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Frequency-following (microphonic-like) neural responses evoked by sound
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Electrcencephaiography and Clinical Neurophysiology Elsevier Publishing Company, Amsterdam - Printed in The Netherlands
FP.EQUENCY-FOLLOWING (MICROPHONIC-LIKE) N E U R A L RESPONSES EVOKED BY SOUND 1 F. G. WORDEN AND J. T. MARSH
Department of Psyckiatry and Brain Research Institute, Center for the Health Sciences, t]nioersity o f California at Los Angeles, Los Angeles, Calif. 90024 (U.S.A.) (Accepted for publication: November 24, 1967)
INTRODUCTION
This report deserihes a form of acoustically evoked electrical activity which can be observed in recordings from gross electrodes in the central auditory pathway. This response, like the cochlear microphonic response (Wever and Bray 1930), reproduces the sine wave of the sound stimulus. Since, however, it is a neural response and differs fundamentally from the cochlear microphonic (CM), we have chosen to call it a "frequencyfollowing response" (FFR). Characteristics of this response and its relationship to the auditory evoked potential (EP), will be described. Evidence will be presented to suggest that FFR, although relatively neglected in the literature, is a s i m r : i ~ t aspect of auditory neurophysiology holding im#ications for a theory of hearing quite different from those of the auditory EP. METHODS AND MATERIALS
The techniques for chronic electrode implantation, sound delivery through earphones and histological verification of electrode placemcnts have been described elsewhere (Worden and Marsh 1963; Marsh and Worden 1964; Worden et al. 1964). Seventeen adult cats, with arrays of chronically implanted electrodes made of diam©l-coated stainless steel wire (0.009"), were used. Electrodes were assembled in side by side pairs or triples, with tip-separation ranging from 0.5 to 2.5 ram, as specified in the text. For round-window recordings, a small, bared loop of wire (0.005") was placed on the round-window membrane and led around the 1 Supported by U.S. Public Health Service Grant M H 03831.
skull to the connector on top of the head. Recordings from the conscious animal were taken only when the animal was sufficiently quiet to yield records free of movement artifacts. The outputs of four low-level differential AC pre-amptifiers (Argonaut LRA 042) were led to a dual-beam oscilloscope (Tektronix 551) with plug-in, beam-splitting amplifiers (Tektronix type CA). The resulting four-beam display was photographed with a Grass camera. Unless otherwise specified, all recording was done with the pre-amplifier filters set for a low cut-off of 1 c/see and a high cut-off of 10 kc/sec. In some instances active filters (Krohn-Hite 330N and 33013) were used for band-pass filtering. The sound stimuli were tone pulses usually of 20 msec duration (5 msec rise time, 10 msec plateau, 5 msec decay). Earphones were calibrated periodically using a condensor microphone with a 2 ml coupling chamber (B and K Instruments) and a sound level meter (General Radio). This calibration assured that undistorted sound stimuli could be delivered to the animal at constant intensity across the frequency range used. All sound pressure levels (SPLs) are specified in decibels re 0.0002 dynes/cmz. A co-axially shielded cabling system was developed to eliminate the cross talk which tends to occur at stimulus frequencies above 1 kc/sec in standard EEG cabling systems. RESULTS
A. Description and definition of FFR In Fig. l there are evident similarities between FFR, recorded from the cochlear nuclei (CN), and the pattern of the sound waves as reflected in the CM responses. It is clear that the wave Eiectroenceph. olin. Neurophysioi., 1968, 25:42-52
FREQUENCY-FOLLOWINGNEURALRESPONSE
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Fi~. 1 Comparison of the frequency-followingresponse (FFR) with the cochlear microphonic(CM)and the auditory evoked potential (EP). Responses to a 2 kc 60 dB tone are recorded from bilatzral electrodes on the round-windows (LRW and RRW), and in the cochlear nuclei (LCN and RCN), with reference to a grounding-screw on the frontal sinus. The four traces are, from top to bottom in each picture: (I) broad-band (I c/see-10 kc/sec) recording of CM from the RW; (2) broad-band recordin~ of FFR from CN; (3) band-pass (1.9-2.1 kc/sec)filtered recording of FFR, adjusted to pass the frequency of the stimulus (2 kc/sec); (4) band-pass (1--40c/sec) filtered recording to pass usual frequencies for EEG recording. Tile right hand pictures represent the same display photographed at a faster sweep. The envelope of the response from RRW is irregular due to noise from a faulty amplificationchanuel; the envelope of the LRW response is typical for CM responses. form of F F R is like the sine wave of the stimulus and that F F R continues throughout the duration of the tone. Some differences are also to be seen and these illustrate the fact that F F R never reproduces the stimulus as accurately as does the CM response. For example, in Fig. 1, distortions of the F F R wave form are seen, especially in the recording fro m the left CN. Band-pass filtering, adjusted to pass the stimulus frequency, greatly reduces these diStortions.
Several types of amplitude variation are also illustrated in Fig. 1. There is a variation o f amplitude from cycle to cycle in the F F R which is not present in the C M (or in the stimulus) and which, in contrast to the wave form distortion, is not much reduced by band-pass filterin~ Also, the amplitude of F F R is greatest at the onset of the tone and gradually shrinks as the tone continues, even though sound intensity and C M amplitude remain constant. SuperElectroenceph. clin. Neuropkysioi., 1968, 25:42-52
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F. G. WORDEN AND J. T. MARSH
Fig. 2 Differences between the CM response (LRW) and the FFR (LCNd) are shown for two eats. Stimulus was a left monaural 2 kc tone. (See Fig. 1 for explanation and recording ~ t h . ) Differences, including abruptness of onset, latency and phase are described in text. The s ~ rate for the right hand pictures is twice that for the left. A slight phMe shift is introdu~d by ~ , p a s s filtering.
imposed on this gradual change, there is a more abrupt swelling of the amplitude near the onset, as well as smaller bulges which occur later during the tone. In this example the onset bulge occupies slightly less than the first 10 msec of the response. After 10 msec the amplitude of F F R has fallen to 72% of its initial value for the left, and 75% for the right, CN. After 130 msec, the corresponding values are 55% for the left, and 56% for the right. The swelling of amplitude of F F R at the onset of the tone is a characteristic feature, but, occasionally, as in Fig. 2 (cat 108), it is not seen.
The onset bulge in F F R amplitude correlates in time with the auditory EP at the onset of the tone. In contrast, the EP at the offset occurs without any corresponding offset bulge in the F F R (Fig. 1). A further point is that the initial swelling of F F R amplitude occurs very early on the slope of the EP deflection (Fig. 2, cat 10Ci), and the amplitude of the EP continues to increase after the amplitude of F F R has begun to decrease. Another difference between F F R and the stimulus is that the onset o f F F R appears with threshold-like abruptness (see Fig. 2) even Electroenceph. clin. NeurophysioL, 1968, 25:42-52
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The effect of stimulus frequency on FFR. (See Fig. I for recording band-widths.) in response to left monaural stimulation with a 4 kc/sec tone (bottom row), the FFR is much smaller, and less regular than it is to the 2 kc/sec tone (top row). This is particularly evident with band-pass filtering, where relatively gross amplitude fluctuations can be seen. In contrast to FFR the amplitude of the auditory EP actually increases with the increase in Frequency of the stimulus.
though the tone pulse has a graded onset. The C M response, in contrast, tends to reproduce the graded onset of the sound 1. Another characteristic of the F F R is that, unlike cross talk, it has a latency of onset apThis observation confirms, and extends, an early observation by Wever (1949) Who noted that, at the eighth nerve, the neural response has a threshold while the CM does not.
propriate for the neural structure from which it is recorded. The latency of F F R recorded from C N can be seen in Fig. 2. Although the actual phase relation of F F R to the stimulus is difficult to measure for tones of gradual onset, observed differences in apparent phase can be measured. For a given neural structure, differences in apparent phase relationship are often observed from one electrode to Electroem~eph. din. Neurophy$iol., 1968, 25:42-52
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F. G. WORDEN AND J. T, MARSH
another. In Fig. 2, the CN recording from one cat (106) has, the appearance of being 180° out of phase w ~ CM, w t ~ ¢ a s for the other cat (108) there appears to be only a flight difference of phase between the CN and the CM responses. During the tone, the evoked activity may be recognizable as F F R only at times, but even when the bursts of F F R occupy only a small portion of the duration o f the sound evoked response, the resemblance to the stimulus during the burst is unmistakable.
