Click train encoding in primary auditory cortex of the awake monkey: Evidence for two mechanisms...

Click train encoding in primary auditory cortex of the awakemonkey: Evidence for two mechanisms subserving pitchperception

Mitchell Steinschneidera)

Departments of Neurology and Neuroscience, Albert Einstein College of Medicine, Rose F. KennedyCenter, Bronx, New York 10461

David H. Reser and Yonatan I. FishmanDepartment of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461

Charles E. SchroederProgram in Cognitive Neuroscience and Schizophrenia, Nathan Kline Institute for Psychiatric Research,Orangeburg, New York 10962

Joseph C. ArezzoDepartments of Neurology and Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461

~Received 23 January 1998; revised 29 June 1998; accepted 24 July 1998!

Multiunit activity ~MUA ! and current source density~CSD! patterns evoked by click trains areexamined in primary auditory cortex~A1! of three awake monkeys. Temporal and spectral featuresof click trains are differentially encoded in A1. Encoding of temporal features occurs at rates of100–200 Hz through phase-locked activity in the MUA and CSD, is independent of pulse polaritypattern, and occurs in high best frequency~BF! regions of A1. The upper limit of ensemble-widephase-locking is about 400 Hz in the input to A1, as manifested in the cortical middle laminae CSDand MUA of thalamocortical fibers. In contrast, encoding of spectral features occurs in low BFregions, and resolves both thef 0 and harmonics of the stimuli through local maxima of activitydetermined by the tonotopic organization of the recording sites. High-pass filtered click trainsdecrease spectral encoding in low BF regions without modifying phase-locked responses in high BFregions. These physiological responses parallel features of human pitch perception for click trains,and support the existence of two distinct physiological mechanisms involved in pitch perception: thefirst using resolved harmonic components and the second utilizing unresolved harmonics that isbased on encoding stimulus waveform periodicity. ©1998 Acoustical Society of America.@S0001-4966~98!01611-7#

PACS numbers: 43.64.Qh, 43.64.Ri, 43.66.Hg@RDF#

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INTRODUCTION

Pitch perception is a fundamental feature of humandition, subserving functions as diverse as speech recognimusic appreciation, and auditory source identification. Dspite this crucial role in hearing, little is known about thcentral nervous system mechanisms that underlie the ening of pitch. Elucidating these neural mechanisms requdetailed investigations of the auditory cortex, as profoudeficits in pitch perception occur following lesions of thposterior temporal lobe~e.g., Zatorre, 1988; Divenyi anRobinson, 1989; Robinet al., 1990!. While these lesion studies suggest a specialized role of auditory cortex in the ndominant hemisphere for pitch perception, neuroanatomand functional imaging studies indicate that primary auditcortex ~A1! of both hemispheres is involved in the initiastages of cortical processing~Galaburda and Pandya, 198Zatorre et al., 1992, 1994; Morelet al., 1993; Pandya andRosene, 1993!. These considerations suggest that A1 iscritical component of the neural network involved in pitcprocessing, and support the need to examine relevant actthat would serve as input for later auditory processing sta

a!Electronic mail: [email protected]

2935 J. Acoust. Soc. Am. 104 (5), November 1998 0001-4966/98/10

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Electrophysiological analysis is critical for defininphysiological mechanisms important for pitch perceptionA1. Functional imaging studies can identify brain regioinvolved with pitch perceptual tasks, but cannot delineateassociated physiological events within the activated cortareas. Noninvasive recordings of human event-related potials and magnetic-evoked responses provide temporallynamic pictures of complex sound encoding, but are also lited in their ability to characterize the specific neurprocesses that generate the waveform components. Retion of these physiological mechanisms requires intracrarecordings. Ethical considerations, however, preclude exsive investigations in humans.

Fortunately, key features of complex sound perceptthat mirror human responses occur in some animals. Tindicates that animals can serve as models for detailing sof the neural events underlying pitch encoding. Monkeys acats respond to the pitch of harmonic tone complexes demined by a missing fundamental frequency (f 0) in a mannersimilar to humans~Heffner and Whitfield, 1976; Tomlinsonand Schwarz, 1988!. This ability is lost in cats after bilateraablation of the auditory cortex~Whitfield, 1980!. The capac-ity to discriminate amplitude-modulated noise is nearly ide

29354(5)/2935/21/$15.00 © 1998 Acoustical Society of America

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tical in monkeys and humans, and both species demonsqualitatively similar critical bands and psychoacoustical ssitivities for multiple phonetic contrasts of speech soun~Gourevitch, 1970; Kuhl and Padden, 1982, 1983; Sinnand Adams, 1987; Sinnott and Kreiter, 1991; Sommerset al.,1992; Pfingst, 1993!. Monkeys also exhibit categorical peception of species-specific vocalizations, aphasia-like defifollowing auditory cortical lesions, and human-like hemspheric specialization~Petersenet al., 1978; Heffner andHeffner, 1986, 1989; Mayet al., 1989!. Thus, many higher-order capacities in complex sound perception are determby general principles of auditory system physiology, and cbe adequately examined in a primate model.

In this study, neural activity associated with pitch encoing of click trains is investigated by examining neuronal esemble responses in A1 of awake monkeys. Click tracomposed of individual pulses with same and alternatinglarity are used as stimuli because they elicit pitch perceptithat are apparently based on two distinct psychoacousmechanisms that lend themselves to physiological anal~Flanagan and Guttman, 1960a, 1960b; Guttman and Flgan, 1964; Rosenberg, 1965!. The pitch of click trains withpulse rates less than 100 Hz equals the pulse rate regarof the click polarity pattern. In contrast, the pitch of clictrains with f 0’s greater than 200 Hz is determined by thef 0

and is dependent on the click polarity pattern. The interving frequency region is a transition zone where pitch baon rate andf 0 are in conflict, leading to determinations ofsingle pitch that are often unsatisfactory. These two pimechanisms are mediated by distinct auditory channels,pitch perception equal to pulse rate encoded by hifrequency channels, and pitch perception based onf 0 medi-ated by low frequency channels. Furthermore, pitch demined by pulse rate is thought to be determined by tempmechanisms, whereas spectral encoding processesthought to mediate pitch encoded by thef 0 .

There is controversy, however, about the need to polate the existence of two distinct pitch mechanisms. A utary model of pitch encoding using autocorrelation withindividual auditory processing channels and subsequentgregation of periodicity estimates across channels has bproposed~Meddis and Hewitt, 1991; Meddis and O’Mard1997!. Physiological data based on autocorrelation of autory nerve fiber activity support this hypothesis~Cariani andDelgutte, 1996a, 1996b!. Other studies describe differentiaprocessing of resolved and unresolved harmonics thatport dual pitch mechanisms~Carlyon and Shackleton, 1994Shackleton and Carlyon, 1994!. As discussed above, audtory cortex is required for complex pitch perceptions. Thefore, if a dual mechanism of pitch processing is valid, phyological support using click train stimuli may be evidentA1. Specifically, we hypothesize that click train stimulatioshould engage two neural mechanisms relevant for pitchcoding. The first should be based in low-frequency tonotoregions of A1 and encode spectral features of click trains,second should be present in high-frequency areas andtain temporal patterns of activity that encode click trains psented at rates up to 100–200 Hz.

