Fiber Characteristic Frequency Research Articles

Abstract TMEM-015: QUANTITATIVE ASSESSMENT OF THE ROLE OF COLLAGEN ALTERATIONS IN OVARIAN CANCER

Abstract A profound remodeling of the extracellular matrix (ECM) occurs in human ovarian cancer but it unknown how this affects tumor growth, where this understanding could lead to better diagnostics and therapeutic approaches. To this end, we utilized collagen-specific Second Harmonic Generation (SHG) imaging microscopy and optical scattering measurements to probe structural differences in the extracellular matrix of normal stroma, benign tumors, endometrioid tumors, and low and high-grade serous (LGS and HGS) tumors. The SHG and scattering metrics are sensitive to the organization of collagen on the sub-micron size. We found these sub-resolution determinations are consistent with the dualistic classification of type I and II serous tumors. However, type I endometrioid tumors have strongly differing ECM architecture than the serous malignancies. Moreover, our analyses are further consistent with LGS and benign tumors having similar etiology. Further, the SHG metrics and optical scattering measurements were then used to form a linear discriminant model to classify the tissues, and we obtained high accuracy (~90%) between the tissue types, and this delineation is superior to current clinical performance. To also quantify these alterations we implemented a new form of 3D texture analysis to classify the collagen morphologies in these tissues. We developed a tailored set of 3D filters which extract textural features in each tissue class and we achieved 83-91% accuracies for the six classes. This classification based on ECM structural changes will complement conventional classification based on genetic profiles and can serve as an additional biomarker. We further investigate the role of these ECM alterations by using multiphoton excited (MPE) polymerization to fabricate biomimetic models to investigate operative cell-matrix interactions in invasion/metastasis. This process is akin to 3D printing except is performed at much higher resolution and with the proteins that comprise the native ECM. We specifically use this technique to create collagen scaffolds with complex, 3D submicron morphology as ovarian stromal models. The scaffold designs are derived directly from “blueprints” based on the SHG images of normal, high risk, benign tumors, and malignant ovarian tissues. The models are seeded with different cancer cell lines and this allows decoupling of the roles of cell characteristics (metastatic potential) and ECM structure and composition (normal vs cancer) on adhesion/migration dynamics. We found the malignant stroma structure promoted enhanced migration persistence and cell proliferation and also cytoskeletal alignment. Moreover, the method allows varying fiber properties such as fiber diameters and characteristic frequency as well as overall alignment. While alignment has been well studied, we found that the migration dynamics are highly dependent upon the morphological properties of the fibers themselves. These models cannot be synthesized by other conventional fabrication methods and we suggest the MPE image-based fabrication method will enable a variety of studies in cancer biology. This work is currently by a new grant from NCI R01 CA206561-01. Citation Format: Visar Ajeti, Manish Patankar, Kevin Eliceiri, and Paul J. Campagnola. QUANTITATIVE ASSESSMENT OF THE ROLE OF COLLAGEN ALTERATIONS IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-015.

Sound coding in the auditory nerve of gerbils

Gerbils possess a very specialized cochlea in which the low-frequency inner hair cells (IHCs) are contacted by auditory nerve fibers (ANFs) having a high spontaneous rate (SR), whereas high frequency IHCs are innervated by ANFs with a greater SR-based diversity. This specificity makes this animal a unique model to investigate, in the same cochlea, the functional role of different pools of ANFs. The distribution of the characteristic frequencies of fibers shows a clear bimodal shape (with a first mode around 1.5 kHz and a second around 12 kHz) and a notch in the histogram near 3.5 kHz. Whereas the mean thresholds did not significantly differ in the two frequency regions, the shape of the rate-intensity functions does vary significantly with the fiber characteristic frequency. Above 3.5 kHz, the sound-driven rate is greater and the slope of the rate-intensity function is steeper. Interestingly, high-SR fibers show a very good synchronized onset response in quiet (small first-spike latency jitter) but a weak response under noisy conditions. The low-SR fibers exhibit the opposite behavior, with poor onset synchronization in quiet but a robust response in noise. Finally, the greater vulnerability of low-SR fibers to various injuries including noise- and age-related hearing loss is discussed with regard to patients with poor speech intelligibility in noisy environments. Together, these results emphasize the need to perform relevant clinical tests to probe the distribution of ANFs in humans, and develop appropriate techniques of rehabilitation.This article is part of a Special Issue entitled <Annual Reviews 2016>.

