Departments of 1Biomedical Engineering and 2Otolaryngology-Head and Neck Surgery and Center for Hearing and Balance, Johns Hopkins University, Baltimore, Maryland 21205
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ABSTRACT |
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Davis, Kevin A., Ramnarayan Ramachandran, and Bradford J. May. Single-Unit Responses in the Inferior Colliculus of Decerebrate Cats II. Sensitivity to Interaural Level Differences. J. Neurophysiol. 82: 164-175, 1999. Single units in the central nucleus of the inferior colliculus (ICC) of unanesthetized decerebrate cats can be grouped into three distinct types (V, I, and O) according to the patterns of excitation and inhibition revealed in contralateral frequency response maps. This study extends the description of these response types by assessing their ipsilateral and binaural response map properties. Here the nature of ipsilateral inputs is evaluated directly using frequency response maps and compared with results obtained from methods that rely on sensitivity to interaural level differences (ILDs). In general, there is a one-to-one correspondence between observed ipsilateral input characteristics and those inferred from ILD manipulations. Type V units receive ipsilateral excitation and show binaural facilitation (EE properties); type I and type O units receive ipsilateral inhibition and show binaural excitatory/inhibitory (EI) interactions. Analyses of binaural frequency response maps show that these ILD effects extend over the entire receptive field of ICC units. Thus the range of frequencies that elicits excitation from type V units is expanded with increasing levels of ipsilateral stimulation, whereas the excitatory bandwidth of type I and O units decreases under the same binaural conditions. For the majority of ICC units, application of bicuculline, an antagonist for GABAA-mediated inhibition, does not alter the basic effects of binaural stimulation; rather, it primarily increases spontaneous and maximum discharge rates. These results support our previous interpretations of the putative dominant inputs to ICC response types and have important implications for midbrain processing of competing free-field sounds that reach the listener with different directional signatures.
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INTRODUCTION |
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Single units in the central nucleus of the
inferior colliculus (ICC) of unanesthetized decerebrate cats can be
classified into three distinct types (not including onset units) based
on the patterns of excitation and inhibition observed in contralateral pure-tone frequency response maps (Ramachandran et al.
1999). These response map types are presumed to reflect
different sources of input from lower auditory nuclei (for review, see
Irvine 1986
; Oliver and Huerta 1992
;
Oliver and Shneiderman 1991
). For example, the response
maps of ICC type V units show V-shaped excitation that resembles the
responses of projection neurons in the medial superior olive (MSO)
(Goldberg and Brown 1969
; Guinan et al.
1972
). In contrast, type I maps show level-tolerant excitation
bounded by strong lateral inhibition, which is the response pattern
associated with the principal cells in the lateral superior olive (LSO)
(Caird and Klinke 1983
). Last, type O units show
excitation when tested with low-level tones at best frequency (BF: the
most sensitive frequency), but show strong inhibition to high-level BF
tones; this behavior is exhibited by principal cells in the dorsal
cochlear nucleus (DCN) (Spirou and Young 1991
;
Young and Brownell 1976
). The present study extends our
description of the sound-evoked activity of ICC neurons
(Ramachandran et al. 1999
) by assessing the ipsilateral
and binaural response map properties of ICC units.
Ipsilateral and binaural properties of ICC neurons have been described
in a large number of studies (see e.g., Aitkin 1986; Caird 1991
; Irvine 1992
for reviews);
these previous investigations have emphasized single-unit responses in
anesthetized animals. Because ICC neurons in anesthetized preparations
lack spontaneous activity, binaural effects often are characterized by
observing how ipsilateral tones at various sound levels influence the
activity evoked by contralateral stimulation. Such testing conditions
mimic the interaural level difference (ILD) cues that play a critical role in high-frequency sound localization and provide a more controlled context for parameter manipulation than is available for free-field stimuli. ILD studies have revealed three broad binaural response patterns in the ICC. For many units, increasing ipsilateral stimulation inhibits excitatory responses to contralateral tones; these neurons are
termed EI units. Some ICC neurons show increased activity as the level
of the ipsilateral tone is manipulated (EE units), whereas others are
unresponsive to ipsilateral stimulation (E0 units).
Most studies of ILD sensitivity in ICC have limited their testing
protocol to one frequency (BF) and one level of contralateral stimulation. Gooler et al. (1993, 1996
), however, used
free-field tones ranging in both frequency and level to examine the
effects of sound direction on the receptive fields of single units in the inferior colliculus of curare immobilized frogs. Their results indicate that movement of sound sources toward ipsilateral locations increases the strength of inhibitory effects at OFF-BF
frequencies and consequently reduces the bandwidth of contralateral
excitatory responses. It is not clear that this enhancement of
frequency selectivity relates to ILD factors present in the mammalian
system because of the predominantly low-frequency hearing in anuran
species and the existence of an anatomic communication that links both middle ears (Narins et al. 1988
).
Our current study provides the first assessment of ILD effects on
single-unit responses in the ICC of decerebrate cats. The presence of
spontaneous activity in this preparation allowed us to examine directly
the ipsilateral response properties that shape ILD sensitivity and
frequency selectivity. These characterizations build on our previous
interpretations of the putative dominant inputs to ICC response types
(Ramachandran et al. 1999) and support comparisons with
traditional ICC binaural classification systems. Our results show that
type V units are equivalent to bilaterally excitable EE units, whereas
the more common type I and type O units exhibit EI properties.
