Enhancement of Neural Synchronization in the ... - KU Leuven

JOURNALOF NEUROPHYSIOLOGY Vol. 71, No. 3, March 1994. Printed

in U.S.A.

Enhancement of Neural Synchronization in the Anteroventral Cochlear Nucleus. II. Responses in the Tuning Curve Tail PHILIP

X. JORIS,

Departments SUMMARY

PHILIP

H. SMITH,

of Neuvophysiology AND

AND

and Anatomy,

TOM

C. T. YIN

University of Wisconsin Medical

CONCLUSIONS

1. Discharges of neurons in the peripheral auditory system contain information about the temporal features of acoustic stimuli. Phase-locking of neurons in the anteroventral cochlear nucleus (AVCN) is usually reported to be less robust than in auditory nerve (AN) fibers, which provide their major input. In a companion paper we reported that some cells in AVCN of the cat show enhanced phase-locking compared with the AN when stimulated at the frequency to which they are most sensitive [characteristic frequency (CF)] . We called neurons “high-sync” when they showed vector strengths (R, a measure of phase-locking) ~0.9. Here we report phase-locking properties to stimuli at frequencies below CF. 2. Horseradish peroxidase-filled glass micropipettes or metal microelectrodes were inserted into the trapezoid body (TB), which is the large output tract of the AVCN. Acoustically driven fibers were classified on the basis of the shape of the poststimulus time (PST) histograms to short tone bursts at CF. We then presented low-frequency tones of increasing SPL and determined the maximum R value at 500 Hz (R,,,) for each fiber. Using the same experimental protocol we studied phase-locking in the ANs of two animals because maximal R values at the tuning curve tail have not been reported for AN fibers. 3. Although phase-locking in AN fibers is usually assumed to be independent of CF, we found that fibers with CF >2 kHz tended to have higher R,,, values than fibers with CF 52 kHz. Moreover, Rsoo was 20.9 in 20% (42 of 196) of the fibers studied and could be as high as 0.95. This population of fibers was defined as having “high-sync tails” and consisted almost entirely of fibers with low or medium spontaneous rate. 4. High-CF TB fibers stimulated at 500 Hz showed very high phase-locking. High-sync tails (R,,, 2 0.9) were found in 4 1 of 70 TB fibers. For a subset of these fibers ( 1 / 3 in total: 23 of 70) phase-locking was higher than is ever observed in the AN (R,,, 2 0.95 ); these fibers were defined as showing synchronization “enhancement.” Virtually all fibers showing synchronization enhancement had primary-like-with-notch (PL,) PST histograms. Chopper and primary-like fibers showed high-sync tails for CFs >3 kHz. 5. Synchronization filter functions were obtained for high-CF AN fibers by determining maximum synchronization for a range of stimuli below CF. These functions were low-pass, but had higher maximal gain and a lower cutoff frequency than the synchronization function for the population of low-CF AN fibers. These data suggest an apical to basal difference in the cochlear low-pass filtering processes that limits synchronization. 6. Synchronization filter functions of some TB fibers showed enhancement for frequencies 0.9. 8. From these results we propose that several pre- and postsynaptic factors account for the high synchronization observed in high-CF TB fibers. First, inputs to high-CF TB fibers are on average better timed than those to low-CF TB fibers, i.e., AN fibers with CFs >3 kHz stimulated at 500 Hz show better timing than low-CF AN fibers tuned to 500 Hz. Second, in responses to lowfrequency tones there is a higher degree of synchronization across the inputs to high-CF TB fibers compared with their low-CF counterparts because of the relatively slow accumulation of phase-lag by basal (high-CF) cochlear regions. Third, the coincidence mechanism, proposed to produce the synchronization enhancement in low-CF TB fibers described in the companion paper, is also operational at high CFs, at least for fibers with PL, responses. 9. AN fibers have tail thresholds that are within levels attained by conversational speech and other environmental sounds. They set up a temporal code over a large range of CFs that is enhanced rather than degraded by convergence of AN fibers on cells in AVCN and that may provide sound localization cues in high-frequency channels.

INTRODUCTION

The mammalian cochlea can be idealized as a bank of sharply tuned filters connected to the central auditory system via a parallel array of auditory nerve (AN) fibers. Early psychophysical evidence (Mayer 1876; Wegel and Lane 1924) suggestedthat these filters were asymmetric, because low-frequency tones interfered more with the detection of high-frequency tones than vice versa. Basilar membrane, hair cell, and AN recordings have since confirmed that filter slopeson the high-frequency side are typically steeper than on the low-frequency side and that structures most sensitive to high frequencies can respond to a broad range of low-frequency stimuli at SPLs commonly encountered. AN fibers with characteristic frequency (CF, frequency of maximal sensitivity) above -2 kHz show a broad lowfrequency region of lowered thresholds (Geisler et al. 1974; Kiang and Moxon 1974). This region, which is referred to asthe low-frequency “tail,” allows high-CF fibers to temporally encode low-frequency energy, e.g., aspresent in speech signals (Kiang and Moxon 1974). Subsequent experimental and modeling studiesof speechencoding in a population of AN fibers have shown that at conversational speechlev-