Temporal modulation transfer functions measured from auditory-nerve responses following sensorineural hearing loss

The ability of auditory-nerve (AN) fibers to encode modulation frequencies, as characterized by temporal modulation transfer functions (TMTFs), generally shows a low-pass shape with a cut-off frequency that increases with fiber characteristic frequency (CF). Because AN-fiber bandwidth increases with CF, this result has been interpreted to suggest that peripheral filtering has a significant effect on limiting the encoding of higher modulation frequencies. Sensorineural hearing loss (SNHL), which is typically associated with broadened tuning, is thus predicted to increase the range of modulation frequencies encoded; however, perceptual studies have generally not supported this prediction. The present study sought to determine whether the range of modulation frequencies encoded by AN fibers is affected by SNHL, and whether the effects of SNHL on envelope coding are similar at all modulation frequencies within the TMTF passband. Modulation response gain for sinusoidally amplitude modulated (SAM) tones was measured as a function of modulation frequency, with the carrier frequency placed at fiber CF. TMTFs were compared between normal-hearing chinchillas and chinchillas with a noise-induced hearing loss for which AN fibers had significantly broadened tuning. Synchrony and phase responses for individual SAM tone components were quantified to explore a variety of factors that can influence modulation coding. Modulation gain was found to be higher than normal in noise-exposed fibers across the entire range of modulation frequencies encoded by AN fibers. The range of modulation frequencies encoded by noise-exposed AN fibers was not affected by SNHL, as quantified by TMTF 3- and 10-dB cut-off frequencies. These results suggest that physiological factors other than peripheral filtering may have a significant role in determining the range of modulation frequencies encoded in AN fibers. Furthermore, these neural data may help to explain the lack of a consistent association between perceptual measures of temporal resolution and degraded frequency selectivity.

Psychophysical suppression measured with bandlimited noise extended below and/or above the signal: effects of age and hearing loss.

The objectives of this study were to measure suppression with bandlimited noise extended below and above the signal, at lower and higher signal frequencies, between younger and older subjects, and between subjects with normal hearing and cochlear hearing loss. Psychophysical suppression was assessed by measuring forward-masked thresholds at 0.8 and 2.0 kHz in bandlimited maskers as a function of masker bandwidth. Bandpass-masker bandwidth was increased by introducing noise components below and above the signal frequency while keeping the noise centered on the signal frequency, and also by adding noise below the signal only, and above the signal only. Subjects were younger and older adults with normal hearing and older adults with cochlear hearing loss. For all subjects, suppression was larger when noise was added below the signal than when noise was added above the signal, consistent with some physiological evidence of stronger suppression below a fiber's characteristic frequency than above. For subjects with normal hearing, suppression was greater at higher than at lower frequencies. For older subjects with hearing loss, suppression was reduced to a greater extent above the signal than below and where thresholds were elevated. Suppression for older subjects with normal hearing was poorer than would be predicted from their absolute thresholds, suggesting that age may have contributed to reduced suppression or that suppression was sensitive to changes in cochlear function that did not result in significant threshold elevation.

Effects of streptomycin and amiloride on the function of the pigeon inner ear

In vitro, streptomycin and amiloride block the mechano-electrical transduction channels in isolated auditory hair cells of mammals and birds. The present in vivo experiments investigate their action in the intact pigeon inner ear. Streptomycin dissolved in artificial endolymph at concentrations between 1.0 and 6.2 mmol/l was applied into the scala media. After a bolus injection (0.09 to 0.36 μl) the endocochlear potential (EP) was elevated from 6.8 to 7.9 mV. Similarly applied boli of 0.09 to 0.55 μl of amiloride in concentrations of 1–2 mmol/l did not significantly elevate EP (8.7 versus 9.4 mV). Compound action potential (CAP) frequency threshold curves (FTCs) were elevated by both streptomycin and amiloride. The threshold elevation increased with frequency. With streptomycin injection, a complete loss of CAPs was found at frequencies above 1.2 kHz. With amiloride, the loss in sensitivity was 40 dB for the same frequency range. Single fibre recordings showed elevated thresholds and decreased sharpness of tuning with both drugs. With streptomycin, the evoked activity was affected regard-less of stimulation frequencies (above or below the fibre's characteristic frequency). Amiloride, however, preferentially elevated thresholds at frequencies above characteristic frequency. Thus amiloride seems to interfere with hair cell tuning mechanisms. Spontaneous activity decreased by about 30%, following the application of streptomycin. In contrast, injections of amiloride into the scala media were followed by an increase in spontaneous discharge rates.