B. Variables affecting FFR I. Stimulus frequency and intensity. At a given stimulus intensity, the amplitude and form of F F R change as a function of the frequency of the stimulus. These changes are especially prominent as one approaches the upper limit of the frequency range within which F F R can be recorded. For example, in the broad-band recordings in Fig. 3, the resemblance of F F R to the 2 kc/se¢ tone is obvious, whereas it is not A
so obvious in the erratic response to the 4 kc/ sec tone: the effect of the increase in frequency is not just to redur.~ th¢ aml~it~de of FFR, but also to increase its variability. For forms of F F R which can be recognized easily on inspection, the relationship of stimulus frequency to response amplitude is relatively simple. The graphs in Fig. 4 are representative of our results. For a stimulus o f constant intensity ( 7 0 d B SPL), the amplitmte curve for F F R extends from 800 c/sec to 4 kc/sec (A). The slope of this curve, from its peak at 2 kc/sec to zero at 4 kc/sec, is in sharp contrast with that for the auditory EP recorded from the same electrode. The amplitude of the auditory El) actually increases from 4 to 6 kc/sec. In B, the effect of stimulus intensity on the frequency amplitude curve is shown. For a 60 dB stimulus, the frequency range of the response is from 1.6 to 3.0 kc/sec, whereas, for an 80 dB stimulus, the range is increased to e x t e n d from below 800 c/see to 5 kc/sec. Our results, so far, suggest that the
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Fig. 4 Changes in F F R amplitude as a function of the frequency of the stimulus. A: Comparison of F F R amplitude with EP amplitude recorded from the same C N ©lcctrode, and with C M recorded from the round window. Stimulus was a 25 msec tone pulse at 70 d B SPL presented t o the right car at a 2/see rate. Note that the C M and EP responses continue above tlm upper f r e q u ~ y limit (4 kc/sec) for FFR. B: Frequency amplitude curves for F F R at three stimulus intensity levels.
Electroenceph. clin. Neurophysiol., 1968, 25" 42-52
FREQUENCY-FOLLOWINGNEURALRESPONSE
47
Fig. 5 Responses from bipolar electrodes in the lateral lernniscus. For the left electrodes, histologies are shown to the left and responses in the top row (A and 6"). Right electrode histology is shown to the right and responses in the bottom row (B and D). Recordings with left monaural stimulation are shown in A and B and those to right stimulation are shown in C and D. In each picture the four traces are (from the top): audio signal, differential recording between the two electrode tips, distal tip with reference to ground and proximal tip with reference to ground. Distal tips were primarily in the ventral nuclei of the lateral lenmiscus, whereas proximal tips were primarily in lemniscal fibers. Note that the recordings from cell masses show predominantly FFR whereas those from fibers show large EPs.
maximum frequency range for F F R at a stimulus intensity of 80 dB, is approximately 500 c/see5 kc/sec at the level of CN. With stimulus intensities higher than 80 dB SPL, the frequency range might be extended. The increase in frequency range as stimulus intensity increases observed for F F R does not hold as much for the CM response or the auditory EP. For these latter, the effect of increasing stimulus intensity is primarily on the amplitude of the response. The possibility was investigated that the upper frequency limit for F F R might be lower in the anesthetized than in thei conscious subject. With intraperitoneal anesthesia (Nembutal, 35 mg/
kg), the differences observed in frequency amplitude curves between conscious and anesthetized states were trivial, and inconsistent in direction, for recordings from CN. The question as to whether the frequency amplitude curve for F F R changes as a function of the level from which it is recorded is complicated by variations of electrode placement; we have, however, sufficient data to indicate that there is a marked tendency for the upper frequency limit to be highest at CN, and to fall at the higher levels. For example, in recordings from the inferior colliculus the only clear instances of F F R we have observed have been at stimulus frequencies of 1000 c/sec or less. Electroenceph. clin. Neurophysiol., 1968, 25:42-52
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F. G. WORDEN AND J. T. MARSH
2. Laterality of stimulus input. The form of FFR recorded from a given electrode may be influenced by shifting the monaural stimulation from one ear to the other. Some of these effects are predictable on the basis of the anatomy of the auditory system (e.g., that contralat©ral stimulation evokes no FFR from the CN). Differences in amplitude of FFR are frequently associated with changes from left to right stimulation. For a given electrode placement, these amplitude differences often, but not always, parallel corresponding differences in the amplitude of the auditory EP. For example, for responses recorded from the lateral lemniscus
the amplitude of both FFR and EP is greater for stimulation of the contralateral than of the i~al ear. This is shown in Fig. 5 in a form which is somewhat mmsual in that, for both right and left electrode ,pairs, the distal tips show a large FFR and small EP, whereas the adjacent (approximate~ 1.5 ram) proximal elvctrode tips show a t a r p EP and small FFR. C h a ~ s in wave form of FFR are also frequc~tly obsexved with changes of stimulation from left to right. 3. Neural locus. Although, for a given stimulus condition, there is a consistency of wave form and amplitude of FFR in the recordings I
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Fig. 6 Distribution of positive (circled stars) and negative (empty circles) brain-stern k)catiom for r~e.ording FFR. Sterootaxically oriented frontal phme sections are shown in ~r,h(mmtic~ a m , ~ consolidation of actual AP level of elc~rode plat(returns was ~ in order to ~ ~ phK~nts using only six diagrams. The negative site indicated above the inferior c o H ~ (m ~ was in the overlyingcerobrurn.
E/ectroenceph. cltn. NeurophyMoL, 19(~ 25:42-52
FREQUENCY-FOLLOWING NEURAL RESPONSE
from one electrode, we have found considerable variation in comparing recordings across electrodes even when both electrodes are placed in the same neural structure. We have not observed any association of particular wave forms with particular neural structures, but there is a strong tendency in our data for the amplitude of FFR to be larger at the cochlear nucleus than at higher auditory centers.
C. Anatomical distribution of recording sites Fig. 6 shows the location of 88 electrode placements in nine cats. All positive placements for an FFR are within, or closely adjacent to, auditory structures. Below the level of the inferior colliculus, only one negative site was clearly within an auditory structure. This is shown in section P6 on the dorsal aspect of the "S" segment of the superior olive. The upper limit for recording FFR appeared to be the afferent side of the inferior colliculus bordering the lateral lemniscus. As is shown in section P2, four positive placements are in this area, whereas five negative placements are more dorsally located in the inferior colliculus. Negative placements within the brachium of the inferior colliculus and medial geniculate body are shown in section A3. We have not observed FFR in recording from auditory cortex (8 electrodes). Negative data have also been recorded from the following electrodes (no histological confirmation is as yet available): three on association cortex, eight in brain-stem reticular formation, eight in centre median, seven in amygdala, three in dorsal hippocampus and eight in ventral hippocampus. In summary, our data support the conclusion that FFR can be recorded from sites within, or very near, the classical auditory pathway up to the level of the inferior colliculus.
