Department of Otolaryngology, University of California, San Francisco, California 94143-0526
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ABSTRACT |
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Vollmer, Maike,
Russell L. Snyder,
Patricia A. Leake,
Ralph E. Beitel,
Charlotte
M. Moore, and
Stephen J. Rebscher.
Temporal Properties of Chronic Cochlear Electrical Stimulation
Determine Temporal Resolution of Neurons in Cat Inferior Colliculus.
J. Neurophysiol. 82: 2883-2902, 1999.
As cochlear implants have become increasingly successful in the
rehabilitation of adults with profound hearing impairment, the number
of pediatric implant subjects has increased. We have developed an
animal model of congenital deafness and investigated the effect of
electrical stimulus frequency on the temporal resolution of central
neurons in the developing auditory system of deaf cats. Maximum
following frequencies (Fmax) and response latencies of isolated single
neurons to intracochlear electrical pulse trains (charge balanced,
constant current biphasic pulses) were recorded in the contralateral
inferior colliculus (IC) of two groups of neonatally deafened,
barbiturate-anesthetized cats: animals chronically stimulated with
low-frequency signals (80 Hz) and animals receiving chronic
high-frequency stimulation (
300 pps). The results were compared with
data from unstimulated, acutely deafened and implanted adult cats with
previously normal hearing (controls). Characteristic differences were
seen between the temporal response properties of neurons in the
external nucleus (ICX; ~16% of the recordings) and neurons in the
central nucleus (ICC; ~81% of all recordings) of the IC:
1) in all three experimental groups, neurons in the ICX
had significantly lower Fmax and longer response latencies than those
in the ICC. 2) Chronic electrical stimulation in
neonatally deafened cats altered the temporal resolution of neurons
exclusively in the ICC but not in the ICX. The magnitude of this effect
was dependent on the frequency of the chronic stimulation.
Specifically, low-frequency signals (30 pps, 80 pps) maintained the
temporal resolution of ICC neurons, whereas higher-frequency stimuli
significantly improved temporal resolution of ICC neurons (i.e., higher
Fmax and shorter response latencies) compared with neurons in control cats. Furthermore, Fmax and latencies to electrical stimuli were not
correlated with the tonotopic gradient of the ICC, and changes in
temporal resolution following chronic electrical stimulation occurred
uniformly throughout the entire ICC. In all three experimental groups,
increasing Fmax was correlated with shorter response latencies. The
results indicate that the temporal features of the chronically applied
electrical signals critically influence temporal processing of neurons
in the cochleotopically organized ICC. We suggest that such plastic
changes in temporal processing of central auditory neurons may
contribute to the intersubject variability and gradual improvements in
speech recognition performance observed in clinical studies of deaf
children using cochlear implants.
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INTRODUCTION |
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For >20 years cochlear implants (CIs) have been
used successfully in the rehabilitation of adult individuals with
profound sensorineural hearing loss. Most implant users demonstrate
gradual improvement in speech recognition with increasing (electrical) auditory experience (Cowan et al. 1993; Dorman et
al. 1990
; Dowell et al. 1992
; Waltzman et
al. 1992
; Zwolan 1995
), although the extent of
improvement varies markedly among subjects and among devices. Many CI
users, however, are able to understand open set speech without
additional visual cues (lip reading) (e.g., Dowell et al.
1986
; Doyle et al. 1991
; Schindler and
Kessler 1989
; Spivak and Waltzman 1990
;
Wilson et al. 1991
).
Because of the substantial benefits seen in adult CI subjects and
improvements in CI technology, the number of pediatric implant subjects
(including very young and congenitally deaf children) has increased
dramatically over the past 10 years. An important rationale for the
implantation of young children is based on data suggesting that the
acquisition of speech and language in humans has a critical period
(Eggermont and Bock 1986; Ruben and Rapin 1980
) occurring within the first few years of life. According to this view, earlier and more extensive auditory deprivation produces
greater deficits in speech and language acquisition. The greatest
deficits are observed when hearing loss occurs around birth with
diminishing consequences if impairment occurs toward the end of the
second year (Ruben 1986
). In addition, the hypothesis of
a critical period for auditory system development is supported by a
number of animal studies suggesting that auditory deprivation during
the early postnatal period induces more profound degeneration (Blatchley et al. 1983
; Coleman and O'Connor
1979
; Coleman et al. 1982
; Evans et al.
1983
; Trune 1982
; Webster 1983
,
1988
; Webster and Webster 1977
, 1979
) and
reorganization in the developing auditory system (Harrison et
al. 1993
, 1996
; Kitzes 1996
; Knudsen et
al. 1984
; Moore and Kitzes 1985
; Moore
and Kowalchuk 1988
; Nordeen et al. 1983
;
Rubel et al. 1984
; Silverman and Clopton
1977
).
There is some evidence indicating that early chronic electrical
stimulation of the developing auditory system can ameliorate or prevent
some of the detrimental effects of auditory deprivation. For example, a
number of quantitative histological studies in animals have shown that
chronic intracochlear electrical stimulation delays or prevents the
degeneration of spiral ganglion cells that occurs after deafness
(Hartshorn et al. 1991; Leake and Snyder 1994
; Leake et al. 1991
, 1992
, 1995
,
1999
; Lousteau 1987
) and ameliorates
degenerative changes in the cochlear nucleus resulting from deafness
(Lustig et al. 1994
; Matsushima et al.
1991
). In addition, clinical studies in young deaf children
have shown a trend for better performance in children implanted at an
earlier age. Children implanted <4-6 yr of age demonstrate better
speech discrimination performance than those implanted at an older age (Osberger 1995
). These findings suggest that the
immature auditory system might be more adaptable to or better able to
interpret the electrical information provided by CIs. However,
relatively little is known about the encoding of electrical stimuli in
the central auditory system. Moreover, even less is known about the functional consequences of this highly artificial stimulation on the
developing auditory system and potential changes in signal processing
which may underlie individual differences and gradual changes in speech
discrimination performance in young CI subjects.
It is widely accepted that the temporal properties of the electrical
stimulation pattern play a critical role in the transfer of information
that enables CI subjects to recognize and discriminate speech.
Moreover, it has been suggested that temporal resolution is critical
for the perception of temporal pitch, prosody, and speech
(Eddington et al. 1978; Shannon 1983
, 1985
,
1992
; Townsend et al. 1987
; Wilson et al.
1991
). These observations suggest that the manner in which
central auditory neurons encode the temporal information of the
electrical stimulus is a particularly important aspect of the
physiological response that may provide specific clues as to how
experience with electrical stimulation affects central auditory processing.
To address these issues, the present study has focused on the temporal response properties of IC neurons in an animal model of congenital or early acquired bilateral deafness. Neonatally deafened animals were implanted with a round window or scala tympani electrode and chronically stimulated. After chronic stimulation, each animal was anesthetized, and the contralateral IC was mapped using tungsten microelectrodes. In these acute electrophysiological studies, the temporal resolution of single neurons was estimated by quantifying the onset latencies and the ability of IC neurons to follow repetitive signals (pulse trains of increasing frequency). The shorter the latencies and the higher the repetition rate that a neuron can follow (Fmax), the greater is its temporal resolution.
