Age reduces response latency of mouse inferior colliculus neurons to AM sounds

Age reduces response latency of mouse inferior colliculusneurons to AM sounds

Henry SimonInternational Center for Hearing & Speech Research, National Technical Institute for the Deaf,Rochester Institute of Technology, Rochester, New York 14623

Robert D. Frisinaa)

Department of Surgery, Otolaryngology Division, Departments of Neurobiology & Anatomy andBiomedical Engineering, University of Rochester School of Medicine and Dentistry, Rochester,New York 14642-8629, and International Center for Hearing & Speech Research, National TechnicalInstitute for the Deaf, Rochester Institute of Technology, Rochester, New York 14623

Joseph P. WaltonDepartment of Surgery, Otolaryngology Division, Department of Neurobiology and Anatomy,University of Rochester School of Medicine and Dentistry, Rochester, New York 14642-8629

~Received 9 December 2003; revised 14 April 2004; accepted 23 April 2004!

Age and stimulus rise time~RT! effects on response latency were investigated for inferior colliculus~IC! neurons in young-adult and old CBA mice. Single-unit responses were recorded tounmodulated and sinusoidal amplitude modulated~SAM! broadband noise carriers, presented at 35to 80 dB SPL. Data from 63 young-adult and 76 old phasic units were analyzed to identify the timeinterval between stimulus onset and driven-response onset~latency!. When controlling for stimulussound level and AM frequency, significant age-related changes in latency were identified. Absolutelatency decreased with age at all stimulus AM frequencies, significantly so for equivalent rise times(RT)<12.5 ms. The linear correlation of latency with AM stimulus RT was significant for bothyoung-adult and old units, and increased significantly with age. It is likely that both the decrease inabsolute latency and the increase in latency/RT correlation with age are consistent with a reductionof inhibitory drive with age in the IC. These latency changes will result in age-related timingvariations in brainstem responses to stimulus onsets, and therefore affect the encoding of complexsounds. ©2004 Acoustical Society of America.@DOI: 10.1121/1.1760796#

PACS numbers: 43.64.Qh, 43.64.Ri@WPS# Pages: 469–477

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I. INTRODUCTION

Speech comprehension difficulties reported by agedteners with mild-to-moderate peripheral hearing impairmhas motivated research efforts to identify age-related chanin more central processes affecting speech comprehen~Takahashi and Bacon, 1992; Gordon-Salant and Fitzbons, 1993; Frisina and Walton, 2001; Frisinaet al., 2001;Snell and Frisina, 2000!. Listeners employ both spectral, oplace, and temporal cues~Rosen, 1992! in speech processingThe relative importance of temporal cues is supported bydemonstration of good speech recognition in the absencspectral cues~Shannonet al., 1995! as well as by the capability of single channel cochlear implants to restore spoklanguage comprehension~Cohenet al., 1993!. Additionally,although some consonants are not fully represented by aporal code, replacing single phonemes in speech with ndoes not substantially reduce comprehension~Sachs, 1984;Warren, 1970!. Moller ~1999! presented evidence supportinthe position that a temporal code is more important for cveying speech information than place codes. In aged lisers, including those with good absolute sensitivity, degratemporal processing, such as elevated gap detection tholds, has been directly linked to speech identification di

a!Electronic mail: [email protected]

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culties ~Fitzgibbons and Gordon-Salant, 1996; Snell, 199Frisinaet al., 2001; Snell and Frisina, 2000!.

Speech temporal cues include fine structural variati~voicing pulses!, the result of abrupt changes in stimulucarrier frequency, and variation in the stimulus envelopecurring over multiple carrier cycles, or amplitude modulati~AM !. Vowels may be modeled by periodic, sinusoidal aplitude modulated~SAM! stimuli. When AM cues weremodified in a phoneme identification task, the performanof aged listeners dropped relative to that of young listen~Souza and Kitch 2001!. It is interesting to note that signalprocessing techniques employed in several types of heaaids, such as wide-dynamic range compression, significaalter the AM envelope of the stimulus introduced into the ecanal~Souza, 2000!.

Both auditory nerve~AN! and primary auditory cortex~AI ! response latencies are known to systematically vwith temporal onset characteristics of the stimulus enveloIn cat, both AN and AI first spike response latency to cosinsquared rise function tones were reported by Heil and Irv~1996; 1997! to be invariant inverse functions of stimulumaximum acceleration of peak pressure (APPmax). For tonestimuli with linear envelopes, Heil~1997! has shown that AIfirst spike timing is an invariant inverse function of stimulurate of change, or velocity, of peak pressure~VPP!. Morerecently, Heil and Neubauer~2001! have presented data sup

469469/9/$20.00 © 2004 Acoustical Society of America

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porting the conclusion that auditory nerve~AN! fiber firstspike latency is a function of the integral of sound pressover time, possibly a reflection of inner hair cell/AN fibemechanisms. Neural temporal processing in AI can chaduring behavior, even when mean firing rates are unchan~DeCharms and Merzenich, 1996!. Population coding theorysuggests that stimulus information is conveyed by the rtive timing and activity level across multiple neuronal ements in an array~Langner and Schreiner 1988; Covey 200Eggermont, 2001!.

IC response latency is influenced by a number of autory stimulus onset characteristics and peripheral audiprocesses, as summarized above, as well as by excitatoryinhibitory processes within the auditory midbrain~Coveyand Casseday, 1999!, all of which could be differentiallyaffected by aging. IC latency can be influenced by the natlength and location of ascending pathways, some of whare relatively direct from the cochlear nucleus, otherswhich involve synaptic processing delays at the levels ofsuperior olivary complex and nuclei of the lateral lemnisc~e.g., Frisinaet al., 1989; 1998; Frisina and Walton, 2001!.Single neuron latency has been shown to decrease whehibitory neurotransmitters in the IC are blocked~Park andPollak, 1993!. Age-related loss of inhibitory neurotransmiters and alteration in synaptic neurochemistry have bdocumented in the IC of aged rats~Casparyet al., 1990;1995; 1999; Helfert, 1999!, offering evidence that the balance of excitation and inhibition processes are disrupteadvanced age. Furthermore, changes in the interplay betwexcitation and inhibition have been implicated in age-relaalteration of temporal processing~Waltonet al., 1998; 2002;Finlayson 2002!. Given the extensive afferent innervatiofrom IC to thalamus~LeBeauet al., 1996; Covey and Casseday, 1999! and ultimately to AI, the onset timing of AI neuronal discharges strongly reflect those of IC neurons. LasIC unit response latencies can be influenced by descen~efferent! projections originating from the auditory cortevia the medial geniculate body and the external and docortex divisions of the IC.

