electrode. We found that the interaural electrode pairings that produced the best aligned IC activation patterns were also those that yielded maximum BIC amplitude. These results suggest that EABR measurements may provide a method for assigning frequency–channel mappings in bilateral implant recipients, such as pediatric patients, for which psychophysical measures of pitch ranking or binaural fusion are unavailable.
doi:10.1007/s10162-006-0069-0
PMCID: PMC1907379  PMID: 17225976
binaural hearing; electric stimulation; neural prosthesis; cochlear implant; inferior colliculus
11.  Lexico-semantic and acoustic-phonetic processes in the perception of noise-vocoded speech: implications for cochlear implantation 
Noise-vocoding is a transformation which, when applied to speech, severely reduces spectral resolution and eliminates periodicity, yielding a stimulus that sounds “like a harsh whisper” (Scott et al., 2000, p. 2401). This process simulates a cochlear implant, where the activity of many thousand hair cells in the inner ear is replaced by direct stimulation of the auditory nerve by a small number of tonotopically-arranged electrodes. Although a cochlear implant offers a powerful means of restoring some degree of hearing to profoundly deaf individuals, the outcomes for spoken communication are highly variable (Moore and Shannon, 2009). Some variability may arise from differences in peripheral representation (e.g., the degree of residual nerve survival) but some may reflect differences in higher-order linguistic processing. In order to explore this possibility, we used noise-vocoding to explore speech recognition and perceptual learning in normal-hearing listeners tested across several levels of the linguistic hierarchy: segments (consonants and vowels), single words, and sentences. Listeners improved significantly on all tasks across two test sessions. In the first session, individual differences analyses revealed two independently varying sources of variability: one lexico-semantic in nature and implicating the recognition of words and sentences, and the other an acoustic-phonetic factor associated with words and segments. However, consequent to learning, by the second session there was a more uniform covariance pattern concerning all stimulus types. A further analysis of phonetic feature recognition allowed greater insight into learning-related changes in perception and showed that, surprisingly, participants did not make full use of cues that were preserved in the stimuli (e.g., vowel duration). We discuss these findings in relation cochlear implantation, and suggest auditory training strategies to maximize speech recognition performance in the absence of typical cues.
doi:10.3389/fnsys.2014.00018
PMCID: PMC3933978  PMID: 24616669
speech perception; individual differences; cochlear implants
12.  Better Temporal Neural Coding with Cochlear Implants in Awake Animals 
Both the performance of cochlear implant (CI) listeners and the responses of auditory neurons show limits in temporal processing at high frequencies. However, the upper limit of temporal coding of pulse train stimuli in the inferior colliculus (IC) of anesthetized animals appears to be lower than that observed in corresponding perceptual tasks. We hypothesize that the neural rate limits have been underestimated due to the effect of anesthesia. To test this hypothesis, we developed a chronic, awake rabbit preparation for recording responses of single IC neurons to CI stimulation without the confound of anesthesia, and compared these data with earlier recordings from the IC of anesthetized cats. Stimuli were periodic trains of biphasic pulses with rates varying from 20 to 1280 pulses per second (pps). We found that the maximum pulse rates that elicited sustained firing and phase-locked responses were 2–3 times higher in the IC of awake rabbits than in anesthetized cats. Moreover, about 25% of IC neurons in awake rabbit showed sustained responses to periodic pulse trains at much higher pulse rates (> 1000 pps) than observed in anesthetized animals. Similar differences were observed in single units whose responses to pulse trains were monitored while the animal was given an injection of an ultra short-acting anesthetic. In general, the physiological rate limits of IC neurons in awake rabbit are more consistent with the psychophysical limits in human CI subjects compared to the data from anesthetized animals.
