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1.  Neural Coding of Interaural Time Differences with Bilateral Cochlear Implants in Unanesthetized Rabbits 
The Journal of Neuroscience  2016;36(20):5520-5531.
Although bilateral cochlear implants (CIs) provide improvements in sound localization and speech perception in noise over unilateral CIs, bilateral CI users' sensitivity to interaural time differences (ITDs) is still poorer than normal. In particular, ITD sensitivity of most CI users degrades with increasing stimulation rate and is lacking at the high carrier pulse rates used in CI processors to deliver speech information. To gain a better understanding of the neural basis for this degradation, we characterized ITD tuning of single neurons in the inferior colliculus (IC) for pulse train stimuli in an unanesthetized rabbit model of bilateral CIs. Approximately 73% of IC neurons showed significant ITD sensitivity in their overall firing rates. On average, ITD sensitivity was best for pulse rates near 80–160 pulses per second (pps) and degraded for both lower and higher pulse rates. The degradation in ITD sensitivity at low pulse rates was caused by strong, unsynchronized background activity that masked stimulus-driven responses in many neurons. Selecting synchronized responses by temporal windowing revealed ITD sensitivity in these neurons. With temporal windowing, both the fraction of ITD-sensitive neurons and the degree of ITD sensitivity decreased monotonically with increasing pulse rate. To compare neural ITD sensitivity to human performance in ITD discrimination, neural just-noticeable differences (JNDs) in ITD were computed using signal detection theory. Using temporal windowing at lower pulse rates, and overall firing rate at higher pulse rates, neural ITD JNDs were within the range of perceptual JNDs in human CI users over a wide range of pulse rates.
SIGNIFICANCE STATEMENT Many profoundly deaf people wearing cochlear implants (CIs) still face challenges in everyday situations, such as understanding conversations in noise. Even with CIs in both ears, they have difficulty making full use of subtle differences in the sounds reaching the two ears [interaural time difference (ITD)] to identify where the sound is coming from. This problem is especially acute at the high stimulation rates used in clinical CI processors. This study provides a better understanding of ITD processing with bilateral CIs and shows a parallel between human performance in ITD discrimination and neural responses in the auditory midbrain. The present study is the first report on binaural properties of auditory neurons with CIs in unanesthetized animals.
doi:10.1523/JNEUROSCI.3795-15.2016
PMCID: PMC4871987  PMID: 27194332
binaural hearing; cochlear implant; inferior colliculus; interaural time difference; temporal coding
2.  Locomotion and task demands differentially modulate thalamic audiovisual processing during active search 
Current biology : CB  2015;25(14):1885-1891.
SUMMARY
Active search is a ubiquitous goal-driven behavior wherein organisms purposefully investigate the sensory environment to locate a target object. During active search, brain circuits analyze a stream of sensory information from the external environment, adjusting for internal signals related to self-generated movement or “top-down” weighting of anticipated target and distractor properties. Sensory responses in the cortex can be modulated by internal state [1–9], though the extent and form of modulation arising in the cortex de novo versus an inheritance from subcortical stations is not clear [4, 8–12]. We addressed this question by simultaneously recording from auditory and visual regions of the thalamus (MG and LG, respectively) while mice used dynamic auditory or visual feedback to search for a hidden target within an annular track. Locomotion was associated with strongly suppressed responses and reduced decoding accuracy in MG but a subtle increase in LG spiking. Because stimuli in one modality provided critical information about target location while the other served as a distractor, we could also estimate the importance of task relevance in both thalamic subdivisions. In contrast to the effects of locomotion, we found that LG responses were reduced overall yet decoded stimuli more accurately when vision was behaviorally relevant, whereas task relevance had little effect on MG responses. This double dissociation between the influences of task relevance and movement in MG and LG highlights a role for extrasensory modulation in the thalamus but also suggests key differences in the organization of modulatory circuitry between the auditory and visual pathways.
doi:10.1016/j.cub.2015.05.045
PMCID: PMC4511122  PMID: 26119749
lateral geniculate nucleus; medial geniculate body; locomotion; movement; attention; plasticity
3.  Auditory Brainstem Implant: Electrophysiologic Responses and Subject Perception 
Ear and hearing  2015;36(3):368-376.