In a previous report Snyder and colleagues (1995)
investigated the ability of IC neurons to follow electrical pulse
trains of increasing frequency. They demonstrated that 1)
the temporal resolution of IC neurons responding to electrical
stimulation was comparable with that observed with acoustic
stimulation, 2) the maximum frequency following rates of IC
neurons to electrical signals are within the range of the
psychophysically estimated temporal resolution of normal hearing and
cochlear implant subjects, and 3) the temporal response
properties of IC neurons were only marginally decreased by complete
auditory deprivation, but temporal resolution was significantly
enhanced by chronic electrical stimulation of the developing auditory system.
The present study extends the investigations of Snyder and colleagues
and focuses on three important additional objectives: first, previous
(acoustic and electrical) studies of temporal resolution in the IC
either did not distinguish between the responses of external nucleus
(ICX) versus central nucleus (ICC) neurons (Snyder et al.
1995) or were focused exclusively on the response properties of
neurons in the ICC (e.g., Langner and Schreiner 1988
).
In view of differences in the physiological response properties between
ICX and ICC neurons (e.g., Aitkin et al. 1975
, 1994
), an
important goal of the present study was to characterize the temporal
response properties of neurons separately for the two nuclei.
Second, from previous studies it is not clear whether the capacity of
the developing auditory system for functional plasticity to electrical
stimuli is dependent on the frequency of the peripheral stimulation.
Because newer CI speech processing strategies use increasingly higher
stimulation rates, a major focus of the present study was to
investigate the effect of chronic stimulation using electrical signals
with different temporal characteristics (e.g., low-frequency
unmodulated pulse trains vs. higher-frequency amplitude-modulated pulse
trains) on the temporal resolution of IC neurons. One hypothesis addressed was that higher stimulus frequencies (300 pps) were temporally more challenging for the auditory system and would result in
increased temporal resolution of IC neurons.
A third objective of the present study was to determine whether Fmax
and response latencies of IC neurons are related systematically to the
tonotopic frequency organization. Acoustic studies have shown that the
characteristic frequencies (CF) of ICX neurons are usually easy to
define although units are broadly tuned (e.g., Aitkin
1978). However, there is only a vague indication in the published literature that the CF of ICX neurons are tonotopically organized (Aitkin et al. 1994
; Binns et al.
1992
). In contrast, it is well known that the ICC exhibits a
precise cochleotopic frequency gradient that is related systematically
to ICC depth in normal hearing cats (e.g., Brown et al.
1997
; Merzenich and Reid 1974
; Oliver
1987
; Oliver and Morest 1984
; Rose et al.
1966
). ICC depth also is related systematically to the
intracochlear electrode location in deafened, implanted cats
(Snyder et al. 1990
, 1991
, 1995
). An hypothesis
addressed in the present study is that chronic stimulation primarily
affects neurons in the high-frequency region of the central nucleus,
i.e., neurons that normally encode higher-frequency auditory
signals (Snyder et al. 1995
). Alternatively, electrical
stimulation might alter responses uniformly in the entire population of
neurons throughout the ICC.
The systematic characterization of changes in the temporal response properties of IC neurons after chronic electrical stimulation should provide a better understanding of the efficacy of this highly artificial mode of stimulation to modify signal processing capacity and the overall functional status of the developing auditory system.
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METHODS |
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Deafening, implantation, chronic stimulation
Experiments were conducted in 29 adult cats: Fifteen animals were neonatally deafened and chronically stimulated ("stimulated cats"). Fourteen cats were acutely deafened, previously normal adults that served as control animals. These animals were deafened and implanted on average 2 wk before the final electrophysiological experiment.
Procedures of deafening, implantation, chronic stimulation, surgical
preparation, and recording techniques in the physiological experiment
have been described in detail in previous reports (Snyder 1990,
1991
, 1995
). All procedures followed National Institutes of
Health guidelines for care and use of laboratory animals.
To briefly summarize: kittens were deafened neonatally by
daily intramuscular injections of neomycin sulfate at a dosage of 50-60 mg/kg body wt beginning 24 h after birth and continuing for
a total of 16-25 days (Table 1). It is
reported that acoustic thresholds in kittens at 1 wk postnatally are
~120 dB, subsequently improving ~10 dB per day and achieving
adult-like levels at ~20 days postnatally (Brugge
1992; Walsh and McGee 1986
). At 16-18 days of
age, auditory brain stem responses (ABRs) to clicks (200 µs/ph, 20 pps) and 500-Hz tone-evoked frequency following responses (FFR) were
measured under ketamine/acepromazine tranquilization. Profound hearing
loss was confirmed by the absence of responses to both stimulus
conditions up to equipment limits (~108 dB SPL). If acoustically
evoked responses still were present, the administration of neomycin was
continued until 21 days postnatally, when thresholds for these animals
were reassessed. None of the animals included in this study had
evidence of residual hearing at 21 days with the exception of a single
animal (K99), which received 25 days of neomycin before
becoming profoundly deaf (Table 1). At ~6-9 wk of age, acoustic
thresholds were again measured before implantation to assure that
hearing had not recovered.
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Normal adult cats were deafened 2-3 wk before implantation
by a single subcutaneous injection of kanamycin monosulfate (400 mg/kg)
followed by a subcutaneous injection of aminooxyacetic acid (25 mg/kg).
ABRs and FFRs were monitored for ~2-3 h after deafening until
thresholds were >108 dB SPL (Leake et al.
1987). Before all surgical procedures the animals were
sedated with an intramuscular injection of ketamine (22-33 mg/kg) in
combination with acepromazine maleate (0.1 mg/kg) or midazolam
(0.06-0.22 mg/kg). An intravenous catheter was inserted through the
cephalic vein and anesthesia was induced with pentobarbital sodium
(7-10 mg/kg iv). The anesthesia was maintained at a surgical areflexic level with supplementary intravenous infusion of pentobarbital sodium
(2-6 mg · kg
1 · h
1 ) in
Ringer solution.
Implantation of the electrode arrays was performed under strict aseptic
conditions. For stimulation, either specially designed intracochlear
electrodes (Rebscher 1985; Rebscher et al.
1988
) or a single wire electrode at the round window were used.
The intracochlear electrodes consisted of four Teflon-coated
platinum-iridium (90-10%) wires, embedded in a cylindrical silicone
rubber (Silastic) carrier. Each wire terminated in a ball-shaped
contact 200-300 µm in diameter. The four wires of the intracochlear
electrode were arranged as two offset-radial pairs. The electrodes of
each pair were separated by 1 mm. The implants were inserted through the round window into the scala tympani of the left cochlea. The cochleae of the chronically stimulated animals (n = 12, excluding the cats with monopolar round window electrodes and
K62) were studied histologically in surface preparations
(Leake et al. 1999
). The length of the basilar membrane
was measured (average length = 23.9 mm), and the precise position
of intracochlear electrodes determined. The depth of electrode
insertion along the basilar membrane varied among animals. The position
of the most apical electrode 1 ranged from a minimum of
37% from the cochlear base in K91 (equivalent to a
represented frequency of ~9.2 kHz) (Liberman 1982
) to
a maximum of 55% in K98 (equivalent to 3.6 kHz). The average position for electrode 1 was 44% from the
cochlear base which is equivalent to 6.4 kHz. The position of the most
basal electrode 4 ranged from 29 to 21% from the base,
equivalent to 13.7 and 20.4 kHz, respectively. The average insertion
depth of electrode 4 was at 23%, which is equivalent to
6.5 mm or 16.1 kHz. Chronic stimulation of the neonatally deafened cats
was delivered by the apical electrode pair 1,2.