doi:10.1007/978-1-4614-1590-9_39
PMCID: PMC3726256  PMID: 23716241
cochlear implants; temporal coding; inferior colliculus; anesthesia
13.  Auditory nerve fiber responses to electric stimulation: Modulated and unmodulated pulse trainsa 
Many modern cochlear implants use sound processing strategies that stimulate the cochlea with modulated pulse trains. Rubinstein et al. [Hear. Res. 127, 108 (1999)] suggested that representation of the modulator in auditory nerve responses might be improved by the addition of a sustained, high-rate, desynchronizing pulse train (DPT). In addition, activity in response to the DPT may mimic the spontaneous activity (SA) in a healthy ear. The goals of this study were to compare responses of auditory nerve fibers in acutely deafened, anesthetized cats elicited by high-rate electric pulse trains delivered through an intracochlear electrode with SA, and to measure responses of these fibers to amplitude-modulated pulse trains superimposed upon a DPT. Responses to pulse trains showed variability from presentation to presentation, but differed from SA in the shape of the envelope of the interval histogram (IH) for pulse rates above 4.8 kpps (kilo pulses per second). These IHs had a prominent mode near 5 ms that was followed by a long tail. Responses to modulated biphasic pulse trains resembled responses to tones in intact ears for small (<10%) modulation depths, suggesting that acousticlike responses to sinusoidal stimuli might be obtained with a DPT. However, realistic responses were only observed over a narrow range of levels and modulation depths. Improved coding of complex stimulus waveforms may be achieved by signal processing strategies for cochlear implants that properly incorporate a DPT.
doi:10.1121/1.1375140
PMCID: PMC2275322  PMID: 11508961
14.  COCHLEAR IMPLANT ELECTRODE CONFIGURATION EFFECTS ON ACTIVATION THRESHOLD AND TONOTOPIC SELECTIVITY 
Hearing research  2007;235(1-2):23-38.
The multichannel design of contemporary cochlear implants (CIs) is predicated on the assumption that each channel activates a relatively restricted and independent sector of the deaf auditory nerve array, just as a sound within a restricted frequency band activates a restricted region of the normal cochlea The independence of CI channels, however, is limited; and the factors that determine their independence, the relative overlap of the activity patterns that they evoke, are poorly understood. In this study, we evaluate the spread of activity evoked by cochlear implant channels by monitoring activity at 16 sites along the tonotopic axis of the guinea pig inferior colliculus (IC). “Spatial tuning curves” (STCs) measured in this way serve as an estimate of activation spread within the cochlea and the ascending auditory pathways. We contrast natural stimulation using acoustic tones with two kinds of electrical stimulation either (1) a loose fitting banded array consisting of a cylindrical silicone elastomer carrier with a linear series of ring contacts; or (2) a space-filling array consisting of a tapered silicone elastomer carrier that is designed to fit snugly into the guinea pig scala tympani with a linear series of ball contacts positioned along it Spatial tuning curves evoked by individual acoustic tones, and by activation of each contact of each array as a monopole, bipole or tripole were recorded. Several channel configurations and a wide range of electrode separations were tested for each array, and their thresholds and selectivity were estimated.
The results indicate that the tapered space-filling arrays evoked more restricted activity patterns at lower thresholds than did the banded arrays. Monopolar stimulation (one intracochlear contact activated with an extracochlear return) using either array evoked broad activation patterns that involved the entire recording array at current levels < 6dB SL, but at relatively low thresholds. Bi- and tripolar configurations of both array types evoked more restricted activity patterns, but their thresholds were higher than those of monopolar configurations. Bipolar and tripolar configurations with closely spaced contacts evoked activity patterns that were comparable to those evoked by pure tones. As the spacing of bipolar electrodes was increased (separations > 1 mm), the activity patterns became broader and evoked patterns with two distinct threshold minima, one associated with each contact.