Consistent with these binaural properties, type V units show lower
thresholds and wider excitatory bandwidths with increasing levels of
ipsilateral stimulation, whereas type I and type O units show higher
thresholds and narrower tuning. Usually the basic effects of binaural
stimulation are not altered when the GABAA
antagonist bicuculline is applied to the recording site; rather the
primary effect of bicuculline is to increase response magnitude. Thus
like the frequency response map types that are elicited by
contralateral stimulation, it appears that the binaural properties of
ICC neurons are largely established in lower auditory nuclei and then
modulated by local inhibitory mechanisms.
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METHODS |
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Surgical procedures
Detailed surgical procedures for acute electrophysiological
recording in the ICC of decerebrate cats are described elsewhere (Ramachandran et al. 1999). Briefly, experiments were
conducted on adult cats (3-4 kg) with clean ears and clear tympanic
membranes. Cats were tranquilized with xylazine (2 mg im), premedicated
with atropine (0.1 mg im), and anesthetized with ketamine (initial dose
40 mg/kg im; supplemental doses 15 mg/kg iv). Thereafter core body
temperature was maintained at 39°C with a regulated heating pad. Cats
were decerebrated by aspiration through the brain stem between the
superior colliculus and thalamus; anesthesia then was discontinued. The
cat's head was secured with a stereotaxic apparatus in a standard
horizontal orientation. The left inferior colliculus was exposed by
opening the skull just rostral to the bony tentorium, aspirating the
underlying cortical tissue, and partially removing the tentorium. At
the end of experiments, cats were euthanized by an injection of
pentobarbital sodium (26 mg/kg iv). If electrode tracks were marked
with electrolytic lesions during the course of recording, this
injection was followed by immediate perfusion and the brain tissue was
processed for histology.
Recording protocol
Recordings were made in a sound-attenuating chamber. Acoustic
stimuli were delivered bilaterally via electrostatic speakers that were
coupled to hollow ear bars. The calibration function of each closed
acoustic system was relatively uniform (±5 dB) across frequency from
40 Hz to 40 kHz and similar in both ears (±2 dB). Therefore applying
equal attenuation to binaural tones of the same frequency was assumed
to create a 0-dB ILD. Interaural crosstalk was 30 dB (and typically
>50 dB) down in the ear opposite to the sound source (Gibson
1982
), which is well below the maximum ILD used during binaural
testing. All test stimuli were 200 ms in duration, had rise/fall times
of 10 ms, and were presented at a rate of 1 burst/s.
Unit activity was recorded with platinum-iridium electrodes. The
electrode signal was amplified (×10,000-30,000) and filtered from 30 Hz to 6 kHz. A variable-threshold Schmitt trigger was used to
discriminate action potentials from background activity. Pharmacological manipulations were performed using "piggy-back" multibarreled electrodes (after Havey and Caspary 1980).
These electrodes were made by attaching a three-barrel glass
micropipette ~10-15 µm behind the tip of the metal recording
electrode. Two barrels of the pipette were filled with bicuculline
methiodide (10 mM, pH 3.5-4.0, Sigma); the third, balancing or sum
channel, was filled with a pH-balanced buffer (pH 4.0, potassium
hydrogen phthalate, CMS). Retention currents of 20 nA (electrode
negative) and ejection currents of 50 nA were produced with
microiontophoresis constant current generators (WPI, Model 260).
Electrodes were advanced dorsoventrally through the IC in 1- to 2-µm
steps with the use of a hydraulic micromanipulator. Search stimuli were
50-ms tone or noise bursts presented in the contralateral ear. When the
IC is sampled along a dorsoventral trajectory, electrodes pass through
the external or dorsal nucleus before entering ICC; a reversal in the
trend of unit BFs was used to mark the transition between subdivisions
(Aitkin et al. 1975; Merzenich and Reid
1974
). Once an ICC unit was isolated, its BF to contralateral
tones (BFc) was determined, then rate-level
functions were obtained with BFc tones and
broadband noise bursts (100-dB range in 1-dB steps) using contra- and
ipsilateral monaural and binaural stimulation. Monaural frequency
response maps were measured using isointensity single-tone frequency
sweeps (across a 4-octave range logarithmically spaced about
BFc) at multiple levels (10 dB below to 70 dB
above threshold); each frequency-intensity combination was presented once. For binaural testing, the same pure tone was presented to both
ears, but a 40-dB range of ILDs was created by varying the level of the
ipsilateral tone relative to a fixed contralateral stimulus.
The responses elicited by auditory stimuli are described in terms of average rates. To minimize adaptation effects, stimulus-evoked rates were computed during the last 150 ms of the stimulus-on interval; and spontaneous rates were computed during the last 400 ms of the stimulus-off interval of each 1-s stimulation period. Excitatory (inhibitory) responses were defined as those for which the stimulus-evoked rate was at least ±1 SD of the spontaneous discharge rate. All data were smoothed with a triangularly weighted moving window filter to reduce noise in frequency response maps.