A monopolar round window electrode was used for chronic stimulation in two animals (K71 and K76) and consisted of a single Teflon-coated platinum-iridium wire ending in a 400-µm ball-shaped contact near the round window. The reference contact for this monopolar electrode was an identical electrode located beneath the temporalis muscle. During the acute physiological experiment the monopolar electrode was replaced by an intracochlear implant to allow the recordings of responses to intracochlear stimulation.
Chronic stimulation of the animals was delivered 4 h/day, 5 day/wk for
periods of 9-46 wk until 1-3 days before the acute electrophysiological study. To study the effects of temporally different stimuli on the temporal resolution of IC neurons, the chronically stimulated animals were divided into "low"- and
"high"-frequency stimulation groups. The choice of the stimulus
frequencies for each group was based on previous studies with acoustic
and electrical stimulation of the cochlea that have shown that the
majority of IC neurons followed stimulus frequencies up to ~100 Hz
(e.g., Batra et al. 1989; Langner and Schreiner
1988
; Snyder et al. 1995
), and only a small
percentage of neurons followed frequencies up to or >300 Hz (e.g.,
Batra et al. 1989
; Rees and Møller 1987
; Snyder et al. 1995
). Therefore the group of
low-frequency-stimulated animals (n = 5) was
stimulated chronically with unmodulated pulse trains of 30 or 80 pps,
i.e., with frequencies that are well below the average maximum
following rate of IC neurons (~100 pps). All stimuli were
capacitively coupled, charge balanced, biphasic square-wave pulses (0.2 ms/phase), and the intensity was set at 2 dB above the electrically
evoked auditory brain stem response (EABR) threshold. The duration of
chronic stimulation for these animals was on average 16.2 ± 5.9 (SD) wk. During the period of chronic stimulation, one animal in this
group (K83) received additional behavioral training with
low-frequency signals (80 pps). Behavioral training (cf. Beitel et al.
1999
) was performed once per day, 5 day/wk for a period of 3.5 wk. The
total duration of suprathreshold stimulation per training session
was on average ~20 s and therefore very short compared with the
duration of chronic (passive) stimulation (4 h/day).
The group of animals with higher-frequency stimulation (n = 10) was stimulated chronically with frequencies at or above the previously estimated maximum frequency following capacity of IC neurons (~300 pps). This group included five animals that received chronic stimulation with 100% sinusoidally amplitude modulated pulse trains (300 pps carrier/30 Hz AM; Table 1). The other five animals in the higher-frequency group were stimulated chronically with an analogue processor that transduced environmental sounds. The frequency spectrum of the analogue stimulation was band-pass filtered from 250 Hz to 3 kHz with a roll-off at the shoulder frequencies of 6 dB/octave. The analogue waveforms were logarithmically amplitude compressed and adjusted to a maximum intensity output of 6 dB above EABR threshold. The average duration of stimulation in the high-frequency group was 32.9 ± 7.3 (SD) weeks. The majority of animals in this group (n = 7) also received behavioral training with unmodulated pulsatile stimuli between 2 and 1,000 pps and/or with AM pulse trains (carrier frequency: 100-500 pps, modulation frequency: 8-30 Hz). The periods of behavioral training for these animals ranged between 5 wk (K91) and 26.6 wk (K86). Again, with an average suprathreshold stimulus duration of ~20 s per training session (1 training session/day, 5 day/wk), the stimulation during the behavioral training was very limited as compared with the chronic passive stimulation (4 h/day at suprathreshold level).
All stimuli were delivered using an optically isolated, constant
current stimulator (Vureck et al. 1981). EABRs were
determined after implantation and consecutively at intervals of 3-4
wk, and the stimulus level was adjusted if necessary. The stimulation histories of all cats are presented in detail in Table 1.
Acute electrophysiological experiment
Anesthesia was induced with ketamine/acepromazine and maintained with pentobarbital sodium (see Deafening, implantation, chronic stimulation). During the entire final physiological experiment, the cats regularly received dexamethasone sodium phosphate (1 mg/kg every 12 h sc) and mannitol (1-2 g/kg iv, as required) to prevent brain edema, atropine (0.045 mg/kg every 12 h sc) to decrease salivation, and prophylactic antibiotics (cefazolin 22-33 mg/kg every 8 h sc). The temperature of the animal was monitored continuously with a rectal temperature probe and kept constant at 37.5°C by a feedback-controlled heating water blanket. Reflexes were tested regularly, and oxygen saturation and heart rate were monitored continuously.
After sedation, the animals head was stabilized in a mouth bar head holder (KOPF). The right temporalis muscle was reflected, and a craniotomy was performed in the right parietal bone just anterior to the tentorium. The occipital cortex was aspirated, and an opening was made in the tentorium to provide access to the dorsal and dorsolateral surface of the right inferior colliculus.
Parylene-coated tungsten microelectrodes (impedances of 0.8-1.5 M
at 1 kHz) were used to record neuronal responses from single IC
neurons. To minimize electrical artifact, the responses were recorded
differentially using two microelectrodes matched in impedance. The
reference electrode was positioned in the surrounding tissue (e.g., in
the cerebellum or the cerebrospinal fluid), and the active recording
electrode was mounted on a remotely controlled hydraulic microdrive
(KOPF), which was held in a micromanipulator. The trajectory of the
recording electrode was in the coronal plane and tilted laterally at an
angle of ~45° from the vertical plane. The electrode was advanced
in the IC from dorsolateral to ventromedial orthogonal to the
orientation of the cochleotopically arranged isofrequency laminae
(Brown et al. 1997
; Oliver and Morest
1984
). On this axis, the electrode passed through the full
range of frequencies represented in the IC. Moreover, penetration depth
corresponded to relative CF (Rose et al. 1966
), with low
frequencies represented most superficially within the central nucleus
of the IC and progressively higher frequencies at progressively deeper sites.
Single-neuron responses were recorded at any location along the penetration where they could be isolated. Neural activity was band-pass filtered (10 Hz to 10 kHz) and amplified (total amplification: 100,000 times) using a battery-powered preamplifier (DAM 50) and a second-stage amplifier (Tektronix 3A90). The activity was displayed on an oscilloscope (Tektronix 565). Spike activity was isolated from background noise and artifact with a window discriminator (BAK-DIS-1). The number of spikes and the time of occurrence of each response after the stimulus onset were stored in an IBM PC and displayed on a monitor.
Biphasic square-wave pulses of nonalternating polarity were used as a search stimulus to isolate single neurons. Threshold levels for single neuron responses to pulses (0.2 ms/ph, 3-10 pps) were determined audiovisually. The stimulus intensity then was set at 2-6 dB above threshold, and single-neuron responses to pulse trains of increasing frequency (beginning at 10 pps, increments between 5 and 20 pps) were recorded until the neuron responded to the stimulus with only an onset response. The duration of the recording window was 320 ms after stimulus onset followed by an interstimulus interval of 1,000 ms. Responses were collected for 20 repetitions of each stimulus condition, and poststimulus time histograms (PSTHs, Fig. 2) were constructed (binwidth 33.3 µm) during the recording.