doi:10.1016/j.heares.2007.09.013
PMCID: PMC2387102  PMID: 18037252
Cochlear implant; cochlear prosthesis; deafness; auditory nervous system; multichannel recording; auditory prosthesis; inferior colliculus
15.  Comodulation Masking Release In Electric Hearing 
Comodulation masking release (CMR) is an improvement in the detection threshold of a masked signal that occurs when the masker envelopes are correlated across frequency (i.e., comodulation). CMR can be observed when flanking bands (FBs) of noise co-modulated with an on-frequency band (OFB) noise masker are added at remote frequencies (CMR1), or when co-modulated envelopes are used instead of anti-modulated envelopes (OFB and FB envelopes out of phase, CMR2). For FBs widely separated from the OFB, this process is assumed to rely mostly on across-channel comparison of temporal envelopes. Since cochlear implants (CIs) rely predominantly on the transmission of envelope cues, we investigated if CMR can be observed in electric hearing. We stimulated the auditory nerve of eight CI users with trains of modulated electric pulses presented on an OFB electrode alone, or together with pulse trains on one or two FB electrodes. Participants had to detect signal-induced changes in the envelope of an electric pulse train masker presented on the OFB electrode. Envelopes on FB electrodes were either co-modulated or anti-modulated with the envelope of the OFB masker. We observed CMR1 in one of the eight CI users. However, significant CMR2 was observed in most CI users. Reducing amplitude-modulation rate from 20 to 8 Hz, reducing envelopes' randomness or increasing electrode separation did not generally improve CMR1, but increased the prevalence of CMR2. The present results suggest that comodulation of envelopes can aid signal detection in electric hearing.
doi:10.1007/s10162-013-0433-9
PMCID: PMC3946139  PMID: 24414194
cochlear implant; temporal processing; signal detection; envelope; temporal fine structure; electrical stimulation
16.  Difference in response reliability predicted by spectrotemporal tuning in the cochlear nuclei of barn owls 
The brainstem auditory pathway is obligatory for all aural information. Brainstem auditory neurons must encode the level and timing of sounds, as well as their time-dependent spectral properties, the fine structure and envelope, which are essential for sound discrimination. This study focused on envelope coding in the two cochlear nuclei of the barn owl, nucleus angularis (NA) and nucleus magnocellularis (NM). NA and NM receive input from bifurcating auditory nerve fibers and initiate processing pathways specialized in encoding interaural time (ITD) and level (ILD) differences, respectively. We found that NA neurons, though unable to accurately encode stimulus phase, lock more strongly to the stimulus envelope than NM units. The spectrotemporal receptive fields (STRFs) of NA neurons exhibit a pre-excitatory suppressive field. Using multilinear regression analysis and computational modeling, we show that this feature of STRFs can account for enhanced across-trial response reliability, by locking spikes to the stimulus envelope. Our findings indicate a dichotomy in envelope coding between the time and intensity processing pathways as early as at the level of the cochlear nuclei. This allows the ILD processing pathway to encode envelope information with greater fidelity than the ITD processing pathway. Furthermore, we demonstrate that the properties of the neurons’ STRFs can be quantitatively related to spike timing reliability.
doi:10.1523/JNEUROSCI.5422-10.2011
PMCID: PMC3059808  PMID: 21368035
Nucleus angularis; STRF; spectrotemporal tuning; cochlear nuclei; barn owl; response reliability
17.  Topographic Spread of Inferior Colliculus Activation in Response to Acoustic and Intracochlear Electric Stimulation 
The design of contemporary multichannel cochlear implants is predicated on the presumption that they activate multiple independent sectors of the auditory nerve array. The independence of these channels, however, is limited by the spread of activation from each intracochlear electrode across the auditory nerve array. In this study, we evaluated factors that influence intracochlear spread of activation using two types of intracochlear electrodes: (1) a clinical-type device consisting of a linear series of ring contacts positioned along a silicon elastomer carrier, and (2) a pair of visually placed (VP) ball electrodes that could be positioned independently relative to particular intracochlear structures, e.g., the spiral ganglion. Activation spread was estimated by recording multineuronal evoked activity along the cochleotopic axis of the central nucleus of the inferior colliculus (ICC). This activity was recorded using silicon-based single-shank, 16-site recording probes, which were fixed within the ICC at a depth defined by responses to acoustic tones. After deafening, electric stimuli consisting of single biphasic electric pulses were presented with each electrode type in various stimulation configurations (monopolar, bipolar, tripolar) and/or various electrode orientations (radial, off-radial, longitudinal). The results indicate that monopolar (MP) stimulation with either electrode type produced widepread excitation across the ICC. Bipolar (BP) stimulation with banded pairs of electrodes oriented longitudinally produced activation that was somewhat less broad than MP stimulation, and tripolar (TP) stimulation produced activation that was more restricted than MP or BP stimulation. Bipolar stimulation with radially oriented pairs of VP ball electrodes produced the most restricted activation. The activity patterns evoked by radial VP balls were comparable to those produced by pure tones in normal-hearing animals. Variations in distance between radially oriented VP balls had little effect on activation spread, although increases in interelectrode spacing tended to reduce thresholds. Bipolar stimulation with longitudinally oriented VP electrodes produced broad activation that tended to broaden as the separation between electrodes increased.