Long-term suppression of the responses of auditory nerve fibers to a characteristic-frequency tone by a low-frequency suppressor

The classical two-tone suppression requires the characteristic-frequency (CF) tone and the suppressor (SUP) tone to act simultaneously. We report a novel phenomenon whereby the responses to the CF tone alone were ‘suppressed’ by a preceding low-side SUP tone. Increasing the repetition interval to about 3000 ms or longer eliminated such suppression. The magnitude of this ‘long-term’ suppression was not dependent upon fiber CF, but fibers with low spontaneous rates (SR) generally showed more suppression than high-SR fibers did. The suppression threshold was not dependent upon fiber SR. This suppression of the CF responses did not affect the phases of responses to either the CF or SUP tone, or the phase of suppression. This phenomenon is not due to adaptation or fatigue, but due to the presence of the preceding SUP tone. The efferent system, particularly the ‘slow’ effect, might be responsible for it.

Responses of auditory nerve fibers of the unanesthetized decerebrate cat to click pairs as simulated echoes.

1. To elucidate the peripheral contribution to "echo" processing in the auditory system, we examined the characteristics of auditory nerve responses to click-pair stimuli in unanesthetized, decerebrate cats. We used equilevel click pairs at peak levels of 45, 65, and 85 dB SPL re 20 microPa. The interclick intervals ranged from 1 to 32 ms. This study reports results from 78 auditory nerve fibers in 7 cats. The fibers were divided into 2 groups: 33 low- and 45 high-spontaneous rate (SR), with SRs less than and > or = 20 spikes/s, respectively. A method was introduced to quantify the second-click response, and its recovery was examined as a function of the interclick interval. 2. In general, auditory nerve fibers showed a gradual recovery of the second-click response as interclick interval was increased. Noticeable differences in the second-click response recovery functions emerged among fiber populations that were related to the SR. Low-SR fibers showed little change in the recovery functions of the second-click response as the click level was increased from 45 to 85 dB SPL. In contrast, high-SR fibers showed slower recoveries with increasing click level from 45 to 85 dB SPL. At 45 and 65 dB SPL, the recovery functions of the two SR groups were similar. At 85 dB SPL, high-SR fibers exhibited slower recovery than low-SR fibers, regardless of fiber characteristic frequency. The interclick intervals at 50% second-click response ranged from 1 to 6 ms (mean, 1.4 ms) among low-SR fibers. The interclick intervals at 50% second-click response for high-SR fibers, whereas similar to those for the low-SR fibers at 45 and 65 dB SPL, ranged from 2 to 16 ms (mean, 3 ms) for high-SR fibers, at 85 dB SPL. 3. We also examined auditory nerve compound action potentials (CAPs) evoked by click-pair stimuli for various interclick intervals and click levels. With increasing interclick interval, the amplitude of the second-click CAP increased, and with increasing level, the second-click CAP showed slower recovery. At 45 dB SPL, the recovery functions of the second-click CAP were similar to those of the high- and low-SR fibers. At higher levels, the CAP exhibited lower second-click response values than both high- and low-SR fiber populations for interclick intervals < 4-8 ms. At 85 dB SPL, as interclick interval increased, between 8 and 16 ms, the CAP second-click response converged with that of the high-SR fibers, and by 32 ms, the second-click response values were similar for the CAP, high- and low-SR fibers. 4. The present results are consistent with those of forward masking studies at the level of the auditory nerve in that both demonstrate a short-term reduction of the neural responses. However, the two results differ in that we observed that high-SR fibers exhibited slower recovery than low-SR fibers in response to click-pair stimuli, opposite of the trend observed in the forward masking studies of responses to pure-tone bursts. 5. The present results on auditory nerve fiber responses to click-pair stimuli provide a reference for comparison with responses of central auditory neurons to similar stimuli. This information should serve to elucidate the peripheral contribution to the processing of echoes in the auditory system.