For each isolated neuron, the maximum stimulus frequency to which the
neuron responded in a synchronized manner was determined. This was
accomplished by constructing period histograms for the entire recording
window (320 ms) excluding the onset response and determining whether
the phase locked response at a given stimulus frequency was significant
(P < 0.01, Rayleigh test) (Mardia
1972). Neurons with maximum following frequencies <10 pps were
excluded from this study. In addition, first spike latencies were
measured using stimuli of 20 pps. Neurons with latencies <4.5 ms were
excluded from further analysis because their responses could be
confused with the synchronized afferent input.
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RESULTS |
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The primary goal of the following analyses is to compare the
effects of low-frequency (30 pps, 80 pps) and temporally challenging higher-frequency (300 pps) stimulation on the temporal resolution (maximum following frequencies, first-spike response latencies) of IC
neurons. In addition, neurons were classified as belonging to either
the ICX or the ICC, and the differences in temporal response
characteristics of the two nuclei are described.
Differentiation of ICX and ICC recording locations
To relate the temporal response properties of IC neurons to a
given subdivision of the IC, minimum response threshold levels for
three cycles of a 100-Hz sinusoidal signal (Kiang and Moxon 1972) and for pulses (0.2 ms/ph, 3-10 pps) were determined for either single- or multiple-neuron responses at intervals of 100 µm
along each penetration. Thresholds were plotted as a function of IC
depth to obtain a spatial tuning curve (STC) (Snyder et al.
1990
) (Fig. 1). A typical spatial
tuning curve has a W-shape with two locations of minimum threshold, one
for the ICX and a second minimum for the ICC. The location of minimum
threshold in the central nucleus is referred to as best location (BL).
It defines the location of maximum sensitivity for the stimulating electrode or electrode pair and is related systematically to the cochleotopic frequency gradient of the ICC, i.e., increasing
penetration depth corresponds to increasingly higher CF and to more
basal intracochlear electrode locations in deaf implanted animals
(Snyder et al. 1990
, 1991
). The high-threshold region
between the two locations of minimum threshold provides an indication
of the border between the two nuclei and allows neurons to be assigned
to either ICX or ICC.
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Because of the differences in charge per phase of the 100-Hz sinusoidal (5 ms/ph) and pulsatile (0.2 ms/ph) signals, STCs obtained with sinusoidal stimuli generally had lower thresholds, markedly sharper tuning, and greater dynamic range than those obtained with pulses. In fact, in a number of penetrations the tuning curves for pulses were so broad or flat that they did not allow a precise definition of the border between the two nuclei. However, in those penetrations in which the STCs for pulses were tuned sufficiently to determine the border between ICX and ICC, the location of the border was always identical or close to that defined by the sinusoidal STC. Therefore, the borders between ICX and ICC generally were determined by STCs for sinusoidal stimuli.
For each group of animals, the ranges of recording depths for both ICX and ICC neurons were documented. Neurons from penetrations in which STCs were incomplete or that did not allow a clear definition of the border between the two nuclei were assigned as ICX or ICC neurons if their recording location fell into the nonoverlapping depth range of either nucleus calculated for the given animal group. Neurons not meeting this criterion were excluded from the analyses. For example, in complete STCs from control animals the recording depths for ICX neurons ranged from 300 to 1,880 µm and for ICC neurons, from 1,355 to 5,500 µm. Subsequently, neurons from incomplete STCs were included as ICX neurons if their recording depth was <1,354 µm and included as ICC neurons if their recording location was >1,881 µm. Neurons recorded between 1,355 and 1,880 µm were not assigned to either nucleus and were excluded from the analyses.
Maximum following frequencies (Fmax)
Figure 2 illustrates examples of
PSTHs reconstructed for two single neurons responding to intracochlear
electrical stimulation with pulse trains (0.2 ms/ph, biphasic pulses)
of increasing frequencies. The number of spikes per pulse (normalized
spike rate) and the vector strength are noted at the top
right of each histogram. The frequency was increased stepwise, and
responses were recorded until each neuron ceased to respond to the
sustained stimulus or produced only an onset response. Period
histograms were used to determine the phase locking capacities of
neurons to given frequencies. The maximum frequency to which the
neurons responded in a synchronized manner (P < 0.01)
was assessed and referred to as the maximum following frequency (Fmax).
Figure 2A shows the responses of a neuron with low temporal
resolution. Fmax of this neuron was ~35 pps; it responded only to the
onset of the stimulus at higher frequencies (50 pps). In contrast,
Fig. 2B illustrates an example of a neuron with high
temporal resolution. It clearly responds vigorously at much higher
pulse rates, and the Fmax of this neuron was ~320 pps.
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In the present study, the responses of 676 single neurons to pulse trains of increasing frequencies were recorded in the IC of 29 cats. Fmax for a total of 254 neurons were determined in 14 control animals, Fmax for 104 neurons were studied in 5 animals that had been stimulated chronically with low-frequency signals, and Fmax for 296 neurons were evaluated in 10 animals that had been stimulated with high-frequency signals. As assessed by the spatial tuning curves constructed for each penetration (Fig. 1), ~16% of all recording sites (a total of 108 single neurons) were located in the ICX, and ~81% (a total of 546 single neurons) were located in the ICC. In total, 22 neurons (~3% of the number recorded) were excluded from this analysis because they could not be classified as either ICX or ICC neurons.
QUANTITATIVE DISTRIBUTION OF FMAX.
The means and standard deviations of Fmax estimated for the individual
animals within each group are presented in Table
2. Figure
3 illustrates the distributions of
Fmax of all IC neurons for the three experimental groups.
Separate distributions are shown for neurons in the ICX () and those
in the ICC (
). In each histogram, the mean Fmax for the two nuclei
is indicated (
). The statistical comparisons of mean Fmax for the
different experimental groups and the two nuclei (t-test)
are summarized in Table 3.
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TOPOGRAPHIC DISTRIBUTION OF FMAX. An additional purpose of the present study was to determine whether the distribution of Fmax is related to the tonotopic frequency representation of the IC and whether changes in temporal resolution following chronic electrical stimulation occur preferentially in specific regions of the ICC.
The spatial distributions of Fmax relative to the border between ICX and ICC are shown in Fig. 4 for single neurons from the three experimental groups. The numbers of neurons are smaller than in Fig. 3 because some neurons for which the nucleus could be classified but the depth of the border between the nuclei could not be determined precisely were excluded. The recording locations of all single neurons were normalized to the border between ICX and ICC for each penetration. The border is marked in each graph (- - -).
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Response onset latencies
QUANTITATIVE DISTRIBUTION OF ONSET LATENCIES. Onset latencies were determined in a total of 698 single neurons in response to 20-pps pulse trains presented at an average of 4 dB above threshold. About 16% (110 neurons) of the first spike latencies were recorded in the ICX, and ~81% (564 neurons) of the latencies were recorded in the ICC. Latencies for a total of 262 neurons were determined in control animals; latencies for 110 neurons were determined in low-frequency-stimulated animals; and latencies for 302 neurons were evaluated in animals that received chronic high-frequency stimulation. About 3% of all response latencies (24 neurons) were excluded from the study because it was not possible to classify the recording location as ICX or ICC.
Because latencies are typically not normally distributed, the central tendency of the data is expressed best by the median response latency. Table 4 shows the medians and quartile deviations (Q) of latencies for the individual animals within each group. The distributions of all onset latencies for the three animal groups are illustrated in Fig. 6. Onset latencies of neurons in the ICX (
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TOPOGRAPHIC DISTRIBUTION OF ONSET LATENCIES.