2936 J. Acoust. Soc. Am., Vol. 104, No. 5, November 1998

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I. METHODS

Three male monkeys~Macaca fascicularis! weighingbetween 2 and 3 kg were studied following approval by oinstitutional Animal Care and Use Committee. Animals wehoused in our AAALAC-accredited Animal Institute antheir health was monitored daily. Surgery was performeding sterile techniques under barbiturate anesthesia andvolved the implantation of electrode guides for repeatedtracortical recordings. Electrode guides were 18-gaustainless steel tubes glued together to form matricesrested upon the intact dura. Implants were positioned aband anterior to A1 at a 30-degree angle, permitting electrpenetrations nearly orthogonal to the surface of A1. Theplants and bars permitting painless head fixation duringlater recordings were embedded in dental acrylic and secto the skull with screws and inverted bolts keyed into tbone. Perioperative medications were used to minimizemal discomfort and the risk of infection. Recordings begaweeks after surgery.

Intracortical recordings were performed with multicotact electrodes constructed in our laboratory~Barna et al.,1981!. They contained 14 electrodes evenly spaced150-mm intervals~,10% error! that permitted simultaneourecordings from the entire laminar width of A1. Individuaelectrodes were 25-mm insulated stainless steel wires thwere fixed in place within the sharpened distal portion o30-gauge needle. Each channel had an impedance of 00.4 MV at 1 kHz. Headstage preamplification was followby amplification with a frequency bandpass down 6 dB aHz and 3 kHz. The reference was an occipital bone electroAuditory evoked potentials~AEPs! were averaged on-line bycomputer with a sampling rate of 1673 Hz. Input signawere simultaneously high-pass filtered above 500 Hz~rolloff24 dB/oct!, further amplified by a factor of 8, full-wave rectified, digitized at a sampling rate of 3346 Hz, and averagby computer for acquisition of multiunit activity~MUA !.

MUA is a measure of the weighted sum of action potetials recorded from neuronal ensembles surrounding thecording contacts~for details see Vaughan and Arezzo, 198!.Electrode impedance determines the radius of recordElectrodes used in the present study are capable of recorsharply differentiated MUA at 75-mm spacing~Schroederet al., 1990!. Increases of MUA above prestimulus baselilevels indicate net cellular excitation, while decreases dena net decrement in the firing rate of the sampled populaof neurons. While multichannel MUA recordings offer thadvantage of rapidly sampling synchronized unit activitymultaneously from multiple cortical laminae, the techniqdoes have important limitations that include: a greater weiin the response from larger cells and those closer to thecording tips, an inability to define the cell types that contrute to the response, and the masking of response patcontributed by individual neurons.

One-dimensional current source density~CSD! analyseswere calculated from the laminar profiles of the AEPs usan algorithm that approximated the second spatial derivaof the field potential voltages (V) from 3 adjacent points:

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2936Steinschneider et al.: Click train encoding in auditory cortex

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whereD is the second spatial derivative approximation,r isthe point at whichD is calculated, andh is the spacing of therecording sites~Freeman and Nicholson, 1975!. CSD analy-sis determines net transmembrane current flow by calculascalar quantities that indicate whether a recording site acan extracellular current source or sink at each time pointhe AEP. Sources and sinks represent locations where cuis either injected or removed from the extracellular spaand primarily index sites of synaptic activity or associatecircuit completing current flow. CSD analysis is enhancwhen active sinks and sources are differentiated from pascurrents effecting circuit closure. Thus, a sink can inda site of net depolarization or it can represent passcurrent drawn to balance hyperpolarization at an adjacsite. A source can occur at a site of net hyperpolarizationrepresent circuit completing current flow for an adjacentpolarization. These possibilities are distinguished by usMUA as an independent measure of cellular excitation ainhibition. A sink coincident with increased MUA indicatethat the sink represents EPSPs, while a source assocwith a reduction in MUA suggests that the source indehyperpolarization.

Multiple requirements must be met for accurate ondimensional CSD analysis~for reviews see Mitzdorf, 1985Vaughan and Arezzo, 1988; Vaughanet al., 1992; Schroederet al., 1995!. One requirement is the need for relatively unform activation of neurons in the planes perpendicular totrajectory of the recording electrode, thereby canceling crent flow in all directions except that orthogonal to the ctical surface. The stimuli in this study evoke nonuniforpatterns of activation that might violate basic requiremefor valid CSD analysis. However, CSD along the verticdimension is not distorted by lateral current flow when tdiameter of a neuronal ensemble generating a specific cuis one to two times the vertical length of the associasources and sinks~Nicholson and Freeman, 1975!. The ex-tended widths of dendritic trees of auditory cortical pyramdal cells indicate that synchronous activation of only a smgroup of adjacent neurons will satisfy our requirementsCSD analysis~Winer, 1984; Mitaniet al., 1985!. These the-oretical considerations are exemplified by demonstratithat, despite nonuniform activation, reliable one-dimensioCSD profiles are obtained that reflect the A1 tonotopic ornization ~Steinschneideret al., 1995; Fishmanet al., 1998!.Another concern of CSD analysis is the frequency respocharacteristics of the technique, which might lead to specaliasing of the responses. However, at frequencies of inte~,1 kHz!, capacitive, inductive, magnetic, and propagateffects of the extracellular medium can be ignored~Mitzdorf,1985!. Furthermore, except for lamina 1, variation in restance across cortical laminae is less than 10%~Hoeltzell andDykes, 1979; Mitzdorf and Singer, 1980!. This indicates thatCSD components predominantly reflect changes in curflow induced by stimulation, and not changes in tissue retance. To minimize the possibility of spatial aliasinwherein interelectrode spacing is too wide to resolve diffential activity occurring between adjacent recording contawe use electrode spacing~150 mm! capable of recordingfrom even the narrowest of cortical laminae. Finally, we d


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not analyze the CSD when there was significant deviat~.20 degrees! from a perpendicular electrode penetratiinto A1, as this might also introduce error into the computions.

Stimuli were click trains with pulse rates of 10 Hz tokHz. They were digitally constructed from clicks 100ms induration that were either of the same or alternating pola~Fig. 1!. Alternating polarity click trains had af 0 that wasone-half that of the same polarity click trains presented atsame rate. The alternating polarity click trains also containodd-numbered harmonic components that were twice theplitude of the same polarity trains, which were composedboth odd and even harmonics. Trains were 175 ms in mmum duration, with the absolute duration dependent onclick rate. Tone bursts ranging in frequency from 0.2–12kHz were presented to define the tonotopic specificity ofrecording sites. They were 175 ms in duration, with 10-

FIG. 1. ~a! Schematic diagram of the click train stimuli used in the presstudy. Trains were composed of pulses that were either of uniform or anating polarity. The fundamental frequency of alternating polarity cltrains was one-half the same polarity trains presented at an equal rate.polarity click trains contained sequential harmonics, while alternating poity stimuli were composed of odd-numbered harmonics that were each tthe amplitude of the former stimuli.~b! Schematic diagram of same analternating polarity click trains presented at pulse rates of 200 and 100~c! Summary of pitch perception findings for click trains~based on Flanaganand Guttman, 1960a, b; Guttman and Flanagan, 1964; Rosenberg, 196!.


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linear rise–decay times. All stimuli were digitally constructed, edited, and delivered at a sampling frequency44.1 kHz~Macintoshcomputer usingdigidesign Turbosynthand Sound Designer IIsoftware and hardware!. In one ani-mal, high-pass filtered click trains~cutoff 2 kHz! were alsodelivered. Fourier analysis confirmed the adequacy offiltering process. Inter-stimulus-interval was 658 ms. Stimwere presented via a dynamic headphone~Sony, MDR-7502!coupled to a 60-cc plastic tube that was placed againstear contralateral to the recording sites. ARane GE60graphicequalizer was used to enhance the headphone’s frequeresponse characteristics for one animal. All stimuli were psented at 60 dB SPL~rms!, and occasionally at 80 dBAcoustic calibrations were performed with the microphoof a sound level meter~Bruel & Kjaer, type 2236! placed inthe same relative position as the animal’s ears.

