Publications using TDT

OBJECTIVE: In chinchillas, moderate doses of carboplatin administered systemically selectively destroy inner hair cells and type I vestibular hair cells; however, it is unclear whether this unique damage pattern persists if carboplatin is applied directly to the cochlea, how quickly the damage develops and what cell death pathways are involved. STUDY DESIGN: To address these questions, carboplatin (5 mg/ml, 50 µl) was applied to the round window. RESULTS: Carboplatin caused a rapid decline in distortion product otoacoustic emissions, significantly increased compound action potential thresholds and caused massive inner hair cell loss and less severe outer hair cell loss. Hair cell loss was initially more severe in the base than the apex of the cochlea, but by 28 days post-treatment most cochlear hair cells were missing and hair cell density in the utricle, saccule and lateral crista was greatly reduced. At one day post-treatment, many hair cell nuclei were condensed or fragmented indicative of apoptosis, and expressed initiator caspase-8 and executioner caspase-3, but not initiator caspase-9. Carboplatin-treated animals circled towards the treated ear and during the swim test rolled towards the treated ear. CONCLUSION: These results indicate that local application of carboplatin causes loss of hair cells that begins near the base of the cochlea and spreads towards the apex with increasing survival time. Hair cell loss is initiated by caspase-8 followed by executioner caspase-3.

When an object is introduced moving in the visual field of view, the object maps with different delays in each of the six cortical layers in many visual areas by mechanisms that are poorly understood. We combined voltage sensitive dye (VSD) recordings with laminar recordings of action potentials in visual areas 17, 18, 19 and 21 in ferrets exposed to stationary and moving bars. At the area 17/18 border a moving bar first elicited an ON response in layer 4 and then ON responses in supragranular and infragranular layers, identical to a stationary bar. Shortly after, the moving bar mapped as moving synchronous peak firing across layers. Complex dynamics evolved including feedback from areas 19/21, the computation of a spatially restricted pre-depolarization (SRP), and firing in the direction of cortical motion prior to the mapping of the bar. After 350 ms, the representations of the bar (peak firing and peak VSD signal) in areas 19/21 and 17/18 moved over the cortex in phase. The dynamics comprise putative mechanisms for automatic saliency of novel moving objects, coherent mapping of moving objects across layers and areas, and planning of catch-up saccades.

Commercially available data acquisition systems for multielectrode recording from freely moving animals are expensive, often rely on proprietary software, and do not provide detailed, modifiable circuit schematics. When used in conjunction with electrical stimulation, they are prone to prolonged, saturating stimulation artifacts that prevent the recording of short-latency evoked responses. Yet electrical stimulation is integral to many experimental designs, and critical for emerging brain-computer interfacing and neuroprosthetic applications. To address these issues, we developed an easy-to-use, modifiable, and inexpensive system for multielectrode neural recording and stimulation. Setup costs are less than US$10,000 for 64 channels, an order of magnitude lower than comparable commercial systems. Unlike commercial equipment, the system recovers rapidly from stimulation and allows short-latency action potentials (<1 ms post-stimulus) to be detected, facilitating closed-loop applications and exposing neural activity that would otherwise remain hidden. To illustrate this capability, evoked activity from microstimulation of the rodent hippocampus is presented. System noise levels are similar to existing platforms, and extracellular action potentials and local field potentials can be recorded simultaneously. The system is modular, in banks of 16 channels, and flexible in usage: while primarily designed for in vivo use, it can be combined with commercial preamplifiers to record from in vitro multielectrode arrays. The system's open-source control software, NeuroRighter, is implemented in C#, with an easy-to-use graphical interface. As C# functions in a managed code environment, which may impact performance, analysis was conducted to ensure comparable speed to C++ for this application. Hardware schematics, layout files, and software are freely available. Since maintaining wired headstage connections with freely moving animals is difficult, we describe a new method of electrode-headstage coupling using neodymium magnets.