doi:10.1007/s10162-004-4026-5
PMCID: PMC2504547  PMID: 15492888
cochlear implant; cochlear prosthesis; deafness; auditory nervous system; multichannel recording; auditory prosthesis
18.  The Frequency Following Response (FFR) May Reflect Pitch-Bearing Information But is Not a Direct Representation of Pitch 
The frequency following response (FFR), a scalp-recorded measure of phase-locked brainstem activity, is often assumed to reflect the pitch of sounds as perceived by humans. In two experiments, we investigated the characteristics of the FFR evoked by complex tones. FFR waveforms to alternating-polarity stimuli were averaged for each polarity and added, to enhance envelope, or subtracted, to enhance temporal fine structure information. In experiment 1, frequency-shifted complex tones, with all harmonics shifted by the same amount in Hertz, were presented diotically. Only the autocorrelation functions (ACFs) of the subtraction-FFR waveforms showed a peak at a delay shifted in the direction of the expected pitch shifts. This expected pitch shift was also present in the ACFs of the output of an auditory nerve model. In experiment 2, the components of a harmonic complex with harmonic numbers 2, 3, and 4 were presented either to the same ear (“mono”) or the third harmonic was presented contralaterally to the ear receiving the even harmonics (“dichotic”). In the latter case, a pitch corresponding to the missing fundamental was still perceived. Monaural control conditions presenting only the even harmonics (“2 + 4”) or only the third harmonic (“3”) were also tested. Both the subtraction and the addition waveforms showed that (1) the FFR magnitude spectra for “dichotic” were similar to the sum of the spectra for the two monaural control conditions and lacked peaks at the fundamental frequency and other distortion products visible for “mono” and (2) ACFs for “dichotic” were similar to those for “2 + 4” and dissimilar to those for “mono.” The results indicate that the neural responses reflected in the FFR preserve monaural temporal information that may be important for pitch, but provide no evidence for any additional processing over and above that already present in the auditory periphery, and do not directly represent the pitch of dichotic stimuli.