Objectives
The primary aim of this study was to compare the perceptual sensation produced by bipolar electrical stimulation of auditory brainstem implant (ABI) electrodes to the morphology of electrically–evoked responses elicited by the same bipolar stimulus in the same unanesthetized, post-surgical state. Secondary aims were to 1) examine the relationships between sensations elicited by the bipolar stimulation used for evoked potential recording and the sensations elicited by the monopolar pulse-train stimulation used by the implant processor and 2) to examine the relationships between evoked-potential morphology (elicited by bipolar stimulation) to the sensations elicited by monopolar stimulation.
Design
Electrically-evoked early latency and middle-latency responses to bipolar, biphasic low-rate pulses were recorded post-operatively in four adults with auditory brainstem implants. Prior to recording, the perceptual sensations elicited by these bipolar stimuli were obtained and categorized as: 1) Auditory sensations only, 2) Mixed sensations (both auditory and non-auditory), 3) Side Effect (non-auditory sensations) or 4) No Sensation. In addition, the sensations elicited by monopolar higher-rate pulse-train stimuli similar to that used in processor programming were also measured for all electrodes in the ABI array and classified using the same categories. Comparisons were made between evoked response morphology, bipolar stimulation sensation and monopolar stimulation sensation.
Results
Sensations were classified for 33 bipolar pairs as follows: 21 pairs were Auditory, 6 were Mixed, 5 were Side Effect and 1 was No Sensation. When these sensations were compared to the electrically-evoked response morphology for these signals, P3 of the electrically-evoked auditory brainstem response (eABR) and the presence of a middle-latency positive wave, usually between 15 and 25 ms (eMLR), were only present when the perceptual sensation had an auditory component (either Auditory or Mixed pairs). The presence of other waves in the early-latency response such as N1 or P2 or a positive wave after 4 ms did not distinguish between only auditory or only non-auditory sensations.
For monopolar stimulation, 42 were classified as Auditory, 16 were Mixed and 26 were classified as Side Effect or No Sensation. When bipolar sensations were compared to monopolar sensations for the 21 bipolar pairs categorized as Auditory, 7 pairs had monopolar sensations of Auditory for both electrodes, 9 pairs had only one electrode with a monopolar sensation of Auditory, with the remainder having neither electrode as Auditory. Of 6 bipolar pairs categorized as Mixed, 3 had monopolar auditory sensations for one of the electrodes.
When monopolar stimulation was compared to evoked potential morphology elicited by bipolar stimulation, P3 and the eMLR were more likely to be present when one or both of the electrodes in the bipolar pair elicited an Auditory or Mixed sensation with monopolar stimulation and were less likely to occur when neither of the electrodes had an auditory monopolar sensation. Again, other eABR waves did not distinguish between auditory and non-auditory sensations.
Conclusions
ABI electrodes that are associated with auditory sensations elicited by bipolar stimulation are more likely to elicit evoked responses with a P3 wave and/or a middle-latency wave. P3 of the eABR and M15-25 of the eMLR are less likely to be present if neither electrode of the bipolar pair evoked an auditory sensation with monopolar stimulation.
doi:10.1097/AUD.0000000000000126
PMCID: PMC4409921  PMID: 25437141
4.  Hearing the light: neural and perceptual encoding of optogenetic stimulation in the central auditory pathway 
Scientific Reports  2015;5:10319.
Optogenetics provides a means to dissect the organization and function of neural circuits. Optogenetics also offers the translational promise of restoring sensation, enabling movement or supplanting abnormal activity patterns in pathological brain circuits. However, the inherent sluggishness of evoked photocurrents in conventional channelrhodopsins has hampered the development of optoprostheses that adequately mimic the rate and timing of natural spike patterning. Here, we explore the feasibility and limitations of a central auditory optoprosthesis by photoactivating mouse auditory midbrain neurons that either express channelrhodopsin-2 (ChR2) or Chronos, a channelrhodopsin with ultra-fast channel kinetics. Chronos-mediated spike fidelity surpassed ChR2 and natural acoustic stimulation to support a superior code for the detection and discrimination of rapid pulse trains. Interestingly, this midbrain coding advantage did not translate to a perceptual advantage, as behavioral detection of midbrain activation was equivalent with both opsins. Auditory cortex recordings revealed that the precisely synchronized midbrain responses had been converted to a simplified rate code that was indistinguishable between opsins and less robust overall than acoustic stimulation. These findings demonstrate the temporal coding benefits that can be realized with next-generation channelrhodopsins, but also highlight the challenge of inducing variegated patterns of forebrain spiking activity that support adaptive perception and behavior.
doi:10.1038/srep10319
PMCID: PMC4441320  PMID: 26000557
5.  Auditory Responses to Electric and Infrared Neural Stimulation of the Rat Cochlear Nucleus 
Hearing research  2014;310:69-75.