0022-3077/94 $3.00 Copyright 0 1994 The American Physiological Society

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P. H. SMITH,

els such temporal features are indeed represented over a large portion of the AN array (Delgutte and ISiang 1984a; Jenison et al. 199 1; Palmer et al. 1986; Young and Sachs 1979). Low-frequency tails are also present in the target cells of AN fibers in the cochlear nucleus (Bledsoe et al. 1982; Bourk 1976; Rhode and Smith 1986). As in the AN, cells in the anteroventral subdivision of the cochlear nucleus (AVCN) show temporal and rate information to lowfrequency stimuli over a broad range of CFs (Blackburn and Sachs 1990; Palmer et al. 1986). In the preceding paper (Joris et al. 1994) we compared phase-locking of fibers in the AN and trapezoid body (TB, contains the output axons of cells in AVCN) to tones at the fiber’s CF and found an enhancement of phase-locking and entrainment (response to every stimulus cycle) in low-CF TB fibers relative to AN fibers of similar CFs. Because many environmental low-frequency sounds probably recruit both low-CF and high-CF fibers by virtue of the lowfrequency tails, we wondered whether enhancement of phase-locking and entrainment also applies to high-CF TB fibers. In the present report we compare responses in AN and TB to a stimulus of a low, fixed frequency. We found that many high-CF TB fibers show exquisite temporal coding with properties similar to low-CF fibers (Joris et al. 1994). Proper interpretation of this finding hinges on a knowledge of high-CF AN responses to such stimuli, because AN fibers provide the dominant inputs to these cells. Although it is only rarely explicitly stated (e.g., Palmer and Russell 1986 ), AN phase-locking is traditionally assumed not to be dependent on CF per se, but there are few data supporting or contradicting this assumption (e.g., Geisler et al. 1974). We found that phase-locking in the AN is to a certain extent dependent on CF: these results are presented first and subsequently contrasted with responses from TB fibers. METHODS

Data collection Our methods are described in detail in the accompanying paper (Joris et al. 1994) and previous reports (Joris and Yin 1992; Smith et al. 199 1, 1993) and are only briefly summarized here. Pentobarbital sodium (40 mg/ kg iv)-anesthetized cats were placed in a soundproof room. A closed acoustic stimulus system was inserted into one or both exposed ear canals and calibrated with a l/2-in. condenser microphone attached to a probe tube. AN data are derived from 196 fibers from two animals whose ANs were exposed via a posterior fossa approach. Recordings were made with glass micropipettes filled with 3 M KCl, inserted under visual control into the nerve trunk, as described in Joris and Yin (1992). TB data, selected for the availability of responses at 500 Hz, were derived from 70 fibers obtained from 19 animals in the course of an anatomic study (Smith et al. 199 1, 1993) as well as from 9 animals in which only physiological data were collected. A ventral approach to the basocranium allowed exposure of the TB. We lowered tungsten microelectrodes or glass micropipettes filled with KC1 and horseradish peroxidase or Neurobiotin into the TB while stimulating both ears with tones of variable frequency. The neural signal was converted to spike times referenced to the stimulus onset with a peak detection triggering circuit. For each fiber encountered a threshold tuning curve was obtained with a tracking algorithm (described by Geisler and Sinex 1982) that

AND

T. C. T. YIN

provided spontaneous rate (SR), CF, and threshold at 500 Hz. A rate-level function to CF tonebursts of increasing SPL (25 ms in duration, presented every 100 ms for 200 repetitions, in steps of 10 or 20 dB SPL) allowed classification of TB fibers on the basis of the shape of the poststimulus time (PST) histogram (Blackburn and Sachs 1989; Bourk 1976; Pfeiffer 1966). Subsequently a ratelevel function at 500 Hz was obtained if the tuning curve indicated a reasonable threshold at that frequency (590 dB). More extensive data at frequencies other than 500 Hz were obtained for a limited number of fibers in the experiments where no intra-axonal labeling was attempted. To avoid threshold shifts stimulus levels only rarely exceeded 94 dB SPL. At the highest SPL used ( 104 dB SPL at 500 Hz) the acoustic distortion components, measured in a test cavity, were all >70 dB below the fundamental.

Data analysis Our main interest was in the strength of phase-locking of the response to the stimulus frequency as measured with the vector strength (R) (Goldberg and Brown 1969). It is important to emphasize that the data reported here differ from those in the accompanying paper (Joris et al. 1994) and most other studies of phaselocking to pure tones in that stimuli at non-CF frequencies were used. To differentiate R values derived from different stimulus frequencies we indicate the frequency (in Hz) in subscript. Except when noted otherwise, the R values presented are the maximum R value (R,,,) obtained to a stimulus series of increasing SPL. Only R values significant at the P < 0.001 level are reported (Mardia 1972). The ability of a fiber to entrain (discharge in response to every cycle of the stimulus) was measured with an entrainment index derived from the interspike interval (ISI) distribution. This index expresses the number of intervals occurring in a window equal to the stimulus period T, centered at T on the IS1 abscissa, as a fraction of the total number of intervals occurring in the response window. R and entrainment index were calculated over a lo- to 25-ms response window for fibers that had 2 100 spikes or intervals, respectively, within that window. For a subset of fibers (see RESULTS) response irregularity was quantified with the coefficient of variation (CV) (Young et al. 1988 ). A binwidth of 1 ms over an analysis window of 12- 18 ms was used for this analysis. The PST classification scheme used for TB fibers shows a good correspondence with morphological parcelations of cells in AVCN (Rhode et al. 1983; Smith and Rhode 1987; Smith et al. 199 1, 1993; Spirou et al. 1990): spherical bushy cells ( SBCs) have a “primary-like” (PL) response, globular bushy cells (GBCs) usually have a “primary-like with notch” (PL,) response, and stellate cells have a “chopper” response. At low CFs these morphological cell types cannot be differentiated on the basis of their PST, which is always of the “phase-locked” (PHL) category. Responses that were ambiguous or that did not easily fit in any of these categories were assigned to an “X” category, which therefore contains a heterogeneous mixture of response types. AN fibers were grouped into a low /medium- or high-SR category with 18 spikes/s as the dividing criterion (Liberman 1978 ) . RESULTS