doi:10.1007/s10162-011-0284-1
PMCID: PMC3214239  PMID: 21826534
complex tones; dichotic presentation; monaural temporal information
19.  The Frequency Following Response (FFR) May Reflect Pitch-Bearing Information But is Not a Direct Representation of Pitch 
The frequency following response (FFR), a scalp-recorded measure of phase-locked brainstem activity, is often assumed to reflect the pitch of sounds as perceived by humans. In two experiments, we investigated the characteristics of the FFR evoked by complex tones. FFR waveforms to alternating-polarity stimuli were averaged for each polarity and added, to enhance envelope, or subtracted, to enhance temporal fine structure information. In experiment 1, frequency-shifted complex tones, with all harmonics shifted by the same amount in Hertz, were presented diotically. Only the autocorrelation functions (ACFs) of the subtraction-FFR waveforms showed a peak at a delay shifted in the direction of the expected pitch shifts. This expected pitch shift was also present in the ACFs of the output of an auditory nerve model. In experiment 2, the components of a harmonic complex with harmonic numbers 2, 3, and 4 were presented either to the same ear (“mono”) or the third harmonic was presented contralaterally to the ear receiving the even harmonics (“dichotic”). In the latter case, a pitch corresponding to the missing fundamental was still perceived. Monaural control conditions presenting only the even harmonics (“2 + 4”) or only the third harmonic (“3”) were also tested. Both the subtraction and the addition waveforms showed that (1) the FFR magnitude spectra for “dichotic” were similar to the sum of the spectra for the two monaural control conditions and lacked peaks at the fundamental frequency and other distortion products visible for “mono” and (2) ACFs for “dichotic” were similar to those for “2 + 4” and dissimilar to those for “mono.” The results indicate that the neural responses reflected in the FFR preserve monaural temporal information that may be important for pitch, but provide no evidence for any additional processing over and above that already present in the auditory periphery, and do not directly represent the pitch of dichotic stimuli.
doi:10.1007/s10162-011-0284-1
PMCID: PMC3214239  PMID: 21826534
complex tones; dichotic presentation; monaural temporal information
20.  Sensitivity of Inferior Colliculus Neurons to Interaural Time Differences in the Envelope Versus the Fine Structure With Bilateral Cochlear Implants 
Journal of neurophysiology  2008;99(5):2390-2407.
Bilateral cochlear implantation seeks to improve hearing by taking advantage of the binaural processing of the central auditory system. Cochlear implants typically encode sound in each spectral channel by amplitude modulating (AM) a fixed-rate pulse train, thus interaural time differences (ITD) are only delivered in the envelope. We investigated the ITD sensitivity of inferior colliculus (IC) neurons with sinusoidally AM pulse trains. ITD was introduced independently to the AM and/or carrier pulses to measure the relative efficacy of envelope and fine structure for delivering ITD information. We found that many IC cells are sensitive to ITD in both the envelope (ITDenv) and fine structure (ITDfs) for appropriate modulation frequencies and carrier rates. ITDenv sensitivity was generally similar to that seen in normal-hearing animals with AM tones. ITDenv tuning generally improved with increasing modulation frequency up to the maximum modulation frequency that elicited a sustained response in a neuron (tested ≤Hz). ITDfs sensitivity was present in about half the neurons for 1,000 pulse/s (pps) carriers and was nonexistent at 5,000 pps. The neurons that were sensitive to ITDfs at 1,000 pps were those that showed the best ITD sensitivity to low-rate pulse trains. Overall, the best ITD sensitivity was found for ITD contained in the fine structure of a moderate rate AM pulse train (1,000 pps). These results suggest that the interaural timing of current pulses should be accurately controlled in a bilateral cochlear implant processing strategy that provides salient ITD cues.
doi:10.1152/jn.00751.2007
PMCID: PMC2570106  PMID: 18287556
21.  Sensitivity to Interaural Time Differences in the Inferior Colliculus with Bilateral Cochlear Implants 
Bilateral cochlear implantation attempts to increase performance over a monaural prosthesis by harnessing the binaural processing of the auditory system. Although many bilaterally implanted human subjects discriminate interaural time differences (ITDs), a major cue for sound localization and signal detection in noise, their performance is typically poorer than that of normal-hearing listeners. We developed an animal model of bilateral cochlear implantation to study neural ITD sensitivity for trains of electric current pulses delivered via bilaterally implanted intracochlear electrodes. We found that a majority of single units in the inferior colliculus of acutely deafened, anesthetized cats are sensitive to ITD and that electric ITD tuning is as sharp as found for acoustic stimulation with broadband noise in normal-hearing animals. However, the sharpness and shape of ITD tuning often depended strongly on stimulus intensity; some neurons had dynamic ranges of ITD sensitivity as low as 1 dB. We also found that neural ITD sensitivity was best at pulse rates below 100 Hz and decreased with increasing pulse rate. This rate limitation parallels behavioral ITD discrimination in bilaterally implanted individuals. The sharp neural ITD sensitivity found with electric stimulation at the appropriate intensity is encouraging for the prospect of restoring the functional benefits of binaural hearing in bilaterally implanted human subjects and suggests that neural plasticity resulting from previous deafness and deprivation of binaural experience may play a role in the poor ITD discrimination with current bilateral implants.