The distribution of latencies along IC depth (i.e., CF gradient) also
was investigated. In Fig. 7 onset latencies of ICX () and ICC (
)
neuron responses to pulse trains of 20 pps are plotted as a function of
normalized depth (depth at border = 0 µm) for the three
experimental groups. The number of ICX and ICC neurons in each group is
smaller than in Fig. 6 because only neurons for which the border
between the two nuclei could be determined unambiguously were included.
The border between ICX and ICC is marked (- - -). The range of
recording locations fell between
1485 and 4,200 µm re border.
Recordings from both extreme locations were achieved in the
high-frequency group, for which the majority of data were collected.
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Covariation of Fmax and response latency
In normal hearing cats, Langner et al. (1987) described onset
latencies of IC neurons responding to amplitude modulated tones as
being significantly correlated with the best modulation frequency (modulation frequency with the strongest neuronal response; BMF) using
an equation based on a multiple linear regression analysis [onset
latency = (7.1 ± 0.9) ms + (1.2 ± 0.2) · 1/CF + (0.16 ± 0.03) · 1/BMF]. In contrast to acoustic stimulation,
electrical pulses have an instantaneous onset and are independent of
any cochlear delays. Therefore Snyder et al. (1995)
modified the equation for electrical stimulation by reducing the
asymptotic value for latency from 7.1 to 5.1 ms. This correction
accounts for the on-ramp of the acoustic signal and a number of
cochlear delays including conduction delay, travel time delay,
transduction delay, and synaptic transmission delay (Ruggero and
Rich 1987
). Further, Snyder and colleagues replaced the period
of the BMF by the period of Fmax (see equation at bottom
of Fig. 9C). Using this
modified equation for electrical stimulation, they found a modest
correlation between onset latencies and Fmax for IC neurons responding
to intracochlear electrical stimulation with pulse trains in acutely
deafened adult cats.
|
Figure 9 shows the relationships between onset latencies and Fmax
(plotted on a logarithmic scale) for ICX and ICC neurons in the three
experimental groups investigated in the present paper. The curves in
each graph encompass onset latencies predicted by the modified equation
(Fig. 9C, bottom): top
curves predict the latencies for neurons with a CF of 2 kHz (equivalent to a cochlear position of 66% or 16.5 mm from the
cochlear base) (Liberman 1982) and the variables in the
equation set to a maximum. Bottom curves approximate the latencies for neurons with a CF of 60 kHz (representing nerve fibers at the cochlear base) and the variables set to a minimum.
The frequency values of the curves were selected to broadly encompass
the regions along the spiral ganglion that might be activated by
electrical stimulation with pulsatile stimuli in the present
experiments. As illustrated in Fig. 1, chronic stimulus levels set at 2 dB above EABR thresholds for electrical pulses often appear to activate
neurons over a relatively broad range of frequencies. A CF of 2 kHz
(equivalent to 66% of the average 23.9 mm basilar membrane, see
METHODS) was chosen for the upper limit curve to encompass
frequencies that might be excited by a spread of current generated by
the apical electrode pair with a maximum insertion depth of
electrode 1 at 55% of the basilar membrane (equivalent
to 3.6 kHz) and stimulus intensities of 2-6 dB above single IC neuron
threshold. A CF of 60 kHz (corresponding to the basal extreme of the
basilar membrane) was selected for the bottom limit curves to fully
encompass frequencies that might be excited by an electrical field
generated by the basal electrode pair with a minimum insertion depth of
electrode 4 at 21% (equivalent to 20.5 kHz) based on
the assumption that the 60-kHz location might be activated due to the
compression of the frequency map of the spiral ganglion at the cochlear
base (Keithley and Cronin-Schreiber 1987
).
Although there were some outlying data points, the majority of both ICX
and ICC neurons in each group fell into the predicted range of
latencies. These observations suggest that 1) for
intracochlear electrical stimulation onset latencies were correlated
inversely with the Fmax of neurons both in the ICX and the ICC, i.e.,
neurons with higher stimulus following rates demonstrated shorter
response latencies, and that 2) this correlation was
maintained despite characteristic changes in the temporal resolution of
IC neurons following chronic low- and high-frequency stimulation. Thus
the present results may reflect the existence of intrinsic coding mechanisms in the temporal processing of periodic signals in central auditory neurons (Langner et al. 1987; Snyder et
al. 1991
, 1995
).
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DISCUSSION |
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Frequency following to acoustic and electrical stimulation
Previous electrophysiological studies have compared the responses
of single neurons to acoustic and electrical stimulation and have
reported similar temporal resolution of IC neurons to both stimulus
conditions. Using acoustic signals, temporal resolution has been
determined in different species by analyzing the ability of single- and
multiple-IC neurons to follow fluctuations in the envelope of
amplitude-modulated tones or broadband noise (Batra et al.
1989; Langner and Schreiner 1988
; Rees
and Møller 1983
, 1987
; Rees and Palmer 1989
;
Schreiner and Langner 1988
). Most relevant to the
present investigation are acoustic studies in cats by Langner
and Schreiner (1988)
, who used amplitude-modulated tones to
determine the BMF of single- and multiple-neuron responses in the central nucleus of the IC. The upper limit of BMFs
reported by Langner and Schreiner exceeded the upper limit of Fmax
observed in the present study: ~8% of the recordings had BMFs >300
Hz including rare examples of responses with BMFs as high as ~1,000
Hz. In comparison, in the present study <1% of all IC neurons from
control animals had Fmax >300 pps, and the highest Fmax was
330 pps. It should be noted, however, that most of the high BMFs (>300
Hz) reported by Langner and Schreiner (1988)
were
derived from multiple-neuron recordings, whereas the present study was
limited to well-isolated single neurons. Further, Langner and Schreiner
suggested that neurons with high BMFs may be harder to isolate than
low-frequency neurons perhaps due to morphological differences. It is
also possible that the recorded high BMFs predominantly originate from
afferent or input fibers rather than from central nucleus neurons per
se (Langner and Schreiner 1988
). On the other hand, for
>80% of the recording locations, Langner and Schreiner reported BMFs
<120 Hz. These data are in close agreement with the present study and confirm the finding that the great majority of neurons preferentially followed modulation frequencies well below those found in the auditory
nerve (e.g., Evans 1978
; Hartmann and Klinke
1989
; Javel 1980
; Joris and Yin
1992
; Palmer 1982
) or the cochlear nucleus (Gersuni and Vartanyan 1973
; Møller 1972
, 1974
,
1976
; Nelson et al. 1966
; Vartanyan
1969
).
In fact, most of the acoustic studies in mammals have described BMFs in
IC neurons that were comparable with the Fmax observed in the present
study: Rees and Møller (1987) reported that for IC
neurons in rats the most effective modulation frequencies were between
100 and 120 Hz, and the highest maximum following frequency they
recorded was 320 Hz. Batra et al. (1989)
recorded
single- and multiple-neuron responses to amplitude-modulated tones in normal hearing unanesthetized rabbits and measured an average BMF of 87 Hz and a maximum BMF of 250 Hz.
In a previous study, Snyder et al. (1995) examined the
temporal resolution of IC neurons in cats using electrical cochlear stimulation. They found that Fmax in "normal," acutely deafened adult animals ranged from 10 to 340 pps with an average of 93 pps. In
the present study, Fmax of all IC neurons from control cats was
virtually identical, ranging from 10 to 330 pps with an average
temporal resolution of 97 pps.