In an effort to improve the auditory brainstem implant, a prosthesis in which user outcomes are modest, we applied electric and infrared neural stimulation (INS) to the cochlear nucleus in a rat animal model. Electric stimulation evoked regions of neural activation in the inferior colliculus and short-latency, multipeaked auditory brainstem responses (ABRs). Pulsed INS, delivered to the surface of the cochlear nucleus via an optical fiber, evoked broad neural activation in the inferior colliculus. Strongest responses were recorded when the fiber was placed at lateral positions on the cochlear nucleus, close to the temporal bone. INS-evoked ABRs were multipeaked but longer in latency than those for electric stimulation; they resembled the responses to acoustic stimulation. After deafening, responses to electric stimulation persisted, whereas those to INS disappeared, consistent with a reported “optophonic” effect, a laser-induced acoustic artifact. Thus, for deaf individuals who use the auditory brainstem implant, INS alone did not appear promising as a new approach.
doi:10.1016/j.heares.2014.01.008
PMCID: PMC3982200  PMID: 24508368
Auditory brainstem implant; prosthesis; laser; optical stimulation
6.  Neural coding of ITD with bilateral cochlear implants: Effects of congenital deafness 
Human bilateral cochlear implant users do poorly on tasks involving interaural time differences (ITD), a cue which provides important benefits to the normal hearing, especially in challenging acoustic environments. Yet the precision of neural ITD coding in acutely-deafened, bilaterally-implanted cats is essentially normal (Smith and Delgutte, J. Neurosci. 27:6740–6750). One explanation for this discrepancy is that the extended periods of binaural deprivation typically experienced by cochlear implant users degrades neural ITD sensitivity, either by impeding normal maturation of the neural circuitry or by altering it later in life. To test this hypothesis, we recorded from single units in inferior colliculus (IC) of two groups of bilaterally-implanted, anesthetized cats that contrast maximally in binaural experience: acutely-deafened cats, which had normal binaural hearing until experimentation, and congenitally deaf white cats, which received no auditory inputs until the experiment. Rate responses of only half as many neurons showed significant ITD sensitivity to low-rate pulse trains in congenitally deaf cats compared to acutely deafened cats. For neurons that were ITD sensitive, ITD tuning was broader and best ITDs were more variable in congenitally deaf cats, leading to poorer ITD coding within the naturally-occurring range. A signal detection model constrained by the observed physiology supports the idea that the degraded neural ITD coding resulting from deprivation of binaural experience contributes to poor ITD discrimination by human implantees.
doi:10.1523/JNEUROSCI.3213-10.2010
PMCID: PMC3025489  PMID: 20962228
binaural hearing; electric stimulation; congenital deafness; cochlear implant; inferior colliculus; ITD
7.  Online Stimulus Optimization Rapidly Reveals Multidimensional Selectivity in Auditory Cortical Neurons 
The Journal of Neuroscience  2014;34(27):8963-8975.
Neurons in sensory brain regions shape our perception of the surrounding environment through two parallel operations: decomposition and integration. For example, auditory neurons decompose sounds by separately encoding their frequency, temporal modulation, intensity, and spatial location. Neurons also integrate across these various features to support a unified perceptual gestalt of an auditory object. At higher levels of a sensory pathway, neurons may select for a restricted region of feature space defined by the intersection of multiple, independent stimulus dimensions. To further characterize how auditory cortical neurons decompose and integrate multiple facets of an isolated sound, we developed an automated procedure that manipulated five fundamental acoustic properties in real time based on single-unit feedback in awake mice. Within several minutes, the online approach converged on regions of the multidimensional stimulus manifold that reliably drove neurons at significantly higher rates than predefined stimuli. Optimized stimuli were cross-validated against pure tone receptive fields and spectrotemporal receptive field estimates in the inferior colliculus and primary auditory cortex. We observed, from midbrain to cortex, increases in both level invariance and frequency selectivity, which may underlie equivalent sparseness of responses in the two areas. We found that onset and steady-state spike rates increased proportionately as the stimulus was tailored to the multidimensional receptive field. By separately evaluating the amount of leverage each sound feature exerted on the overall firing rate, these findings reveal interdependencies between stimulus features as well as hierarchical shifts in selectivity and invariance that may go unnoticed with traditional approaches.