Shapes of cat auditory nerve fiber tuning curves

Tuning curves of auditory nerve fibers in normal-hearing cats were fitted by a computational model comprising four processes. One process accounts for sensitivity in tuning curve tails and consists of an approximation to bandpass filtering by extracochlear structures. The second and third processes describe passive and active components of basilar membrane (BM) mechanics, respectively. The former consists of a lowpass filter function, which provides baseline threshold sensitivity and filtering above characteristic frequency (CF), and the latter consists of a Gaussian that accounts for sharp tuning and high sensitivity around CF. A fourth process, modeled as a high-pass filter, was needed in many fits to account for breaks and plateaus in threshold sensitivity at frequencies above CF. The latter three processes operated on cochlear spatial coordinates rather than stimulus frequency. The four-process description closely accounted for shapes of most tuning curves. Tuning curve tails possessed minima at 40–80 dB SPL, and minima increased with fiber CF. High-frequency cutoffs of tail filters tended to increase with CF, but low-frequency cutoffs were generally constant across CF. Functions describing tails varied from ear to ear but behaved in a similar manner for fibers from a single ear. Passive components of BM resonances possessed baselines with sensitivities that decreased with CF and cutoff slopes that increased with CF. The magnitude of the active component increased smoothly with CF over an 80 + dB range, and its spatial extent was essentially constant at 1.5 mm or 6% of cochlear length regardless of gain magnitude, fiber CF, or threshold sensitivity. Tuning curves from fibers with high and medium spontaneous rates (SRs) and similar CFs had nearly identical shapes, with the sole difference being essentially constant differences in sensitivity across the entire excitatory frequency range. Tuning curve shapes from fibers with low SRs were more variable. These could either resemble those obtained from similarly-tuned fibers with higher SRs, or they could exhibit lower tip-to-tail ratios and reduced active component magnitudes. The latter were typically associated with low maximum discharge rates.

Temperature dependence of two-tone rate suppression in the northern leopard frog, Rana pipiens pipiens

The existence region of two-tone rate suppression in frog low-frequency auditory-nerve fibers was found to include a suppressive region below a fiber's characteristic frequency, contrary to previous reports. In response to 3 degrees C rise in core temperature, the area and the best suppressive frequency (BSF) of the low-side suppressive region significantly increased. Increasing core temperature of the frog by 6 degrees C resulted in significant changes in the high-side suppressive region: Its area decreased, and its BSF and best suppressive threshold (BST) increased. Constant-temperature control trials were designed to partially simulate the relative movement of the probe tone within the excitatory tuning curve which occurred during temperature shifts. Lowering the probe tone by 0.5 oct had no effect on the low-side suppressive region, but significantly increased the area and lowered the BSF and BST of the high-side suppressive region. Temperature shifts in the frog appear to have a differential effect on the low-side and high-side suppressive areas of low-frequency auditory-nerve fibers. Moreover, excitation and suppression also respond differentially to temperature shifts.

Detection of gaps in sinusoids by frog auditory nerve fibers: importance in AM coding.

Physiological studies were carried out in the frog (Rana pipiens pipiens) eighth nerve to determine: (i) whether the modulation rate or the silent gap was the salient feature that set the upper limit of time-locking to pulsed amplitude-modulated (PAM) stimuli, (ii) the gap detection capacity of individual eighth nerve fibers. Time-locked responses of 79 eighth nerve fibers to PAM stimuli (at the fiber's characteristic frequency) showed that the synchronization coefficient was a low-pass function of the modulation rate. In response to PAM stimuli having different pulse durations, a fiber gave rise to non-overlapping modulation transfer functions. The upper cut-off frequency of time locking was higher when tone-pulses in PAM stimuli had shorter duration. The fact that the cut-off frequency was different for the different PAM series suggested that the AM rate was neither the sole, nor the main, determinant for the decay in time-locking at high AM rates. Gap detection capacity was determined for 69 eighth nerve fibers by assessing fiber's spiking activities to paired tone-pulses during an OFF-window and an ON-window. It was found that the minimum detectable gap of eighth nerve fibers ranged from 0.5 to 10 ms with an average of 1.23-2.16 ms depending on the duration of paired tone pulses. For each fiber, the minimum detectable gap was longer when the duration of tone pulses comprising the twin-pulse stimuli was more than four times longer. When the synchronization coefficient was plotted against the silent gap between tones pulses in the PAM stimuli, the gap response functions of a fiber as derived from multiple PAM series were equivalent to gap response functions deriving from twin-pulse series suggesting that it was the silent gap which primarily determined the upper limit of time-locking to PAM stimuli.