doi:10.1523/JNEUROSCI.0052-07.2007
PMCID: PMC2041852  PMID: 17581961
binaural hearing; electric stimulation; neural prosthesis; cochlear implant; inferior colliculus; ITD
22.  Unanesthetized Auditory Cortex Exhibits Multiple Codes for Gaps in Cochlear Implant Pulse Trains 
Cochlear implant listeners receive auditory stimulation through amplitude-modulated electric pulse trains. Auditory nerve studies in animals demonstrate qualitatively different patterns of firing elicited by low versus high pulse rates, suggesting that stimulus pulse rate might influence the transmission of temporal information through the auditory pathway. We tested in awake guinea pigs the temporal acuity of auditory cortical neurons for gaps in cochlear implant pulse trains. Consistent with results using anesthetized conditions, temporal acuity improved with increasing pulse rates. Unlike the anesthetized condition, however, cortical neurons responded in the awake state to multiple distinct features of the gap-containing pulse trains, with the dominant features varying with stimulus pulse rate. Responses to the onset of the trailing pulse train (Trail-ON) provided the most sensitive gap detection at 1,017 and 4,069 pulse-per-second (pps) rates, particularly for short (25 ms) leading pulse trains. In contrast, under conditions of 254 pps rate and long (200 ms) leading pulse trains, a sizeable fraction of units demonstrated greater temporal acuity in the form of robust responses to the offsets of the leading pulse train (Lead-OFF). Finally, TONIC responses exhibited decrements in firing rate during gaps, but were rarely the most sensitive feature. Unlike results from anesthetized conditions, temporal acuity of the most sensitive units was nearly as sharp for brief as for long leading bursts. The differences in stimulus coding across pulse rates likely originate from pulse rate-dependent variations in adaptation in the auditory nerve. Two marked differences from responses to acoustic stimulation were: first, Trail-ON responses to 4,069 pps trains encoded substantially shorter gaps than have been observed with acoustic stimuli; and second, the Lead-OFF gap coding seen for <15 ms gaps in 254 pps stimuli is not seen in responses to sounds. The current results may help to explain why moderate pulse rates around 1,000 pps are favored by many cochlear implant listeners.
doi:10.1007/s10162-011-0293-0
PMCID: PMC3254721  PMID: 21969022
auditory prosthesis; pulse rate; guinea pig; temporal acuity; forward masking
23.  Unanesthetized Auditory Cortex Exhibits Multiple Codes for Gaps in Cochlear Implant Pulse Trains 
Cochlear implant listeners receive auditory stimulation through amplitude-modulated electric pulse trains. Auditory nerve studies in animals demonstrate qualitatively different patterns of firing elicited by low versus high pulse rates, suggesting that stimulus pulse rate might influence the transmission of temporal information through the auditory pathway. We tested in awake guinea pigs the temporal acuity of auditory cortical neurons for gaps in cochlear implant pulse trains. Consistent with results using anesthetized conditions, temporal acuity improved with increasing pulse rates. Unlike the anesthetized condition, however, cortical neurons responded in the awake state to multiple distinct features of the gap-containing pulse trains, with the dominant features varying with stimulus pulse rate. Responses to the onset of the trailing pulse train (Trail-ON) provided the most sensitive gap detection at 1,017 and 4,069 pulse-per-second (pps) rates, particularly for short (25 ms) leading pulse trains. In contrast, under conditions of 254 pps rate and long (200 ms) leading pulse trains, a sizeable fraction of units demonstrated greater temporal acuity in the form of robust responses to the offsets of the leading pulse train (Lead-OFF). Finally, TONIC responses exhibited decrements in firing rate during gaps, but were rarely the most sensitive feature. Unlike results from anesthetized conditions, temporal acuity of the most sensitive units was nearly as sharp for brief as for long leading bursts. The differences in stimulus coding across pulse rates likely originate from pulse rate-dependent variations in adaptation in the auditory nerve. Two marked differences from responses to acoustic stimulation were: first, Trail-ON responses to 4,069 pps trains encoded substantially shorter gaps than have been observed with acoustic stimuli; and second, the Lead-OFF gap coding seen for <15 ms gaps in 254 pps stimuli is not seen in responses to sounds. The current results may help to explain why moderate pulse rates around 1,000 pps are favored by many cochlear implant listeners.