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RESULTS |
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Physiological characterizations are based on the responses of 92 ICC units (10 type V, 37 type I, and 45 type O units) that were
recorded in six cats. Ramachandran et al. (1999)
described the effects of contralateral monaural stimulation for 80 of
these units. The present study expands on those results by measuring ipsilateral response patterns for the entire sample of units and binaural interaction data in 53 units (6 type V, 21 type I, and 26 type
O units). Pharmacological manipulations were performed on a few units
(1 type V, 2 type I, and 5 type O) to investigate the effects of
GABAA inhibitory inputs that may shape binaural properties in ICC.
Comparison of frequency response maps and ILD functions
Our previous analyses of frequency response maps have indicated
that single units in ICC can be classified by their distribution of
excitatory and inhibitory response areas for contralateral monaural
stimulation. Type V units show a strictly excitatory V-shaped receptive
field (Fig. 1A); whereas, type
I and O units are inhibited by most combinations of stimulus frequency
and sound pressure level. For type I units, the inhibitory receptive
field is confined to sidebands that flank BF and thereby reduces the range of excitatory frequencies to a narrow I-shaped response area
(Fig. 1D). Type O units show almost exclusively inhibitory responses except for a consistent O-shaped island of excitation near BF
at low-stimulus levels (Fig. 1G). Other response properties associated with these unit types are described in detail by
Ramachandran et al. (1999).
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The responses of ICC units to ipsilateral stimulation also can be
separated into distinct classes. Type V units show only excitatory
responses for ipsilateral stimulation (Fig. 1B), which is
equivalent to the response properties of EE units in usual binaural
classification systems (see e.g., Irvine 1992). Although type V units respond well to contralateral stimulation, 5/10 of the
units in this response class attained higher BF tone-driven rates with
ipsilateral stimulation (e.g., Fig. 1B). Type I and type O
units were inhibited by ipsilateral stimulation (Fig. 1, E
and H, respectively), which is a characteristic of EI units in binaural classification systems.
Differences in the ipsilateral response properties that distinguish the response maps of ICC units also are reflected in ILD functions. The functions plotted in Fig. 1, right, were created by presenting a 10 dB re threshold BFc tone to the contralateral ear while varying the intensity of a BFc tone in the ipsilateral ear across a ±20 dB range of levels (the excitatory monaural intensity, EMI, constant method). By convention, positive ILDs indicate stronger sounds at the contralateral ear. For the type V unit (Fig. 1C), firing rates remained relatively constant at low levels of ipsilateral stimulation (positive ILDs) because responses were dominated by the fixed contralateral tone. The excitatory drive to the unit increased at more intense levels of ipsilateral stimulation (negative ILDs) and higher firing rates were achieved. By contrast, the discharge rates of both type I (Fig. 1F) and type O units (Fig. 1I) decreased when the balance of inputs shifted toward inhibition at increased levels of ipsilateral stimulation (negative ILDs).
The threshold for transition from a contralateral to ipsilateral
dominant response has been defined as the half-maximal ILD (ILD50). Typically this measure is used to
characterize the threshold of ipsilateral inhibitory effects
(Park and Pollak 1993; Wenstrup et al.
1988
) and is defined to be the ILD at which the driven response
to the binaural stimulus declines by 50% from the response evoked by
contralateral monaural stimulation (horizontal arrows in Fig. 1,
C, F, and I). For example, the
ILD50s for the type I and type O units in Fig. 1,
F and I, respectively, are reached at slightly
negative ILDs (vertical arrows). In this report, the ILD50 of a type V unit indicates the binaural
condition that elicits a response that is 50% greater than the
contralateral response; for the type V unit in Fig. 1C, the
ILD50 is reached at an ILD of +15 dB.
Table 1 summarizes the relationships
between ipsilateral frequency response maps and binaural interaction
classes for type V, type I, and type O units. Note that most of the
units fall along the shaded diagonal in the table, indicating a
one-to-one correspondence between response map properties and binaural
interactions. All six type V units showed excitation for contralateral
and ipsilateral tones (EE properties) and an ILD function that
displayed rate increases at higher levels of ipsilateral stimulation.
The majority of type I (15/21) and type O units (14/26) showed
ipsilateral inhibition (EI properties) and an ILD function that
declined as ipsilateral stimulation increased. A subset of units (3 type I and 7 type O units, most with BFs 3 kHz) showed
ipsilateral response maps that changed from excitation at
low-stimulation levels to inhibition at high levels. These units tended
to have complex ILD functions, called EI/f after Park and Pollak
(1993)
, that showed facilitation at low levels of ipsilateral
stimulation and inhibition at higher levels.
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Our system of response map classification did not always predict the
binaural properties of ICC neurons. For example, five units (3 type I
and 2 type O) exhibited no excitation in their ipsilateral maps but
produced ILD functions with EI/f properties. These results are
consistent with the idea that some binaural facilitation is created
within the ICC (Park and Pollak 1993). Conversely, one
type O unit without any detectable inhibition in its ipsilateral map
showed an EI ILD function. In all, 4/37 type I and 15/45 type O units
showed little or no response to ipsilateral tones; however, in almost
all cases, these units showed clear inhibitory responses to broadband
noise bursts. Therefore tones may not be the most effective stimuli for
direct determination of a unit's ipsilateral response properties.