Recordings were performed in an electrically-shieldand sound-attenuated chamber. The animals were painlerestrained in custom-fitted primate chairs with their heaimmobilized using pressure fits against the bars implantethe time of surgery. Monkeys maintained an alert stthroughout the recordings. Positive food reinforcements wgiven periodically. Intracortical positioning of the electrodwas guided by the on-line analysis of the AEP and MUevoked by isolated clicks~80 dB!. Click trains and tonebursts were presented when the multicontact electrstraddled the inversion of the AEP components and midelectrode channels recorded MUA of cortical origin. Rsponse averages were generated from 75 or 100 stimrepetitions.

Animals were deeply anesthetized with sodium penbarbital and perfused through the heart with physiologicline and 10% buffered formalin when recordings were copleted. A1 was anatomically delineated using publishcriteria ~Morel et al., 1993!, and the electrode tracks weridentified and reconstructed in coronal sections stained wcresyl violet. Laminar locations of the recording sites wedefined using a combined histological and physiological pcedure. Depths of the earliest click-evoked current sinksconcurrent sources were used to locate lamina 4 and lolamina 3~Steinschneideret al., 1992!. The physiologic lami-nar profiles of the CSD and MUA were then correlated wthe measured widths of A1 and its laminae for each electrpenetration, and checked by relating the remainder oflaminar CSD and MUA profiles to expected locations fprominent current sources and sinks~Steinschneideret al.,1994!. MUA recorded in subjacent white matter and wionset and peak latencies earlier than intracortical activityascribed to activity in thalamocortical afferents.

II. RESULTS

Results are based on 40 electrode penetrations intoConsistent with earlier studies, a tonotopic organizationthe tone-evoked CSD and MUA is observed, with low bfrequencies~BF! located anterolaterally and higher BFs poteromedially ~e.g., Merzenich and Brugge, 1973; Moret al., 1993!. BFs ranged from 200–12 000 Hz in 37 penettions. Three penetrations in histologically identified postemedial A1 are included in the sample and are assume


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have BFs greater than 12 000 Hz. Twenty-two penetratihave a BF less than 2000 Hz. No differences are noamong the responses from the three animals or from theand right hemispheres.

A. Encoding of click trains in low BF regions of A1

Spectral features of click trains are predominantly ecoded within low BF regions of A1. Responses reflect tentire harmonic structure of the click trains and not justpitch, or f 0 , of the sounds. Demonstrating this result firrequires an illustration of how spectral sensitivity of recoring sites is determined. Figure 2 depicts tone-evokedsponses recorded at an electrode penetration site~site A!with a BF of 700–800 Hz. The laminar profile of CSevoked by the 700 Hz tone is shown in the left-hand columwith approximate laminar locations shown at the far leftthe figure. A characteristic sequence of cortical activationengaged. Initial current sinks are located in the thalamecipient zone of lamina 4 and lower lamina 3~depths 5 and6!. The location and timing of these sinks and surroundcurrent sources are consistent with the initial depolarizatof lamina 4 stellate cells, basilar regions of lower laminapyramidal cells and terminal portions of thalamocorticalferents ~Steinschneideret al., 1992; Tenkeet al., 1993!.These initial sinks are rapidly followed by supragranular ativation, shown by the current sinks at depths 3 and 4, wassociated passive current sources in more superficial lnae ~depths 1 and 2!. This dipolar configuration indicatedepolarization of more apical portions of pyramidal celThese initial components are followed by more variabsources and sinks that will not be further discussed.

The middle column of Fig. 2 depicts the lower laminaCSD profiles~depth 5! evoked by the indicated tone burstThere is an increase in the size of the initial current sinktone frequency increases from 200 to 700 Hz, a plateautween 700 and 1000 Hz, and a rapid change from a cursink to initial current sources at higher tone frequencies. TMUA patterns parallel the CSD findings, as shown in tright-hand column of the figure. There is an increase in bthe initial burst of MUA and the sustained activity as tofrequency increases to 700 Hz, a decline in activityslightly higher frequencies, and a sustained decreaseMUA to levels below baseline for tone frequencies greathan 1000 Hz. Association of the decreases in MUA wconcurrent sources in the CSD indicate that these lamincurrent sources represent active hyperpolarization of loneurons. Absence of a large excitatory current sink andsociated MUA increases preceding the hyperpolarizationdicate that the current sources index synaptically mediainhibition and not passive afterhyperpolarization.

Data are quantified in the graphs at the bottom of Figwhich depict both the area~solid lines! and peak response~dotted lines! elicited by the tones. Area and peak measuare taken from 5 to 35 ms following stimulus onset for tinitial CSD sinks at depths 5 and 6, and 15 to 45 ms forlater supragranular activity. There is a consistent maximbetween 700 and 800 Hz in the CSD peak and area measacross the granular and supragranular laminae. MUAsponses are measured from 5 ms following stimulus on


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FIG. 2. Tone-evoked CSD and MUA recorded from an A1 site whose BF is 700–800 Hz. The CSD laminar profile elicited by the 700-Hz tone is sthe left-hand column. Arrows denote locations of principal current sources and sinks, beginning with the earliest activation in lower lamina 3 and~initial sinks at depths 5 and 6!, followed by later supragranular sinks~depths 3 and 4!. The sources at depths 1 and 2 reflect passive current return fodeeper sinks. Approximate laminar boundaries are shown at the far left of the figure. CSD and MUA recorded to the presented tones in lower lamin~depth5! are shown in the middle and right-hand columns, respectively. Tone frequencies are shown to the left of the middle column. Arrowheads immediathe timelines indicate stimulus onset and offset. The graphs at the bottom of the figure illustrate the spectral sensitivity of the CSD components anlamina 3 MUA. Solid curves denote area measurements of the responses, while dotted curves denote peak responses. Maximum responses occand 800-Hz tones in all cases. See text for details.

2939 2939J. Acoust. Soc. Am., Vol. 104, No. 5, November 1998 Steinschneider et al.: Click train encoding in auditory cortex

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FIG. 3. MUA recorded from the same lower lamina 3 site~depth 5! as that shown in Fig. 2. Responses evoked by the same and alternating polarity clickare shown in the left-hand and middle columns, respectively. Click train rate is shown at the far left of the figure. Note the absence of phase-lockelicited by the lower rate click trains. Complex changes in response amplitudes are related to the relationship between the harmonic structure ofand the spectral sensitivity of the recording site. The right-hand column depicts this relationship by illustrating the harmonic structure of the clickrelation to the 700–800 Hz region of maximum spectral sensitivity. Large amplitude responses contain harmonics within this spectral region. Thgraphs summarize measurements of sustained and peak responses to the same~solid lines! and alternating~dotted lines! polarity click trains. See text fordetails.

2940 2940J. Acoust. Soc. Am., Vol. 104, No. 5, November 1998 Steinschneider et al.: Click train encoding in auditory cortex

inar CSDequenced columnsoked bythe400-Hz same

FIG. 4. CSD evoked by the click trains during the same electrode penetration as that shown in Figs. 2 and 3. The left-hand column depicts the lamprofile evoked by the 500-Hz alternating polarity click train. This stimulus, which evokes large amplitude MUA in lower lamina 3, also initiates a sof current sources and sinks nearly identical to the 700-Hz BF tone. Arrows denote the principal current sources and sinks. The middle and right-hanillustrate the lower lamina 3~depth 5! CSD evoked by the same and alternating polarity click trains, respectively. Largest amplitude responses are evthe 400-Hz same polarity and 500-Hz alternating polarity click trains~arrows!, which can be ascribed to low-order harmonics of these stimuli lying withinBF region of this site. Graphs at the bottom of the figure depict area response measures at the principal sites of sources and sinks. In all cases, thepolarity and 500-Hz alternating polarity click trains evoke maximal or near maximal responses.