doi:10.1007/s10162-011-0293-0
PMCID: PMC3254721  PMID: 21969022
auditory prosthesis; pulse rate; guinea pig; temporal acuity; forward masking
24.  Variation in the Phase of Response to Low-Frequency Pure Tones in the Guinea Pig Auditory Nerve as Functions of Stimulus Level and Frequency 
The directionality of hair cell stimulation combined with the vibration of the basilar membrane causes the auditory nerve fiber action potentials, in response to low-frequency stimuli, to occur at a particular phase of the stimulus waveform. Because direct mechanical measurements at the cochlear apex are difficult, such phase locking has often been used to indirectly infer the basilar membrane motion. Here, we confirm and extend earlier data from mammals using sine wave stimulation over a wide range of sound levels (up to 90 dB sound pressure level). We recorded phase-locked responses to pure tones over a wide range of frequencies and sound levels of a large population of auditory nerve fibers in the anesthetized guinea pig. The results indicate that, for a constant frequency of stimulation, the phase lag decreases with increases in the characteristic frequency (CF) of the nerve fiber. The phase lag decreases up to a CF above the stimulation frequency, beyond which it decreases at a much slower rate. Such phase changes are consistent with known basal cochlear mechanics. Measurements from individual fibers showed smaller but systematic variations in phase with sound level, confirming previous reports. We found a “null” stimulation frequency at which little variation in phase occurred with sound level. This null frequency was often not at the CF. At stimulation frequencies below the null, there was a progressive lag with sound level and a progressive lead for stimulation frequencies above the null. This was maximally 0.2 cycles.
doi:10.1007/s10162-008-0151-x
PMCID: PMC2674197  PMID: 19093151
auditory nerve; phase response; basilar membrane; guinea pig
25.  The multiple-channel cochlear implant: the interface between sound and the central nervous system for hearing, speech, and language in deaf people—a personal perspective 
The multiple-channel cochlear implant is the first sensori-neural prosthesis to effectively and safely bring electronic technology into a direct physiological relation with the central nervous system and human consciousness, and to give speech perception to severely-profoundly deaf people and spoken language to children.
Research showed that the place and temporal coding of sound frequencies could be partly replicated by multiple-channel stimulation of the auditory nerve. This required safety studies on how to prevent the effects to the cochlea of trauma, electrical stimuli, biomaterials and middle ear infection. The mechanical properties of an array and mode of stimulation for the place coding of speech frequencies were determined.
A fully implantable receiver–stimulator was developed, as well as the procedures for the clinical assessment of deaf people, and the surgical placement of the device. The perception of electrically coded sounds was determined, and a speech processing strategy discovered that enabled late-deafened adults to comprehend running speech. The brain processing systems for patterns of electrical stimuli reproducing speech were elucidated. The research was developed industrially, and improvements in speech processing made through presenting additional speech frequencies by place coding. Finally, the importance of the multiple-channel cochlear implant for early deafened children was established.
doi:10.1098/rstb.2005.1782
PMCID: PMC1609401  PMID: 16627295
multiple-channel cochlear implant; electrical stimulation of the auditory nerve; management of severe-profound hearing loss

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