Presence of tails in AN and TB fibers The three exemplary AN tuning curves in Fig. 1A illustrate how the shape of such functions differs in different CF regions, as first described by Kiang and Moxon ( 1974). Although all tuning curves are roughly symmetrical around the tip, fibers in mid-frequency ( - l-3 kHz) and high-fre-

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FIG. 1. A : illustration of tuning curve low-frequency tails in 3 auditory nerve (AN) fibers. The tuning curves, consisting of the thresholds of excitation to a tone of increasing frequency, were obtained with a tracking algorithm that did not exceed 90 dB SPL. Vertical line: thresholds at 500 Hz. B: threshold SPLs for a constant stimulus of 500 Hz (heavy arrow along abcissa) as a function of characteristic frequency (CF) for a population of 13 1 AN fibers. If threshold was not exceeded at the highest stimulus level used (90 dB SPL) the fiber is represented by an upward arrow. Data in A and B are from the same animal.

quency ( >3 kHz) regions have relatively low thresholds over a broad range of low frequencies, referred to as the tail of the tuning curve (Kiang and Moxon 1974; Kiang et al. 1986). The presence of broadly tuned tails allows the recruitment of high-CF fibers to low-frequency tones despite the steep slopes near the tuning curve tip (Kiang and Moxon 1974; Liberman 1978; ozdamar and Dallos 1976). For example, rate threshold to a 500-Hz stimulus for the three AN fibers in Fig. 1A is exceeded at the point where the vertical line crosses the tuning curves. Although the tips of the tuning curves are equally spaced on the abscissa by ~2 octaves, the increase in sound pressure needed to recruit the highest CF fiber with a 500-Hz stimulus is < 10 dB above the threshold for the mid-frequency fiber, whereas the corresponding threshold difference for the low- and midfrequency fiber exceeds 30 dB. This increase in recruitment of high-CF fibers at high SPLs makes the population threshold distribution to a low-frequency stimulus resemble the mirror image of a tuning curve (Fig. 1B), as shown by previous investigators (Kiang and Moxon 1974; Liberman 1978). Tuning curves for fibers in the TB resembled those of AN

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fibers in their general shape, with low-frequency tails present in mid- and high-frequency fibers. Figure 2 shows sample tuning curves from axons of SBC, GBC, or stellate cells with CFs similar to the AN fibers of Fig. 1. These fibers were intra-axonally labeled and classified on the basis of the axonal projection and branching patterns (Smith et al. 199 1, 1993 ) , except for the low-CF cell in Fig. 2C that was tentatively classified as a chopper/ stellate cell on the basis of its PST histogram. Thresholds at 500 Hz for the labeled axons whose tuning curves extended down to that frequency are shown in Fig. 20. As was the case for the AN (Fig. 1B), fibers over a broad range of CFs are responsive to the lowfrequency stimulus. Because the maximum SPL used in the collection of most TB tuning curves was lower than in the AN experiment of Fig. 1, fewer points at high SPLs and high CFs are available. Phase-locking

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We quantified the phase-locking ability of each fiber by its R,,, obtained to a level series at CF ( RCF) and at 500 Hz (I?,,,). Figure 3 illustrates responses of a low-CF (CF = 500 Hz, top panels) and high-CF (CF = 12,600 Hz, bottom panels) AN fiber. Rate-level functions (asterisk, left ordinate) and synchrony-level functions (open circles, right ordinate) in response to CF tones show a stereotypical sigmoidal shape with a lower threshold for the increase in R than for the increase in rate (Johnson 1980). Phase-locking at CF in the high-CF fiber was nonsignificant and is not shown, but robust phase-locking was present in this fiber to low-frequency stimuli presented at high SPLs (open circles, bottom panel). The average rate in response to this stimulus (plus signs) shows a steep increase over the 15-dB range presented. Maximum discharge rate and R500were obtained at the highest level presented ( 89 dB SPL). As is the case for the majority of high-CF fibers studied at 500 Hz, we are uncertain whether a further increase in rate or R would be obtained at even higher stimulus levels. Period histograms for both fibers of Fig. 3 A are compared in Fig. 3 B at the SPL yielding R,,,. The histogram of the high-CF fiber clearly has a narrower distribution, reflected in a higher R,oo value (R50, = 0.9 1) than is typically observed in fibers tuned to 500 Hz (top panel, R,,, = 0.85) (Johnson 1980; Joris et al. 1994). Superior phase-locking of high-CF AN fibers relative to low-CF fibers, when presented with the same low-frequency stimuli, was a common occurrence. Population R,,, data (N = 134) from one animal are shown in Fig. 4A, sorted according to SR. The dashed lines indicate the upper and lower boundaries for the range of RCF values reported by Johnson ( 1980). Fibers that showed “peak splitting” (period histograms showing 2 or more modes centered at different phases) at any SPL are represented with half-shaded symbols. Three more or less distinct CF zones can be discerned. At CFs < 1 kHz, R,,, values are in the same range as RCF values of fibers tuned to 500 Hz. Fibers with CFs >2 kHz have, on average, higher R,,, values than low-CF fibers tuned at 500 Hz; many (30 of 82, 37%) fibers, especially those with low/medium SRs (triangles: 28 of 36 fibers have R 5oo20.9), had higher R,oo values than are ever observed at

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FIG. 2. Sample tuning curves (A-C) and population thresholds at 500 Hz (D) for labeled trapezoid body (TB) fibers. Same format as in Fig. 1. Highest SPL used to track tuning curve was usually lower than in AN experiment of Fig. 1 and tuning curves therefore do not extend over as wide a range of SPLs and frequencies. Points for which threshold was not exceeded at highest SPL used are indicated with horizontal dotted lines in tuning curves (B and C) and arrows and unfilled symbols in scatter diagram (D). The lowCF fiber in C was not labeled (see text). SBC, spherical bushy cell; GBC, globular bushy cell; STEL, stellate cell.