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falling below baseline levels. This finding indicates the preence of a flanking, inhibitory region at frequencies somewhigher than the BF.

Responses to click trains reflect the tonotopic sensitivof recording site A. Figure 3 illustrates MUA recorded frothe same lower lamina 3 site~depth 5! as shown in the pre-


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FIG. 5. Salient CSD and MUA waveforms evoked by the 500- and 1000-Hz alternating click trains and low-frequency tones from an electrode siteis 200–300 Hz:~A! depicts the supragranular sink,~B! the lower lamina 3 MUA, and~C! the granular CSD sink. Lower lamina 3 MUA is recorded 600mmbelow the supragranular sink and 150mm above the granular sink. Tone-evoked lower lamina 3 MUA ‘‘on’’~D! and sustained~E! response graphs indicatmaximum activity at 200 and 300 Hz, respectively;~F! illustrates the click train-evoked MUA, and shows that the 500-Hz alternating polarity click t( f 05250 Hz) elicits the largest response. Drop lines facilitate comparisons between tone- and click train-evoked MUA and CSD components. In~B!, note thatthe ‘‘on’’ response in the MUA evoked by low-frequency tones~unfilled arrow! is absent in the click train responses. See text for details.

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vious figure. Comparisons between responses to the spolarity ~left-hand column! and alternating polarity~middlecolumn! click trains reveal a complex pattern of activity this best explained by relating the harmonic structure ofstimuli to the tonotopic specificity. For instance, MUA to th500-Hz alternating polarity click train is much larger than t


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ing site. Similarly, the second harmonic of the 400-Hz sapolarity click train is near the BF, while harmonics of thalternating polarity click train fall outside this spectral rgion. These differential spectral patterns explain the maedly enhanced response evoked by the 400-Hz same poclick train when compared to its alternating polarity countpart. Identical rationales can explain the differences insponse sensitivity for the other click train comparisons. Finstance, the 300-Hz alternating polarity click train elicitsmuch larger response than its same polarity counterpart.fifth harmonic of the alternating polarity stimulus is near tBF, in contrast to the harmonics of the same polarity cltrain. A 50-Hz reduction in click train rate evokes a larg

FIG. 6. Click train-evoked MUA recorded from a lower lamina 3 site. Tlower left-hand graph depicts the sustained activity evoked by the toMaximum activity is evoked by the 1000-Hz tone. Frequencies betw1600 and 2500 Hz elicit sustained inhibition. Same polarity and alternapolarity click train responses are shown in the left- and right-hand columrespectively. Click train rate is shown at the far left of the figure. Phalocked activity is only evoked by click trains with rates less than 50 Hz. Tlower right-hand graph depicts the sustained MUA amplitudes evokedthe click trains. The largest amplitude sustained response is evoked b1000 Hz same polarity click train~solid arrow in the above waveforms!,consistent with the BF of this site. The largest alternating polarity click trresponses are evoked at rates of 300 and 2000 Hz~asterisks!. The seventhharmonic of the former, and thef 0 of the latter click train, are near the BF‘‘Off’’ responses are evoked by the 2000-Hz same polarity and 1000alternating polarity click trains~unfilled arrows!.


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response for the same polarity stimulus. Now, the third hmonic of the 250-Hz same polarity click train lies near tBF, while the harmonics of the alternating polarity fall ouside this region. There is also a lack of response to the 10and 2000-Hz click trains in both the same and alternatpolarity conditions. For these four stimuli, low harmoncomponents are present in the inhibitory surround flankthe spectral sensitivity curve and appear to dominate thesponse to the total sound. Of importance is the absencsynchronized phase-locked activity in the neuronalsembles to the individual click pulses for even the lowfrequency click trains.

Response differences are quantified at the bottom of3. The 500-Hz alternating polarity click train elicits thmaximum area response~left-hand graph!. The next largestresponse is to the 200-Hz alternating polarity click train.seventh harmonic is at the BF of 700 Hz. The 250- a400-Hz same polarity click trains elicit the next largest rsponses, and their harmonics are also near the BF. Simpatterns, with minor variation, are seen for the peak iniresponses~right-hand graph!.

CSD profiles at site A demonstrate comparable featuof spectral sensitivity to click trains~Fig. 4!. The left-handcolumn illustrates the laminar CSD profile elicited by th500-Hz alternating polarity click train. This stimulus, whicelicits large amplitude MUA as shown in the previous figuproduces a laminar profile of activity very similar to thevoked by the 700-Hz tone~see Fig. 2, left-hand column!.This finding indicates that excitatory stimuli engage a simisequence of synaptic events across laminae and illustratestability of the multicontact electrode recordings over timThe middle and right-hand columns depict the lower lam3 CSD at depth 5 to same and alternating polarity cltrains. Once again, there is a near absence of ensemble-phase locking to the individual click pulses. The largest itial current sinks are evoked by the 400-Hz same polaand 500-Hz alternating polarity click trains~arrows!, mirror-ing the MUA responses shown in Fig. 3. Furthermore, trelative specificity is maintained in the amplitudes of tother granular and supragranular current sources and sas depicted in the graphs at the bottom of the figure. Forthree measures, the 400-Hz same polarity and 500-Hz anating polarity click trains evoke maximal or near maximresponses. Thus, the combined data for the MUA and Cindicate that this site is sensitive to the spectral contenclick trains, and responds most vigorously when low numharmonics are in the vicinity of the 700-Hz BF.

Remarkably, the previous example demonstratesdifferential spectral encoding of click trains in A1 can begwith the earliest depolarization in the thalamorecipient zoof lamina 4 and lower lamina 3. Spectral encoding occdespite the fact that all trains contain the same initial clickstimulus onset. Thus, there is a very rapid integrationinformation pertaining to spectral content in the earliest ctical responses, suggesting that subcortical processingforms some form of spectral encoding. However, onsetsponses evoked by thalamocortical fiber input may not bconsistent indicator of click train spectral content. Instelater and more sustained activity reflecting intracortical p

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FIG. 7. The upper half of the figure depicts middle laminae MUA simultaneously recorded at 150-mm intervals in response to 100-Hz click trains presentas same polarity stimuli and at 60 dB~left-hand column!, 80 dB ~middle column!, and as an alternating polarity train at 80 dB~right-hand column!.Approximate depth of lamina 4 is indicated at the far left of the figure. Peak tone-evoked responses at depth ‘‘A,’’ located in lower lamina 3, arethe lower right-hand graph and indicate a maximum response at 2600 Hz. Responses at the same middle laminae locations are nearly identical,ensemble-wide phase-locking at 100 Hz, and are independent of suprathreshold intensity and pulse polarity pattern. MUA evoked by same polaritypresented at 60 dB and recorded from depth ‘‘A’’ are shown in the bottom of the figure, and demonstrate phase-locked activity that dissipates at r125 Hz.

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cessing may represent a better measure of the spectralposition of these complex stimuli~Fig. 5, site B!. At this sitewith a BF of 200–300 Hz, tone-evoked MUA consist of ainitial ‘‘on’’ response~unfilled arrow! followed by later andmore sustained activity@Fig. 5~B!#. Alternating click trainsof 500 and 1000 Hz fail to evoke an ‘‘on’’ response. In thgranular layer, CSD sinks are temporally coincident with


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initial ‘‘on’’ response components in the MUA to the lowfrequency tones@Fig. 5~C!, left-most vertical drop line#. De-spite the presence of these current sinks evoked by the ctrains, they are not associated with coincident MUA rsponses.