D. Relationship of FFR to auditory EP Both FFR and the EP are evoked by sound, both have approximately the same response latency and both may be recorded simultaneously from the same electrode. Within the subcortical auditory pathway both responses tend to show large changes in amplitude as a function of small changes in electrode placement. One of the most prominent differences
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between the two responses is that auditory EPs, unlike the FFR, can be recorded from all levels of the classical auditory pathway as well as from most areas of the non-auditory brain. For example, the non-auditory electrode placements we have listed as negative for FFR often show good auditory EPs. On the other hand, we have not observed a single instance of FFR from an electrode from which no auditory EP could be recorded under any stimulus conditions. Another point of difference, as we have shown earlier, is that, as stimulus frequency increases the amplitude of FFR always declines sharply, whereas the amplitude of the EP may, and often does, increase. With increasing anesthesia leading to anoxia and death, a progressive deterioration of FFR occurred in parallel with that of the EP, whereas the CM response persisted for a considerably longer time. This fact suggests that FFR is a neural response and not a remote pick-up of CM. DISCUSSION
Our results confirm the original conclusion of Wever and Bray (1930) that FFR is, indeed, a real neural response and indicate that, insofar as gross electrode recording is concerned, this form of response is a prominent aspect of the electrophysiology of the auditory pathway up to the level of the inferior colliculus. Also confirmed were the results obtained by Tsuchitani and Boudreau (1964) and Boudreau (1965a, b) in their investigation of wave activity of the medial accessory olive in acute and chronic cats. In our observations, however, the best frequency and lower limit for FFR were both somewhat higher than those reported by these authors. These differences may be related to the fact that in their experiments stimuli were presented through hollow earbars rather than earphones and, at low frequencies, stimuli 30-40 dB higher in intensity than ours were used. Boudreau (1965a) infers from his results that "'temporal information encoded in the eighth nerve by means of inter-fiber volleying is encoded in the same way by the trapezoid fibers innervating the SOC". According to our results, this inference could be extended up through the Electroent'eph. clin. NeurophysioL, 1968, 25:42-52
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F . G . WORDEN AND J. T. MARSH
level of the lateral lemniscus to the inferior colliculus. Derbyshire and Davis (1935) described a following response recorded from the auditory nerve of cats. These authors observed sharp decreases in amplitude of FFR at "critical frequencies" in the neighborhood of 1 and 2 kc/sec, and changes in adaption rates associated with these critical frequencies. They interpreted these results in terms of the concepts of "equilibration" (Gerard and Marshall 1933) and "alternation" (Forbes and Rice 1929). As is evident in our frequency amplitude curves, we did not observe such critical frequencies. The upper frequency limits for FFR reported in earlier papers (Davis et al. 1933; Kemp et al. 1937) were not as high as those observed by Boudreau (1965a) and ourselves. Although some early studies (Saul and Davis 1932; Gerard et al. 1936) reported FFR from levels in the auditory pathway as high as the acoustic radiations, it seems to us likely that some kind of cross-talk might have been involved. Our results suggest that FFR represents a type of neural activity different from that which underlies the auditory EP. Processes related to FFR continue during the sound, whereas those related to the EP, whatever they may be, occur only at the onset and the offset of the sound. Furthermore, as postulated by Wever (1949), the excitatory process underlying FFR must be phasic and the neural firing must occur at some reasonably regular phase position in the cycle of the sound wave. That phase-locked firing occurs in the eight nerve was first demonstrated by Galambos and Davis (1943). Recent work by Rose et al. (1967) confirms and extends these observations. For single fibers of the auditory nerve of the squirrel monkey, these latter authors report that, in the steady-state response to pure tone, the discharges are spaced at intervals grouped around integral multiples of the period of the tone. This phase-locking is independent of the discharge rate of the fiber, and holds for all frequencies which activate it, regardless of the best frequency for the unit or the intensity of the stimulus. This phase-locking was observed for stimulus frequencies up to 4.5-5.0 kc/sec. The fact that this is the same upper limit as we have observed for FFR
supports the notion that FFR is, indeed, the envelope of some aspect of phase-locked unit activity. If so, it may be inferred from our results that unit activities of the sort described by Rose et al. (1967) are characteristic of all brain sites from which FFR can be recorded, namely the classical auditory pathway up to the inferior colliculus (see also Rose et al. 1966). The fact that FFR cannot be recorded at higher auditory levels, such as the primary cortex, suggests that, as proposed by Wever (1949), at these levels there is such a dispersion of the responding units that their activities are no longer detectable in gross electrode recording. An alternative hypothesis is that phase-locking is a special characteristic of neural activity at lower levels. The neurophysiological differences between FFR and the auditory EP ought to be associated with some functional difference. Although little is known about the functional significance of either form of response, our results provide the basis for some speculative ideas. Assuming that FFR is associated with pitch discrimination, its restriction to the lower auditory pathway suggests, as Brkrsy (1963)pointed out, that pitch discrimination might take place below thalamic levels. This would be congruent with experiments which have demonstrated that pitch discrimination is not destroyed by total ablation of cortical areas (Neff 1960; Goldberg and Neff 1961a). The fact that bilateral section of the brachium of the inferior cotliculus is followed by severe impairment of pitch discrimination (Goldberg and Neff 1961b) suggests that it involves levels proximal to the latter structure; i.e., above those from which we have so far observed FFR. This does not rule out the possibility that the acoustic information processing requisite to pitch discrimination has been completed below thalamic levels (where FFR is observed), but that section of the brachium impairs transmission of the result to higher levels. If FFR is a correlate of pitch discrimination, a problem is posed by the fact that hearing extends well above the upper limit for FFR (5000 c/sec). A traditional solution, recently reviewed by Brkrsy (1963), is to assume that the periodicity principle holds for lower frequencies, and the place principle for higher frequencies. Electroenceph. clin. Neurophysiol., 1968, 25:42-52