Nonlinear input-output functions derived from the responses of guinea-pig cochlear nerve fibres: Variations with characteristic frequency

Rate-versus-level functions (RLFs) were recorded from individual cochlear nerve fibres in anaesthetised guinea-pigs. Variations in the shapes of these functions with frequency were used to derive input-output (IO) relationships for the mechanical preprocessing mechanisms in the cochlea. It was assumed that these preprocessing mechanisms operated linearly at frequencies well below each fibre's characteristic frequency (CF). The IO functions derived at each fibre's CF provided strong evidence of compressively nonlinear preprocessing in most regions of the cochlea. However, the apparent degree of compression depended on the fibre's CF, and hence on the presumed site of cochlear innervation. For fibres with CFs of between 1.5 and 3.6 kHz, the CF derived IO functions grew at rates of around 0.5 dB/dB. For fibres with CFs above 4 kHz, the IO functions were more compressive, with high-intensity asymptotic slopes of around 0.13 dB/dB. In the highest (>- 10 kHz) CF fibres, the degree of compression depended on the physiological condition of the cochlea; the derived IO functions becoming more linear as the cochlea became less sensitive. The derived IO technique was not well suited to analyse responses evoked by very low frequency (e.g., < 500 Hz) tones. Nonetheless, the CF RLFs from fibres with CFs lower than ~ 1 kHz provided little evidence of mechanical nonlinearity near the apex of the cochlea. These findings imply a longitudinal variation in the mechanisms of cochlear preprocessing, and provide important new tests for functional models of the cochlea.

Antimasking effects of the olivocochlear reflex. II. Enhancement of auditory-nerve response to masked tones

1. The antimasking effects of olivocochlear (OC) efferent feedback were studied in anesthetized or decerebrate cats by comparing responses of single auditory-nerve fibers (ANFs) to tone bursts in continuous masking noise seen with and without addition of a moderate-level contralateral noise known to activate the OC reflex. Responses were measured as a function of tone-burst intensity, tone-burst frequency, and masker intensity and were analyzed so as to allow quantitative estimates of the detectability of the tone bursts against the noise background. 2. Addition of the contralateral OC elicitor both increased the maximum discharge rates to the masked tone bursts and decreased the rates to the ipsilateral masker. The rate increases to the tone bursts could be explained on the basis of a decrease in adaptation caused by decreasing the steady response to the masker. The result is a steepening of the rate-versus-level function for masked tone bursts and a concomitant increase in the estimated discriminability of small increments of tone-burst intensity. 3. For tone bursts at the fiber's characteristic frequency (CF), the OC effects on detection threshold for the masked tone bursts depended on masker level, with small increases in threshold for low masker levels and somewhat larger decreases in threshold for higher masker levels. For tone bursts below CF, OC effects, when present, always decreased the detection threshold. 4. The largest antimasking effects were seen for fibers with CFs between 6 and 12 kHz and for masker levels within 20 dB of the fiber's threshold to the masker. These trends appeared to hold for fibers of all spontaneous rates (SRs). 5. Enhancement of the response to unmasked tone bursts and concomitant decrease in the "spontaneous rate" was elicited by OC activation in fibers if threshold sensitivity approached -10 dB SPL. This "enhancement-in-quiet" appears to arise when an animal-generated noise produces a continuous response (in the absence of purposely applied sound) that is suppressed by OC activity. This finding raises questions as to the range of "true" spontaneous rates in the cat. 6. The results highlight two important distinctions between the effects of OC feedback in quiet versus those in noise. In quiet, the effects are predominately suppressive and are restricted to stimuli at frequencies near a fiber's CF and at intensities within its dynamic range. In continuous background noise, the OC reflex can enhance the responses to transient stimuli. Such effects are seen throughout the fiber's response area.(ABSTRACT TRUNCATED AT 400 WORDS)