ILD functions obtained with the EMI-constant method summarize the binaural properties of auditory neurons in terms of responses obtained at one frequency (BFc) across a restricted range of stimulus levels (±20 dB re contralateral level). Analyses of binaural frequency response maps, on the other hand, have the potential to assess binaural interactions over the entire receptive field of ICC neurons. Although results presented in Table 1 suggest that the EMI-constant method provides a good estimation of basic binaural properties, the question remains as to what extent this outcome is determined by the choice of stimulus parameters. For example, a comparison of the monaural frequency response maps in Fig. 1 suggests that the most sensitive frequency for the contralateral ear (BFc) is not necessarily the most effective stimulus for the ipsilateral ear (e.g., for the type O unit, BFc is 3.4 kHz lower than the BF of the inhibitory response to ipsilateral stimulation).
Figure 2A shows the differences in the
most sensitive frequency of the ipsilateral versus the contralateral
ear for all units in this study with completely sampled ipsilateral
response maps. Each symbol plots the ratio in octaves of the
ipsilateral best frequency (BFi, e.g., vertical
lines in Fig. 1, B, E, and H) to BFc as a function of BFc.
The BF ratio changes from negative to positive values as
BFi moves from lower to higher frequencies relative to BFc and equals 0 when BFs are equal
in both ears (- - -). For type V units (), there is a tendency for
BFi to be lower than BFc
(P < 0.001, paired t-test); Semple
and Kitzes (1985)
found a similar pattern for EE units in
anesthetized gerbil. In contrast, for type O units (
),
BFi is typically above BFc
(P < 0.001). This difference does not simply reflect a
dependence on BF (type V units have low BFs, whereas type O units have
high BFs) because type I units (vertical lines) also tend to have
widely ranging BFcs yet show the same tendency as
type V units for BFi to be below
BFc (P < 0.001). Notwithstanding
these consistent differences, BFc and
BFi deviated by less than ±0.1 octaves in 39/59
cases, suggesting that ILD tests with BFc tones
will evoke ipsilateral responses that are strong enough to characterize
the binaural interactions of ICC neurons.
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The substantial overlap of contralateral and ipsilateral response areas (e.g., Fig. 1, A and B) suggests further that the basic nature of ILD functions should not alter for stimulus frequencies away from BFc but still within the excitatory area of the contralateral map. This interpretation was tested by examining the effects of frequency on ILD functions. Figure 2B compares BFc ILD functions of the three representative ICC units (dotted line, data shown in Fig. 1) with results obtained when the stimulus frequency was shifted below BFc by one-quarter of the excitatory bandwidth at 10 dB re threshold (solid line; ~0.25 octaves for the type V unit and 0.1 octaves for the type I and O units). For all 3 unit types, the ILD functions for the off-BFc stimuli show shallower slopes, at least over the initial portion of the curves, and thus increased ILD50 values (solid arrows to right of dotted arrows). Change in slope reflects the decreased modulatory effect an ipsilateral response can have on the reduced discharge rate evoked by the off-BF contralateral stimulus; nonetheless, it is clear that the pattern of binaural interaction did not change with choice of base frequency.
The importance of stimulus level on ILD measures is illustrated in Fig.
3A by plotting the
ILD50 for 6 type V, 21 type I, and 26 type O
units in relation to each unit's difference in ipsilateral and
contralateral thresholds for BFc tones. The
rising slope of the regression line indicates that
ILD50 is correlated positively with ipsilateral
sensitivity (P < 0.05, t-test). Type V
units have relatively low ipsilateral thresholds and reach the
threshold of binaural interaction at the lowest levels of ipsilateral
stimulation (positive ILDs). The majority of type I and O units
required higher levels of ipsilateral stimulation to meet the criteria
for both monaural threshold and ILD50. When data
from all unit types are combined, the average difference in ipsilateral
versus contralateral threshold is 11 dB (vertical arrow); therefore the
EMI-constant method with a contralateral base intensity of 10 dB
creates an ipsilateral stimulus condition that is just below threshold
at an ILD of 0 dB. On average, only a slight increase in ipsilateral stimulation was needed to attain the ILD50
(ILD = 5 dB, horizontal arrow). The complete distribution of
ILD50s fell between
23 and 12 dB, which
suggests that the range of stimulus conditions used in the EMI-constant
method is well suited for describing the binaural properties of ICC
neurons.
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Figure 3B shows how ILD functions for the representative ICC
neurons changed when the base intensity of the contralateral stimulus
was raised to 40 dB re threshold. For each unit type, the slope of the
ILD function was shallower for the higher level of contralateral
stimulation () than for the standard 10 dB stimulus (· · ·). Modulation of discharge rates along the ILD function of the
type V unit was diminished by the increase in minimum rate that
accompanied stronger ipsilateral excitation at the +20 dB ILD
condition. In contrast, the ILD function for the type I unit showed a
smaller modulation of rates when tested at 40 dB re threshold because
its maximum rate (at 20 dB ILD) was suppressed by the ipsilateral
response at the higher stimulus level. Strong contralateral and
ipsilateral stimulation drove the type O unit to complete inhibition
along the length of the ILD function. Consistent with the enhanced
ipsilateral response at the lowest ILD tested, most units failed to
show thresholds of transition (ILD50) from
contralateral to ipsilateral dominant responses; in those cases where
an ILD50 was present, it was shifted toward more
positive ILDs (a smaller increase in ipsilateral stimulation was required).