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60 SBC GBC STEL 0.9 for the GBC but not for the SBC (Fig. 5, solid symbols). Regularity analysis of the chopper responses to CF tones yielded CVs that were all ~0.50, consistent with their designation as choppers (Blackburn and Sachs 1989; Young et al. 1988). The CV was x0.30 in five fibers (including the 2 choppers with the highest R,,,) that may therefore be subclassified as sustained choppers (Blackburn and Sachs 1989). There were no systematic differences in CVs to CF tones of PL, fibers with low or high R,oo. We did not calculate CVs at 500 Hz because they are a less meaningful and less well studied metric at frequencies in the phase-locking range (Blackburn and Sachs 1989; Rothman et al. 1994). Figure 6 shows the response at CF (A) and at 500 Hz (B-D) for the TB fiber with the highest &OO in each PST class as well as for the AN fiber with the highest R,,o. All fibers had R,oo >0.9 and thus had a high-sync tail. The PST histogram at CF is that at the highest SPL presented (Fig. 6A); the other histograms (Fig. 6, B-D) are at the SPL at which R,oo was obtained. Despite very different responses to CF tones, the responses of the PL,, chopper, and PHL fibers to 500 Hz are very similar to each other and to the high-sync responses obtained in low-CF TB fibers (Joris et al. 1994) for both synchronization and IS1 statistics. The IS1 histograms (Fig. 60) indicate that all or most of the interspike intervals closely approximate the stimulus period. This property, referred to as entrainment (Joris et al. 1994; Rhode and Kettner 1987; Rhode and Smith 1986), is described in more detail below. The AN and PL fibers have lower R,,, values than the other fibers and, more strikingly, show no entrainment. For some TB fibers phase-locking at 500 Hz is especially

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high at the first few stimulus cycles after onset so that the PST modes broaden with time after stimulus onset, very similar to low-frequency TB fibers stimulated at CF (Joris et al. 1994). Such temporal adaptation was not seen in AN fibers, even for those that had high-sync tails. Figure 7A shows rate (top row) and synchronization measures (bottom TOW) for individual cycles of 500-Hz responses of a high-sync AN and PL, fiber. The PL, fiber (right column) entrains maximally throughout the response (i.e., the Xs in the top panel equal the number of stimulus repetitions), whereas the AN fiber (lefi column) adapts after a peak in discharge rate near the stimulus onset. The reverse is true for the temporal measures (bottom panels), which systematically change in the PL, but not in the AN fiber. The spike time SD (a) of the PST histogram modes (+ in bottom panels) of the PL, fiber increase from a low of 24 pus(2nd mode) to a high of 55 ,US(2nd to last mode), whereas 0 for the modes of the AN fiber’s PST histogram have an average of 134 pusand show no systematic change with time. In many TB fibers entrainment to a low-frequency tone was not sustained for the whole stimulus duration but limited to the first few stimulus cycles, so that there was both a temporal and rate adaptation. The individual modes of 500-Hz responses of PL, fibers resemble the onset component of their response at CF, which is also very secure ( 1 spike per stimulus presentation) and well timed (e.g., PST histogram in Fig. 6). Because this onset is separated from the sustained part of the response by a notch that is usually > 1 ms in duration, its SD (a,,) can be calculated and compared with the shortest CTat 500 Hz, calculated as in Fig. 7 ( a,,,). The two measures are poorly correlated (r = 0.52, N = 37), but the shortest US are similar for both measures ( ~25 ps).

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Tail synchronization functions of AN and TBJibers So far we have described the phase-locking of AN and TB fibers to CF and 500-Hz t.ones. For a smaller sample of fibers we obtained rate- and synchronization-level functions at a number of frequencies and determined R,,, at each frequency: the collection of R,,, values for a given fiber was called the tail synchronization function. Figure 8 shows representative examples of such functions for a low/ medium-SR (a) and high-SR ( 0) AN fiber superimposed on the boundary values of phase-locking at CF (Johnson 1980). Compared with the & boundaries the high-CF fibers had high &OO values, as was shown in Fig. 4A. However, the opposite was true at 2 kHz and above, where R values straddled the lower boundary of Johnson’s ( 1980) low-CF population data. R was particularly low for the fiber with the higher CF (0; CF = 6.2 kHz). This double mismatch, at both low and high frequencies, between high-CF synchronization functions and the population synchronization range for low-CF fibers was found in a sample of 59 fibers from two animals. R,,, at 1,000 Hz ( RIooo values) closely overlapped RCF values at 1 kHz and never exceeded the upper R,, boundary, whereas at higher frequencies R was on average lower than RCF for corresponding frequencies. Tail synchronization functions were obtained for TB fibers from three PST histogram categories shown in Fig. 9. As shown above (Fig. 5), phase-locking at 500 Hz was n cm-.

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FIG. 4. A: COmparkOn Of R,,, values at 500 Hz (.&,) for 134 AN fibers from 1 animal (symbols) with R,,, at CF (RCF) values for AN (dashed lines; Johnson 1980). Different symbols indicate SR category and presence, at one or more SPLs, of peak splitting (ps) (see key). Dotted horizontal lines are at R,,, = 0.90 (high-sync criterion) and 0.95, which indicates the upper boundary for this set of AN data. B: phase values from same responses at 500 Hz. The 7 fibers with the lowest Rsoo values (~0.65) in A showed peak splitting at all levels: phase measurements for these fibers are not shown.