Walton et al. ~2002! reported age-related differencesthe level of IC driven-spike activity and the relationshipsdriven-spike activity for best-AM frequency~BMF! and un-modulated stimuli. In the present report, the effects of agethe relationships between AM frequency~effective rise time!and IC latency were characterized to investigate age-reldifferences in IC temporal processing of a stimulus onfeatures. To allow detailed comparisons of results betwstudies, identical SAM broadband noise stimuli and, toextent possible, the same IC units, were utilized in bothvestigations.

II. METHODS

A. Experimental procedures: Subjects and surgery

The procedures and data set here were those of Waet al. ~2002!. Young-adult~2- to 4-months-old! and old~24-to 28-months-old! CBA/CaJ mice were obtained from thNational Institute of Aging and Jackson Lab mouse colonand kept in an isolated, noise-controlled vivarium on a 1

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light:dark cycle. Food and water were provided ad lib. Prto each experiment, animals were lightly anesthetized wMetofane ®, Pittman-Moore and the external auditory matus was examined down to the tympanic membraneblockage. Only animals found to have clear external canwere used. Animals were prepared under aseptic conditaccording to the guidelines for recovery surgery approvedthe University of Rochester’s Committee on Animal Rsources. Prior to surgery, mice were deeply anesthetizedAvertin ~20 mg/g!; the skull was shaved, and the craniuwas exposed by reflecting the scalp musculature. Suquently, a 2% solution of lidocaine was applied locally. Tarea was cleaned and dried, and a small, threaded metalwas attached to the skull surface using cyanoacrylate asive and dental acrylic. A sharpened tungsten wire servethe indifferent electrode and was implanted in the skull asecured with dental acrylic. Using stereotaxic coordinatesmall ~0.5 mm! hole was made in the skull over the IC anthen filled with bone wax, after which the animal was alowed to fully recover and then was returned to its cage.

On the experimental day, the animal was mildly traquilized ~Taractan 5-12m g/g! and placed in a plastic restraint attached to a custom-built stereotaxic frame. Tycally, old mice were administered one-third to one-half tdose required for young-adult animals. The frame wascated in the middle of a heated (27– 30 °C), double-wallsound-attenuated room~IAC!, lined with sound-absorbingfoam~Sonex!. The head was fixed to the frame by bolting ththreaded tube to a rigid bar attached to the stereotaxic fraCare was taken to ensure that the animal was as comfortas possible to avoid undue distress and body movement

B. Stimuli

Stimuli were generated using a digital signal-processplatform ~Tucker-Davis Technologies AP2! running on aPentium PC. Broadband noise was digitally generated~2–60kHz!, amplified, and fed to a high-frequency leaf twee~Panasonic THD 100! located on the horizontal plane 30contralateral to the recording site. Sound calibration was pformed by sampling the noise using a calibrated 1/4 in. cdenser microphone~Bruel and Kjaer model 4135! placed atthe location of the pinna and connected to a measuringplifier ~Bruel and Kjaer model 2610!. The output of the mea-suring amplifier was fed to an A/D converter, and, vinverse-fast Fourier transform~FFT! signal processing, aspeaker’s transfer function was equalized to within62 dBfrom 2 to 60 kHz. Noise bursts and AM stimuli were synthsized on-line. SAM noise bursts were synthesized by muplying a wideband noise carrier by asine-wave modulawith m51, thereby producing 100% amplitude-modulatnoise. SAM stimuli were 100 ms in duration with rise/fatimes that followed the SAM envelope. The modulation frquency~MF! was varied from 10 to 800 Hz. Unmodulatestimuli were also 100 ms in duration with 1-ms, linear risfall times. Unmodulated and 10 Hz SAM stimuli are illustrated in Fig. 1. Stimuli were presented 50 times at a rate4/s, typically at 65 dB SPL. Intensity was varied betweenand 80 dB SPL as required for a strong unit response.

Simon et al.: Age, rise time alter response latency

BF, B

50 ms RTr responseassessed for

FIG. 1. PSTH representations of typical unit responses from young-adult and old animals are displayed for short and long RT stimuli. Unit number,MFand MTn are listed. The solid bar beneath the abscissa denotes stimulus timing and duration.~a! Two of fifty noise burst waveforms from unmodulated~toppanel! and 10 Hz SAM~bottom panel! stimulus presentations with 1 ms, linear and 50 ms, sine wave, RTs, respectively.~b! Typical PSTHs with responselatencies of 12.5 and 15.5 ms for the young-adult unit and 7.0 and 13.5 ms for the old unit to the 1 ms~top panels! and 50 ms~bottom panels! RT stimuli,respectively. Units show no background spike activity prior to stimulus onset.~c! Examples of clear~top panels! and potentially ambiguous~bottom panels!latency results in the presence of background spike activity. Young-adult unit latency was assessed as 13.0 ms for the 1 ms RT stimulus. With thestimulus however, the relatively modest response at a latency of 17.5 ms was identified as the driven response onset as opposed to the strongeata latency of 20.5 ms. Old unit latency was assessed as 12.5 ms for the 1 ms RT stimulus. Some ambiguity exists regarding the 30.5 ms latencythe 50 ms RT stimulus. Bin width: 1 ms.