Sensitivity of auditory nerve fibers to spectral notches

1. Listeners use direction-dependent spectral cues introduced by the torso, head, and pinnae to localize the source of a sound in space. Among the prominent direction-dependent spectral features in the free field-to-eardrum transfer function are narrow regions of low acoustic energy referred to as spectral notches. In this paper, we studied the sensitivity of single auditory nerve fibers in the barbiturate-anesthetized cat to broadband noise that had been filtered by a function whose shape approximated natural notches in the free field-to-eardrum transfer function. 2. Two experimental paradigms were employed. The first was the repeated presentation of a burst of broadband noise filtered by the simulated-notch function. Center frequency of the notch was held constant at or around the fiber characteristic frequency (CF). We refer to this as a "stationary" notch stimulus. The second paradigm was the repeated presentation of a broadband noise that was constructed from noise segments, each filtered by the simulated notch, whose CF was incremented and then decremented in a systematic way. We refer to this as a "moving" notch stimulus. Results from these two paradigms were compared with respect to notch detection. 3. Data were obtained from 161 single auditory nerve fibers having CFs ranging from 0.4 to 40 kHz. Most fibers studied had CFs > 5 kHz, and they detected the presence of the spectral notch in an intensity- and frequency-dependent manner. Each fiber responded vigorously to the presence of broadband noise. When the CF of the notch encroached on the response area of the fiber, there was a demonstrable reduction in discharge rate. The greatest reduction in discharge rate occurred when the notch was centered at the fiber's CF and when the level of the notch signal was some 15-55 dB above the fiber's noise threshold. There was close association in the frequency-intensity plane between the position of the most effective notch and the fiber's threshold tuning curve. 4. For high-spontaneous rate fibers, a moving-notch stimulus, but not a stationary one, reduced the discharge below the spontaneous rate at and in the immediate vicinity of the most effective notch frequency. This increases sensitivity to a spectral notch and suggests a mechanism by which localization ability is enhanced when there is relative motion between a sound source and the head.(ABSTRACT TRUNCATED AT 400 WORDS)

Cochlear nerve fiber responses to amplitude-modulated stimuli: variations with spontaneous rate and other response characteristics

1. Single-fiber responses to sinusoidally amplitude-modulated (AM) tones were recorded from the cochlear nerves of anesthetized guinea pigs. Stimuli were presented at the fiber's characteristic frequency (CF) and covered the intensity range between the fiber's minimum rate threshold and 90-100 dB SPL in 5- or 6-dB steps. The amount of modulation in each fiber's response and the average rate of the responses were quantified. The observed response modulation was compared with the modulation to be expected on the assumption that the instantaneous discharge rates varied with intensity in the same way that the average rates did (i.e., as predicted from each fiber's average-rate vs. level function). 2. The difference between the observed and expected response modulation varied widely across fibers. In most fibers' the responses to a limited range of stimulus intensities (typically between 20 and 30 dB above the fiber's rate threshold) were modulated far more than expected on the basis of their average rates, with responses to stimuli either above or below this range differing progressively less from expectation. Little or no response modulation was observed above approximately 70 dB SPL in these fibers. Other fibers exhibited response modulation that exceeded the expected modulation by smaller amounts, but maintained this modulation to much higher sound pressure levels. 3. The discrepancy between the observed and expected responses to AM stimuli also varied with the frequency of modulation (fm) within individual fibers. The discrepancies were least pronounced at low fms (e.g., 10 Hz) but became progressively larger as fm was increased to between 50 and 320 Hz (subject to the inter-fiber variations described in 2, above). 4. The AM response characteristics varied systematically with the fiber's spontaneous rate and other response characteristics (e.g., rate threshold, CF rate vs. level function type, and rapid adaptation characteristics). In particular, the most sensitive, high spontaneous rate fibers had responses that adapted rapidly after the onset of a stimulus, and showed the greatest enhancement of AM-related information at low-to-moderate stimulus intensities. However, these fibers appeared incapable of encoding AM-related information at high intensities, since their response rates "saturated" and their AM response enhancements diminished around 30 dB above threshold. In contrast, the less sensitive (i.e., higher threshold), lower spontaneous rate fibers showed less evidence of rapid adaptation near the onsets of their response, and lesser enhancements of the modulated responses predicted from their average-rate versus level functions.(ABSTRACT TRUNCATED AT 400 WORDS)

Periodicity extraction in the anuran auditory nerve. II: Phase and temporal fine structure.