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Since FFR is at best a crude envelope of unit activities, the upper limit we found for it does not bear critically on the theoretical question. If, however, the upper limit for phase-locking of unit responses is really about 5000 c/see, this would be a serious difficulty for the application of the periodicity concept to hearing at frequencies above that level. Rose et al. (1967) have observed, in isolated instances, phase-locking of unit responses to frequencies as high as 12,000 c/see. They discuss problems of measurement at these frequencies and limit themselves to concluding that phase-locking is usually demonstrable up to 5000 c/see. It appears to us that the possibility has not been ruled out for extending the periodicity concept to the whole range of audible frequencies. The EP, on the other hand, relates possibly to neural activities concerned more with changes of state of auditory stimulation (e.g., onset and offset) than with the actual quality of sound. For very brief sounds (clicks or short tone burst), the change of state constitutes, perhaps, most of the information. For longer, and more complex, sounds the informational value of the EP may consist of little more than that a sound has started, or stopped or changed abruptly in some stimulus parameter. The fact that the EP is so widely distributed throughout the brain provides the basis for assuming that, through the wide dissemination of relatively meager acoustic information, the EP underlies the mediation of generalized reactions to sound, such as startle and arousal. The alerting and motivational aspects of such reactions might prepare the organism for the more detailed acoustic information being processed in neural activities such as those underlying the FFR. SUMMARY
1. An acoustically evoked response is described which reproduces the frequency and wave form of the stimulus. This frequency-following response (FFR) is recordable from gross electrodes in the central auditory pathway. 2. The FFR differs from an acoustic stimulus of graded onset, and the cochlear microphonic response (CM), in that it has a sharp onset, a latency appropriate to the locus from which it is
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recorded, an amplitude burst at the onset mad a decrement of amplitude over time. 3. The frequency range of FFR increases with stimulus intensity. At 80 dB sound pressure level the range is approximately 50~-5000 c/see. For recordings from the cochlear ~aloleus these frequency limits are not influenced !by iMembutal anesthesia. 4. The wave form and amplitude of FFR vary with stimulus frequency and with laterality of stimulus input. 5. In contrast to the auditory evoked potential, which can be recorded widely i~ the brain, FFR is recordattle only within, or close to, the auditory pathway. We have observed it only at, and below the level of the inferior colliculus. 6. FFR has implications for the neurophysiology of hearing which are different from those of the auditory evoked potential. 'Some of these are discussed. R~SUM~ RI~PONSES NERVEUSES (SEMBLABLES AU POTENTIEL MICROPHONIQUE) ]~VOQU~ PAR LE SON, QUI SUIVENT LA FR~QUENCE DU STIMULUS
1. Les auteurs d6crivent une r6ponse 6voqu6e auditive qui reproduit la fr6quence et la forme d'onde du stimulus. Cette r6ponse ("frequencyfollowing response"--FFR) peut 8tre recueillie ~tl'aide de macro-61ectrodes dans la voie auditive centrale. 2. La FFR diff6re du stimulus acoustique d6but graduel et du potentiel microphonique, en ce qu'eUe pr6sente un d6but brusque, une latence correspondant au lieu de d6rivation, une bouff~e ample ~ son d~but, et une d~croissance de son amplitude dans le temps. 3. La bande de frrquence de la FFR s'accroit avec l'intensit6 du stimulus. A 80 dB, celleci s'rtend approximativement de 500 c/see 5 kc/sec. Pour les enregistrements dans le noyau cochlraire les limites de la frrquence ne sont pas modifires par l'anesthrsie au Nembutal. 4. La forme et l'amplitude de la FFR varient avecla frrquence du stimulus et avec sa latrralit6. 5. En contraste avec le potentiel 6voqu6 auditif, qui peut 8tre recueilli dans des rrgions 6tendues du cerveau, la FFR ne peut l'~tre que Eleetroenceph. clin. NeurophysioL, 1968, 25:42-52
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F. G. WORDEN AND J. T. MARSH
darts la voie auditive, ou tr6s pr6s d'elle. Cette r6ponse n ' a 6t6 observ6e q u ' a u niveau du colliculus inf6rieur et au dessous. 6. La F F R a p o u r la neurophysiologie de I ' a u d i t i o n des implications diff6rentes de celles du potentiel 6voqu6 auditif. Quelques-unes de celles-ci sont discut6es ici. It is a pleasure to acknowledge the technical assistance of Mr. J. Martin and Mr. J. Smith and the assistance of Mrs. S. Oozier in the preparation oftbe manuscript. REFERENCES B~g~V, G. vow. Hearing theories and complex sounds. J. aeoust. Sac. Amer., 1963, 35: 588-601. BOODmEAU, J. C. Neural volleying: upper frequency limits detectable in the auditory system. Nature (Lond.), 19~a, 208: 1237-1238. BOUO~AU, J. C. Stimulus correlates of wave activity in the superior-olivary complex of the cat. J. acoust. Soc. Amer., 1965b, 37: 779-785. DAVIS,H., DEimYSHmE,A. J., LURIE,M. H. and SAUL,L.J. Further analysis of cochlear activity and auditory action currents. Trans. Amer. otol. Soc., 1933, 23: 106-116. DERnYSmRE,A. J'. and DAvis, H. The action potentials of the auditory nerve. Amer. J. Physiol., 1935, ll3: 476-504. FORBES,A. and RACE,L. Quantitative studies of the nerve impulse. IV. Fatigue in the peripheral nerve. Amer. J. Physiol., 1929, 90: 119-145. GALAMBOS, R. and DAVIS, H. The response of single auditory-nerve fibers to acoustic stimulation. J. Neurophysioi., 1943, 6: 39-58. GERmiO, R, W. and MARSHALL,W. H. Nerve conduction velocity and equilibration. Amer. J. Physiol., 1933, 104: 575-585. GERARD, R.W., MARSHALL,W.H. and SAUL,L. J. Electrical activity of the cat's brain. Arch. Neurol. Psyehiat. (Chic.), 1936, 36: 675-735. GOLOmG, J. M. and NEEV, W. D. Frequency discrimination after bilateral ablation of cortical auditory
Reference: W ~ , sound. ~
areas. J. Neurophysiol., 1961a, 24:119-128.
GOLDBERG,J. M. and NET, W. D. Frequency discrimination after bilateral section of the brachium of the inferior colliculus. J. comp. Neurol., 1961b, 116: 265-290. KEMP, E. H., COPP~E,G. E. and Roan~SON,E. H. Electric responses of the brain stem to unilateral auditory stimulation. Amer. J. Physiol., 1937, 120: 304-315. MARSH, J. T. and WOR~N, F. G. Auditory potentials during acoustic habituation: cochlear nucleus, cerebellum, and auditory cortex. Eiectroeneeph. din. Neurophysiol., 1964, 17: 685-692. NEFF, W. D. Role of auditory cortex in sound discrimination. In G. L. RAS~US~N and W. F. WlNDLECEds.), Neural mechanisms of the auditory and vestibular systems. Thomas, S p r i ~ e i d , Ill., 1960: 211-223. RosE, J. E., BRUGGE,J. F., ANDER,qON,D. J. and HIND, J. E. Phase-locked response to low-frequency tones in single auditory nerve fibers of the squirrel monkey. J. Neurophysiol., 1967, 30: 769-793. RosE, J. E., GROSS,N. B., GEtst~"n,C. D. and HIND, J. E. Some neural mechanisms in the inferior colliculus of the eat which may be relevant to localization of a sound source. J. Neurophysiol., 1966, 29: 288"314. SAUL, L. J. and DAVlS, H. Electrical phenomena of the auditory mechanism. Trans. Amer. otol. Soc., 1932, 22: 137-145. TSUCHITANI,C. and BOUmtEAU,J. C. Wave activity in the superior olivary complex of the cat. J. Neurophystol., 1964, 27: 814-827. WEVER, E. G. Theory of hearing. Wiley and Sons, New York, 1949, 484 p. WEVER,E. G. and BRAY,C. W. The nature of the acoustic response: The relation b e t w ~ soun frequency and frequency of impulses in the auditory nerve. J. exp. Psychol., 1930, 13: 373-387. WORD~q, .F.G. and MARSH,J. T. Amplitude changes of auditory potentials evoked at cochlear nucleus during acoustic habituation, Electroenceph. din. Neurol~ysiol., 1963, 15: 866-881. WOADS, F. G., MARSH, J. T., AI~AHAM, F. D. and WmTrLr~V, J. R. B. Variability of evoked auditory potentials and acoustic input control. Electroenecph, din. Neurophysiol., 1964, 17: 524-530.