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C. Measurement protocol

After a single-unit was isolated, the following expermental protocol was followed:~1! the audio-visual determination of BF and minimum noise threshold~MTn!; ~2! mea-surement of BF and noise rate-intensity functions; and~3!presentation of AM series. The BMF, defined as the Mwhich resulted in the largest total spike count, was demined from modulation transfer functions of spike activityresponse to SAM noise carriers with MFs from 10 to 800 Hspecifically 10, 20, 40, 60, 80, 100, 200 400, and 800The intensity of the noise carriers never exceeded 80SPL. MTn, defined as the lowest intensity at which ancrease in activity above the background rate was just notable, was determined using the unmodulated noise stimu

D. Data analysis

Evoked spikes were time-stamped~10 ms accuracy! andavailable for display on-line in PSTH form. Automateanalysis programs which have been routinely used inother studies~Frisina et al., 1996; Lesseret al., 1990! wereused off-line to obtain rate measures from SAM respofiles. To measure latency, a new automated programused to analyze each unit’s spike response during 50, 110time intervals, each starting 10 ms prior to stimulus onsetdetermine both the level of background activity and the poin time when spike activity exceeded the background activ

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by a user specified multiple. If no discharge occurred durthe initial 15 ms of recording~i.e., background activity waszero!, then latency was identified as the difference betwethe beginning of the first 0.5 ms bin containing one or mospikes and stimulus onset.

A visual inspection of the unit PSTHs revealed no obous increase in spike activity within 5.0 ms of stimulus oset. Consequently, the first 15 ms of recorded spike cowas used to assess background activity. For the determtion of background activity, the algorithm summed spikes0.5 ms bins and identified the maximum number of spikper bin during the initial 15 ms of recorded data. The begning of the first, subsequent, 0.5 ms bin in which spike coexceeded this maximum level by more than 1.5 times, widentified as the onset response. Latency was set equal ttime interval between this point and stimulus onset. Appromately 3% of all latency measurements exceeded 30.0The PSTH associated with each of these latency measments was visually examined to judge the accuracy ofcalculated value. The bin width and the amount by whspike count must exceed background activity, or zero, inder to be identified as a driven response, were user specA 0.5 ms bin width was selected to permit resolution of 0ms latency differences. The one spike criteria for identifyia driven response when no background activity was preduring the initial 15 ms of recording reduced the probabilof the misidentification of a background spike as a driv

471Simon et al.: Age, rise time alter response latency

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response to,3.3% since no background activity occurreduring the previous 30, 0.5 ms, intervals. In the presencbackground spike activity, the 1.5 times criteria insured ta driven response was at least 50% greater than the mmum background activity in any 0.5 ms interval. With onetwo background spikes, this criterion dictated a 100%crease over the background activity level.

Latency at stimulus MFs from 0 to 800 Hz was mesured for 63 young-adult and 76 old units from 11 andanimals, respectively, and analyzed in three young-adultthree old unit sample groups based on stimulus intensnamely:Group 1—all intensity levels~63 young-adult and76 old units!; Group 2—a subset of Group 1 at 65 dB SP~60 young-adult and 34 old units!, andGroup 3—a subset ofGroup 2 composed of 27 young-adult and old units selecto provide equal sensation level~SL! distributions. The unitpairs were analyzed so as to confirm that the age effobserved for Groups 1 and 2, were statistically significwhen both the absolute and relativesound level were controlled for. For all three analysis groups, SLs ranged fr10–45 dB. BF, BMF and MTn distributions for each sampgroup were also evaluated. Stimulus RT values used inanalysis were 1.0 ms for unmodulated stimuli and a linapproximation of 1/2 MF for SAM stimuli. Note that, fomodulated stimuli at a fixed SPL, RT was inversely proptional to the maximum VPP (VPPmax) and that VPPmax oc-curred at the stimulus onset~Heil 1997!. For the unmodu-lated stimulus, VPP was constant.

Throughout this report, mean differences were evaluaby use of thet-test, while median differences were evaluatby use of the Mann-WhitneyU-test. All statistically signifi-cant results indicate ap,0.05 for the relevant test. MannWhitneyU-test Z absolute values>1.96 are considered significant at the 0.05 level using a two-tailed test.

E. Histological verification of unit locations

In addition to close inspection of specific response tyaccording to area, horseradish peroxidase~HRP! microinjec-tions were used to estimate locations of recording swithin the IC. HRP~10% Sigma type XII in 0.5 M KCl, 0.05M Tris buffer, pH 7.3! was iontophoretically injected~elec-trode positive! using 1.5mA constant DC for 15–20 mininto the center of the area of the IC in which recordings wmade ~Meininger et al., 1986; Waltonet al., 1997, 1998!.Animals were returned to their cage and perfusedtransdially 24 h later with heparinized saline and fixed wiglutaraldehyde/paraformaldehyde. Three serial sets of cnal sections were cut at 60mm. Two sets were processewith tetramethylbenzidine~TMB!, and one was counterstained with safranin-O. The third set was reacted withaminobenzidine~DAB! and counterstained with cresyl violet. The total diameters of the injection sites were 500–9mm in diameter, the dense-core centers were more restricand were confined to the central nucleus of the IC. Thprocedures were similar to our previous reports of structufunction HRP mapping studies in the IC of unanesthetizmammals~Frisinaet al., 1989, 1997, 1998!.