Chronic microstimulation-based devices are being investigated to treat conditions such as blindness, deafness, pain, paralysis, and epilepsy. Small-area electrodes are desired to achieve high selectivity. However, a major trade-off with electrode miniaturization is an increase in impedance and charge density requirements. Thus, the development of novel materials with lower interfacial impedance and enhanced charge storage capacity is essential for the development of micro-neural interface-based neuroprostheses. In this report, we study the use of conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) as a neural interface material for microstimulation of small-area iridium electrodes on silicon-substrate arrays. Characterized by electrochemical impedance spectroscopy, electrodeposition of PEDOT results in lower interfacial impedance at physiologically relevant frequencies, with the 1 kHz impedance magnitude being 23.3 +/- 0.7 kOmega, compared to 113.6 +/- 3.5 kOmega for iridium oxide (IrOx) on 177 mum(2) sites. Further, PEDOT exhibits enhanced charge storage capacity at 75.6 +/- 5.4 mC/cm(2) compared to 28.8 +/- 0.3 mC/cm(2) for IrOx, characterized by cyclic voltammetry (50 mV/s). These improvements at the electrode interface were corroborated by observation of the voltage excursions that result from constant current pulsing. The PEDOT coatings provide both a lower amplitude voltage and a more ohmic representation of the applied current compared to IrOx. During repetitive pulsing, PEDOT-coated electrodes show stable performance and little change in electrical properties, even at relatively high current densities which cause IrOx instability. These findings support the potential of PEDOT coatings as a micro-neural interface material for electrostimulation.

Induction of peripheral tolerance by oral administration of low-dose β-tubulin antigen may be an effective, antigen-specific method to suppress experimental autoimmune hearing loss. Five groups of mice were fed with phosphate-buffered saline (PBS), ovalbumin (OVA), 20, 30 or 200 μg of β-tubulin, respectively. All mice were then immunized by β-tubulin. Hearing thresholds were measured before and after immunization. Inner ear histology and cytokine profile were examined. Mice fed with 20 or 30 μg of β-tubulin showed less hearing loss and less inner ear damage compared to the groups treated with PBS, OVA or 200 μg of β-tubulin. Interferon-gamma (IFN-γ) was decreased while interleukin-4 (IL-4), IL-5, IL-13 and TGF-β were increased in both sera and in cell culture supernatants of the mice fed with 20 or 30 μg of β-tubulin. However, no cytokine profile change was found in the group treated with 200 μg of tubulin. These results suggest that a low dose of β-tubulin is active orally in an antigen-specific fashion and capable of inhibiting the autoimmune reactions in the inner ear by suppressingTh1 (IFN-γ) and increasing Th2 and Th3 (IL-4, IL-5, IL-13 and TGF-β) cytokines. Oral antigen tolerance may be used to treat autoimmune inner ear disease.

Increasing evidence suggests the involvement of oxidative stress in noise-induced hearing loss. The present study analysed, in an animal experimental model, the time course of the pathogenic mechanisms of noise-induced cochlear damage and the efficacy of the antioxidant drug N-acetylcysteine in reducing noise ototoxicity. Animals were divided into two groups, exposed to noise one treated with N-acetylcysteine for 3 days and one (the control group) with saline. Acoustic trauma was induced by a continuous pure tone of 6 kHz, at 120 dB SPL for 30 minutes. Electrocochleographic recordings were made from an implanted round window electrode and the compound action potentials were measured daily at 2-16 kHz for 7 days. Morphological changes were analysed by scanning electron microscopy. The acoustic threshold measured 1 hour after acoustic trauma was elevated in the control group to 70-90 dB in the higher frequencies of the compound action potential audiogram, with a maximum threshold elevation ranging between 12 and 16 kHz. During the first 24 h, following acoustic trauma, there was a partial recovery of compound action potential thresholds of about 20 dB to reach a final threshold elevation of about 50-70 dB; there was no further improvement over the remaining experimental week. Animals treated with N-acetylcysteine showed a similar temporary threshold shift but a clear improvement in the recovery of compound action potential thresholds, with significantly reduced permanent threshold shift and hair cell loss. These data suggest that N-acetylcysteine is able to attenuate the toxic effect of acoustic trauma and could represent an interesting molecule for preventing inner ear injuries.