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Electrcencephaiography and Clinical Neurophysiology Elsevier Publishing Company, Amsterdam - Printed in The Netherlands
FP.EQUENCY-FOLLOWING (MICROPHONIC-LIKE) N E U R A L RESPONSES EVOKED BY SOUND 1 F. G. WORDEN AND J. T. MARSH
Department of Psyckiatry and Brain Research Institute, Center for the Health Sciences, t]nioersity o f California at Los Angeles, Los Angeles, Calif. 90024 (U.S.A.) (Accepted for publication: November 24, 1967)
INTRODUCTION
This report deserihes a form of acoustically evoked electrical activity which can be observed in recordings from gross electrodes in the central auditory pathway. This response, like the cochlear microphonic response (Wever and Bray 1930), reproduces the sine wave of the sound stimulus. Since, however, it is a neural response and differs fundamentally from the cochlear microphonic (CM), we have chosen to call it a "frequencyfollowing response" (FFR). Characteristics of this response and its relationship to the auditory evoked potential (EP), will be described. Evidence will be presented to suggest that FFR, although relatively neglected in the literature, is a s i m r : i ~ t aspect of auditory neurophysiology holding im#ications for a theory of hearing quite different from those of the auditory EP. METHODS AND MATERIALS
The techniques for chronic electrode implantation, sound delivery through earphones and histological verification of electrode placemcnts have been described elsewhere (Worden and Marsh 1963; Marsh and Worden 1964; Worden et al. 1964). Seventeen adult cats, with arrays of chronically implanted electrodes made of diam©l-coated stainless steel wire (0.009"), were used. Electrodes were assembled in side by side pairs or triples, with tip-separation ranging from 0.5 to 2.5 ram, as specified in the text. For round-window recordings, a small, bared loop of wire (0.005") was placed on the round-window membrane and led around the 1 Supported by U.S. Public Health Service Grant M H 03831.
skull to the connector on top of the head. Recordings from the conscious animal were taken only when the animal was sufficiently quiet to yield records free of movement artifacts. The outputs of four low-level differential AC pre-amptifiers (Argonaut LRA 042) were led to a dual-beam oscilloscope (Tektronix 551) with plug-in, beam-splitting amplifiers (Tektronix type CA). The resulting four-beam display was photographed with a Grass camera. Unless otherwise specified, all recording was done with the pre-amplifier filters set for a low cut-off of 1 c/see and a high cut-off of 10 kc/sec. In some instances active filters (Krohn-Hite 330N and 33013) were used for band-pass filtering. The sound stimuli were tone pulses usually of 20 msec duration (5 msec rise time, 10 msec plateau, 5 msec decay). Earphones were calibrated periodically using a condensor microphone with a 2 ml coupling chamber (B and K Instruments) and a sound level meter (General Radio). This calibration assured that undistorted sound stimuli could be delivered to the animal at constant intensity across the frequency range used. All sound pressure levels (SPLs) are specified in decibels re 0.0002 dynes/cmz. A co-axially shielded cabling system was developed to eliminate the cross talk which tends to occur at stimulus frequencies above 1 kc/sec in standard EEG cabling systems. RESULTS
A. Description and definition of FFR In Fig. l there are evident similarities between FFR, recorded from the cochlear nuclei (CN), and the pattern of the sound waves as reflected in the CM responses. It is clear that the wave Eiectroenceph. olin. Neurophysioi., 1968, 25:42-52
FREQUENCY-FOLLOWINGNEURALRESPONSE
43 CAT 108 7-27-67
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Fi~. 1 Comparison of the frequency-followingresponse (FFR) with the cochlear microphonic(CM)and the auditory evoked potential (EP). Responses to a 2 kc 60 dB tone are recorded from bilatzral electrodes on the round-windows (LRW and RRW), and in the cochlear nuclei (LCN and RCN), with reference to a grounding-screw on the frontal sinus. The four traces are, from top to bottom in each picture: (I) broad-band (I c/see-10 kc/sec) recording of CM from the RW; (2) broad-band recordin~ of FFR from CN; (3) band-pass (1.9-2.1 kc/sec)filtered recording of FFR, adjusted to pass the frequency of the stimulus (2 kc/sec); (4) band-pass (1--40c/sec) filtered recording to pass usual frequencies for EEG recording. Tile right hand pictures represent the same display photographed at a faster sweep. The envelope of the response from RRW is irregular due to noise from a faulty amplificationchanuel; the envelope of the LRW response is typical for CM responses. form of F F R is like the sine wave of the stimulus and that F F R continues throughout the duration of the tone. Some differences are also to be seen and these illustrate the fact that F F R never reproduces the stimulus as accurately as does the CM response. For example, in Fig. 1, distortions of the F F R wave form are seen, especially in the recording fro m the left CN. Band-pass filtering, adjusted to pass the stimulus frequency, greatly reduces these diStortions.
Several types of amplitude variation are also illustrated in Fig. 1. There is a variation o f amplitude from cycle to cycle in the F F R which is not present in the C M (or in the stimulus) and which, in contrast to the wave form distortion, is not much reduced by band-pass filterin~ Also, the amplitude of F F R is greatest at the onset of the tone and gradually shrinks as the tone continues, even though sound intensity and C M amplitude remain constant. SuperElectroenceph. clin. Neuropkysioi., 1968, 25:42-52
44
F. G. WORDEN AND J. T. MARSH
Fig. 2 Differences between the CM response (LRW) and the FFR (LCNd) are shown for two eats. Stimulus was a left monaural 2 kc tone. (See Fig. 1 for explanation and recording ~ t h . ) Differences, including abruptness of onset, latency and phase are described in text. The s ~ rate for the right hand pictures is twice that for the left. A slight phMe shift is introdu~d by ~ , p a s s filtering.
imposed on this gradual change, there is a more abrupt swelling of the amplitude near the onset, as well as smaller bulges which occur later during the tone. In this example the onset bulge occupies slightly less than the first 10 msec of the response. After 10 msec the amplitude of F F R has fallen to 72% of its initial value for the left, and 75% for the right, CN. After 130 msec, the corresponding values are 55% for the left, and 56% for the right. The swelling of amplitude of F F R at the onset of the tone is a characteristic feature, but, occasionally, as in Fig. 2 (cat 108), it is not seen.
The onset bulge in F F R amplitude correlates in time with the auditory EP at the onset of the tone. In contrast, the EP at the offset occurs without any corresponding offset bulge in the F F R (Fig. 1). A further point is that the initial swelling of F F R amplitude occurs very early on the slope of the EP deflection (Fig. 2, cat 10Ci), and the amplitude of the EP continues to increase after the amplitude of F F R has begun to decrease. Another difference between F F R and the stimulus is that the onset o f F F R appears with threshold-like abruptness (see Fig. 2) even Electroenceph. clin. NeurophysioL, 1968, 25:42-52
45
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The effect of stimulus frequency on FFR. (See Fig. I for recording band-widths.) in response to left monaural stimulation with a 4 kc/sec tone (bottom row), the FFR is much smaller, and less regular than it is to the 2 kc/sec tone (top row). This is particularly evident with band-pass filtering, where relatively gross amplitude fluctuations can be seen. In contrast to FFR the amplitude of the auditory EP actually increases with the increase in Frequency of the stimulus.
though the tone pulse has a graded onset. The C M response, in contrast, tends to reproduce the graded onset of the sound 1. Another characteristic of the F F R is that, unlike cross talk, it has a latency of onset apThis observation confirms, and extends, an early observation by Wever (1949) Who noted that, at the eighth nerve, the neural response has a threshold while the CM does not.
propriate for the neural structure from which it is recorded. The latency of F F R recorded from C N can be seen in Fig. 2. Although the actual phase relation of F F R to the stimulus is difficult to measure for tones of gradual onset, observed differences in apparent phase can be measured. For a given neural structure, differences in apparent phase relationship are often observed from one electrode to Electroem~eph. din. Neurophy$iol., 1968, 25:42-52
46
F. G. WORDEN AND J. T, MARSH
another. In Fig. 2, the CN recording from one cat (106) has, the appearance of being 180° out of phase w ~ CM, w t ~ ¢ a s for the other cat (108) there appears to be only a flight difference of phase between the CN and the CM responses. During the tone, the evoked activity may be recognizable as F F R only at times, but even when the bursts of F F R occupy only a small portion of the duration o f the sound evoked response, the resemblance to the stimulus during the burst is unmistakable.