In summary, despite the different stimulus conditions (acoustic vs. electrical stimulation), different animal species and different criteria used for the determination of temporal resolution (BMF vs. Fmax), similar estimates of temporal resolution of IC neurons are reported for both acoustic and electrical stimulation, and most estimates are clearly below the frequency following capacity of the auditory nerve.
Effects of chronic stimulus frequency on Fmax
The main goal of this study was to examine the effect of
temporally different types of chronic electrical stimuli on the
temporal resolution of IC neurons. The selection of the specific
signals for chronic stimulation was based on earlier acoustic and
electrical studies of the temporal resolution of IC neurons. As
mentioned in the preceding text, most studies report an average
frequency following of IC neurons in normal cats of ~100 pps and a
maximum frequency following of ~300 pps. In respect to these
findings, animals chronically stimulated with frequencies below the
average frequency following capacity of IC neurons (<100 pps)
therefore were categorized as the "low-frequency stimulation"
group. This group included animals stimulated with continuous
unmodulated pulse trains at 30 or 80 pps. Animals chronically
stimulated with frequencies around or above the maximum frequency
following capacity of IC neurons (300 pps) were categorized as the
temporally challenging, "high-frequency stimulation" group. This
group included animals stimulated with continuous 300 pps/30 Hz AM
signals and those stimulated with an analogue speech processor (SP;
band-passed filtered 250 Hz to 3 kHz). Besides the higher frequency
components of these signals, one rationale for combining the results
from both AM and SP stimulated animals was that Fmax of neither ICX nor
ICC neurons varied significantly among the two populations. Another
rationale for the selection of 300 pps/30 Hz AM and analogue SP was to
model speech processing strategies that are currently used in human CI
subjects. Specifically, stimulation with 300 pps/30 Hz AM modeled
speech processing strategies that employ higher-frequency,
amplitude-modulated pulsatile stimulation (CIS, MSPEAK, SMSP)
(e.g., McDermott et al. 1992
, Wilson et al.
1991
); and stimulation with the analogue speech processor
modeled the analogue waveform used in compressed analogue (CA) speech
processing strategies.
The present study has shown that chronic stimulation of neonatally deafened cats resulted in marked alterations in the frequency following capacity (Fmax) of neurons in the auditory midbrain. The magnitude of this effect was related to two specific factors: 1) the frequency of the chronically applied electrical signal critically influenced the temporal responses of IC neurons. That is, low frequency stimulation maintained the normal frequency following capacities of neurons; in contrast, high-frequency stimulation markedly enhanced the temporal resolution of IC neurons. 2) However, significant changes in temporal resolution following chronic electrical stimulation were observed only for neurons in the ICC and not for neurons located in the ICX.
Snyder et al. (1995) previously reported a significant
increase in temporal resolution in IC neurons from chronically
stimulated animals as compared with normal control cats. As stated in
the preceding text, they estimated a mean Fmax of 93.2 pps (range 10-340 pps) in control animals, whereas in stimulated animals, they
reported an increase in average Fmax to 139.5 pps (range 10-710 pps).
This increase in average Fmax is comparable with the average frequency
following capacity of ICC neurons from high-frequency stimulated
animals of the present report (134.2 pps). However, Snyder et al. did
not distinguish between low- and higher-frequency stimulated animals:
four of the six stimulated cats included in this previous study had a
history of low-frequency stimulation (30 or 80 pps), one cat received
high-frequency stimulation with an analogue processor, and another cat
(K90) received chronic passive stimulation with 30 pps
followed by extensive behavioral training with predominantly 100-Hz
sinusoidal stimuli. Moreover, responses from both ICX and ICC neurons
were included in the estimates. Both of these conditions would suggest
that Fmax should have been lower than in the present observations.
Instead, IC neurons from stimulated animals reported by Snyder
et al. (1995)
had higher average and peak Fmax than
corresponding measures in the present study (low-frequency group: mean
Fmax for all IC neurons = 103 pps, range = 10-250 pps;
high-frequency group: mean Fmax for all IC neurons = 119 pps,
range = 10-324 pps). The individual variation of frequency
following among the animals included in Snyder et al.
(1995)
might have contributed to this difference. One of their animals (K90) demonstrated an average Fmax for all IC neurons (166 pps)
that markedly exceeded the average following capacities of IC neurons
in high-frequency stimulated cats reported in the present study (119 pps). Thus given the limited number of animals (n = 6)
in their group of combined low- and
high-frequency-stimulated animals, this animal clearly increased the
average temporal resolution of neurons reported by Snyder and
colleagues. In addition, one animal of the present study
(K98) failed to show increased temporal resolution following
higher frequency stimulation. In fact, the average Fmax of this animal
for ICC neurons (82.9 pps; Table 2) was well below that of control
animals (101.6 pps) and thus reduced the average Fmax for IC neurons in
the higher-frequency group. Review of the stimulation history revealed
no features that might explain the low temporal resolution of this
animal. Although we have emphasized the role of stimulus rate, further
investigations are required to understand any additional factors (e.g.,
stimulus waveform complexity, behavioral training) that may contribute to the variability in temporal resolution among individual animals.
The mechanism(s) underlying the observed changes in temporal resolution
of ICC neurons following chronic high-frequency stimulation are not
known. On the basis of studies using acoustic stimulation, it has been
proposed that the duration of inhibition for cortical neurons is
directly related to the period of the BMF (Eggermont 1992; Krueger and Schreiner 1994
;
Schreiner and Joris 1986
). Thus the ability of cortical
neurons to follow higher frequencies suggests that the inhibitory
period ends earlier. This earlier termination of the inhibitory period
may effectively reduce the temporal scatter of the inhibitory inputs to
IC neurons and could be explained by either a shorter duration of
inhibition and/or by an earlier onset of inhibition, as suggested by
Schreiner and Raggio (1996)
. Assuming a similar
relationship between the duration of inhibition and the period of Fmax
for neurons at the level of the IC, the results from the present study
suggest that chronic electrical stimulation of the cochlea leads to
long term changes in the inhibitory circuits. Specifically,
higher-frequency chronic stimulation may be more effective in
modulating the inhibitory mechanisms, whereas low-frequency stimulation
at least maintains or regenerates the "normal" degree of inhibitory contributions in neonatally deafened animals. Results from animals that were neonatally deafened for prolonged periods (>2 yr) and not chronically stimulated
showed a significant degradation in the temporal resolution of central nucleus neurons, thus supporting this hypothesis (Vollmer et al. 1998a
,b
).
Further, nothing presently is known about the specific nature or extent
of structural changes that may underlie the observed long-term changes in temporal resolution of central auditory neurons following chronic high-frequency stimulation. There are at least two
different ways in which structural modifications in afferent projections might occur prior to and/or at the level of the IC (e.g.,
Eysel et al. 1981; Kaas 1996
;
Keller et al. 1990
). First, "strengthening" of
already existing (either previously active or
ineffective) connections may occur as a consequence of chronic electrical stimulation. For example, synapses may undergo modification in size to become persistently more effective or synapses may move to
more effective locations on the target neurons. Second, "sprouting"
of new axonal and dentritic connections may result in an
increased number of synapses and/or more effectively located synapses.