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Maximum phase-locking at 500 Hz for 70 TB fibers, with poststimulus time (PST) histogram classesidentified by different symbols (see key). Filled symbols: labeled fibers. Half-shaded symbols: presence of peak splitting. Horizontal dotted lines: criteria for high-sync (R,,, 2 0. 9 ) and synchronization enhancement (0.95: highest R,, value for AN fibers). PHL, phase-locked; PL, primary-like; PL,, primary-like with notch; CHOP, chopper. FIG.

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tighter in PL, than in PL fibers, and this is also the case at higher frequencies. Particularly striking, however, is the observation that all PL and PL, functions show a steep slope and/ or a low upper cutoff frequency, so that at high frequencies phase-locking is actually poorer or at best similar to the phase-locking found in low-CF AN fibers. This trend is qualitatively the same as discussed for high-CF AN fibers (Fig. 8) and was also found in low-CF TB fibers (Joris et al. 1994), as illustrated by the synchronization functions for PHL fibers (Fig. 9, left panel). Previous studies (e.g., Johnson 1980; Palmer and Russell 1986) have shown that AN fibers with CF < 1 kHz have R,F values close to the R value of a half-wave rectified sinusoid (0.785 ) , and indeed, to a first approximation, PST histograms of low-CF fibers are well-described as half-wave rectified, low-pass filtered replicas of the stimulus waveform, where the low-pass filter has a corner frequency of 2.5 kHz (Weiss and Rose 1988). The same description can be applied to the period histograms of the high-CF, high-SR fiber shown in Fig. 10 A, except that its synchronization function (see Fig. 8, 0) falls off faster. In contrast, the high-sync AN and TB tail synchronization functions are qualitatively different. To compare the precision of firing across frequencies the histograms were plotted on a constant time scale: the phase axis was shifted to center the histogram and scaled to the stimulus period. Figure 1OC shows period histograms for the PL, fiber for which we obtained the most complete synchronization function. The dispersion of the cycle histograms is remarkably similar over 3.5 octaves, which suggests that the ceiling of the precision of synchronization is determined by a source of time jitter that is independent of frequency. The histograms of the high-sync, low/medium-SR AN fiber (Fig. 10 B) also show little

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change in dispersion as a function of frequency, although our data do not extend to frequencies (500 Hz. If we make the assumption that the spike time distributions for these histograms are invariant with frequency, then any of these cycle histograms should allow a prediction Of Rnmc at any other frequency and thus predict the slope of the tail synchronization function. Figure 11 compares the synchronization function of the PL, fiber of Fig. 1OC with functions calculated from the cycle histogram at each frequency. To calculate these functions we centered the cycle histogram by shifting the phase to 0.5 and iterated the calculation of R after removal of the first and last bins (which were usually empty). For example, R for the original cycle histogram at 500 Hz, with the 2-ms stimulus period divided into 150 bins, was 0.97 (Fig. 11, inset). After 25 iterations of removing the first and last bins, 100 bins remain. Calculation of R on the remaining histogram, corresponding to a frequency of 750 Hz, gives R = 0.934. This procedure was continued until the remaining histogram corresponded to a frequency approaching 3 kHz, and was repeated for each “original” histogram. A family of functions is thus ob-

tained: the slopes of these functions agree well with each other and with the slope of the empirical synchronization function (this function is obtained by connecting the triangles in Fig. 11 and is shown in the right panel of Fig. 9). This observation reinforces the visual impression (Fig. 10) that there is little difference in the jitter of spike times around the preferred phase at different frequencies. Entrainment TB3hers

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It was mentioned above (Fig. 7) that TB fibers with highsync tails tend to entrain to the stimulus. To quantify this we calculated the entrainment index of each fiber for the responses to a 500-Hz tone. The maximum entrainment index usually occurred at or near the highest stimulus level presented (not shown). Comparison of these values with those of the AN (Fig. 12 A) clearly shows higher entrainment indexes for the TB fibers, with a dividing line occurring at -0.6: only 1 AN fiber had a maximal entrainment index >0.6, whereas the index was ~0.6 in only 4 of 41

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high-sync TB fibers. Different symbols in Fig. 12 identify AN fibers with I?,,, 20.9 (+, N = 26) and R,,, ~0.9 ( X, N = 75 ). High entrainment is absent in AN fibers, even in the fibers with high-sync tails An entrainment index of 1 implies a discharge rate equal to the stimulus frequency. Because of entrainment, TB fibers with high-sync tails typically show a large response rate difference between stimulation at CF and at 500 Hz (see below, Fig. 13) when compared with AN fibers (Fig. 3, bottom panel). Comparison of maximal discharge rates of TB and AN fibers (Fig. 12@ shows distributions that very much resemble those for entrainment (Fig. 12A) and that clearly separate the two populations. Whereas AN fibers have maximum rates ~250 spikes/s ( 1 exception), highsync TB fibers typically exceed that value (5 exceptions). As in Fig. 12A, AN fibers with R,,, 20.9 do not show the behavior of the TB high-sync fibers. The average SPL at which the maximum rate was obtained was nearly identical for high-sync AN and TB fibers (84 and 85 dB, respectively), so that their dichotomous distribution in Fig. 12 B is not due to a simple di fference in the levels at which the responses were sampled. In the accompanying PaPer we showed entrainment of low-frequency TB fibers stimulated at CF up to -600-700 Hz; at higher frequencies entrainment and maximum discharge rate showed a sharp decrease, even in the presence of RCF val ues >0.9. A simil ar pattern of increase and sharp drop in entrainm en t and average rate occurred in the TB fibers with high-sync tail synchronization functions. The top panel in Fig. 13 shows the entrained average rate at 500 Hz and the low rate at CF for the PLN fiber of Figs. 1OC and 11. At 600 Hz and below the average rate closely follows a slope of 1 ( . , bottom panel), followed by a decrease at still higher frequencies. This holds true irrespective of l