doi:10.1523/JNEUROSCI.0260-14.2014
PMCID: PMC4078078  PMID: 24990917
auditory cortex; closed-loop; genetic algorithm; online neural characterization; optimization algorithm; sparse coding
8.  A Physiologically Based Model of Interaural Time Difference Discrimination 
Interaural time difference (ITD) is a cue to the location of sounds containing low frequencies and is represented in the inferior colliculus (IC) by cells that respond maximally at a particular best delay (BD). Previous studies have demonstrated that single ITD-sensitive cells contain sufficient information in their discharge patterns to account for ITD acuity on the midline (ITD = 0). If ITD discrimination were based on the activity of the most sensitive cell available (“lower envelope hypothesis”), then ITD acuity should be relatively constant as a function of ITD. In response to broadband noise, however, the ITD acuity of human listeners degrades as ITD increases. To account for these results, we hypothesize that pooling of information across neurons is an essential component of ITD discrimination. This report describes a neural pooling model of ITD discrimination based on the response properties of ITD-sensitive cells in the IC of anesthetized cats.
Rate versus ITD curves were fit with a cross-correlation model of ITD sensitivity, and the parameters were used to constrain a population model of ITD discrimination. The model accurately predicts ITD acuity as a function of ITD for broadband noise stimuli when responses are pooled across best frequency (BF). Furthermore, ITD tuning based solely on a system of internal delays is not sufficient to predict ITD acuity in response to 500 Hz tones, suggesting that acuity is likely refined by additional mechanisms. The physiological data confirms evidence from the guinea pig that BD varies systematically with BF, generalizing the observation across species.
doi:10.1523/JNEUROSCI.0762-04.2004
PMCID: PMC2041891  PMID: 15306644
auditory; binaural; hearing; inferior colliculus; localization; psychophysics
9.  Coding of Electric Pulse Trains Presented through Cochlear Implants in the Auditory Midbrain of Awake Rabbit: Comparison with Anesthetized Preparations 
The Journal of Neuroscience  2014;34(1):218-231.
Cochlear implant (CI) listeners show limits at high frequencies in tasks involving temporal processing such as rate pitch and interaural time difference discrimination. Similar limits have been observed in neural responses to electric stimulation in animals with CI; however, the upper limit of temporal coding of electric pulse train stimuli in the inferior colliculus (IC) of anesthetized animals is lower than the perceptual limit. We hypothesize that the upper limit of temporal neural coding has been underestimated in previous studies due to the confound of anesthesia. To test this hypothesis, we developed a chronic, awake rabbit preparation for single-unit studies of IC neurons with electric stimulation through CI. Stimuli were periodic trains of biphasic pulses with rates varying from 20 to 1280 pulses per second. We found that IC neurons in awake rabbits showed higher spontaneous activity and greater sustained responses, both excitatory and suppressive, at high pulse rates. Maximum pulse rates that elicited synchronized responses were approximately two times higher in awake rabbits than in earlier studies with anesthetized animals. Here, we demonstrate directly that anesthesia is a major factor underlying these differences by monitoring the responses of single units in one rabbit before and after injection of an ultra-short-acting barbiturate. In general, the physiological rate limits of IC neurons in the awake rabbit are more consistent with the psychophysical limits in human CI subjects compared with limits from anesthetized animals.