In contrast, the later, supragranular sinks shown in F5~A!, located 600mm above~B!, are associated with the


FIG. 8. MUA recorded from a lower lamina 3 site with a maximum tone-evoked response elicited at 5000 Hz~lower right-hand graph!. Phase-lockedresponses are evoked by same polarity click trains at rates as high as 150 Hz.

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click train-evoked MUA and demonstrate the spectral encing of these stimuli. The current sinks in Fig. 5~A! evoked bythe tones are characterized by an increase in latency afrequency of stimulation decreases from 500 to 200 Hz. Ting of these supragranular sinks is nearly identical topeaks of the more sustained tone-evoked MUA in Fig. 5~B!.The current sink in Fig. 5~A! evoked by the 500-Hz alternaing polarity click train is longer in latency than that asso


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ated with the 1000-Hz alternating polarity click train, and tpeaks of these sinks are temporally coincident with the pein the sustained MUA to the same stimuli. Latencies of tsupragranular sink and MUA to the 500-Hz alternating plarity click train are nearly coincident with those elicited bthe 200- and 300-Hz tones. The latter are near thef 0 of thisclick train. A different pattern is seen for the 1000-Hz altenating polarity click train, where timing of the supragranul


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FIG. 9. CSD recorded from the same lower lamina 3 site shown in the previous figure. Phase-locked CSD components are evoked by click trainsto 300 Hz.
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sink and MUA is coincident with the 500-Hz tone, consistewith its f 0 . These findings illustrate that the click trainevoked MUA is dependent on the tonotopic sensitivitythis site, and that this sensitivity is based on activity derivfrom intracortical processing and not the initial cortical acvation.


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Responses are quantified in the graphs shown in~D!,~E!, and ~F! of Fig. 5. The 200-Hz tone evokes the largeMUA initial ‘‘on’’ response @Fig. 5~D!# and the 300-Hz toneelicits the largest sustained response@Fig. 5~E!#. A troughthat dips below baseline levels between about 1000 and 2Hz is also observed, suggesting an inhibitory flank at th


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FIG. 10. CSD and MUA laminar profiles simultaneously recorded at 150-mm intervals in response to an 8500-Hz tone. CSD and MUA located at depthmaximally responsive to the 8500-Hz tone~left and center graphs!. MUA recorded 900mm deeper at depth 2, located at the boundary of lamina 6 andwhite matter, has an onset and peak that is 3 ms earlier than that at depth 1. This indicates the MUA is of thalamocortical fiber origin. The dottedin the MUA profile facilitates this comparison. These afferents are maximally responsive to a 6000-Hz tone, suggesting that they are primarilypassage.

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higher frequencies. As predicted by the tone response spficity, the 500-Hz alternating polarity click train with it250-Hz f 0 yields the largest response for this class of stim@Fig. 5~F!#. The largest same polarity click train respon


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harmonic interactions that are more intense for the formstimuli. This in turn may be due to a greater numberharmonics lying within the inhibitory surround region of thsite. While not shown, the lowest rate click trains~i.e., 10–100 Hz! fail to elicit phase-locked activity in the ensembresponses.

MUA phase-locked to individual click train pulses is na prominent feature of the responses at most low BF sWhen it does occur, the upper limit is almost always lethan 100 Hz~Fig. 6, site C!. MUA at this lower lamina 3 siteis phase-locked to individual pulses at rates less than 50It is important to stress that the absence of phase-lockinthe synchronized activity of neuronal ensembles at higrates, as measured in the MUA or CSD, does not preclthe possibility that isolated neurons are capable of generaa phase-locked response in these low BF regions of A1.BF of site C is 1000 Hz, as measured by sustained actifrom 35 ms after tone onset until offset~lower left-handgraph!. Suppression of MUA to levels below baseline occufrom 1600 to 2500 Hz. Similar to other low BF sites, thlocation encodes click train spectral content. Because ‘‘oresponses evoked by click trains at this site contain spectinsensitive activity elicited by isolated clicks, sustainMUA beginning immediately after the transient responsdissipate at 35 ms and extending until stimulus offset atms is quantified~lower right-hand graph!. Maximum MUAis evoked by the 1000-Hz same polarity click train, whihas af 0 equal to the BF of this site~solid arrow!. The nextbest same polarity click train response occurs at a stimularate of 500 Hz. Now, the second harmonic equals theThe largest responses evoked by alternating polarity ctrains occur at rates of 300 and 2000 Hz~asterisks!. Theseventh harmonic of the 300-Hz alternating polarity clitrain and thef 0 of the 2000-Hz train are near the BF. Th2000-Hz same polarity click train and the 1000-Hz alterning polarity train elicit minimal sustained activity. Thef 0 ofthe former, and third harmonic of the latter, fall within thinhibitory flank of the spectral sensitivity curve. Both rsponses contain an ‘‘off’’ component, presumably due torebound from inhibition~open arrows!. The CSD profilesand MUA from other depths evoked by the tones and cltrains demonstrate a similar organization~not illustrated!.

B. Encoding of click trains in high BF regions of A1

The previous section demonstrates that low BF regiof A1 are sensitive to the spectral composition and polapattern of the click trains, and have response maxima demined by the tonotopic organization. Phase-locking withneuronal ensembles consistently remains below 100 Hz,psychoacoustic boundary for temporal encoding of cltrain pitch. In contrast, higher BF regions of A1 displaydifferent pattern of activity in response to click trains. Thelocations are relatively insensitive to spectral characterisof click trains, but are instead sensitive to temporal stimufeatures.

Figure 7~D! depicts, in its upper half, MUA simultaneously recorded at 150-mm intervals through middle cortical laminae in response to 100-Hz click trains of samelarity presented at 60 and 80 dB, and alternating pola


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presented at 80 dB. The BFs of these locations are ab2600 Hz. Peak tone-evoked response measures for d‘‘A,’’ located in lower lamina 3, are shown in the graph ithe lower right-hand portion of the figure. This site responto 100-Hz click trains with prominent ensemble-wide phalocking to the click rate that is insensitive to suprathreshintensity changes, as well as changes in pulse polarityalter the stimulus spectrum. Phase-locked responsesmaximal in lamina 3, and are presumably dominated by schronized action potentials of local pyramidal cells. Addtionally, the phase-locked activity in lower lamina 3 MUdissipates above 125 Hz, within the transition zone demcating temporal from spectral pitch perception mechanis~bottom left portion of figure!.

As discussed earlier, temporal encoding mechanismstermining click train pitch are dominant at rates less than 1Hz and are mediated by high-frequency auditory chann~Rosenberg, 1965!. An ever decreasing degree of pitch bason temporal periodicity, however, occurs for click trainsf 0’s up to 200 Hz. If phase-locked activity in A1 is relatedthis temporal pitch representation, then evidence of perioresponses at these higher repetition rates should be presthe cortical level. Supporting evidence is observed intemporal encoding capabilities of a lower lamina 3 swith a 5000-Hz BF~Fig. 8, site E!. Tone frequency plottedagainst peak response amplitude is shown in the lower rihand portion of the figure. Synchronized phase-locked acity is present at click train rates up to 150 Hz. However, tCSD simultaneously recorded from the same site contaphase-locking of the current sources and sinks at click raup to 300 Hz~Fig. 9!. This finding indicates that synchronized synaptic activity in A1, derived from subcortical inpucan phase-lock to click rates that support even the higrates of click train pitch perception based on temporal podicity.