Effects of binaural stimulation on frequency-tuning characteristics
Ipsilateral inputs influence the binaural frequency-tuning and
threshold characteristics of ICC units. Figure
4 shows binaural frequency response maps
for a representative type V, type I, and type O unit. Each plot
indicates the discharge rates produced when binaural tone bursts were
swept in frequency across the unit's receptive field. This is
essentially the same testing procedure that was used to produce the
monaural frequency response maps in Fig. 1, but here fewer levels are
shown to facilitate the comparison of ILD effects. The level of the
contralateral tones was fixed at 10 dB (bottom) or 40 dB
(top) above the BFc threshold; the level of the ipsilateral tones was 20 dB below (ILD = +20 dB, · · · ) or 20 dB above (ILD = 20 dB,
)
this fixed value. Excitatory responses appear as peaks that rise above
spontaneous activity (- - -); inhibitory responses are indicated by
troughs in the discharge rate profile. In response to increased
ipsilateral stimulation (
), most frequencies in the receptive field
of the type V unit show rate increases. Binaural facilitation expands
the excitatory receptive field to include sound pressure levels and
frequencies that were not effective stimulus conditions under monaural
conditions. In contrast, stronger ipsilateral stimulation reduces the
discharge rate of type I and type O units at most frequencies in their
receptive fields; this sharpens the frequency tuning of their
excitatory areas. For all units, the changes in bandwidth were most
pronounced when the contralateral stimulus was near threshold
(bottom plots); as a result, a type O unit was likely to
lose one or more levels of its low-level island of excitation by
shifting binaural stimuli to extreme (
20 dB) ipsilateral-dominant
ILDs (
).
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The effects of ILD on tuning characteristics were quantified by
comparing the bandwidth of the excitatory response area at ILDs of ±20
dB; measures of excitatory bandwidth were based on Q10 (BFc/excitatory bandwidth 10 dB
re threshold; Fig. 5A)
and Q40 values (BFc/excitatory
bandwidth 40 dB re threshold; Fig. 5B). Each symbol
indicates the Q values of an individual unit (6 type V, 19 type I, and
21 type O units) at the 20 dB versus +20 dB ILD condition, symbols
falling along the dashed lines represent units that showed no change in
tuning under the ipsilaterally dominate binaural conditions. Consistent
with qualitative observations for the representative units in Fig. 4,
Q10 values showed the largest changes with ILD.
Type V units showed decreases in Q10 values
(symbols below the dashed line), indicating that frequency selectivity
near threshold broadened with higher levels of ipsilateral stimulation.
In contrast, higher levels of ipsilateral stimulation increased the
Q10 values of most type I and O units; this
sharpening of frequency tuning frequently lead to complete loss of BF
excitation and even BF inhibition (symbols plotted above the ordinate).
Similar, though smaller, changes in excitatory bandwidth were observed for type V and type I units at tone levels 40 dB re threshold (Q40s are not available for type O units because
they have no BFc excitatory response area at this
level of stimulation).
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Implicit in the preceding comparisons of tuning characteristics is the
assumption that the excitatory BF of the unit does not change
appreciably with ILD. Figure 6
illustrates the effects of ILD on the binaural BFs; the measures are
derived from rate plots like those shown in Fig. 4. Each symbol plots
one unit's BF at ILDs of 20 versus +20 dB. Two trends are apparent
in the data. First, of the 33 units that maintained excitatory
responses during binaural stimulation, all units showed nearly
identical BFs under the two ILD conditions (- - -; P > 0.05, paired t-test); thus units do remain tuned to the
same BF as a function of ILD. The second trend is that type O (11/21
cases) but not type I units (2/19 cases) were very likely to lose
altogether their excitatory responses when tests were performed at
20
dB ILD (units plotted above the ordinate). The apparently greater
effect of ipsilateral stimulation on type O than type I units likely
reflects the lower maximum rates type O units attain to contralateral
stimulation (Ramachandran et al. 1999
).
|
ICC units showed distinct changes in threshold as a function of
ILD manipulations; statistical box plots of these effects are shown in
Fig. 7. The measure of threshold change
was calculated by subtracting the binaural threshold at +20 dB ILD from
the threshold at 20 dB ILD; positive values indicate a decrease in
sensitivity with stronger ipsilateral stimulation. The length of each
box along the ordinate indicates the interquartile range of the
distribution (i.e., the middle 50% of the range of threshold changes);
error bars extend to the largest deviation within ±1.5 quartiles of the median score. Outliers beyond these limits are plotted as symbols
(Sokal and Rohlf 1995
). The magnitude of threshold
changes was estimated to the nearest 5 dB, which reflects the 10-dB
resolution of ILD measures for these tests. Strong ipsilateral
excitation produced a
5- to
10-dB change in threshold for type V
units; conversely, the thresholds of most type I units increased by
5-15 dB with two units showing a complete lack of excitatory response (data plotted above the ordinate). Ipsilateral inhibitory effects were
even stronger among type O units; the entire interquartile range of
this response class showed no excitation, while outliers exhibited a
mean increase of 2.5 dB (symbols).
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The effects of ILD on frequency tuning (Figs. 4 and 5) may
reflect processing mechanisms that reside in the ICC or extrinsic binaural interactions that modify inputs to the ICC. To determine how
local GABAergic inhibitory inputs shape the binaural properties of ICC
neurons, frequency response maps were measured at ILDs of ±20 dB
during application of bicuculline. These results are summarized by data
from representative type V, I, and O units in Fig.