B. Variables affecting FFR I. Stimulus frequency and intensity. At a given stimulus intensity, the amplitude and form of F F R change as a function of the frequency of the stimulus. These changes are especially prominent as one approaches the upper limit of the frequency range within which F F R can be recorded. For example, in the broad-band recordings in Fig. 3, the resemblance of F F R to the 2 kc/se¢ tone is obvious, whereas it is not A
so obvious in the erratic response to the 4 kc/ sec tone: the effect of the increase in frequency is not just to redur.~ th¢ aml~it~de of FFR, but also to increase its variability. For forms of F F R which can be recognized easily on inspection, the relationship of stimulus frequency to response amplitude is relatively simple. The graphs in Fig. 4 are representative of our results. For a stimulus o f constant intensity ( 7 0 d B SPL), the amplitmte curve for F F R extends from 800 c/sec to 4 kc/sec (A). The slope of this curve, from its peak at 2 kc/sec to zero at 4 kc/sec, is in sharp contrast with that for the auditory EP recorded from the same electrode. The amplitude of the auditory El) actually increases from 4 to 6 kc/sec. In B, the effect of stimulus intensity on the frequency amplitude curve is shown. For a 60 dB stimulus, the frequency range of the response is from 1.6 to 3.0 kc/sec, whereas, for an 80 dB stimulus, the range is increased to e x t e n d from below 800 c/see to 5 kc/sec. Our results, so far, suggest that the
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Fig. 4 Changes in F F R amplitude as a function of the frequency of the stimulus. A: Comparison of F F R amplitude with EP amplitude recorded from the same C N ©lcctrode, and with C M recorded from the round window. Stimulus was a 25 msec tone pulse at 70 d B SPL presented t o the right car at a 2/see rate. Note that the C M and EP responses continue above tlm upper f r e q u ~ y limit (4 kc/sec) for FFR. B: Frequency amplitude curves for F F R at three stimulus intensity levels.
Electroenceph. clin. Neurophysiol., 1968, 25" 42-52
FREQUENCY-FOLLOWINGNEURALRESPONSE
47
Fig. 5 Responses from bipolar electrodes in the lateral lernniscus. For the left electrodes, histologies are shown to the left and responses in the top row (A and 6"). Right electrode histology is shown to the right and responses in the bottom row (B and D). Recordings with left monaural stimulation are shown in A and B and those to right stimulation are shown in C and D. In each picture the four traces are (from the top): audio signal, differential recording between the two electrode tips, distal tip with reference to ground and proximal tip with reference to ground. Distal tips were primarily in the ventral nuclei of the lateral lenmiscus, whereas proximal tips were primarily in lemniscal fibers. Note that the recordings from cell masses show predominantly FFR whereas those from fibers show large EPs.
maximum frequency range for F F R at a stimulus intensity of 80 dB, is approximately 500 c/see5 kc/sec at the level of CN. With stimulus intensities higher than 80 dB SPL, the frequency range might be extended. The increase in frequency range as stimulus intensity increases observed for F F R does not hold as much for the CM response or the auditory EP. For these latter, the effect of increasing stimulus intensity is primarily on the amplitude of the response. The possibility was investigated that the upper frequency limit for F F R might be lower in the anesthetized than in thei conscious subject. With intraperitoneal anesthesia (Nembutal, 35 mg/
kg), the differences observed in frequency amplitude curves between conscious and anesthetized states were trivial, and inconsistent in direction, for recordings from CN. The question as to whether the frequency amplitude curve for F F R changes as a function of the level from which it is recorded is complicated by variations of electrode placement; we have, however, sufficient data to indicate that there is a marked tendency for the upper frequency limit to be highest at CN, and to fall at the higher levels. For example, in recordings from the inferior colliculus the only clear instances of F F R we have observed have been at stimulus frequencies of 1000 c/sec or less. Electroenceph. clin. Neurophysiol., 1968, 25:42-52
48
F. G. WORDEN AND J. T. MARSH
2. Laterality of stimulus input. The form of FFR recorded from a given electrode may be influenced by shifting the monaural stimulation from one ear to the other. Some of these effects are predictable on the basis of the anatomy of the auditory system (e.g., that contralat©ral stimulation evokes no FFR from the CN). Differences in amplitude of FFR are frequently associated with changes from left to right stimulation. For a given electrode placement, these amplitude differences often, but not always, parallel corresponding differences in the amplitude of the auditory EP. For example, for responses recorded from the lateral lemniscus
the amplitude of both FFR and EP is greater for stimulation of the contralateral than of the i~al ear. This is shown in Fig. 5 in a form which is somewhat mmsual in that, for both right and left electrode ,pairs, the distal tips show a large FFR and small EP, whereas the adjacent (approximate~ 1.5 ram) proximal elvctrode tips show a t a r p EP and small FFR. C h a ~ s in wave form of FFR are also frequc~tly obsexved with changes of stimulation from left to right. 3. Neural locus. Although, for a given stimulus condition, there is a consistency of wave form and amplitude of FFR in the recordings I
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Fig. 6 Distribution of positive (circled stars) and negative (empty circles) brain-stern k)catiom for r~e.ording FFR. Sterootaxically oriented frontal phme sections are shown in ~r,h(mmtic~ a m , ~ consolidation of actual AP level of elc~rode plat(returns was ~ in order to ~ ~ phK~nts using only six diagrams. The negative site indicated above the inferior c o H ~ (m ~ was in the overlyingcerobrurn.
E/ectroenceph. cltn. NeurophyMoL, 19(~ 25:42-52
FREQUENCY-FOLLOWING NEURAL RESPONSE
from one electrode, we have found considerable variation in comparing recordings across electrodes even when both electrodes are placed in the same neural structure. We have not observed any association of particular wave forms with particular neural structures, but there is a strong tendency in our data for the amplitude of FFR to be larger at the cochlear nucleus than at higher auditory centers.
C. Anatomical distribution of recording sites Fig. 6 shows the location of 88 electrode placements in nine cats. All positive placements for an FFR are within, or closely adjacent to, auditory structures. Below the level of the inferior colliculus, only one negative site was clearly within an auditory structure. This is shown in section P6 on the dorsal aspect of the "S" segment of the superior olive. The upper limit for recording FFR appeared to be the afferent side of the inferior colliculus bordering the lateral lemniscus. As is shown in section P2, four positive placements are in this area, whereas five negative placements are more dorsally located in the inferior colliculus. Negative placements within the brachium of the inferior colliculus and medial geniculate body are shown in section A3. We have not observed FFR in recording from auditory cortex (8 electrodes). Negative data have also been recorded from the following electrodes (no histological confirmation is as yet available): three on association cortex, eight in brain-stem reticular formation, eight in centre median, seven in amygdala, three in dorsal hippocampus and eight in ventral hippocampus. In summary, our data support the conclusion that FFR can be recorded from sites within, or very near, the classical auditory pathway up to the level of the inferior colliculus.