Discharge patterns of single eighth nerve fibers in the bullfrog, Rana catesbeiana, were analyzed in response to signals consisting of multiple harmonics of a common, low-amplitude fundamental frequency. The signals were chosen to reflect the frequency and amplitude spectrum of the bullfrog's species-specific advertisement call. The phase spectrum of the signals was manipulated to produce envelopes that varied in their shapes from impulselike (sharp) to noiselike (flattened). Peripheral responses to these signals were analyzed by computing the autocorrelation functions of the spike trains and their power spectra, as well as by constructing period histograms over the time intervals of the low-frequency harmonics. In response to a phase aligned signal with an impulsive envelope, most fibers, regardless of their characteristic frequencies or place of origin within the inner ear, synchronize to the fundamental frequency of the signal. The temporal patterns of fiber discharge to these stimuli are not typically captured by that stimulus harmonic closet to the fiber characteristic frequency, as would be expected from a spectral coding mechanism for periodicity extraction, but instead directly reflect the periodicity of the stimulus envelope. Changing the phase relations between the individual harmonics constituting the signal produces changes in temporal discharge patterns of some fibers by shifting predominant synchronization away from the fundamental frequency to the low-frequency spectral peak in the complex stimuli. The proportion of fibers whose firing is captured by the fundamental frequency decreases as the waveform envelope becomes less impulselike. Fiber characteristic frequency is not highly correlated with the harmonic number to which synchronization is strongest. The higher-harmonic spectral fine structure of the signals is not reflected in fiber temporal response, regardless of the shape of the stimulus envelope, even for those harmonics within the range of phase locking to simple sinusoids. Increasing stimulus intensity also shifts the synchronized responses of some fibers away from the fundamental frequency to one of the low-frequency harmonics in the stimuli. These data suggest that the synchronized firing of bullfrog eighth nerve fibers operates to extract the waveform periodicity of complex, multiple-harmonic stimuli, and this periodicity extraction is influenced by the phase spectrum and temporal fine structure of the stimuli. The similarity in response patterns of amphibian papilla and basilar papilla fibers argues that the frog auditory system employs primarily a temporal mechanism for extraction of first harmonic periodicity.

Auditory nerve representation of a complex communication sound in background noise.

A population study of auditory nerve responses in the bullfrog, Rana catesbeiana, analyzed the relative contributions of spectral and temporal coding in representing a complex, species-specific communication signal at different stimulus intensities and in the presence of background noise. At stimulus levels of 70 and 80 dB SPL, levels which approximate that received during communication in the natural environment, average rate profiles plotted over fiber characteristic frequency do not reflect the detailed spectral fine structure of the synthetic call. Rate profiles do not change significantly in the presence of background noise. In ambient (no noise) and low noise conditions, both amphibian papilla and basilar papilla fibers phase lock strongly to the waveform periodicity (fundamental frequency) of the synthetic advertisement call. The higher harmonic spectral fine structure of the synthetic call is not accurately reflected in the timing of fiber firing, because firing is "captured" by the fundamental frequency. Only a small number of fibers synchronize preferentially to any harmonic in the call other than the first, and none synchronize to any higher than the third, even when fiber characteristic frequency is close to one of these higher harmonics. Background noise affects fiber temporal responses in two ways: It can reduce synchronization to the fundamental frequency, until fiber responses are masked; or it can shift synchronization from the fundamental to the second or third harmonic of the call. This second effect results in a preservation of temporal coding at high noise levels. These data suggest that bullfrog eighth nerve fibers extract the waveform periodicity of multiple-harmonic stimuli primarily by a temporal code.

Round-window recorded potential of single-fibre discharge (unit response) in normal and noise-damaged cochleas

Unit responses (URs) of eight-nnerve fibres have been determined at the round window by spike-triggered averaging in both normal and pathological guinea pig cochleas. The pathology was mainly noise-induced damage. The URs have been analysed with respect to their dependence on the fibre's threshold, characteristic frequency (CF) and spontaneous rate (SR). The results from normal cochleas confirmed earlier data (Prijs, 1986): the UR has a diphasic waveform and the amplitude of its negative first peak is about 0.1 μV. From the six parameters (amplitude, latency, and width of the two peaks) by which the UR was described only the amplitude of the positive peak showed a significant variation with CF: a small decrease with increasing CF (CF-range 0.1 to 20 kHz). This finding may possibly be caused by oscillations in the spike-triggered average for low CFs. URs for most low- and medium-SR fibreswere found to be large (greater than 0.3 μV). However, this result is interpreted as an artefact caused by synchrony of fibre spontaneous activity. In damaged cochleas only slight changes of the UR were found: the waveform duration became significantly shorter and on some occasions the positive peak increased in amplitude, but latency and amplitude of the negative component of the UR remained unchanged.