Both mechanisms would lead to increased synaptic efficacy, a higher
synchrony in the neuronal excitation pattern, and, consequently, in
increased temporal resolution of IC neurons.
It should be noted that low-frequency-stimulated animals had a mean
duration of chronic stimulation of 3.8 ± 1.4 (SD) mo that was
markedly shorter than the mean duration of stimulation in high-frequency-stimulated animals of 7.6 ± 1.7 mo. Thus it is not
clear at present if the duration of chronic stimulation also played a
role in the observed differences in temporal resolution between the two
groups. However, a comparison of data from age matched individuals in
low (K63 and K83)- and high
(K62 and K92)-frequency stimulation
groups showed the same results as in the overall comparisons, with
markedly lower average Fmax (114 pps) and a significantly longer median
latency (7.87 ms; P < 0.05) in
low-frequency-stimulated animals than in high-frequency-stimulated
animals (136 pps and 7.36 ms, respectively). Further, although
stimulation periods in the low-frequency stimulation group ranged
between 9 and 23 wk, the average Fmax for the individual animals showed
only a relatively small variability (mean Fmax = 109.9 ± 4.37 pps). These observations suggest that at least for stimulation
periods 9 wk, the frequency of the chronically applied signal is more
important in determining the temporal response properties of ICC
neurons than the duration of chronic stimulation per se.
In contrast to results in the ICC, the temporal resolution of ICX
neurons was not significantly different in any of the experimental groups, regardless of the stimulation history. There is no clear explanation for this finding. One possibility is that additional somatosensory input (e.g., Aitkin 1986) modulates or
maintains the temporal response properties of ICX neurons such that
they are less sensitive to deprivation or modulation of auditory
inputs. Furthermore the ICX is distinguished from the ICC by its major descending inputs from both primary and nonprimary auditory cortex (e.g., Andersen et al. 1980
; Coleman and Clerici
1987
; Faye-Lund 1985
; Gonzalez-Hernandez
et al. 1987
; Oliver and Huerta 1992
; Willard and Martin 1983
). Because Fmax of auditory
cortical neurons are approximately an order of magnitude lower than
those of neurons in the ICC (Schreiner and Raggio 1996
),
the cortical projections to the ICX may modulate the temporal
resolution of ICX neurons and may therefore explain the overall
lower-frequency following capacity observed in ICX neurons compared
with neurons in the ICC. Furthermore, cortical projections to the ICX
may prevent or counteract the influence of high-frequency stimulation
on long-lasting functional or structural changes of afferent
connections as suggested for ICC neurons. Clearly, additional studies
are required to more fully understand the role of ICX neurons in the
processing of auditory signals.
Topographic distribution of Fmax
Another major goal of this study was to investigate the
topographic distribution of temporal response properties along IC depth
and to determine if temporal resolution was related systematically to
the cochleotopically organized frequency gradient of the ICC (e.g.,
Brown et al. 1997; Merzenich and Reid
1974
), in which increasing penetration depth corresponds to
increasingly higher CF and to more basal intracochlear electrode
locations in implanted animals (Snyder 1990
).
Specifically, we investigated how selective changes in temporal
resolution following low- versus high-frequency chronic electrical
stimulation are distributed along the CF gradient of the IC.
In all three experimental groups Fmax did not vary systematically with
IC depth. That is, neither average nor peak maximum following
frequencies increased along the gradient of increasing CF. Moreover,
there was a slight tendency for the average Fmax to reach a maximum in
the center of the ICC. It is interesting to note that Rees and
Møller (1987), using amplitude-modulated noise in rats, also
did not see a consistent relationship with characteristic frequency of
either peak MTF (modulation transfer function) or the high-frequency
cutoff of the MTF. In contrast, other studies report a systematic
increase of BMF or Fmax with the tonotopic (CF) gradient
(Langner and Schreiner 1988
; Snyder et al.
1995
).
One possible explanation for the differences between the present and
some previous reports is a difference in sampling strategies. Langner and Schreiner (1988) attempted to achieve a high
sampling density in certain CF areas. Furthermore, as mentioned
previously, the inclusion of single- and multiple-neuron
responses by these investigators may have played a role in defining the
distributions of temporal resolution across the tonotopic gradient. The
majority of high BMFs were obtained from multiple-neuron recordings and might reflect characteristics of neural inputs to the IC rather than
response properties of IC neurons per se.
Snyder et al. (1995) also reported increased average and
peak Fmax with increasing depth, with a steeper slope of the regression lines especially for chronically stimulated animals, but the
correlation coefficients for these measures were small
(R < 0.3). Moreover, in that study responses were not
separated between ICX and ICC. As demonstrated in the present study,
neurons from the ICX have significantly lower Fmax than neurons from
the ICC. Thus including neurons from both nuclei in the same
correlation analysis likely explains the correlation between increasing
Fmax with the tonotopic gradient observed by Snyder and colleagues.
In the present study, the sample size of single neurons in the most superficial and deepest recording locations was smaller than in more central locations of the IC (Fig. 5), and this might have influenced the distribution of Fmax averaged over given depth ranges. Regardless of the smaller samples in the two extreme depth ranges, however, the average Fmax in the two animal groups with the overall highest number of recorded neurons (control and high-frequency-stimulated animals) clearly showed a comparable distribution, indicating that temporal resolution across IC depth does indeed reach a broad maximum in the center of the ICC.
Finally, changes in temporal resolution of IC neurons following
high-frequency stimulation were not restricted to circumscribed regions
(e.g., the best location for the chronically stimulated electrode pair
or region of highest CF) but occurred broadly across the entire ICC.
The broad increase in Fmax of single neurons across the entire ICC
following high-frequency stimulation may be related to the relatively
broad current spread of the electrical pulsatile stimuli. The chronic
stimulus level was set at 2 dB above EABR threshold. It has been shown
that the EABR threshold is on average ~4-6 dB above psychophysical
and minimum single IC neuron threshold (Abbas and Brown
1991; Beitel et al. 1999
; Smith et al.
1994
). Because the dynamic range of IC neurons for electrical
pulsatile stimulation (0.2 ms/ph) is usually <10 dB (unpublished
observations), a stimulus intensity of ~6-8 dB above minimum IC
threshold is likely to activate a broad region of the IC (Fig. 1) and
may explain the broad distribution of increased temporal resolution
following higher-frequency stimulation.
Response latencies
Neurons in central auditory nuclei receive their inputs via
multiple pathways that differ in length, number of synapses, and intrinsic timing properties of the afferent neurons (De
Ribaupierre et al. 1980; Møller 1975
).
Therefore response latencies of neurons may vary considerably at
different locations in the same nucleus (Langner et al.
1987
). The findings of the present study confirmed the large
variation of neural response latencies in the inferior colliculus.
Latencies in all three animal groups ranged between 5 and 10 ms at most
locations throughout the entire IC (Fig. 7).
It should be noted that studies using acoustic stimulation have shown
that latency to the stimulus onset decreases with increasing sound
intensity (Anderson et al. 1971; Møller
1975
). This effect also was observed to some degree with
intracochlear electrical stimulation. Thus depending on the separation
of the neuronal response and the electrical artifact, our approach in
the acute electrophysiological experiments was to consistently select
stimulus intensities between 2 and 6 dB above single-unit threshold.