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III. RESULTS

A. Representative stimuli and PSTH responses

Clearly identified stimulus driven onset responses, aslustrated by the PSTHs shown in the top and bottom panof Fig. 1~b!, and the top panel of Fig. 1~c!, were typical of allunits measured, regardless of the pre-stimulus backgroactivity level. PSTHs were recorded for each unit in respoto unmodulated and SAM noise burst stimuli. Two of thfifty noise bursts comprising stimulus presentation for tunmodulated and 10 Hz MF SAM stimulus are shown scmatically in Fig. 1~a!. The unmodulated stimulus@Fig. 1~a!,top panel# had a 1.0 ms, linear RT while the SAM stimuRTs followed the SAM envelope, resulting in sine-washaped RTs from 50 ms at a MF of 10 Hz@Fig. 1~a!, bottompanel# to 0.625 ms at a MF of 800 Hz. 96% of the 140PSTHs analyzed yielded driven onset response latenfrom 5.0 to 30.0 ms and were included in subsequent danalyses. Latency values calculated from the remainingPSTHs~12 young-adult, 29 old! ranged from 30.5 to 190 ms

B. Sample group characteristics

1. Group 1. All stimulus intensities

MTn, BF and BMF were measured for 63 young-adand 76 old phasic IC units from 11 and 13 animals, resptively ~Table I!. Young-adult median MTn was significantlless than old~35.0 and 52.0 dB SPL, respectively!. Young-adult and old BF distributions were similar with medians20.4 and 18.7 kHz, respectively. The median BMF of bogroups was 80 Hz, although median SPL and SL werenificantly different. Young-adult median SPL was 5.0 dB lewhile median SL was 10.0 dB greater than those of old un

2. Group 2. 65 dB SPL

In the young-adult and old sample groups of units stimlated at 65 dB SPL~60 and 34 units, respectively!, medianMTns were significantly different~35 and 40 dB SPL, re-spectively!, median BFs were significantly different~20.2and 15.1 kHz, respectively!, median BMFs were identica~80 Hz! and, median SLs were significantly different~30 dBand 25 dB, respectively!. Approximately 99% of young-aduland 98% of old latencies measured for units in these samgroups were<30.0 ms.

3. Group 3. 65 dB SPL, equal SL

Twenty seven pairs of young-adult and old units stimlated at 65 dB SPL with equal MTn, and therefore equal Swere identified. In the sample groups containing these unSL values ranged from 10 to 45 dB; median BFs were sim~18.3 and 16.1 kHz, respectively!; median BMFs were sig-nificantly different~100 and 80 Hz, respectively!. 98.5% ofyoung-adult and 100% of old latencies measured for unitthese sample groups were<30.0 ms.

C. Sample group comparisons

Since most young-adult units were stimulated at 65SPL ~60 out of 63!, absolute stimulus intensity differencewere minimal between Group 1~the all stimulus-intensity


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TABLE I. Sample group characteristics.

Sample groups

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2. All SL 3. Equal SL

Young Old Young Old Young Old

Animals 11 13 10 8 8 6Units 63 76 60 34 27 27Unit characteristics, median

MTn ~dB SPL! 35 52 35 40 40 40BF ~kHz! 20.4 18.7 20.2 15.1 18.3 16.1BMF ~Hz! 80 80 80 80 100 80

Stimulus Level, medianSPL ~dB! 65 70 65 65 65 65SL ~dB! 30 20 30 25 25 25

Latency, median~ms!Unmodulated stimulus, 1 ms RT 10.5 9.5 10.5 8.5 11.5 810 Hz MF stimulus, 50 ms RT 14.0 17.0 14.0 14.0 16.5 14

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sample!, and Group 2~the 65 dB SPL sample!, young-adultunit groups. When the old sample group was limited to unstimulated at 65 dB SPL~Group 2!, most group parameterchanged significantly from the all stimulus intensity gro~Group 1!, namely: the sample size decreased from 76 tomedian MTn declined from 52 to 40 dB SPL; median Bdecreased from 18.7 to 15.1 kHz; median SPL declined fr70 dB, and; median SL increased from 20 to 25 dB. Medlatencies in response to 50.0 and 1.0 ms RT stimuli drop3.0 and 1.0 ms, respectively@see Figs. 2~a!, 2~b!#.

The situation was reversed in moving from sampgroups stimulated at 65 dB SPL~Group 2! to those stimu-lated at 65 dB SPL and of equal SL~Group 3!, and therefore,equal MTn. Minimal changes in group parameters occurbetween old sample groups while a number of young-acharacteristics changed significantly, namely the sampledropped from 60 to 27; the median MTn increased fromto 40 dB SPL; and the median SL decreased from 30 todB. Median response latency to 50.0 and 1.0 ms RT stimincreased by 2.5 and 1.0 ms, respectively@see Figs. 2~b!,2~c!.#

D. Sample group latencies

Median latencies were plotted as a function of stimuRT in Fig. 2 for each of the six sample groups analyzedalmost all cases, median latency increased with RT, or mprecisely, with decreasing VPPmax. For all stimulus intensitysample groups@Fig. 2~a!#, old unit latencies were significantly less than those of a young-adult at short RTs~1.25,2.5, 5.0, and 6.25 ms!, and considerably greater at 50.0 mRT. 65 dB SPL stimulus intensity sample groups@Fig. 2~b!#exhibited similar median latencies at long RT and a signcant, age-related, decrease in median latency at<12.5 ms. When 65 dB SPL, equal SL stimulus intenssample group latencies were compared@Fig. 2~c!#, the age-related decrease in median latency at longer RTs was mpronounced, and differences at RTs<12.5 ms remained sig

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FIG. 2. Plots showing the relationship between median latency and stimRT for young-adult~diamond! and old~square! sample groups containing~a! all units analyzed;~b! units stimulated at 65 dB SPL; and~c! MTn-matched young-adult and old units stimulated at 65 dB SPL and equal


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nificant. The lack of significance at RTs of 25.0 and 50.0may reflect Type II errors resulting from the small sampsizes.

E. Scatter plots and linear regressions for 65 dB SPL,equal SL groups

Although latency–RT scatter plots of young-adult aold equal SL sample groups exhibited considerable ove@Fig. 3~a!#, linear regression analysis of the data showedrelationships to be highly significant (F,0.001), and age-related differences in correlation~Rickers and Todd, 1967!,intercept, and slope to be significant at the 95% confidelevel @Fig. 3~b!#. The regressions were based on 266 youadult and 270 old data points. Nominal and 95% confidevalues for young-adult and old regression parameters wrespectively, correlations of 0.31 and 0.62~range: 0.25 to0.45 and 0.55 to 0.75!; intercepts of 11.7 and 8.7 ms~range:11.2 to 12.2 and 8.4 to 9.1!; and slopes of 0.075 and 0.12ms/ms~range: 0.047 to 0.103 and 0.106 to 0.144!.