Coding of spectral fine structure in the auditory nerve. II: Level-dependent nonlinear responses

Phase-locked discharge patterns of single cat auditory-nerve fibers were analyzed in response to complex tones centered at fiber characteristic frequency (CF). Signals were octave-bandwidth harmonic complexes defined by a center frequency F and an intercomponent spacing factor N, such that F/N was the fundamental frequency. Parameters that were manipulated included the phase spectrum, the number of components, and the intensity of the center component. Analyses employed Fourier transforms of period histograms to assess the degree to which responses were synchronized to the frequencies present in the acoustic stimulus. Several nonlinearities were observed in the response as intensity was varied between threshold and 80-90 dB SPL. Response nonlinearities were strong for all signals except those with random phase spectra. The most commonly observed nonlinearity was an emphasis of one or more stimulus components in the response. The degree of nonlinearity usually increased with intensity and signal complexity and decreased with fiber frequency selectivity. Half-wave rectification introduced synchronization to the missing fundamental. The strength of the response at the fundamental was related to stimulus crest factor. Signals with low center frequencies and high crest factors often elicited instantaneous discharge rates at the theoretical maximum of pi CF. This suggests that the probability of spike generation approaches one during high-amplitude waveform segments. Response nonlinearity was interpreted as arising from three sources, namely, cochlear mechanics, compression of instantaneous discharge rate, and saturation of average discharge rate. At near-threshold intensities, fibers with high spontaneous rates exhibited responses that were linear functions of stimulus waveshape, whereas fibers with low spontaneous spike rates produced responses that were best described in terms of an expansive nonlinearity.

Two-tone rate suppression in auditory-nerve fibers: Dependence on suppressor frequency and level

The growth of two-tone rate suppression with suppressor level was studied for auditory-nerve fibers in anesthetized cats. The level of a tone at the characteristic frequency (CF) was adjusted by an adaptive procedure (PEST) so that, when presented with a suppressor tone, the CF tone would produce a criterion discharge rate. Suppression (in dB) was defined as the CF-tone level that met criterion in the presence of a suppressor minus the level that met criterion in quiet. The growth of suppression with suppressor level was well characterized by a straight line whose slope (in dB-excitor/dB-suppressor) varied with suppressor frequency by as much as a factor of 10 in the same fiber. These slope differences were systematically related to the position of the suppressor frequency relative to the fiber CF: for below-CF suppressors, slopes ranged from 1 to 3 dB/dB, while, for above-CF suppressors, they were between 0.15 and 0.7 dB/dB. Slopes decreased rapidly with increasing suppressor frequency near the CF, but, for frequencies well below the CF, the slope reached a maximum that increased gradually with CF. These results resemble psychophysical data on the growth of masking and psychophysical suppression and pose difficulties for existing models of two-tone suppression.

Endbulbs of held and spherical bushy cells in cats: morphological correlates with physiological properties.

Single auditory nerve fibers of type I spiral ganglion cells in cats were electrophysiologically characterized by recording with micropipettes inserted into the axon and then labeled by intracellular injections of horseradish peroxidase (HRP) through the same pipettes. This method for staining and studying single neurons allowed us to describe structure-function relationships for labeled endbulbs of Held and the somata of their postsynaptic spherical bushy cells. The silhouette areas of terminal endbulbs and the corresponding somata of spherical bushy cells were determined by planimetry from drawings made with a light microscope and drawing tube. On the presynaptic side, endbulb area is related to fiber characteristic frequency (CF, the frequency to which a fiber is most sensitive) such that the largest endbulbs arise from fibers having CFs between 1 and 4 kHz; smaller endbulbs can arise from fibers of any CF. Endbulb area is not correlated with fiber spontaneous discharge rate (SR). Dividing the endbulb's silhouette area by its silhouette perimeter, however, yields a "form factor" that is a reliable indicator of fiber SR: Endbulbs from fibers of low-medium SR (less than or equal to 18 spikes/second) have form factor values less than 0.52, whereas endbulbs of high SR fibers (greater than 18 spikes/second) have values greater than 0.52. This form factor should therefore be predictive of SR groupings in auditory fibers for which physiological data are not available. On the postsynaptic side, the somata of spherical bushy cells receiving endbulbs from low-medium SR fibers are on average smaller than those receiving endbulbs from high SR fibers. In contrast, the nuclei of the spherical bushy cells are the same size regardless of presynaptic fiber SR. Some of the effects of low-medium SR fibers on their postsynaptic targets, when compared to those of high SR fibers, appear to be mimicked by effects of experimentally induced deprivation.