8A. Plotting conventions are
the same as in Fig. 4; results obtained before and after the
bicuculline injection are contrasted in the left and
right columns of the figure. These tests were performed at a fixed contralateral stimulus level of 10 dB relative to
the BFc threshold, which is a stimulus level
where the tuning properties of ICC units were susceptible to ILD
manipulations (see Q10 values in Fig. 5). ILDs of
±20 dB were created by setting the ipsilateral tone 20 dB below (
· · · ) or 20 dB above () the level of the
contralateral tone. The major effects of bicuculline for the entire
sample of pharmacologically tested units were increases in the level of
spontaneous activity (Fig. 8B) and maximum stimulus-driven rates (Fig. 8C). These increases were evident for all unit
types (P < 0.05), including the type V units that
produced only excitatory frequency response maps and ILD functions. The
general effects of binaural stimulation on frequency tuning did not
change after bicuculline administration (Fig. 8A): that is,
the excitatory bandwidth of the type V unit (top) broadened
with increased ipsilateral stimulation and the tuning of type I
(middle) and type O units (bottom) narrowed. In
fact, because of higher stimulus-driven rates, these changes in
frequency tuning were even more apparent during GABAergic blockade.
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DISCUSSION |
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Comparisons with previous studies of the ICC
The overwhelming majority of ICC neurons (51/53, 96%) in the
present study exhibited binaural interactions. This preponderance of
binaurality is at odds with the relatively high incidence of monaural
response patterns that have prevailed in previous studies (e.g., 46%,
Schreiner and Langner 1988; and 49%, Irvine and
Gago 1990
). Such differences may arise from our focus on units
with sustained responses, which are quite common in the ICC of
decerebrate cats (Ramachandran et al. 1999
). In studies
that have examined both sustained and onset responders, it has been
found that the onset component of the response is relatively
insensitive to ILDs (Geisler et al. 1969
; Irvine
and Gago 1990
; Moore and Irvine 1981
). The
importance of onset effects may be exaggerated in studies involving
barbiturate anesthesia. Although binaural interactions are not
substantially altered by blocking GABAA-ergic
inhibition (Fig. 8A), the potentiation of inhibition by
barbiturates could mask binaural response patterns that are present in
unanesthetized cats by eliminating sustained discharge rates and in
effect changing sustained responders into onset units. If our analysis
of ILD effects is restricted to the initial 25 ms of stimulus-evoked discharge rates, the proportion of units showing binaural interactions falls to only 36/53 (68%) units.
The most common binaural interactions were inhibitory in nature. In
part, this observation may reflect a sampling bias toward BFs >3 kHz,
where the binaurally excitable type V units were never encountered. Our
system for classifying ICC units has not been used before, but other
studies also have noted a positive correlation between high BFs and
binaural inhibition. Certainly EI units can be found across the entire
range of audible frequencies (Schreiner and Langner
1988; Semple and Aitkin 1979
), but
high-frequency units were exclusively EI in the present study. This
finding may appear to contradict previous reports that a subpopulation
of high-frequency ICC units shows excitatory responses for monaural stimulation of either ear (22%, Semple and Aitkin 1979
;
8%, Schreiner and Langner 1988
; 9%, Irvine and
Gago 1990
); however, the classification of these pseudo-EE
units was not based on the effects of binaural stimulation. Ipsilateral
tones elicited excitatory responses over a limited range of monaural
stimulus conditions from 4/53 (7.5%) type I and O units in the present
study; all of these units demonstrated EI or EI/f ILD functions under
binaural conditions.
Origins of binaural response patterns in ICC
On the basis of responses to contralateral stimulation,
Ramachandran et al. (1999) have speculated that type V
units are shaped by inputs from the medial superior olive (MSO), that
type I units receive input primarily from the lateral superior olive
(LSO), and that type O units are derived from projections originating in the dorsal cochlear nucleus (DCN). The ipsilateral response map
characteristics of these unit types and their sensitivity to binaural
stimuli provide further constraints on their potential sources of input.
Type V units show purely excitatory responses when stimulated with BF
tones in either ear (Fig. 1) and are equally likely to attain their
maximum discharge rates when monaural stimuli are presented to the
ipsilateral or contralateral ear. Only one source of direct ICC
projections, the MSO (Aitkin and Schuck 1985; Henkel and Spangler 1983
), exhibits similar response
properties (Goldberg and Brown 1969
; Guinan et
al. 1972
). In addition, only type V and MSO units surpass their
maximum monaural discharge rates at highly negative ILDs (Fig. 1)
(Goldberg and Brown 1969
). MSO units traditionally are
associated with temporal coding, and this apparent ILD sensitivity is
perhaps misleading. When binaural tests are conducted with the
EMI-constant method, as in the present study, the average binaural
intensity (ABI) at the two ears grows with increasing levels of
ipsilateral stimulation; as a result, units with EE binaural properties
exhibit enhanced discharge rates. Goldberg and Brown
(1969)
have pointed out that MSO units are relatively
insensitive to ILD changes if they are presented using ABI-constant
methods (for a direct comparison of EMI and ABI testing procedures, see
Irvine 1987
). Figure 9
shows the excitatory receptive field of a type V unit that was measured
with the ABI-constant procedure; ipsilateral and contralateral stimulus
levels were symmetrically manipulated about an ABI level of 10 dB re
contralateral threshold to create ILDs of +20 (· · ·)
and
20 dB (
). Like the MSO neurons in the Goldberg and Brown study,
the type V unit's stimulus-driven rates were nearly identical under
the two binaural conditions in spite of extreme (+20 to
20 dB)
differences in ILD properties.
|
The typical type I unit is excited when BFc tones
are presented to the contralateral ear and inhibited when ipsilateral
stimulation dominates binaural testing conditions (Fig. 1). These
response patterns also are seen in the inhibitory/excitatory (IE)
binaural interactions of LSO neurons (Brownell et al.