IV. DISCUSSION

A. Influence of IC unit and stimulus characteristicson latency: Comparisons with previouslyreported AN, IC and AI latencies

In young-adult animals, a number of IC unit and stimlus parameters are known to nonlinearly and interdep

FIG. 3. Scatter plots~a! and 95% confidence linear regression lines~b!showing the relationship between latency and RT for the 27 unit, matcSL, Group 3 units. Linear regressions are presented at minimum interminimum slope and maximum intercept, maximum slope values for youadult ~ ! and old~ ! groups. Nominal intercept and slope lineregression latencies were: 11.710.075 ~RT! for young-adult; and 8.710.125 ~RT!. Young-adult and old correlations (r ) were 0.31 and 0.63,respectively, with respective explained variations of 0.09 and 0.39.


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dently influence IC latency, including unit MTn, BF, BMFstimulus SPL~or more precisely, peak plateau level!, RT,VPP, APPmax, and SL. In the present investigation, thestimulus parameters were controlled for to a first approximtion, and the findings strongly suggest that the latency difences identified here were age-related.

Langner and coworkers~1987, 1988! reported that aver-age IC latency varied inversely with BF and BMF in caHere, all old sample groups had median BFs and BMFswere equal to or less than those of the corresponding youadult group. Consequently, to the extent latency findingsported here were influenced by BF or BMF differences,Langner and coworkers results would predict a relativecrease in median latencies of the old sample groups cpared to the young-adult.

At a given BF, IC latencies have been shown to vawidely in response to the same stimulus. Langner aSchreiner~1988! reported that 90% of onset latencies todB SL characteristic frequency~CF! tones ranged from 5 to15 ms in cat IC. Latencies from 5 to 15 ms were measufor CF’s from 0.5 to 15 kHz. Latencies at higher CF’s narowed to a 5 to 10 msrange. Given the effect of SL on IClatency, as discussed below, the 5 to 30 ms latency rareported here is consistent with these findings.

For BF tone stimuli, decreases in latency with increasSPL, and consequently SL, have been widely reportedAN fibers ~Anderson 1971, Phillipset al., 2001!, cochlearnucleus~Moller, 1975!, IC ~Langner and Schreiner, 1988Phillips et al., 2001!, and AI ~Heil and Irvine 1996; Heil1997!. The peak latency of acoustic brainstem respo~ABR! has also been reported to show a similar dependeon SPL~Boettcheret al., 1993!. Such latency dependenceillustrated in the current data by a comparison of 65 dB Sto 65 dB SPL, equal SL young-adult sample groups, andstimulus intensity to 65 dB SPL old sample groups~Table I!.

The effects of stimulus onset parameters on respolatency have been reported at various locations withinauditory system. In anesthetized cat, Heil and Irvine~1997!have shown that the timing of both AN and AI, the mean fispike response to onsets of CF tone bursts with cos2-gatedRT, were invariant, inverse functions of stimulus APPmax, acharacteristic of the second derivative of the stimulus. Flinear RT stimuli, Heil ~1997! has also shown, in anesthetized cat, AI latency to be a function of stimulus VPP,characteristic of the first derivative of the stimulus. SimilarPhillips et al. ~2001! have shown in anaesthetized chinchlas, gross near-field AN and IC mean latency responseslinear rise time noise burst stimuli, to be inverse functionsstimulus VPP. For the 65 dB SPL SAM stimuli used here,varied inversely with maximum VPP (VPPmax), and in-versely with (APPmax)

1/2. The range of values for VPPmax, inPascals/second~Pa/s!, and APPmax, in Pascals/(second)2

(Pa/s2), for the 65 dB SPL stimuli used here, are shownTable II. In their Fig. 6~a!, Heil and Irvine~1997! showedAN latency values of approximately 6 to 18 ms at an APPmax

of 70 Pa/s2, and 3 to 5 ms at an APPmax of 4.53105 Pa/s2.At these same APPmax values, AI latencies to contralaterastimulation@Fig. 6~b!# were approximately 15 and 12.5 mrespectively. Here, for 65 dB SPL, equal SL sample grou

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at 70 and 4.53105 Pa/s2, median latencies were, respetively, 16.5 and 11.5 ms for the young-adult and 14.0 andms for the old sample groups. At all other APPmax measure-ment points, median latencies fell between the corresponAN and AI data points shown in Heil and Irvine~1997!, theirFigs. 6~a! and 6~b!.

The IC latencies shown in Phillipset al. @2001, Fig.7~b!#, are considerably less than those reported here. Forear RT stimuli VPP values of 1 and 100 Pa/s, Phillipset al.showed near-field recorded IC potential latencies of 5.52.5 ms, respectively, as compared with median lateranges measured here of 17.0 to 14.0 and 10.5 to 8.0 mthe respective VPPmax values of 1.1 and 91.2 Pa/s. Given thextent of these differences, the relationship between the nfield and single unit measurements suggests that the Phet al. recordings may have been dominated by lateral lemcus fibers’ potentials as they enter the IC.