Quantitative analysis has shown that recordings made at the upper and
lower limit of our intensity range (i.e., 2 and 6 dB above threshold, respectively) vary in onset latencies by
0.5 ms (unpublished observations). Because this effect was relatively small and applied similarly to the single neuron recordings of all three experimental groups, it is assumed that any possible intensity dependent variation in latencies did not affect the overall conclusions. In fact, the
presented range and distribution of onset latencies from the control
animals were in close agreement with results from normal animals
reported in previous studies using both electrical (Snyder et
al. 1991
, 1995
) and, adjusted for the lack of cochlear delay, acoustic stimulation (Irvine and Gago 1990
;
Langner and Schreiner 1988
).
Regardless of the stimulation history, ICX neurons generally had significantly longer average response latencies than neurons in the ICC, and chronic electrical stimulation did not significantly influence the latencies of ICX neurons. In contrast, response latencies of neurons in the ICC were affected by the frequency of the stimulus in two ways. First, low-frequency stimulation did not maintain temporal resolution of ICC neurons, i.e., average latencies in the low-frequency group were significantly longer than those in the control group. Secondly, high-frequency stimulation resulted in significantly shorter latencies for ICC neurons compared with control animals and appeared to be the more effective stimulus for maintaining or enhancing temporal resolution.
In the high-frequency group, neurons from animals stimulated with 300 pps carrier/30 Hz AM demonstrated significantly shorter latencies (P < 0.05) than those from animals stimulated with an analogue processor. The underlying mechanisms for this difference in latency are presently unknown, but it is tempting to speculate that the sharp onset of the square pulse waveform might have produced greater synchrony (resulting in shorter latency) than the less abrupt onset of analogue stimuli. However, the relatively broad range of frequencies delivered by the speech processor (band-pass filtered from 250 Hz to 3 kHz, see METHODS), additional behavioral training with a variety of different frequency signals and the possible behavioral relevance of auditory information delivered by a speech processor make it impossible to draw definite conclusions relating the differences in average latency between the two high-frequency-stimulated subpopulations (300 pps/30 Hz AM vs. analogue processor) to a specific characteristic of the stimulus. Also, further studies are required to understand the extent to which different time patterns of the chronic higher-frequency stimuli (i.e., periodic pulsatile AM stimulation with a constant time pattern vs. analog broadband stimulation with changing, frequency-modulated time patterns) may contribute to specific differences in the frequency-encoding capability of ICC neurons. However, it should be noted that ICC latencies from both high-frequency-stimulated subpopulations were significantly shorter than those from normal and low-frequency-stimulated animals, and no differences were observed in the Fmax between the two populations. Therefore the results from both populations were summarized in the high-frequency stimulation group.
Finally, in the present study onset latencies did not vary
systematically with IC depth (i.e., CF gradient). These results were in
close agreement with earlier studies using acoustic stimulation that
found only a weak correlation between onset latency and CF (Langner et al. 1987). In the present study, average
latencies were relatively uniformly distributed across the entire ICC
with only a slight minimum in the center of the nucleus in all three experimental groups. In fact, we observed a correlation between response latency and Fmax that was independent of the frequency characteristics of the chronic stimulation or the recording location (i.e., CF). These findings support the suggestion of Langner and Schreiner that the covariation of frequency following and latencies may
reflect the existence of intrinsic neuronal mechanisms in the temporal
processing or coding of periodic signals in central auditory neurons
(Langner and Schreiner 1988
; Langner et al.
1987
; Schreiner and Langner 1988
). The present
study suggests that 1) these intrinsic mechanisms are
applicable to both acoustic and electrical signals, 2) not
altered by the temporal properties of the chronically applied
peripheral stimulation pattern, and 3) valid for neurons in
both ICX and ICC.
Implications for future studies
The ability to encode and resolve the temporal patterns of the
electrical signal is crucial for the speech recognition performance of
cochlear implant subjects (e.g., Eddington et al. 1978;
Shannon 1992
; Townsend et al. 1987
;
Wilson et al. 1991
). In psychophysical studies on rate
pitch discrimination, Shannon (1983
1985
, 1992
) has
reported that implant subjects can discriminate repetition or
modulation frequencies up to ~300 pps. This upper frequency roughly
reflects the upper limit in frequency following for ~90% of IC
neurons (Langner and Schreiner 1988
; Snyder et
al. 1995
; present study). On the other hand, Wilson et
al. (1991)
demonstrated that modulated carrier frequencies of
800 pps resulted in improved speech recognition when compared with
slower pulse frequencies. Because none of the IC neurons in this study
was able to follow such high frequencies, it raises the question how
this improvement can be explained. Presumably once the carrier
frequency exceeds Fmax, the neurons begin to follow the modulation
frequency instead, and (depending on the relation between modulation
and carrier frequencies) carrier frequencies that are well above the
frequency following capacities of central auditory neurons are able to
shape the modulation frequency in more detail. To better understand the
encoding of high-frequency amplitude-modulated signals, one important
goal of further studies is to investigate the response characteristics
of IC neurons to different combinations of carrier and modulation frequencies.
Evidence from several laboratories is now available that indicates that
the neural representations of behaviorally important stimuli in the
mammalian auditory forebrain can be modified by behavioral training
with acoustic (Lennartz and Weinberger 1992; Recanzone et al. 1993
; Scheich 1991
;
Weinberger and Diamond 1987
) and electrical signals
(Raggio et al. 1995
). Furthermore Snyder et al.
(1990
, 1991
, 1995
) have shown that chronic electrical
stimulation of the cochlea can induce spatial (spectral) and temporal
plasticity in the inferior colliculus of neonatally deafened cats. The
present study has established that high-frequency electrical stimuli
more effectively increase temporal resolution in the tonotopically organized central nucleus of the inferior colliculus than low frequency
stimulation. Although the mechanisms involved in representational plasticity are not well understood, there is evidence that plasticity of the sensory system can be based e.g., on local (auditory)
Hebbian-type synaptic processes (Cruikshank and Weinberger
1996
, Diamond et al. 1993
), changes in the
topographic and synaptic organization of afferent connections (e.g.,
Eysel et al. 1981
; Kaas 1996
;
Keller et al. 1990
), diffuse neuromodulatory systems
that project to the auditory system (Barkin and Weinberger
1996
; Kilgard and Merzenich 1998
), and
behavioral context (Ahissar et al. 1992
). The animal model described allows us to control the entire "hearing" history of neonatally deafened cats. In future experiments, behavioral training
with well defined electrical signals will be combined with chronic and
acute electrophysiological recordings to understand the contribution of
behaviorally relevant electrical stimuli for representational
plasticity in the temporal processing of signals in the central
auditory system.
Further experiments are required to determine whether the observed plasticity in temporal resolution is limited to the immature, early deafened auditory system or to what extent chronic electrical stimulation can modulate the functional status of neurons in the adult auditory system.
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ACKNOWLEDGMENTS |
---|
We thank E. Dwan for daily maintenance of the animals and M. Fong for electrical engineering.
This work was supported by National Institute on Deafness and Other Communication Disorders Contracts NO1-DC-4-2143 and N01-DC-7-2105, and by Deutsche Forschungsgemeinschaft Grant Vo 640/1-1.
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FOOTNOTES |
---|
Address for reprint requests: M. Vollmer, Dept. of Otolaryngology, Epstein Laboratory, University of California, 500 Parnassus Ave., U-490, San Francisco, CA 94143-0526.
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 24 November 1998; accepted in final form 7 July 1999.
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REFERENCES |
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