D. Relationship of FFR to auditory EP Both FFR and the EP are evoked by sound, both have approximately the same response latency and both may be recorded simultaneously from the same electrode. Within the subcortical auditory pathway both responses tend to show large changes in amplitude as a function of small changes in electrode placement. One of the most prominent differences
49
between the two responses is that auditory EPs, unlike the FFR, can be recorded from all levels of the classical auditory pathway as well as from most areas of the non-auditory brain. For example, the non-auditory electrode placements we have listed as negative for FFR often show good auditory EPs. On the other hand, we have not observed a single instance of FFR from an electrode from which no auditory EP could be recorded under any stimulus conditions. Another point of difference, as we have shown earlier, is that, as stimulus frequency increases the amplitude of FFR always declines sharply, whereas the amplitude of the EP may, and often does, increase. With increasing anesthesia leading to anoxia and death, a progressive deterioration of FFR occurred in parallel with that of the EP, whereas the CM response persisted for a considerably longer time. This fact suggests that FFR is a neural response and not a remote pick-up of CM. DISCUSSION
Our results confirm the original conclusion of Wever and Bray (1930) that FFR is, indeed, a real neural response and indicate that, insofar as gross electrode recording is concerned, this form of response is a prominent aspect of the electrophysiology of the auditory pathway up to the level of the inferior colliculus. Also confirmed were the results obtained by Tsuchitani and Boudreau (1964) and Boudreau (1965a, b) in their investigation of wave activity of the medial accessory olive in acute and chronic cats. In our observations, however, the best frequency and lower limit for FFR were both somewhat higher than those reported by these authors. These differences may be related to the fact that in their experiments stimuli were presented through hollow earbars rather than earphones and, at low frequencies, stimuli 30-40 dB higher in intensity than ours were used. Boudreau (1965a) infers from his results that "'temporal information encoded in the eighth nerve by means of inter-fiber volleying is encoded in the same way by the trapezoid fibers innervating the SOC". According to our results, this inference could be extended up through the Electroent'eph. clin. NeurophysioL, 1968, 25:42-52
50
F . G . WORDEN AND J. T. MARSH
level of the lateral lemniscus to the inferior colliculus. Derbyshire and Davis (1935) described a following response recorded from the auditory nerve of cats. These authors observed sharp decreases in amplitude of FFR at "critical frequencies" in the neighborhood of 1 and 2 kc/sec, and changes in adaption rates associated with these critical frequencies. They interpreted these results in terms of the concepts of "equilibration" (Gerard and Marshall 1933) and "alternation" (Forbes and Rice 1929). As is evident in our frequency amplitude curves, we did not observe such critical frequencies. The upper frequency limits for FFR reported in earlier papers (Davis et al. 1933; Kemp et al. 1937) were not as high as those observed by Boudreau (1965a) and ourselves. Although some early studies (Saul and Davis 1932; Gerard et al. 1936) reported FFR from levels in the auditory pathway as high as the acoustic radiations, it seems to us likely that some kind of cross-talk might have been involved. Our results suggest that FFR represents a type of neural activity different from that which underlies the auditory EP. Processes related to FFR continue during the sound, whereas those related to the EP, whatever they may be, occur only at the onset and the offset of the sound. Furthermore, as postulated by Wever (1949), the excitatory process underlying FFR must be phasic and the neural firing must occur at some reasonably regular phase position in the cycle of the sound wave. That phase-locked firing occurs in the eight nerve was first demonstrated by Galambos and Davis (1943). Recent work by Rose et al. (1967) confirms and extends these observations. For single fibers of the auditory nerve of the squirrel monkey, these latter authors report that, in the steady-state response to pure tone, the discharges are spaced at intervals grouped around integral multiples of the period of the tone. This phase-locking is independent of the discharge rate of the fiber, and holds for all frequencies which activate it, regardless of the best frequency for the unit or the intensity of the stimulus. This phase-locking was observed for stimulus frequencies up to 4.5-5.0 kc/sec. The fact that this is the same upper limit as we have observed for FFR
supports the notion that FFR is, indeed, the envelope of some aspect of phase-locked unit activity. If so, it may be inferred from our results that unit activities of the sort described by Rose et al. (1967) are characteristic of all brain sites from which FFR can be recorded, namely the classical auditory pathway up to the inferior colliculus (see also Rose et al. 1966). The fact that FFR cannot be recorded at higher auditory levels, such as the primary cortex, suggests that, as proposed by Wever (1949), at these levels there is such a dispersion of the responding units that their activities are no longer detectable in gross electrode recording. An alternative hypothesis is that phase-locking is a special characteristic of neural activity at lower levels. The neurophysiological differences between FFR and the auditory EP ought to be associated with some functional difference. Although little is known about the functional significance of either form of response, our results provide the basis for some speculative ideas. Assuming that FFR is associated with pitch discrimination, its restriction to the lower auditory pathway suggests, as Brkrsy (1963)pointed out, that pitch discrimination might take place below thalamic levels. This would be congruent with experiments which have demonstrated that pitch discrimination is not destroyed by total ablation of cortical areas (Neff 1960; Goldberg and Neff 1961a). The fact that bilateral section of the brachium of the inferior cotliculus is followed by severe impairment of pitch discrimination (Goldberg and Neff 1961b) suggests that it involves levels proximal to the latter structure; i.e., above those from which we have so far observed FFR. This does not rule out the possibility that the acoustic information processing requisite to pitch discrimination has been completed below thalamic levels (where FFR is observed), but that section of the brachium impairs transmission of the result to higher levels. If FFR is a correlate of pitch discrimination, a problem is posed by the fact that hearing extends well above the upper limit for FFR (5000 c/sec). A traditional solution, recently reviewed by Brkrsy (1963), is to assume that the periodicity principle holds for lower frequencies, and the place principle for higher frequencies. Electroenceph. clin. Neurophysiol., 1968, 25:42-52
FREQUENCY-FOLLOWINGNEURAL RESPONSE