B. Variables affecting IC response latency

IC response latency can be divided into two typessignal delay, namely, propagation and processing. The prgation time from stimulus onset to IC discharge reflectslays introduced by outer ear to oval window conductiobasilar membrane wave mechanics, inner hair cell synakinetics, and AN-fiber action potential transmission, amulti-nuclei, polysynaptic brainstem processing. Periphesignal processing delays are dependent on stimulus tempenvelope parameters~Heil and Irvine, 1997! and their effecton basilar membrane/inner hair cell discharge dynamicprocess which is also influenced by efferent feedbthrough the outer hair cells. Sound reflex feedback tomiddle ear tensor tympani and stapedius muscles mayinfluence processing delays. Given that AN latency sensity to stimulus VPP has been established for severalshapes~Heil and Irvine, 1997; Heil 1997!, it is likely that theage-related increase in the IC latency rate of change wstimulus RT reported here was also present in AN latenand resulted from age-related, peripheral signal proceschanges. Within the IC, signal processing delays are mated by excitatory and inhibitory processes which are depdent on neural interconnection pathways and chemistry,cifically the number, location, strength, and typeexcitatory and inhibitory synapses associated with a givenunit. These may come from interneurons, or from descendpathways from the cortex and thalamus, via the dorsal coand external nucleus of the IC.

The significant age-related decrease in latency identibetween 65 dB SPL, equal SL sample groups at all R<12.5 ms, and the age-related increase in the correlatiolatency with RT, are consistent with an age-related reduc

TABLE II. 65 dB SPL stimulus ranges—VPPmax, APPmax, RT

Stimulus VPPmax, Pa/s APPmax, Pa/s2 RT, ms

Unmodulateda 36.0 1.010 Hz SAM 1.1 70 50.0800 Hz SAM 91.2 4.53105 0.625

aFor linear RT stimuli, VPP and RT are constant, and APP is undefined


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in IC inhibition as documented by Caspary and colleag~Casparyet al., 1990, 1995, 1999!, and the decrease in latency demonstrated by blocking the inhibitory neurotramitter GABA with the application of the GABAA antagonistbicuculline in the IC of mustache bats~Park and Pollak,1993!. Park and Pollak reported that the degree of bicculline induced latency reduction varied with unit type, loction within the IC and with SL. For all unit locations, at 2and 30 dB SL, they reported that the mean latency of 1phasic unit responses to a 0.5 ms RT, CF tone burst stimwas reversibly decreased by 2 ms~13.5 to 11.5 ms! with abicuculline application. As mentioned above, IC latencyinfluenced by a number of auditory processes occurring freardrum to IC. The Park and Pollak data illustrate thathibitory processes within the IC can account for at least 2of 13.5 ms, or 8% of total latency, consistent with the preous study by LeBeauet al. ~1996!. If inhibition-driven pro-cesses declined with age, then the influence of the remailatency determinants, such as stimulus RT, would becreased. The age-related increase in latency correlationRT ~0.31 to 0.62! and latency variation explained by R~0.09 to 0.39! are consistent with such a reduction in thinfluence of inhibition on latency. Additionally, the agerelated increase in driven spike activity reported in Waltet al. ~2002! is consistent with a reduction in IC inhibitionduring aging.

C. Age-related changes in threshold

Age-related increases in threshold have been domented at various locations in the auditory system periphto the IC. Mills et al. ~1990! reported an age-related increain auditory thresholds of Mongolian gerbils. Thresholds weestimated from the measurement of evoked potentials onating in the auditory nerve and brainstem. When compawith those of 6 to 8 month old animals, mean auditothresholds increased by about 10 dB at 22 to 24 monthsby 25 to 35 dB at 36 months of age. Similar results wereported by Li~1991! for ABR in CBA mice. When com-pared with those of 1 and 6 month old animals, mean Athresholds~collapsed across frequencies! increased by 10 dBat 18 months and by 30 dB at 24 months of age. Conquently, it is most likely that the 17.0 dB median age-relaincrease in IC MTn reported here originated peripherally,result of increased AN thresholds.

Although IC unit MTn has been treated as an indepdent variable in this study, Heil and Neubauer~2001! arguethat in AN fibers, MTn is not a constant but varies asfunction of the time integral of sound pressure and, therefocannot be treated as an independent property of a neuThis distinction is not material to the age-related findinreported here for sample groups stimulated at 65 dB Ssince the time integral of the sound pressure at each MFidentical for all units, and consequently, did not influencereported latency findings.


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D. Comparison of latency and mean first spikelatency measures

Mean first spike latency, an average over all stimupresentations of the timing of the first spike elicited in rsponse to a stimulus, is commonly used to quantify stimuto-IC-response delay. When assessing mean first spiketency, a stimulus-driven response, as opposed tobackground response, is typically identified by visual insption of recorded spike data in appropriately positioned msurement time windows. In some cases, researcherschosen to disregard units with spontaneous activity becaof the difficulty they pose to accurate latency measurem~Park and Pollak, 1993!. The latency parameter used in thpresent study permitted computer controlled assessmenunit background activity and the application of quantitaticriteria for identifying the first response to occur abovebackground level. Over 97% of all computed latency valuwere <30 ms, and were included in the analysis. Furthmore, measurements of phasic IC unit mean first spiketency by Barszet al. ~1998!, in young-adult CBA mice, wereconsistent with latency values determined here. Barszet al.found that mean first spike latency to 20 dB SL unmodulanoise carriers, were 10.0 and 14.4 ms with linear rise timof 0.5 and 16.0 ms, respectively.

E. Speech comprehension implications of findings

Given the 17 dB higher median MTn of all old IC unimeasured here~relative to young-adult MTns!, in actual lis-tening situations, old units would be stimulated at lowerthan young-adult units. Consequently, age-related permance comparisons made at SLs that differed by 17would be more representative of actual listening circustances. It could be argued that the age-related increasthreshold and in the rate of change of latency with RT, rresent age-related plasticity intended to increase responstency at typical speech formant RTs, thereby compensafor the age-related decrease in inhibition-driven IC respolatency. The effect of such changes can be seen by a cparison of Figs. 2~a! and 2~c!. At equal SL@Fig. 2~c!#, oldmedian latencies were 2.5–3.0 ms less than those of yoadults at each RT.

An age-related change in IC response latency depdence on RT will cause an age-related alteration in therepresentation of stimulus element onset timing. With spestimuli, this will introduce a RT dependent variation in Arepresentation of formant onset timing and, in the casetiming of the second formant transition, degradation ocritical place-of-articulation cue.