1979; Caird and Klinke 1983
; Goldberg and
Brown 1969
; Guinan et al. 1972
). Most excitatory LSO projections cross the midline before they ultimately terminate in
the contralateral inferior colliculus (Glendenning et al.
1992
); as a result, IE output patterns in the LSO are expected
to create EI properties in the ICC. Consistent with their mixed
excitatory/inhibitory inputs, type I and LSO units respond to strong
binaural stimulation with reduced discharge rates relative to responses
elicited by monaural stimulation of the excitatory ear (Boudreau
and Tsuchitani 1968
; Caird and Klinke 1983
;
Guinan et al. 1972
; Tsuchitani and Boudreau
1969
).
Type O units show essentially the same binaural input (EI) and
inhibitory interaction patterns as type I units. However, the basic
features of the contralateral frequency response maps of type O units
(Fig. 1) are similar to those of type IV responses that are found in
the DCN of decerebrate cats (Spirou and Young 1991;
Young and Brownell 1976
). These similarities led
Ramachandran et al. (1999)
to suggest that type O
responses may reflect direct projections from type IV units in the
contralateral DCN (Adams 1979
; Ryugo et al.
1981
; Young 1980
; for a review, see
Oliver and Huerta 1992
; Rhode and Greenberg
1992
). The binaural properties of DCN principal cells have not
been studied in detail, but it has been established that type IV units
do show the EI response pattern that is expected of the lower-order
inputs to type O units (Davis and Young 1998
;
Mast 1970
; Young and Brownell 1976
).
Moreover, DCN type IV units and ICC type O units share an enhancement
of binaural inhibitory interactions when broadband sounds instead of
pure tones are presented to the inhibitory ear.
Multiple lines of evidence suggest, however, that the ILD sensitivity
of ICC neurons does not simply reflect that of its putative inputs.
First, although the basic nature of an ICC unit's ILD sensitivity
usually is unchanged in the presence of inhibitory blockers applied
locally (Fig. 8A), specific properties of the ILD function
such as ILD50 point are likely to change; and, in some cases, a unit may lose its ILD sensitivity altogether
(Faingold et al. 1989; Klug et al. 1995
;
Park and Pollak 1993
; Vater et al. 1992
).
Second, reversible inactivation of nuclei that project to the IC also
can reduce or occasionally eliminate the effectiveness of stimulation
of the ipsilateral ear (Faingold et al. 1993
;
Kelly and Li 1997
; Li and Kelly 1992
).
Finally, in vivo whole cell patch-clamp (Covey et al.
1996
) and intracellular (Kuwada et al. 1997
)
recordings show that most IC neurons receive synaptic inputs from
multiple sources and that intrinsic membrane properties can shape a
neuron's response to stimuli. Consistent with these observations,
Park (1998)
found several differences between the ILD
sensitivity of LSO and IC neurons in bat. Thus the majority of IC
neurons appear to modify their ILD-sensitive properties.
In addition to their ILD sensitivity, many low-frequency ICC neurons
are sensitive to interaural time differences (ITDs) (Kuwada et
al. 1987, 1989
; McAlpine et al. 1998
;
Palmer et al. 1990
; Yin and Kuwada
1983a
,b
). This property could provide another test for
identifying potential sources of input to response-map-identified ICC
units because lower-order auditory neurons have largely different ITD
sensitivities. In particular, Batra et al. (1997)
found
that in response to 1-Hz binaural beat stimuli, MSO units tended to exhibit rate modulations that attained a maximum (peak) at the same ITD
(i.e., the best phase) regardless of carrier frequency, whereas LSO
units tended to attain a minimum rate (trough). As predicted from the
associations described in the preceding text, preliminary results in
the ICC of decerebrate cat show that MSO-like type V units exhibit
peak-type and not trough-type responses, LSO-like type I units exhibit
the opposite behavior, and most DCN-like type O units fail to show
temporally structured responses to ITD stimuli (Ramachandran and
May 1999
). Some ICC units, however, showed neither peak- nor
trough-type responses. McAlpine et al. (1998)
have
suggested that such responses result from convergence at the level of
the IC of inputs from lower-order coincidence detectors. Thus it is
likely that ICC neurons also receive, but modify, their ITD-sensitive properties.