.+

. . ..+ .+ .+.+.+.+..+-+--f’

l~

whether maximum rate ( 0) or rate at R,,, ( X ) is considered. Thus high-CF TB fibers have the potential of providing powerful temporal and average rate cues about low-frequency stimuli. DISCI

SSION

AN and TB fibers over a wide range of CFs respond to low-frequency stimuli at SPLs commonly present in our auditory environment. Previous reports of this phenomenon have usually focused on measures of threshold, average rate, or phase of synchronization to pure tones, rather than on the precision of phase-locking. The present study quantifies phase-locking of TB fibers to low-frequency tones and shows enhanced synchronization and entrainment in highCF TB fibers. The enhancement shows similarities to that observed in the response of low-CF TB fibers stimulated at CF. When we use phase-locking in the AN to stimuli presented at CF (Johnson 1980) as a reference, the results from the current and accompanying study can be summarized as follows: 1) GBCs of all CFs show enhanced phase-locking to stimuli below - 1 kHz. 2) SBCs at low, but not high, CFs show enhanced phaselocking. 3) High-CF stellate cells can show enhanced phase-locking. 4) High-CF AN fibers show better phase-locking at low frequencies than low-CF AN fibers. The single most important technical difference that sets our study apart from previous studies of phase-locking in AVCN is the fact that we recorded from the ou tput tract rather tha n from the n ucleus itself. The absence Of-P repotentials and phase-locked (PHL) field potentials in these re-

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of information on cell location-was offset by the intra-axonal labeling of some physiologically characterized highsync fibers. Although only two of the TB fibers studied in the low-frequency tail were intra-axonally labeled, the morphology-physiology correlations of our previous studies (Smith et al. 199 1, 1993) leave little doubt that all TB fibers reported in this study originated from cells in AVCN. For the discussion that follows it is important to restate the definition of our terms synchronization enhancement and high-sync. The latter term was defined in Joris et al. ( 1994) for responses with an R value 20.9 and identified low-CF TB fibers that showed more precise phase-locking than AN fibers of similar CF. The current results show that high-CF AN fibers can have R values 20.9 too and thereby show high-sync tails. For consistency, we keep the term high-sync here to identify all R values 20.9, whether obtained in the AN or TB. The AN results (Fig. 4) necessitated the introduction of an additional term, because highCF TB fibers can only be said to have more precise phaselocking than AN fibers if their maximal R value exceeds the highest value found in the AN (0.95): such fibers show synchronization enhancement.

- AN

\.

0.8

0.7 0.6 0.5

Phase-locking

0.0

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(Hz)

cordings, even at the higher SPLs necessary to drive highCF fibers, allows for relatively noise-free single-unit recordings and excludes the possibility that the temporal effects observed are an artifact of contamination by far-field potentials originating from the cochlea, neural structures, or acoustic driver. The drawback of TB recordings-the loss

PHL

at tail frequencies in TBJibers

Perhaps the most surprising aspect of the high-sync responses at tail frequencies is that the phenomenon is present in cells with pronounced differences in morphology, input configurations, and intrinsic properties. Entrainment and enhancement of synchronization in high-CF fibers are not only found in bushy and stellate cells in AVCN but are also found in multipolar and octopus cells in the posteroventral cochlear nucleus (Joris et al. 1992; Rhode and Kettner 1987; Rhode and Smith 1986). This prevalence in neurons of very different cellular makeup suggests that the most critical component of the high-sync mechanism is in the AN input discharge properties. We will argue below that this input component is the presence of “massive” phaselocking in converging AN inputs, caused by the high phaselocking, uniform thresholds, and coherence in phase that

FIG. 8. Tail synchronization functions for 2 AN fibers. Abscissa is stimulus frequency for the 2 functions, and CF for the dashed lines that represent the R,, boundaries. Fiber with CF of 3.6 kHz (solid triangle indicates R,,) had highest R,oo value (R,,, = 0.948) of our sample; its SR was 3 spikes/s. R,, in other fiber (0 ) was nonsignificant and is not indicated (CF = 6.2 kHz, SR = 30 spikes/s).

0.99

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PL

G 0.9 E CL 0.8 0.7 0.6 0.5

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1000

100

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FIG. 9. Tail synchronization functions for TB fibers of 3 PSTH categories. Large shaded symbols: R,,. Unshaded square in left panel: CF for a PHL fiber for which R,, value was not available.

P. X. JORIS, P. H. SMITH,

1046

B

AND T. C. T. YIN

C PL N

AN 2500

I

I

,1

2000

2400

2140

.I

A

1600

1500 A

A 800

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(CF)

for 2 AN fibers (A FIG. 10. Cycle histograms at R,,, and B) and 1 PL, fiber (C). The abscissas and binwidths are scaled to the same timescale, shown in the bottom Zeft corner; the ordinate is normalized to maximum and is identical for all histograms. The AN fibers had high (A ) and low/medium (B) SR and are the same fibers as in Fig. 8. The PL, fiber is the fiber of Fig. 9 (right panel) with the most complete synchronization function (CF = 2.14 kHz) .