ACKNOWLEDGMENTS

We appreciate the critical comments of Dr. Sandra MFadden and Dr. Robert Burkard in the preparation of tarticle, and the comments of two anonymous reviewers.computer program for analysis of driven response latewas written by Beth Hickman, and we are grateful for hdiligence. This work was supported by National InstituteHealth Grants No. P01 AG09524 from the National Instituon Aging, No. P30 DC05409 from the National Institute


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Deafness and Communication Disorders, and the Intetional Center for Hearing and Speech Research, RocheNY, USA.

Anderson, D. J., Rose, J. E., Hind, J. E., and Brugge, J. F.~1971!. ‘‘Tem-poral position of discharge in single auditory nerve fibers within the cyof a sine-wave stimulus: Frequency and intensity within the cycle osine-wave stimulus: Frequency and intensity effects,’’ J. Acoust. Soc. A49, 1131–1139.

Barsz, K., Benson, P. K., and Walton, J. P.~1998!. ‘‘Gap encoding by infe-rior collicular neurons is altered by minimal changes in signal envelopHear. Res.115, 13–26.

Boettcher, F. A., Mills, J. H., Norton, B. L., and Schmiedt, R. A.~1993!.‘‘Age-related changes in auditory evoked potentials of gerbils. II. Rsponse latencies,’’ Hear. Res.71, 146–156.

Caspary, D. M., Raza, A., Armour, B. A. K., Pippin, J., and Arneric, S.~1990!. ‘‘Immuno-cytochemical and neurochemical evidence for agrelated loss of GABA in the inferior colliculus: implications for neurapresbycusis,’’ J. Neurosci.10, 2363–2372.

Caspary, D. M., Milbrandt, J. C., and Helfert, R. H.~1995!. ‘‘Central audi-tory aging: GABA changes in the inferior colliculus,’’ Exp. Gerontol.30,349–360.

Caspary, D. M., Holder, T. M., Hughes, L. F., Milbrandt, J. C., McKernaR. M., and Naritoku, D. K.~1999!. ‘‘Age-related changes in GABAAreceptor subunit composition and function in rat auditory system,’’ Nroscience93, 307–312.

Cohen, N. K., Waltzman, S. B., and Fisher, S. G.~1993!. ‘‘A prospective,randomized study of cochlear implants. The Department of Veteransfairs Cochlear Implant Study Group,’’ N. Engl. J. Med.328, 233–237.

Covey, E., and Casseday, J. H.~1995!. ‘‘The lower brainstem auditory path-ways,’’ in Hearing by Bats, Springer Handbook of Auditory Researc,edited by A. Popper and R. Fay~Springer-Verlag, New York!, pp. 235–295.

Covey, E., and Casseday, J. H.~1999!. ‘‘Timing in the auditory system of thebat,’’ Annu. Rev. Physiol.61, 457–476.

Covey, E.~2000!. ‘‘Neural population coding and auditory temporal patteanalysis,’’ Physiol. Behav.69, 211–220.

DeCharms, R. C., and Merzenich, M. M.~1996!. ‘‘Primary cortical repre-sentation of sounds by the coordination of action-potential timing,’’ Nat~London! 381, 610–613.

Eggermont, J. J.~2001!. ‘‘Between sound and perception: reviewing thsearch for a neural code,’’ Hear. Res.157, 1–42.

Finlayson, P.~2002!. ‘‘Paired-tone stimuli reveal reductions and alteratioin temporal processing in the inferior colliculus of aged animals,’’ J. Asoc. Res. Otolaryngol.3, 321–330.

Fitzgibbons, P. J., and Gordon-Salant, S.~1996!. ‘‘Auditory temporal pro-cessing in elderly listeners,’’ J. Am. Acad. Audiol7, 183–189.

Frisina, D. R., Frisina, R. D., Snell, K. B., Burkard, R., Walton, J. P., aIson, J. P.~2001!. ‘‘Auditory temporal acuity during aging,’’ in:FunctionalNeurobiology of Aging~Academic, San Diego!, pp. 565–579.

Frisina, R. D., Karcich, K., Tracy, T., Sullivan, D., and Walton, J. P.~1996!.‘‘Preservation of amplitude modulation coding in the presence of baground noise by chinchilla auditory-nerve fibers,’’ J. Acoust. Soc. Am.99,465–490.

Frisina, R. D., O’Neill, W. E., and Zettel, M. L.~1989!. ‘‘Functional orga-nization of mustached bat inferior colliculus. II. Connections of the FM2

region,’’ J. Comp. Neurol.284, 85–107.Frisina, R. D., Walton, J. P., Lynch-Armour, M. A., and Klotz, D.~1997!.

‘‘Outputs of a functionally-characterized region of the inferior colliculuof the young adult CBA mouse model of presbycusis,’’ J. Acoust. SAm. 101, 2741–2753.

Frisina, R. D., and Walton, J. P.~2001!. ‘‘Aging of the mouse central audi-tory system,’’ inHandbook of Mouse Auditory Res: Behavior to MoleculBiology, edited by J. P. Willott~CRC Press, New York!, Chap. 24, pp.339–379.

Frisina, R. D., Walton, J. P., Lynch-Armour, M. A., and Byrd, J. D.~1998!.‘‘Inputs to a physiologically-characterized region of the inferior colliculuof the young adult CBA mouse,’’ Hear. Res.115, 61–81.

Gordon-Salant, S., and Fitzgibbons, P. J.~1993!. ‘‘Temporal factors andspeech recognition performance in young and elderly listeners,’’ J. SpeHear. Res.36, 1276–1285.

Heil, P., and Irvine, D. R. F.~1996!. ‘‘On determinants of first-spike latencyin auditory cortex,’’ NeuroReport7, 3073–3076.


ke

e

.fe

t’s

ar

re-io

fop.

er-

of

-’’ J.

d the

d

.

M.

J.