Since FFR is at best a crude envelope of unit activities, the upper limit we found for it does not bear critically on the theoretical question. If, however, the upper limit for phase-locking of unit responses is really about 5000 c/see, this would be a serious difficulty for the application of the periodicity concept to hearing at frequencies above that level. Rose et al. (1967) have observed, in isolated instances, phase-locking of unit responses to frequencies as high as 12,000 c/see. They discuss problems of measurement at these frequencies and limit themselves to concluding that phase-locking is usually demonstrable up to 5000 c/see. It appears to us that the possibility has not been ruled out for extending the periodicity concept to the whole range of audible frequencies. The EP, on the other hand, relates possibly to neural activities concerned more with changes of state of auditory stimulation (e.g., onset and offset) than with the actual quality of sound. For very brief sounds (clicks or short tone burst), the change of state constitutes, perhaps, most of the information. For longer, and more complex, sounds the informational value of the EP may consist of little more than that a sound has started, or stopped or changed abruptly in some stimulus parameter. The fact that the EP is so widely distributed throughout the brain provides the basis for assuming that, through the wide dissemination of relatively meager acoustic information, the EP underlies the mediation of generalized reactions to sound, such as startle and arousal. The alerting and motivational aspects of such reactions might prepare the organism for the more detailed acoustic information being processed in neural activities such as those underlying the FFR. SUMMARY
1. An acoustically evoked response is described which reproduces the frequency and wave form of the stimulus. This frequency-following response (FFR) is recordable from gross electrodes in the central auditory pathway. 2. The FFR differs from an acoustic stimulus of graded onset, and the cochlear microphonic response (CM), in that it has a sharp onset, a latency appropriate to the locus from which it is
51
recorded, an amplitude burst at the onset mad a decrement of amplitude over time. 3. The frequency range of FFR increases with stimulus intensity. At 80 dB sound pressure level the range is approximately 50~-5000 c/see. For recordings from the cochlear ~aloleus these frequency limits are not influenced !by iMembutal anesthesia. 4. The wave form and amplitude of FFR vary with stimulus frequency and with laterality of stimulus input. 5. In contrast to the auditory evoked potential, which can be recorded widely i~ the brain, FFR is recordattle only within, or close to, the auditory pathway. We have observed it only at, and below the level of the inferior colliculus. 6. FFR has implications for the neurophysiology of hearing which are different from those of the auditory evoked potential. 'Some of these are discussed. R~SUM~ RI~PONSES NERVEUSES (SEMBLABLES AU POTENTIEL MICROPHONIQUE) ]~VOQU~ PAR LE SON, QUI SUIVENT LA FR~QUENCE DU STIMULUS
1. Les auteurs d6crivent une r6ponse 6voqu6e auditive qui reproduit la fr6quence et la forme d'onde du stimulus. Cette r6ponse ("frequencyfollowing response"--FFR) peut 8tre recueillie ~tl'aide de macro-61ectrodes dans la voie auditive centrale. 2. La FFR diff6re du stimulus acoustique d6but graduel et du potentiel microphonique, en ce qu'eUe pr6sente un d6but brusque, une latence correspondant au lieu de d6rivation, une bouff~e ample ~ son d~but, et une d~croissance de son amplitude dans le temps. 3. La bande de frrquence de la FFR s'accroit avec l'intensit6 du stimulus. A 80 dB, celleci s'rtend approximativement de 500 c/see 5 kc/sec. Pour les enregistrements dans le noyau cochlraire les limites de la frrquence ne sont pas modifires par l'anesthrsie au Nembutal. 4. La forme et l'amplitude de la FFR varient avecla frrquence du stimulus et avec sa latrralit6. 5. En contraste avec le potentiel 6voqu6 auditif, qui peut 8tre recueilli dans des rrgions 6tendues du cerveau, la FFR ne peut l'~tre que Eleetroenceph. clin. NeurophysioL, 1968, 25:42-52
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F. G. WORDEN AND J. T. MARSH
darts la voie auditive, ou tr6s pr6s d'elle. Cette r6ponse n ' a 6t6 observ6e q u ' a u niveau du colliculus inf6rieur et au dessous. 6. La F F R a p o u r la neurophysiologie de I ' a u d i t i o n des implications diff6rentes de celles du potentiel 6voqu6 auditif. Quelques-unes de celles-ci sont discut6es ici. It is a pleasure to acknowledge the technical assistance of Mr. J. Martin and Mr. J. Smith and the assistance of Mrs. S. Oozier in the preparation oftbe manuscript. REFERENCES B~g~V, G. vow. Hearing theories and complex sounds. J. aeoust. Sac. Amer., 1963, 35: 588-601. BOODmEAU, J. C. Neural volleying: upper frequency limits detectable in the auditory system. Nature (Lond.), 19~a, 208: 1237-1238. BOUO~AU, J. C. Stimulus correlates of wave activity in the superior-olivary complex of the cat. J. acoust. Soc. Amer., 1965b, 37: 779-785. DAVIS,H., DEimYSHmE,A. J., LURIE,M. H. and SAUL,L.J. Further analysis of cochlear activity and auditory action currents. Trans. Amer. otol. Soc., 1933, 23: 106-116. DERnYSmRE,A. J'. and DAvis, H. The action potentials of the auditory nerve. Amer. J. Physiol., 1935, ll3: 476-504. FORBES,A. and RACE,L. Quantitative studies of the nerve impulse. IV. Fatigue in the peripheral nerve. Amer. J. Physiol., 1929, 90: 119-145. GALAMBOS, R. and DAVIS, H. The response of single auditory-nerve fibers to acoustic stimulation. J. Neurophysioi., 1943, 6: 39-58. GERmiO, R, W. and MARSHALL,W. H. Nerve conduction velocity and equilibration. Amer. J. Physiol., 1933, 104: 575-585. GERARD, R.W., MARSHALL,W.H. and SAUL,L. J. Electrical activity of the cat's brain. Arch. Neurol. Psyehiat. (Chic.), 1936, 36: 675-735. GOLOmG, J. M. and NEEV, W. D. Frequency discrimination after bilateral ablation of cortical auditory
Reference: W ~ , sound. ~
areas. J. Neurophysiol., 1961a, 24:119-128.
GOLDBERG,J. M. and NET, W. D. Frequency discrimination after bilateral section of the brachium of the inferior colliculus. J. comp. Neurol., 1961b, 116: 265-290. KEMP, E. H., COPP~E,G. E. and Roan~SON,E. H. Electric responses of the brain stem to unilateral auditory stimulation. Amer. J. Physiol., 1937, 120: 304-315. MARSH, J. T. and WOR~N, F. G. Auditory potentials during acoustic habituation: cochlear nucleus, cerebellum, and auditory cortex. Eiectroeneeph. din. Neurophysiol., 1964, 17: 685-692. NEFF, W. D. Role of auditory cortex in sound discrimination. In G. L. RAS~US~N and W. F. WlNDLECEds.), Neural mechanisms of the auditory and vestibular systems. Thomas, S p r i ~ e i d , Ill., 1960: 211-223. RosE, J. E., BRUGGE,J. F., ANDER,qON,D. J. and HIND, J. E. Phase-locked response to low-frequency tones in single auditory nerve fibers of the squirrel monkey. J. Neurophysiol., 1967, 30: 769-793. RosE, J. E., GROSS,N. B., GEtst~"n,C. D. and HIND, J. E. Some neural mechanisms in the inferior colliculus of the eat which may be relevant to localization of a sound source. J. Neurophysiol., 1966, 29: 288"314. SAUL, L. J. and DAVlS, H. Electrical phenomena of the auditory mechanism. Trans. Amer. otol. Soc., 1932, 22: 137-145. TSUCHITANI,C. and BOUmtEAU,J. C. Wave activity in the superior olivary complex of the cat. J. Neurophystol., 1964, 27: 814-827. WEVER, E. G. Theory of hearing. Wiley and Sons, New York, 1949, 484 p. WEVER,E. G. and BRAY,C. W. The nature of the acoustic response: The relation b e t w ~ soun frequency and frequency of impulses in the auditory nerve. J. exp. Psychol., 1930, 13: 373-387. WORD~q, .F.G. and MARSH,J. T. Amplitude changes of auditory potentials evoked at cochlear nucleus during acoustic habituation, Electroenceph. din. Neurol~ysiol., 1963, 15: 866-881. WOADS, F. G., MARSH, J. T., AI~AHAM, F. D. and WmTrLr~V, J. R. B. Variability of evoked auditory potentials and acoustic input control. Electroenecph, din. Neurophysiol., 1964, 17: 524-530.
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