Behavioral detection of a low-frequency (40 Hz) vibratory dipole at source distances of 1.5-24 cm was measured by classically conditioned respiratory suppression in goldfish (Carassius auratus). Detection thresholds were compared across distances and before and after ablation of individual octavolateralis sensory channels. Detection thresholds, expressed in units of pressure (SPL), remained roughly constant as distance between the stimulus source and animal increased. Lateral line inactivation, using CoCl2, had no measurable effect on sensitivity, although some other results can be construed as weak evidence for a small contribution of the lateral line to dipole detection when source distances are <or=6 cm (<1 body length). Gas bladder deflation resulted in a large increase in threshold (17 dB), demonstrating that the gas bladder contributes to audition at low frequencies. The present study confirms an auditory role for the gas bladder-enhanced inner ear of goldfish in the detection of low-frequency vibratory sources. Sonic audition (detection of pressure fluctuations) appears to be the dominant mode of dipole-source detection for goldfish when measured by conditioned behaviors in psychophysical experiments.

The Python programming language is steadily increasing in popularity as the language of choice for scientific computing. The ability of this scripting environment to access a huge code base in various languages, combined with its syntactical simplicity, make it the ideal tool for implementing and sharing ideas among scientists from numerous fields and with heterogeneous methodological backgrounds. The recent rise of reciprocal interest between the machine learning (ML) and neuroscience communities is an example of the desire for an inter-disciplinary transfer of computational methods that can benefit from a Python-based framework. For many years, a large fraction of both research communities have addressed, almost independently, very high-dimensional problems with almost completely non-overlapping methods. However, a number of recently published studies that applied ML methods to neuroscience research questions attracted a lot of attention from researchers from both fields, as well as the general public, and showed that this approach can provide novel and fruitful insights into the functioning of the brain. In this article we show how PyMVPA, a specialized Python framework for machine learning based data analysis, can help to facilitate this inter-disciplinary technology transfer by providing a single interface to a wide array of machine learning libraries and neural data-processing methods. We demonstrate the general applicability and power of PyMVPA via analyses of a number of neural data modalities, including fMRI, EEG, MEG, and extracellular recordings.

Improvements in performance on many perceptual skills can occur with only a single training session. Of interest here is what aspects of the training experience are being learned during this brief exposure. Although there is considerable evidence that learning associated with specific feature values of the stimulus used in training (stimulus learning) contributes to these rapid improvements, there has been little direct investigation of the possibility that other types of learning do so as well. Here the authors show that not only stimulus learning but also learning of more general aspects of the training experience (procedure learning) contributed to rapid improvements in performance on interaural time difference discrimination. However, practice on the type of judgment to be made did not appear to aid performance (no task learning). These results are consistent with physiological reports that different neural mechanisms are engaged at different time points during even a brief training session, and imply that the circuits that are engaged and likely modified vary in the degree of their selectivity to the target condition. Such changes presumably enable further learning.

Talkers show sensitivity to a range of perturbations of auditory feedback (e.g., manipulation of vocal amplitude, fundamental frequency and formant frequency). Here, 50 subjects spoke a monosyllable (“head”), and the formants in their speech were shifted in real time using a custom signal processing system that provided feedback over headphones. First and second formants were altered so that the auditory feedback matched subjects’ production of “had.” Three different instructions were tested: (1) control, in which subjects were naïve about the feedback manipulation, (2) ignore headphones, in which subjects were told that their voice might sound different and to ignore what they heard in the headphones, and (3) avoid compensation, in which subjects were informed in detail about the manipulation and were told not to compensate. Despite explicit instruction to ignore the feedback changes, subjects produced a robust compensation in all conditions. There were no differences in the magnitudes of the first or second formant changes between groups. In general, subjects altered their vowel formant values in a direction opposite to the perturbation, as if to cancel its effects. These results suggest that compensation in the face of formant perturbation is relatively automatic, and the response is not easily modified by conscious strategy.