Binaural processing and frequency tuning
Closed-field ILD manipulations in the present study were designed
to simulate how the directional properties of free-field sounds
influence binaural processing. A major finding for these pseudo-sound
localization experiments was that the excitatory receptive fields of
ICC units can grow (type V units) or shrink (type I and O units)
depending on the relative strength of contralateral versus ipsilateral
stimulation. When other studies examined binaural interactions in ICC
(or its amphibian analogue) using actual free-field sounds,
correlations between stimulus azimuth and excitatory tuning have been
observed (cat, Leiman and Hafter 1972; frog,
Gooler et al. 1993
, 1996
; mouse, Cain and Jen
1995
; bat, Chen et al. 1995
). Although these
independent lines of evidence generally support our interpretations of
ILD effects, important differences in species morphology must be
considered. For example, units with EE binaural properties showed
directionally dependent narrowing of frequency tuning in the amphibian
studies of Gooler et al. (1993
, 1996
). By contrast,
binaurally excitable type V units in this study were insensitive to ILD
changes under comparable ABI-constant conditions (Fig. 9). One
explanation for this apparent species differences is that EE responses
in the amphibian ICC do not reflect excitatory inputs in both ears but
acoustic crosstalk via anatomic communications of the middle ear (i.e.,
the monaurally excitable ear is easily driven by sounds reaching either
typanum). Indeed, like type I and O units (Fig. 1), ILD functions of EE
units in the Gooler et al. studies show inhibitory interactions at
higher levels of ipsilateral stimulation (Gooler et al.
1996
, Fig. 2).
Pharmacological evidence also suggests that binaural processing in the
auditory midbrain may involve different mechanisms for different
species. Xu and Feng (1996) found that local
iontophoretic application of bicuculline eliminated the directionally
dependent frequency tuning characteristics of ICC units in frogs. In
contrast, the same manipulation had little effect on frequency tuning
in the ICC of decerebrate cats (Fig. 8A). Although our
observations are based on a small sample of units (n = 8), they show consistency within themselves and agree with a larger
body of data showing minimal effects of bicuculline on ILD functions in
the decerebrate cat (12/14 cases). In addition, the increases in
spontaneous activity (on average 80% over control; Fig. 8B)
and maximum driven rates (mean 80% over control; Fig. 8C)
that were observed during these experiments are consistent with the
known effects of bicuculline in a variety of species (chinchilla,
Palombi and Caspary 1996
; bat, Fuzessery and Hall
1996
; frog, Xu and Feng 1996
) and indicate that
an effective level of bicuculline reached its target sites.
Directionally dependent changes in excitatory bandwidth are likely to
impact the signal processing capabilities of ICC units. Type V units
are not influenced by ILD manipulations (in the ABI scheme); rather,
the threshold and tuning characteristics of these units are changed by
ITDs (Ramachandran and May 1999). Consequently type V
units likely are specialized to play a role in auditory behaviors
requiring faithful transmission of temporal information (Kuwada
and Yin 1983
; Yin et al. 1986
, 1987
) such as
sound source detection and location (Heffner and Heffner
1988
), processing motion of a sound source
(Spitzer and Semple 1993
), or detecting signals in noise
(Caird et al. 1991
; Jiang et al. 1997
;
McAlpine et al. 1996
).
Directional properties exhibited by type I and O units also may have
important implications for the neural representation of sounds that
occur at the same time but from different places. To illustrate this
process, consider as competing sound sources a narrowband auditory
signal near the contralateral ear and broadband environmental noise
near the ipsilateral ear. Our ILD experiments indicate that binaural
inhibitory interactions elicited by the spatially disparate noise
masker will decrease the excitatory bandwidths of ICC units that are
responding to the auditory signal in the contralateral ear. These
changes in filter shape will exert minimal effects on the processing of
the narrowband signal but will result in greater rejection of broadband
noise; consequently, signal-to-noise ratios will be enhanced. An
assumption implicit in this model is that the ipsilateral noise that
enters the contralateral ear will not suppress entirely the response to
the contralateral narrowband signal via activation of the inhibitory
sidebands in these units. In this regard, preliminary data indicates
that spatially disparate noise causes weaker masking effects than
cospatial noise (Ramachandran et al. 1997), consistent
with data obtained in frog ICC (Ratnam and Feng 1998
).
The ILD sensitivities of ICC units appear to be dominated by inputs
from lower-order nuclei. Because these data have been obtained in
decerebrate cats, however, descending influences have been eliminated.
There is a strong descending input that originates in primary auditory
cortex and terminates in the dorsal cortex of the IC (Coleman
and Clerici 1981); these descending influences may be
communicated to the ICC via GABAergic inhibitory projections (Moore et al. 1998
). When GABAA
inhibitory effects are modulated in decerebrate cats by local
administration of bicuculline, basic response characteristics do not
change; rather large increases in spontaneous activity and
stimulus-driven discharge rates are observed. On the basis of these
results, it is intriguing to speculate that descending inputs from
higher auditory centers might use inhibitory effects as attentional
filters for gating biologically important information in the ascending
auditory pathway. Such questions cannot be answered in the decerebrate
auditory system, but the binaural effects described by the present
study will provide a strong foundation for future studies of
single-unit responses in the ICC of intact, awake animals.
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ACKNOWLEDGMENTS |
---|
The authors thank E. D. Young for comments on an earlier version of the manuscript and A. Palmer and an anonymous reviewer for critical review of the paper. The authors thank P. P. Taylor for figure production.
This work was supported by the National Institute of Deafness and Other Communications Disorders Grant DC-00979.
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FOOTNOTES |
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Address for reprint requests: B. May, Dept. of Otolaryngology-HNS, Johns Hopkins University, 720 Rutland Ave./505 Traylor Research Bldg., Baltimore, MD 21205.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 19 October 1998; accepted in final form 23 March 1999.
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REFERENCES |
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