-A

.o PHASE

1 ms

0.5

1 .o

0.0

0.5

1 .o

(cycles)

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characterize AN tail responses. However, high-sync responses in GBCs seem qualitatively different from those of other cell types because of their consistent presence and very high R values. As hypothesized in the companion paper, we believe that these cells stand out because of their special properties, which make them well-suited for the coding of temporal information. Phenomenologically, the enhancement of synchronization in high-CF GBC fibers parallels the behavior in low-CF fibers (Joris et al. 1994) in the following respects: the range of frequencies over which enhancement occurs and its magnitude, the presence of temporal adaptation and entrainment, and the poor synchronization above -2 kHz. These parallels suggest that a common mechanism may be involved over the entire CF range. It was proposed in the accompanying paper that enhancement of phase-locking in low-CF bushy cells depends on the necessity of coincident inputs to bring the postsynaptic cell above firing threshold. High-CF cells allow better testing of this coincidence hypothesis than low-CF cells, because it is possible to have either uncorrelated or correlated inputs by changing the stimulus frequency: as stimulus frequency increases, AN inputs become less synchronized to the stimulus (Johnson 1980) and presumably to each other. In other words, the AN spike trains providing the input to a high-CF cochlear nucleus cell become decorrelated as the stimulus frequency increases beyond the limit for phase-locking. If correlated GBCS.

inputs are required to bring the cell suprathreshold, then decorrelation will result in a decrease in discharge rate. In the few GBCs with high-sync tails for which synchronization functions were available at multiple frequencies there was a sharp reduction in maximal discharge rate at higher frequencies (Fig. 13 ), consistent with the coincidence proposal. This decrease in rate is even more remarkable in view of the fact that in AN fibers average rates in the tail were lower than or comparable to but never higher than at CF (e.g., Fig. 3). In the above interpretation it is assumed that, aside from stimulus-induced correlations, high-CF AN spike trains to a single AVCN cell are independent of each other. This assumption would be violated if AN fibers impinging on an AVCN cell would have temporally correlated spike trains, for example because they innervate the same inner hair cell. There is, however, no evidence for such correlation between high-CF AN fibers (Johnson and Kiang 1976; Kiang 1990). Our interpretation is essentially a monaural analogue to that of Yin and Chan ( 1990), who tested the crosscorrelation hypothesis proposed for binaural cells in the medial superior olive (Jeffress 1948). For these cells the degree of correlation between inputs from both ears can be varied by the independent control of the signals to each ear and has been shown to affect the firing rate of the postsynaptic cell (Yin and Chan 1990). SBCS. Although enhanced phase-locking is found in GBCs at all CFs, in SBCs it is limited to low CFs (Fig. 5 and Joris

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0.9 OL 0.8 0.7 0.6 0.5

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1

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cells. This difference was proposed to account for the observation in a model of bushy cell discharge patterns that small input synaptic conductances were required to obtain highsync responses at low CFs but large conductances were needed to obtain sufficiently irregular response patterns at high CFs (Rothman et al. 1994). We found that high-CF GBCs phase-lock as well as low-CF GBCs, and that no correlation exists between regularity (measured at CF) and degree of phase-locking (measured at 500 Hz) for high-CF GBCs. Moreover, in the coincidence model described in the accompanying paper, the highest phase-locking values were obtained with large, subthreshold synaptic conductances (Joris et al. 1994). An alternative explanation is that the irregularity in high-frequency responses is a result of inhibitory inputs (cf. Banks and Sachs 199 1; Tsuchitani 1988 ). Rothman et al. ( 1994) have pointed out additional reasons to suspect a role for inhibitory inputs. STELLATE CELLS. Cells with chopper responses, presumed to be stellate cells (Bourk 1976; Smith and Rhode 1989), have repeatedly been shown to phase-lock poorly to pure tones at CF (Blackburn and Sachs 1989; Bourk 1976;

1

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AA

t:a

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AA 0.6-

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AN R3 kHz was 0.89 (Fig. 5 ), whereas R,,, CR5oo= R,,) values for choppers tuned at 500 Hz are -0.7 (Blackburn and Sachs 1989). The AN data (Fig. 4) suggest three possible sources for the CF dependence of phase-locking. First, R,,, values are lower in AN fibers tuned to low and middle frequencies than in fibers in the high-frequency range. Second, peak splitting is more common in the midfrequency range. Third, in response to a low-frequency tone, high-CF AN fibers are in phase over a wider CF region than mid-frequency fibers, and converging inputs of slightly different CF will therefore be more coherent in phase for high-CF than for low-CF fibers. The latter point deserves some further explanation. Phase-locking in postsynaptic cells is not only dependent on the strength of phase-locking of the afferents but presumably also on the phase relationships across afferents. One source of phase-shifting across afferents arises as a consequence of cochlear mechanics: a slow accumulation of phase lag occurs as the cochlear traveling wave first excites AN fibers in the basal turn and travels apically, followed by a rapid accumulation of phase as the traveling wave approaches the cochlear region most sensitive to the stimulus freauencv (Kiang and Moxon 1974: Kim et al. 1980: Liber-