-

-

.

eech

he

theci.

s,’’

Heil, P. ~1997!. ‘‘Auditory cortical onset responses revisited. I. First-spitiming,’’ J. Neurophysiol.77, 2616–2641.

Heil, P., and Irvine, D. R. F.~1997!. ‘‘First-spike timing of auditory-nervefibers and comparison with auditory cortex,’’ J. Neurophysiol.78, 2438–2454.

Heil, P., and Neubauer, H.~2001!. ‘‘Temporal integration of sound pressurdetermines thresholds of auditory-nerve fibers,’’ J. Neurosci.21, 7404–7415.

Helfert, R. H., Sommer, T. J., Meeks, J., Hofstetter, P., and Hughes, L~1999!. ‘‘Age-related synaptic changes in the central nucleus of the inrior colliculus of Fisher-344 rats,’’ J. Comp. Neurol.406, 285–298.

Kiang, N. Y.-S. ~1965!. Discharge Patterns of Single Fibers in The CaAuditory Nerve, M.I.T. Research Monograph No. 35~MIT Press, Cam-bridge!.

Langner, C., Schreiner, C., and Merzenich, M. M.~1987!. ‘‘Covariation oflatency and temporal resolution in the inferior colliculus of the cat,’’ HeRes.31, 197–202.

Langner, C., and Schreiner, C. E.~1988!. ‘‘Periodicity coding in the inferiorcolliculus of the cat. I. Neuronal mechanisms,’’ J. Neurophysiol.60,1799–1822.

Le Beau, F. E., Rees, A., and Malmierca, M. S.~1996!. ‘‘Contribution ofGABA- and glycine-mediated inhibition to the monaural temporalsponse properties of neurons in the inferior colliculus,’’ J. Neurophys75, 902–919.

Lesser, H. D., O’Neill, W. E., Frisina, R. D., and Emerson, R. C.~1990!.‘‘ON–OFF units in the mustached bat inferior colliculus are selectivetransients resembling ‘‘acoustic glint’’ from fluttering insect targets,’’ ExBrain Res.82, 137–148.

Li, H.-S., and Borg, E.~1991!. ‘‘Age-related loss of auditory sensitivity intwo mouse genotypes,’’ Acta Otolaryngol.~Stockholm! 111, 827–834.

Mills, J. H., Schmiedt, R. A., and Kulish, L. F.~1990!. ‘‘Age-related changesin auditory potentials of Mongolian gerbil,’’ Hear. Res.46, 201–210.

Meininger, V., Pol, D., and Derer, P.~1986!. ‘‘The inferior colliculus of themouse. A Nissl and Gorge study,’’ Neuroscience17, 1159–1179.

Moller, A. R. ~1975!. ‘‘Latency of unit responses in cochlear nucleus detmined in two different ways,’’ J. Neurophysiol.38, 812–821.

Moller, A. ~1999!. ‘‘Review of the roles of temporal and place codingfrequency in speech discrimination,’’ Acta Otolaryngol.~Stockholm! 119,424–430.


F.-

.

l.

r

Park, T. J., and Pollak, G. D.~1993!. ‘‘GABA shapes a topographic organization of response latency in the mustached bat’s inferior colliculus,Neurosci.13, 5172–5187.

Phillips, D. P., Hall, S. E., Guo, Y., and Burkard, R.~2001!. ‘‘Sensitivity ofunanaesthetized chinchilla auditory system to noise burst onset, aneffects of carboplatin,’’ Hear. Res.155, 133–142.

Rickers, A. D., and Todd, H. N.~1967!. ‘‘Confidence belts for the coeffi-cients of correlation,’’ inStatistics: An Introduction~McGraw-Hill, NewYork!, p. 570.

Rosen, S.~1992!. ‘‘Temporal information in speech: Acoustic, auditory anlinguistic aspects,’’ Philos. Trans. R. Soc. London, Ser. B336, 367–373.

Sachs, M. B.~1984!. ‘‘Neural coding of complex sounds: speech,’’ AnnuRev. Physiol.46, 261–273.

Shannon, R. V., Zeng, F. G., Kamath, V., Wygonski, J., and Ekelid,~1995!. ‘‘Speech recognition with primarily temporal cues,’’ Science270,303–304.

Snell, K. B. ~1997!. ‘‘Age-related changes in temporal gap detection.’’Acoust. Soc. Am.101 2214–220.

Snell, K. B., and Frisina, D. R.~2000!. ‘‘Relations among age-related differences in gap detection and speech perception,’’ J. Acoust. Soc. Am.107,1615–1626.

Souza, P. E.~2000!. ‘‘Older listeners’ use of temporal cues altered by compression amplification,’’ J. Speech Lang. Hear. Res.43, 661–674.

Souza, P. E., and Kitch, V.~2001!. ‘‘The contribution of amplitude envelopecues to sentence identification in young and aged listeners,’’ Ear Hear22,112–119.

Takahashi, G. A., and Bacon, S. P.~1992!. ‘‘Modulation detection, modula-tion masking, and speech understanding in noise in the elderly,’’ J. SpHear. Res.35, 1410–1421.

Walton, J. P., Frisina, R. D., Ison, J. E., and O’Neill, W. E.~1997!. ‘‘Neuralcorrelates of behavioral gap detection in the inferior colliculus of tyoung CBA mouse,’’ J. Comp. Physiol.@A# 181, 161–176.

Walton, J. P., Frisina, R. D., and O’Neill, W. E.~1998!. ‘‘Age-related alter-ation in neural processing of silent gaps in the central nucleus ofinferior colliculus in the CBA mouse model of presbycusis,’’ J. Neuros18, 2764–2776.

Walton, J. P., Simon, H., and Frisina, R. D.~2002!. ‘‘Age-related alterationsin the neural coding of envelope periodicities,’’ J. Neurophysiol.88, 565–578.

Warren, R. M.~1970!. ‘‘Perceptual restoration of missing speech soundScience167, 392–393.


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Age reduces response latency of mouse inferior colliculus neurons to AM sounds