Confirmation that A1 has access to synchronizthalamocortical fiber input with the capacity to temporaencode click trains at rates of at least 300 Hz is provideda penetration into a site with a BF of 8500 Hz~Fig. 10, siteF!. Laminar recordings at 150-mm intervals in response topresentation of an 8500-Hz tone reveal a cortical MUmaximum at the base of lamina 3 that principally represeensemble activity of cortical cells~depth 1!. The MUA atthis depth occurs at the focus of the earliest, large amplitcurrent sink. The MUA at depth 2 is recorded near tboundary between the gray and white matter~900mm belowdepth 1!. This activity has a peak latency 3 ms earlier ththat recorded from depth 1, and primarily reflects activwithin thalamocortical afferent fibers. The graphs at the btom of the figure illustrate that maximum amplitudes of tlower lamina 3 sink and MUA are elicited by the 8500-Htone. The thalamocortical fibers have a different BF fromcortical MUA and CSD~6000 Hz!, suggesting that thesafferents are primarily fibers of passage.

Comparison of click train-evoked MUA simultaneousrecorded from lower lamina 3~depth 1! and thalamocorticalfiber afferents~depth 2! illustrates the differential capacityfor phase-locking between the two populations~Fig. 11!.Synchronized activity in the cortical responses at this lo


activityty at rates

FIG. 11. MUA evoked by click trains at depths 1 and 2 shown in the previous figure. MUA of cortical origin in lower lamina 3 contains phase-lockedthat dissipates above 75 Hz. In contrast, the simultaneously recorded MUA of thalamocortical fiber origin contains prominent phase-locked activiof 300 Hz.

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tion is markedly diminished at a rate of 100 Hz~left-handcolumn!, whereas thalamocortical fiber MUA containsphase-locked response through rates of 300 Hz~right-handcolumn!. In our sample, five penetrations~12.5%! containthalamocortical fiber afferent MUA in infragranular laminaor subjacent white matter that phase-lock to click trains


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high rates. The upper limit of synchronized phase-locking300 Hz in three cases, 400 Hz in another, and 200 Hz inlast.

Synchronized phase-locking to the 100-Hz click traare segregated in the higher BF regions of A1~Fig. 12!. Thissummary depiction of all recorded lower lamina 3 MU


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sites reveals that of the 24 penetrations whose BFs are 2Hz or less, only 1 location~900-Hz BF! has prominentphase-locking of the MUA at 100 Hz. MUA at six of eighpenetrations with a BF of 1000–2250 Hz consists of‘‘on’’ and ‘‘off’’ response with an intervening period of suppression that is most pronounced immediately after the ‘‘oresponse and persists throughout the duration of the stimuAt locations with a BF less than 1000 Hz, the 100-Hz clitrain either fails to evoke a clear MUA response, or tstimulus elicits an ‘‘on’’ or low-amplitude sustained response. In contrast, phase-locked activity is evoked by100-Hz click train at 12 of 16 locations with a BF of 260Hz or greater. This activity can be superimposed on eitsustained increases or decreases in the MUA. At sites wthere is both phase-locked activity and MUA suppressbelow baseline levels, there is a tendency for the perioresponses to be delayed and begin following an initial ‘‘oresponse and period of MUA inhibition.

A greater extent of synchronized phase locking to100-Hz click train occurs in the CSD profiles at the salower lamina 3 sites~not illustrated!. Phase-locking is ob-served at 13 of 17 locations with a BF between 500 and 2Hz, and at the higher BF sites that do not display thissponse pattern in the MUA. This finding indicates that th

FIG. 12. Summary of all MUA recorded in lower lamina 3 and evoked100-Hz click trains from the 40 electrode penetrations of the study. BFthe sites are indicated to the left of the waveforms. Asterisks above theindicate click train presentation at 80 dB. Phase-locked activity is differtially distributed within higher BF sites.


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is a greater capacity for phase-locking at 100 Hz in the schronized activity of thalamocortical afferents, which in tuevokes synchronized synaptic responses as manifested iCSD. There is also a greater extent of phase-locking incortical MUA at lower repetition rates. For instance, t50-Hz click train was presented during 38 of 40 electropenetrations into A1. Synchronized responses occur at msites with a BF greater than 700 Hz. The 50-Hz click traevokes minimal activity at the lowest BF sites in our samp

The effects of increasing click intensity from 60 to 8dB on the encoding of click train rate was examined durfour penetrations with BFs ranging from 2600–10 000 HNo increase in the upper limit of synchronized responsesobserved in the CSD and MUA, though a modest increasresponse amplitude was seen at one site. At two siteslower BFs where 100-Hz click trains presented at 60 dBnot evoke synchronized responses, increasing the intensi80 dB failed to elicit a qualitative change in the respon

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FIG. 13. MUA summed across middle laminae evoked by a 200-Hz ctrain that is unfiltered and high-pass filtered above 2 kHz. BF of this sit700 Hz. The sustained response evoked by the unfiltered stimulus is enated after filtering. See text for details.

FIG. 14. Click train-evoked MUA at a lower lamina 3 site whose BF8500 Hz. Phase-locked activity is present at rates up to 200 Hz. High-filtering has no significant effect on the response patterns.


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patterns. These findings suggest that stimulus intensity isa major determinant of the synchronized responses at tsuprathreshold levels.

C. Effects of high-pass filtered click trains on A1responses

High-pass filtering of click trains raises the perceptuboundary at which the transition from periodicity to spectpitch occurs to levels above the usual 100–200 Hz ra~Guttman and Flanagan, 1964!. This effect could be due toan increase in the upper limit of synchronized phase-locresponses in higher BF regions of A1. On the other hahigh-pass filtering could decrease competing spectral ening information emanating from lower BF regions of Athereby making more salient weaker temporally basedsponse patterns, especially at high rates of stimulation.ditionally, phase-locked activity could appear in lower Bregions. In order to investigate these possibilities, we exined the physiological effects produced by click trains higpass filtered above 2 kHz during 15 electrode penetrationone monkey.

High-pass filtering elicits characteristic changes inevoked activity within low and middle BF regions of A1 thare related to effects on spectral encoding of the stimTypically, there is a decrease in the degree of excitation pduced by click trains, exemplified by the summed, midlaminae MUA from a site with a BF of 700 Hz~Fig. 13, siteG!. An unfiltered 200-Hz click train evokes MUA with asustained increase above baseline levels that persistsmore than 100 ms after stimulus offset. The response is mlikely based on harmonic components of the stimulus fallwithin the spectral response area of the recording site. Tsupposition is supported by the absence of evoked actwhen the same stimulus is high-pass filtered above 2 kHzthis condition, remaining spectral components lie outsidespectral response area of the site and fail to elicit evoactivity. This pattern is observed in six of eight penetratiowith a low to moderate BF. In the seventh penetration, stained suppression produced by a 100-Hz click train at awith a BF of 600 Hz is decreased following high-pass filteing. In the eighth site with a BF of 2250 Hz, a high-pafiltered 100-Hz click train elicits a stronger sustainedsponse than its unfiltered counterpart, presumably beclow-frequency harmonic components that evoke inhibitare removed from the stimulus. In no case did phase-locresponses appear in these BF regions following high-pfiltering of the click trains. High-pass filtering has no majeffect on synchronized phase-locked activity in high BFgions, exemplified by the lower lamina 3 MUA from a siwith a BF of 8500 Hz~Fig. 14, site H!. Both filtered andunfiltered click trains evoke phase-locked activity of simiamplitude at rates up to 200 Hz.