The presence of low-frequency tails in high-CF fibers (Kiang and Moxon 1974) has been exploited in AN studies directed at gaining insights into cochlear mechanisms by studying the rate or phase information present in the response of a large population of AN fibers to a single low-frequency stimulus (e.g., Liberman 1978; Miller et al. 1987; Pfeiffer and Kim 1975; Ruggero and Rich 1983; Sellick et al. 1982). In these studies the question of whether AN fibers with different CFs show different degrees of phaselocking to the same stimulus has received little attention. Variables known to affect AN phase-locking to a single pure tone are stimulus frequency, SPL, and, to a lesser extent, SR (Anderson et al. 197 1; Johnson 1974, 1980; Rose et al. 1967 ) . The degree of phase-locking is traditionally assumed or has been reported (e.g., Geisler et al. 1974; Palmer and Russell 1986) not to be dependent on CF per se, implying that any AN fiber will show similar phase-locking to a lowfrequency pure tone provided the chosen parameters make the stimulus suprathreshold. It was therefore rather surprising to find evidence to the contrary in the present study (Fig. 4). We found that on average fibers with CF >2 kHz have higher R,oo values than low-CF fibers. This was particularly true for fibers with SR < 18 spikes/ s, where R,,, was as high as 0.95. Even though the studies cited above do not report a dependency of phase-locking on CF, evidence of enhanced phase-locking at the tuning curve tail is sometimes visible in the data provided even when no measures of synchronization are given. Some high-CF fibers in the studies of Kiang and Moxon (1974), Ruggero and Rich (1983, 1989), and Sellick et al. ( 1982) show tightly distributed period histograms to stimuli 3 kHz) fibers, which is the CF region where the largest R,,, values were obtained (Fig. 4). Also, the response phase across fibers was very uniform (Fig. 4). Presumably all of these responses are therefore based on component I. We usually restricted our stimuli to SPLs ~90 dB: higher levels may have revealed component II (Ruggero and Rich 1989). An alternative explanation for the differences in phaselocking at different CFs is an apical to basal difference in micromechanical, transduction, or synaptic events (cf. Cheatham and Dallos 1993). Interestingly, in a comparison of AN phase-locking with the AC/DC ratio of inner hair cell receptor potentials, Palmer and Russell ( 1986 ) noticed a discrepancy in the same direction: the inner hair cell data obtained from the basal turn showed a lower corner frequency than the AN data obtained from low-CF fibers. Another piece of evidence consistent with an apex to base difference in temporal properties comes from envelope

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phase-locking data (Joris and Yin 1992). R values to the modulation frequency of sinusoidally amplitude-modulated signals show a low-pass characteristic. The upper limit of the range of modulation frequencies to which significant phase-locking can be obtained in high-CF fibers is -0.8 octaves lower than the range of pure tone phase-locking in low-CF fibers. Functional

relevance

Phenomenologically, the enhancement of phase-locking in the AVCN to CF and tail stimuli can be regarded as an example of an improvement in signal-to-noise ratio by ensemble averaging of AN inputs (Kiang 1990). Intuitively, this temporal improvement seems advantageous for neural “channels” most sensitive to low frequencies, which are specialized for extraction of binaural temporal cues. It is a different matter for high-frequency channels, where the importance of temporal cues for low-frequency carriers is unclear. The abundance of phase-locking to low-frequency spectral components in AN fibers and cells in AVCN, provided a sufficiently high stimulus level (AN: Delgutte and Kiang 1984a; Kiang and Moxon 1974; Palmer et al. 1986; Young and Sachs 1979; AVCN: Blackburn and Sachs 1990; Bledsoe et al. 1982), has led to the suggestion (Jenison et al. 199 1; Kiang and Moxon 1974) that high-CF AN fibers play a role in the coding of low-frequency information in speech signals. For example, high-CF fibers phase-lock to a speech signal in the presence of a low-frequency masking noise at lower signal-to-noise ratios than low-CF fibers (Kiang and Moxon 1974). Our observation of enhanced phase-locking to pure tones in high-CF TB fibers is consistent with a role for high-frequency channels in temporal coding. Behavioral data on frequency difference limens after apical hair cell destruction also suggest a perceptual contribution of temporal information in high-frequency nerve fibers (Prosen and Moody 1991). A problem with this suggestion is that, in the presence of speech-shaped or broadband noise, phase-locking in highCF fibers is degraded at signal-to-noise levels that cause significant phase-locking in low-CF fibers in both AN and TB (Delgutte and Kiang 1984b; Bledsoe et al. 1982; Miller et al. 1987). Psychophysical evidence (Strickland et al. 1994; Thornton and Abbas 1979) also suggests that the contribution of high-CF fibers to coding of the low-frequency content in speech signals is weak. Thus the available evidence suggests that the temporal information contained in responses of high-CF fibers may be a cue that is redundant to the central processor, except under a limited set of stimulus conditions. Similar attempts to assessthe role of high-CF neurons in the spatial localization of low-frequency sounds have been limited. Detection thresholds for interaural time differences at 500 Hz are higher in listeners with a high-frequency hearing loss ( Smoski and Trahiotis 1986). Given our observation that especially GBCs, which are part of a circuit thought to be important for sound localization, show enhanced synchronization to low-frequency signals, it seems worthwhile to examine more centrally located high-CF neu-

1050

P. X. JORIS,

rons for interaural quency signals.

time difference sensitivity

P. H. SMITH,

to low-fre-

17 June 1993; accepted

T. C. T. YIN

to Single Tones: Synchrony and Average Discharge Rate ( PhD dissertation).

Cambridge,

MA:

MIT,

1974. between spike rate and synchrony in fibers to single tones. J. Acoust. Sot. Am. 68:

JOHNSON, D. H. The relationship

We thank D. Johnson for auditory nerve synchronization data and L. Carney for critical comments on a previous version of the manuscript. Thanks to the staff of the Dept. of Neurophysiology for technical support, in particular R. Kochhar (software) and T. Stewart (photography). This work was supported by National Institute of Deafness and Other Communications Disorders Grant DC-00 116 and National Science Foundation Grant BNS 890 1993. Address for reprint requests: P. X. Joris, Dept. of Neurophysiology, University of Wisconsin Medical School, Madison, WI 53706. Received

AND

in final form

11 November

1993.

REFERENCES

ANDERSON, D.J.,

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