This paper suggests that critical ratios obtained in noise-masked tone studies are not good indicators of critical bandwidths obtained in both human and nonhuman animal subjects. A probe-tone detection study using chinchilla subjects suggests that they may be broadband processors in detection tasks as opposed to human subjects who use narrow-band, critical-band processing. If chinchilla and other nonhuman animal subjects are wideband processors, this can partially explain why their critical ratios are significantly greater than those measured in human subjects. Thus, large critical ratios obtained for nonhuman animals may indicate processing inefficiency rather than wide critical bands.

Maskers made up of comodulated narrow bands of noise can result in a signal detection advantage due to both within- and across-channel processes. The purpose of this study was to determine whether contributions from these processes could be differentiated on the basis of two stimulus manipulations: (1) onset/offset asynchrony across bands and (2) introduction of a random temporal fringe surrounding the comodulated bands. The hypothesis was that only masking release due to across-channel processing would be disrupted by these manipulations. Five-band comodulated maskers were constructed, and the availability of within- and across-channel cues was varied by adjusting the frequency spacing of the bands; both logarithmic and linear spacings were tested. The signal was a 1kHz pure tone. Onset/offset asynchrony had different effects depending on the characteristics of the asynchrony. The results were consistent with an interpretation that across-channel, but not within-channel, masking release was disrupted when the flanking bands were presented continuously and the on-signal band was gated. However, the results suggested that both the across-channel and the within-channel masking release were disrupted in conditions where the on-signal band was continuous and the flanking bands were gated on, as well as in conditions where a random temporal fringe was present.

Cochlear hair cells use SK2 currents to shape responses to cholinergic efferent feedback from the brain. Using SK2(-/-) mice, we demonstrate that, in addition to their previously defined role in modulating hair cell membrane potentials, SK2 channels are necessary for long-term survival of olivocochlear fibers and synapses. Loss of the SK2 gene also results in loss of electrically driven olivocochlear effects in vivo, and down regulation of ryanodine receptors involved in calcium-induced calcium release, the main inducer of nAChR evoked SK2 activity. Generation of double-null mice lacking both the alpha10 nAChR gene, loss of which results in hypertrophied olivocochlear terminals, and the SK2 gene, recapitulates the SK2(-/-) synaptic phenotype and gene expression, and also leads to down regulation of alpha9 nAChR gene expression. The data suggest a hierarchy of activity necessary to maintain early olivocochlear synapses at their targets, with SK2 serving an epistatic, upstream, role to the nAChRs.

Most sensory stimuli do not reach conscious perception during sleep. It has been thought that the thalamus prevents the relay of sensory information to cortex during sleep, but the consequences for cortical responses to sensory signals in this physiological state remain unclear. We recorded from two auditory cortical areas downstream of the thalamus in naturally sleeping marmoset monkeys. Single neurons in primary auditory cortex either increased or decreased their responses during sleep compared with wakefulness. In lateral belt, a secondary auditory cortical area, the response modulation was also bidirectional and showed no clear systematic depressive effect of sleep. When averaged across neurons, sound-evoked activity in these two auditory cortical areas was surprisingly well preserved during sleep. Neural responses to acoustic stimulation were present during both slow-wave and rapid-eye movement sleep, were repeatedly observed over multiple sleep cycles, and demonstrated similar discharge patterns to the responses recorded during wakefulness in the same neuron. Our results suggest that the thalamus is not as effective a gate for the flow of sensory information as previously thought. At the cortical stage, a novel pattern of activation/deactivation appears across neurons. Because the neural signal reaches as far as secondary auditory cortex, this leaves open the possibility of altered sensory processing of auditory information during sleep.

Background: Cisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained. Methods: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8.8- to 9.8-fold), to 5.1-fold (95% CI = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration-time curve (AUC). Statistical tests were two-sided. Results: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold to 3.1-fold induction) (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% CI = 8.8- to 9.8-fold, to 5.1-fold, 95% CI = 4.4- to 5.8-fold). Oxaliplatin (20 microM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 microg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 microM x minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics. Conclusion: Cisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity.