III. DISCUSSION

A. Summary of findings and relationship to click trainpitch perception

Correlating neural responses with psychoacoustical pnomena is a necessary first step for identifying physiolog


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mechanisms that underlie pitch perception. Ideally, neuresponses would be identified that differentiate betweencoding of click train pitch based on pulse rate andf 0 ~Flana-gan and Guttman, 1960a, b; Guttman and Flanagan, 1Rosenberg, 1965!. f 0 encoding of click trains should occur af 0’s greater than 200 Hz and be dependent on the polapattern of the clicks. Pitch based on pulse repetition rshould be independent of click polarity pattern, and occurates of at least 100 Hz. Furthermore,f 0 encoding of clicktrain pitch should occur in low-frequency channels of tauditory system, while rate encoding should be locatedhigh-frequency channels. A1 responses conform to theseceptual requirements. Both temporal and spectral formsclick train encoding are demonstrated. Rate of stimulationtemporally encoded at pulse rates below 100–200through synchronized phase-locked responses of neurensembles, is independent of click polarity pattern, andcurs in higher BF regions. Limiting frequencies foensemble-wide phase-locking occurs in the transition zbetween which the spectral and temporal forms of click trpitch predominate. In contrast, the spectral form of encodis dependent on the polarity pattern of the stimuli, occurslower BF regions, and resolves both thef 0 of higher clicktrain rates and the major harmonics of the stimuli throulocal maxima of activity. These maxima are determinedthe tonotopic organization of the A1 sites.

Boundary shifts between spectral pitch and pitch baon repetition rate elicited when high-pass filtered click traare used, or when low- or high-frequency masking noisesimultaneously presented with the click trains, can beplained by A1 activity~Guttman and Flanagan, 1964; Roseberg, 1965!. The temporal form of pitch perception gradualweakens at rates above 100 Hz as the upper limit of syncnized phase-locked activity is approached. High-frequenoise would mask the less secure and lower amplitude phlocked activity to faster click train rates, allowing the competition in pitch perception between temporal encodwithin high BF regions of A1 and spectral encoding in loBF regions to shift in favor of the latter. In contrast, lowfrequency noise or high-pass filtered click trains would dgrade the spectral representation of very lowf 0’s and shiftthe perception towards a temporally based pitch encodehigher BF regions.

Compelling evidence supporting the existence of tseparate mechanisms for pitch perception is presentedseries of experiments by Carlyon and colleagues~Carlyonand Shackleton, 1994; Shackleton and Carlyon, 1994; Pand Carlyon, 1995!. In these studies, harmonic complexwere summed in either same or alternating phase, andbandpass filtered to accentuate low, middle, or high frequcies. The pitch of alternating phase complexes was an ochigher~i.e., twice the pitch! than that generated by summinsame phase harmonics when the sounds were high-pastered. This finding is consistent with the pitch of the sounbeing determined from the periodicity of the stimulus wavforms, because the high-pass filtered alternating phstimuli had twice the number of waveform peaks thansame phase complexes. Low-pass filtered complexes wequated according tof 0 , and not stimulus periodicity. Band


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pass filtering at moderate frequencies produced two differesults based on the resolvability of the harmonics. Whigher f 0’s and resolved harmonic components, pitch wdetermined by thef 0 . At lower f 0’s and filtered stimuli con-taining only unresolved harmonics, pitch was basedstimulus periodicity. Transition between the two formspitch perception occurred at af 0 of about 125 Hz. Sensitivityto f 0 differences was best when the combination off 0 andlow-, middle-, or high-pass filtering was such that bostimuli were composed of only resolved or unresolved hmonics, and worse when comparisons were between stiwith resolved versus unresolved harmonics. Furthermoref 0

encoding using only unresolved components was degrawith stimuli less than 100 ms in duration, whereas the satask using resolved harmonics was accurate even wsounds had a duration of only 25 ms. These experimeprovide strong evidence that resolved and unresolvedmonics are processed using different perceptual mechaniand that the mechanism associated with unresolved harmcomponents uses waveform periodicity as a key featurethe process.

Our data are in agreement with these results, providadditional weight to the hypothesis that temporal encodwithin A1 based on synchronized phase-locked activity iphysiological finding relevant for pitch perception and njust an epiphenomenon of cortical activity. For instance,find that neural activity in A1 reflects twice thef 0 at lowerrates of stimulation for alternating polarity components, athat 125 Hz is within a transition region between spectral aperiodicity encoding. When the extent of ensemble-wphase-locking in A1 between 50- and 100-Hz click trawas compared, we found that periodic MUA responsestend into middle BF regions at the lower stimulus repetitirate. This finding parallels those of Carlyon and colleaguand indicates that an important parameter determinwhether phase-locking in A1 occurs is the critical bandspecific BF regions. Thus, when multiple harmonic compnents fall within a critical band of a BF region, phase-lockresponses will be generated and repetition pitch will be amented. There are also parallels in our data and the reqment that pitch encoding of unresolved harmonics needprolonged stimulus duration, while spectral encoding canperformed within 25 ms. Examination of Fig. 12 reveals that many A1 locations, phase-locking is delayed relativestimulus onset. Additionally, measures of pitch basedpulse rate would require a number of stimulus cycles tocur in order for rate to be determined in the neural responIn contrast, spectral components of click trains can besolved in the initial cortical responses, though sustainedtivity does yield more accurate measures.

The ability of amplitude-modulated~AM ! noise andother sounds with absent spectral cues to evoke sensatiopitch and melody provides additional evidence for the extence of pitch-related mechanisms based on the encodinwaveform periodicity~Burns and Viemeister, 1981; Warreand Wrightson, 1981; Pierce, 1991!. Upper limits of period-icity pitch ranged from 200 to 500 Hz, higher than the phalocked activity observed in our sample of cortical MUAHowever, thalamocortical fiber MUA input into A1 and su


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sequent thalamorecipient zone CSD components do phlock at these higher rates, suggesting that informationevant for temporal pitch at high rates has a cortical correlHigher stimulus repetition rates generally evoke very wepitch perceptions based on timing cues, perhaps secondathe inability of A1 ensembles to synchronously fire at raprates of stimulation. It must be conceded, however, that wperiodicity pitch at high rates of stimulation may be bassolely on other mechanisms, including its mediation by scortical auditory centers.

Phase-locked activity in A1 populations may also berelevant mechanism for the perception of sensory connance and dissonance. Sensations of roughness, the petual correlate for audible beats in a sound, correlate wjudgments of sensory dissonance~Terhardt, 1974a, 1977!.These beats are thought to be encoded by the temporavelope of evoked neural responses~Terhardt, 1974b!. Thepronounced amplitude fluctuations in the cortical responevoked by lower frequency click trains could be a powersignal for sensory roughness. Psychoacoustical studiescate that consonance of two-tone complexes is maintawhen the frequency difference exceeds the critical bawidth, while maximal dissonance occurs when the frequedifference is about one quarter the bandwidth~Plomp andLevelt, 1965!. Published values of maximum dissonancespecific mean frequencies of two-tone complexes andclick trains are in accord with present findings~Plomp andSteeneken, 1968; Terhardt, 1974b!, wherein high BF regionsdisplay synchronized phase-locking at 100 Hz, while sychronized phase-locking in regions with BFs between 7and 2000 Hz are generally limited to rates of 50 Hz.