doi:10.1523/JNEUROSCI.2084-13.2014
PMCID: PMC3866485  PMID: 24381283
anesthesia; cochlear implant; inferior colliculus; temporal coding
10.  Congenital and Prolonged Adult-Onset Deafness Cause Distinct Degradations in Neural ITD Coding with Bilateral Cochlear Implants 
Bilateral cochlear implant (CI) users perform poorly on tasks involving interaural time differences (ITD), which are critical for sound localization and speech reception in noise by normal-hearing listeners. ITD perception with bilateral CI is influenced by age at onset of deafness and duration of deafness. We previously showed that ITD coding in the auditory midbrain is degraded in congenitally deaf white cats (DWC) compared to acutely deafened cats (ADC) with normal auditory development (Hancock et al., J. Neurosci, 30:14068). To determine the relative importance of early onset of deafness and prolonged duration of deafness for abnormal ITD coding in DWC, we recorded from single units in the inferior colliculus of cats deafened as adults 6 months prior to experimentation (long-term deafened cats, LTDC) and compared neural ITD coding between the three deafness models. The incidence of ITD-sensitive neurons was similar in both groups with normal auditory development (LTDC and ADC), but significantly diminished in DWC. In contrast, both groups that experienced prolonged deafness (LTDC and DWC) had broad distributions of best ITDs around the midline, unlike the more focused distributions biased toward contralateral-leading ITDs present in both ADC and normal-hearing animals. The lack of contralateral bias in LTDC and DWC results in reduced sensitivity to changes in ITD within the natural range. The finding that early onset of deafness more severely degrades neural ITD coding than prolonged duration of deafness argues for the importance of fitting deaf children with sound processors that provide reliable ITD cues at an early age.
doi:10.1007/s10162-013-0380-5
PMCID: PMC3642270  PMID: 23462803
binaural hearing; congenital deafness; inferior colliculus; cochlear implants; ITD
11.  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
12.  Sound-Evoked Olivocochlear Activation in Unanesthetized Mice 
Genetic tools available for the mouse make it a powerful model to study the modulation of cochlear function by descending control systems. Suppression of distortion product otoacoustic emission (DPOAE) amplitude by contralateral acoustic stimulation (CAS) provides a robust tool for noninvasively monitoring the strength of descending modulation, yet investigations in mice have been performed infrequently and only under anesthesia, a condition likely to reduce olivocochlear activation. Here, we characterize the contralateral olivocochlear reflex in the alert, unanesthetized mouse. Head-fixed mice were restrained between two closed acoustic systems, while an artifact rejection protocol minimized contamination from self-generated sounds and movements. In mice anesthetized with pentobarbital, ketamine or urethane, CAS at 80 dB SPL evoked, on average, a <1-dB change in DPOAE amplitude. In contrast, the mean CAS-induced DPOAE suppression in unanesthetized mice was nearly 8 dB. Experiments in mice with targeted deletion of the α9 subunit of the nicotinic acetylcholine receptor confirmed the contribution of the medial olivocochlear efferents to this phenomenon. These findings demonstrate the utility of the CAS assay in the unanesthetized mouse and highlight the adverse effects of anesthesia when probing the functional status of descending control pathways within the auditory system.
doi:10.1007/s10162-011-0306-z
PMCID: PMC3298614  PMID: 22160753
olivocochlear; corticofugal; arousal; attention; anesthesia; contralateral reflex; outer hair cell
13.  Robustness of cortical topography across fields, laminae, anesthetic states, and neurophysiological signal types 
The Journal of Neuroscience  2012;32(27):9159-9172.
Topographically organized maps of the sensory receptor epithelia are regarded as cornerstones of cortical organization as well as valuable readouts of diverse biological processes ranging from evolution to neural plasticity. However, maps are most often derived from multiunit activity recorded in the thalamic input layers of anesthetized animals using near-threshold stimuli. Less distinct topography has been described by studies that deviated from the formula above, which brings into question the generality of the principle. Here, we explicitly compared the strength of tonotopic organization at various depths within core and belt regions of the auditory cortex using electrophysiological measurements ranging from single units to delta-band local field potentials (LFP) in the awake and anesthetized mouse. Unit recordings in the middle cortical layers revealed a precise tonotopic organization in core, but not belt, regions of auditory cortex that was similarly robust in awake and anesthetized conditions. In core fields, tonotopy was degraded outside the middle layers or when LFP signals were substituted for unit activity, due to an increasing proportion of recording sites with irregular tuning for pure tones. However, restricting our analysis to clearly defined receptive fields revealed an equivalent tonotopic organization in all layers of the cortical column and for LFP activity ranging from gamma to theta bands. Thus, core fields represent a transition between topographically organized simple receptive field arrangements that extend throughout all layers of the cortical column and the emergence of non-tonotopic representations outside the input layers that are further elaborated in the belt fields.
doi:10.1523/JNEUROSCI.0065-12.2012
PMCID: PMC3402176  PMID: 22764225

Results 1-13 (13)