Auditory neurons are selective for temporal sound information that is important for rhythm, pitch, and timbre perception. Traditional models assume that periodicity information is represented either by the discharge rate of tuned modulation filters or synchrony in the discharge pattern. Compelling evidence for an invariant rate or synchrony code, however, is lacking and neither of these models account for how the sound envelope shape is encoded. We examined the neuronal representation for envelope shape and periodicity in the cat central nucleus of the inferior colliculus (CNIC) with modulated broadband noise that lacks spectral cues and produces a periodicity pitch percept solely based on timing information. The modulation transfer functions of CNIC neurons differed dramatically across stimulus conditions with identical periodicity but different envelope shapes implying that shape contributed significantly to the neuronal response. We therefore devised a shuffled correlation procedure to quantify how periodicity and envelope shape contribute to the temporal discharge pattern. Sustained responses faithfully encode envelope shape at low modulation rates but deteriorate and fail to account for timing and envelope information at high rates. Surprisingly, onset responses accurately entrained to the stimulus and provided a means of encoding repetition information at high rates. Finally, we demonstrate that envelope shape information is accurately reflected in the population discharge pattern such that shape is readily discriminated for repetition frequencies up to ∼100 Hz. These results argue against conventional rate- or synchrony-based codes and provide two complementary temporal mechanisms by which CNIC neurons can encode envelope shape and repetition information in natural sounds.

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.

Humans perceive a harmonic series as a single auditory object with a pitch equivalent to the fundamental frequency (F0) of the series. When harmonics are presented to alternate ears, the repetition rate of the waveform at each ear doubles. If the harmonics are resolved, then the pitch perceived is still equivalent to F0, suggesting the stimulus is binaurally integrated before pitch is processed. However, unresolved harmonics give rise to the doubling of pitch which would be expected from monaural processing (Bernstein and Oxenham, J. Acoust. Soc. Am., 113:3323-3334, 2003). We used similar stimuli to record responses of multi-unit clusters in the central nucleus of the inferior colliculus (IC) of anesthetized guinea pigs (urethane supplemented by fentanyl/fluanisone) to determine the nature of the representation of harmonic stimuli and to what extent there was binaural integration. We examined both the temporal and rate-tuning of IC clusters and found no evidence for binaural integration. Stimuli comprised all harmonics below 10 kHz with fundamental frequencies (F0) from 50 to 400 Hz in half-octave steps. In diotic conditions, all the harmonics were presented to both ears. In dichotic conditions, odd harmonics were presented to one ear and even harmonics to the other. Neural characteristic frequencies (CF, n = 85) were from 0.2 to 14.7 kHz; 29 had CFs below 1 kHz. The majority of clusters responded predominantly to the contralateral ear, with the dominance of the contralateral ear increasing with CF. With diotic stimuli, over half of the clusters (58%) had peaked firing rate vs. F0 functions. The most common peak F0 was 141 Hz. Almost all (98%) clusters phase locked diotically to an F0 of 50 Hz, and approximately 40% of clusters still phase locked significantly (Rayleigh coefficient >13.8) at the highest F0 tested (400 Hz). These results are consistent with the previous reports of responses to amplitude-modulated stimuli. Clusters phase locked significantly at a frequency equal to F0 for contralateral and diotic stimuli but at 2F0 for dichotic stimuli. We interpret these data as responses following the envelope periodicity in monaural channels rather than as a binaurally integrated representation.

Belgian Waterslager canaries (BWC), bred for a distinct low-pitched song, have an inherited high-frequency hearing loss associated with hair cell abnormalities. Hair cells near the abneural edge of the papilla, which receive primarily efferent innervation in normal birds, are among the most severely affected. These cells are thought to support nonlinear active processing in the avian ear, though the mechanisms are poorly understood. Here we present psychophysical evidence that suggests degraded active processing in BWC compared to normal-hearing non-BWC. Critical ratios, psychophysical masking patterns and phase effects on masking by harmonic complexes were measured in BWC and non-BWC using operant conditioning procedures. Critical ratios were much larger in BWC than in non-BWC at high frequencies. Psychophysical tuning curves derived from the masking patterns for BWC were broadened at high frequencies. BWC also showed severely reduced phase effects on masking by harmonic complexes compared to non-BWC. As has been hypothesized previously for hearing-impaired humans, these results are consistent with a loss of active processing mechanisms in BWC.