Present data support models of pitch perception thatlize template matching of resolved, harmonic componentdetermine thef 0 ~e.g., Goldstein, 1973; Terhardt, 1974a!.Responses within low BF regions of A1 encode stimuharmonics, without special regard to thef 0 . Foci of maxi-mum activity are determined by the harmonic structure ofstimulus interacting with the excitatory and inhibitory frequency bands of the A1 sites. Our findings thus support edence indicating that A1 utilizes a rate code for encodingspectral structure of complex stimuli, producing distributpatterns of activation across tonotopically organized auditcortex unique for each sound~e.g., Ehret, 1997; Schreine1998!. However, this scheme does not identify mechanisthat might be used for template matching in order to formunitary perception of virtual pitch. It is also unclear wheththese distributed patterns of A1 activation are capable of sporting the fine pitch discrimination capacities for thef 0 ofharmonic sounds. Most importantly, these findings doexclude other mechanisms, such as those that use autoclation, which might be operative in A1 but underappreciatby our techniques, or occurring at other levels of the auditsystem~e.g., Meddis and O’Mard, 1997!.

B. Relationship to other auditory physiologicalstudies

Cariani and Delgutte~1996a, b! provide powerful ex-perimental data supporting an autocorrelation methodpitch perception by demonstrating that most pitch pheno


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ena can be adequately explained by defining the peakall-order interspike interval distributions within the summactivity of auditory nerve fibers. The major difficulty wittheir analysis was the failure to account for pitch basedrate for lower frequency alternating polarity click trains. Taccount for this discrepancy, the authors suggest that a mlikely mechanism uses phase-locking to click rate in theditory nerve fiber population, especially those with highBFs. This conclusion is similar to that presented here,suggests that mechanisms important for low-frequency podicity pitch is initiated in the auditory nerve and maintainthrough A1.

For stimuli that might engage autocorrelation methowithin the auditory nerve to encode pitch, a transformatfrom a temporal code to a code utilizing rate of excitatiand topographic organization has been suggested to occthe inferior colliculus ~Langner and Schreiner, 1988Schreiner and Langner, 1988!. This finding suggests the development of a topographic organization based not on sptral content, but rather one based on pitch. A pitch represtation in human auditory cortex has been proposed franalysis of neuromagnetic responses to multiharmonic tcomplexes~Pantevet al., 1989, 1996!. While provocative,this and other studies found no evidence for an A1 orgazation based on thef 0 of harmonic sounds~Schwartz andTomlinson, 1990; Fishmanet al., 1998!. In contrast, re-sponses reflect the harmonic structure of the stimuli and trelationship to spectral tuning curves. Other means of pencoding are clearly not excluded by these data, and incthe possibility of differential activity along isofrequenclines in A1 to distinguish stimuli with similar spectral content but different pitches, or pitch representation due to sptral integration within nonprimary auditory cortex~Raus-checker et al., 1995; Langneret al., 1997!. The latterpossibility is especially intriguing, since studies in the humhave indicated that nonprimary auditory cortex in the nodominant hemisphere plays a key role in pitch process~Zatorre, 1988; Divenyi and Robinson, 1989; Robinet al.,1990; Zatorreet al., 1992, 1994!. In this scheme, A1 activityencoding temporal and spectral features of harmonic cplexes would serve as input for later processing stages wsecondary auditory cortex in order to extract the pitch ofsounds.

There is close correspondence between the presensults and previous examinations of click train-evoked phalocking activity in A1. The upper limit of phase-lockeevoked potentials in the unanesthetized cat is 200 Hz~Gold-steinet al., 1959!. Isolated pyramidal cells recorded from thunanesthetized cat typically phase-lock to the repetitionof click trains with a median limiting rate of 50–100 Hz,limiting rate greater than 100 Hz in 32%, and an upper limgreater than 300 Hz~Ribaupierreet al., 1972!. An additionalpopulation of cortical neurons, characterized by short dution action potentials~‘‘thin spikes’’! and thought to represent lamina 4 stellate cells, is able to phase-lock to ctrains at rates up to 400 Hz. The present study has shphase-locking in the cortical CSD and thalamocortical affent MUA at rates comparable to both the ‘‘thin spikingcells in A1 and other studies examining click train encod


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in the medial geniculate nucleus~Rouiller et al., 1981;Rouiller and Ribaupierre, 1982!. Thus, it appears that phaselocked input into auditory cortex may reflect the upper limof pitch encoding based on temporal mechanisms.

Limiting rates for A1 phase-locked activity in both ouensemble data and in the studies cited above are greatersimilar investigations examining single unit responses inof anesthetized cats~e.g., Eggermont, 1991, 1994; Eggemont and Smith, 1995; Schreiner and Raggio, 1996!. In thesestudies, phase-locked responses always dissipate atgreater than 32 Hz. However, a profound decrease in phlocked activity occurs in cat A1 following administration obarbiturates~Goldsteinet al., 1959; Makelaet al., 1990; Eg-germont and Smith, 1995!. This consideration minimizes thdiscrepancy between the upper limit of synchronized phalocking to clicks trains in our study using awake monkeand those performed in anesthetized cats.

Finally, it is necessary to address the relevance ofsemble activity as physiological indices important for encoing of click trains. Using a technique of MUA recording versimilar to that utilized in the present study, Nelken and cleagues~1994! determined that ensemble recordings are stistically more stable than single unit activity in cat A1, anhave comparable temporal and spectral response specties. These findings indicate that ensemble recordings gfidelity without significant loss of response specificipresent in single unit responses. Additionally, analysisresponses in A1 evoked by complex stimuli has led toconclusion that synchronized activity of neuronal ensembis more likely relevant for sound processing than the activof single neurons, may more accurately encode imporsound parameters, and may lead to improved activationcortical areas involved in further sensory process~Creutzfeldt et al., 1980; Eggermont, 1994; Wanget al.,1995; deCharms and Merzenich, 1996!.

IV. SUMMARY AND CONCLUSIONS

Encoding of click trains in primary auditory cortex oawake monkeys is examined in order to clarify neumechanisms associated with pitch perception. A1 differtially encodes temporal and spectral features of click traTemporal features are encoded within high best frequeregions, and occur at rates less than 100–200 Hz via schronized phase-locked activity in the responses of cortensembles. Activity reflecting thalamocortical input into Ahas an upper limit of ensemble-wide phase-locking abtwice that of the cortical ensembles. Spectral features of ctrains are encoded in low best frequency regions of A1, aoccur at higher rates of stimulation. Responses in low bfrequency regions are sensitive to the pitch polarity patteand encode both thef 0 and other harmonics of the trains va rate code that is determined by the tonotopic sensitivitythe recording sites. High-pass filtered click trains decrespectral encoding in low best frequency regions but doalter phase-locked activity in other locations. Physiologiresponses parallel multiple features of human pitch perction for click trains, and support the existence of two, distinmechanisms in A1 involved in pitch perception. The firmechanism utilizes resolved harmonic components, prod


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ing patterns of distributed neural activity across A1 withsponse maxima based on the tonotopic organization andmonic composition of the sounds. This form of neuencoding supports models of pitch perception that hypoesize template matching of spectral patterns as a key comnent for determining thef 0 of complex sounds. The seconmechanism uses unresolved harmonics, is based on thecoding of stimulus waveform periodicity, and is dominantlower rates of stimulation.

ACKNOWLEDGMENTS

This research was supported in part by Grant NDC00657 from NIH, the Beth Abraham Hospital Institute fMusic and Neurologic Function, and the Rose F. KenneCenter at Albert Einstein College of Medicine Core GraThe authors thank the two journal reviewers for their insigful comments, and C. Freeman, M. Huang, M. Litwak,O’Donnell, and S. Seto for excellent technical, secretarand histological assistance.

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Click train encoding in primary auditory cortex of the awake monkey: Evidence for two mechanisms...

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