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P300 wave elicited by a stimulus-change paradigm in acutely prepared rats
Physiology & Behavior, Voi. 28, pp. 711-713. Pergamon Press and Brain Research Publ., 1982. Printed m the U.S.A.
P300 Wave Elicited by a Stimulus-Change Paradigm in Acutely Prepared Rats JAMES H. O'BRIEN
Department of Medical Psychology, The Oregon Health Sciences University, Portland, OR 97201 R e c e i v e d 3 A u g u s t 1981 O'BRIEN, JAMES H. P300 wave elicited by a sttmulus-change paradigm in acutely prepared rats. PHYSIOL. BEHAV. 28(4) 711-713, 1982.--Presentation of a long sequence of stimuli in one modality followed by infrequent substitution of stimuli in a different modality produced a very large P300 wave in the evoked potential to the infrequent stimulus. The P300 wave was never observed in a repetitive train of stimuli in one modality or to the background stimuli during the stimuluschange procedure. This phenomenon was observed in cortical recordings from anesthetized rats. This P300 wave corresponds in latency to that observed in human cognitive studies, and the use of this paradigm in animal studies could greatly facilitate work to determine the neural basis of the P300 wave. P300 wave
Event-related potentials
Cognition
D U R I N G the last few years there has been increasing interest in relating measures of brain activity to cognitive function in humans. The most common measure is that referred to as event-related potentials, particularly the contingent negative variation and P300 wave o f sensory evoked activity. The objective has been to relate the brain measure to some particular type of cognitive function. The studies have been primarily with humans, and a stimulus-change paradigm is the procedure most often employed. A stimulus in a different sensory modality, or a qualitative or quantitative change in the stimulus being presented, is introduced irregularly and infrequently into a repetitive background train of stimuli [6, 8, 9,]. The P300 wave is elicited by the unpredictable stimuli, but not by the repetitive stimuli. A number of signal detection studies have also been performed, and stimulus-change and unpredictability are features of the designs [1, 2, 3, 4, 5, 7, 10]. The P300 wave has been observed to the stimulus requiring a response in all o f these studies. Even a simple paradigm, with the stimulus presented irregularly at an average 45 sec interval, produces the P300 wave [11]. The purpose of this report is to describe a P300 wave elicited by a stimulus-change paradigm used with acutely prepared rats. METHOD
Experiments were performed on 12 Long-Evans rats anesthetized with Nembutal (50 mg/kg IP). Most experiments were completed with the initial dose of Nembutal and in no case were the animals allowed to become light enough for spontaneous or elicited movement. Different sequences of stimuli were examined in different animals, and the P300 wave described in this report was observed both soon and a few hours after a single anesthetic dose. All experiments were performed in an IAC sound-proof chamber. Recordings were taken from the bregma association area (1 mm caudal to bregma, 1 mm lateral of midline) through a
Evoked potential
0.01 inch stainless steel wire (0.5 mm tip bared) placed on the surface of the dura through a small Burr hole; all recordings were monopolar referenced to a hemostat on the temporal muscle. The signals were amplified and led to an A/D converter on a PDP-12 computer. The somatic stimulus was three 0.1 msec pulses at 250 Hz and 5 volts (50/xA) presented through subcutaneous hypodermic needles inserted on the two sides of the hindpaw contralaterai to the cortical recording electrode. This stimulus intensity was just subthreshold for producing muscle movement. The visual stimulus was a flash from a Grass photo-stimulator set at intensity 8. Atropine was placed on the cornea every 4 hours. RESULTS
A large number of stimulus sequences were examined, including the omitted stimulus and stimulus change paradigms. The successful procedure was found to be to present a large number of repetitive stimuli in one modality and then to substitute a stimulus in a different modality infrequently into the background train. A modality change of 1 out o f every 16 stimuli was used in the experiments reported here. F o r the first rat, trains of 16 stimuli were presented at a frequency of one/second with a one minute inter-train intervai. The sequence was: (1) 24 trains of light alone to form a control AEP; (2) 24 trains of paw-alone; (3) 24 trains of paw background with a light flash substituted for every 16th stimulus. The results with this sequence are shown in the left column of Fig. 1 ; the responses are 24 trial average evoked potentials. The top A E P is from the repetitive light sequence, the middle A E P is from the stimulus change sequence and the lower A E P is the somatic background response in the stimulus change paradigm. There is no evidence for a P300 wave in the control light response or in the somatic response, whereas the light response from the
C o p y r i g h t © 1982 B r a i n R e s e a r c h P u b l i c a t i o n s Inc.--0031-9384/82/040711-04503.00/0
712
O'BRIEN ASSOCIATION CORTEX AEP Ret#l
ASSOCIATION CORTEX AEP LRh! FIosh Paw Shin Rot d~7 Rot #11
Rat #5
Light Flesh
i' IJ ~00ms
l \//
,
Novel ~
II
'v ,illj,,I 3(X) ml
Stlm Re~ltlh~ l ~ ' ~ , ~ . ~ .
300~
/
I1'~
/
'!'
/i;
I,
~90ms SOOmi 1
l
"-~ ~VI /
Novel
//i Ij,
t
0
I
k
768ml 0
4
768ms
FIG. 1. Cortical average evoked potentmls (AEPs) to a repetmve hght flash (top row), a light flash interspersed in a background repetitive train of paw stimuli (middle row), and a repetitive paw stimulus (bottom row). Left column, 24 trial AEPs; fight column, 100 trial AEPs. Stimulus occurrence at t~me zero, total time base of 768 msec AEPs plotted positive up
stimulus change paradigm has a very large P300 wave. In this rat the 'P300' wave was negative, but it should be noted that the electrode was introduced 1 mm into the cortex and it was not a surface recording. In all of the remaining rats the recording electrode was placed on the surface of the cortex, and the P300 wave was always positive. For the remaining rats, stimuli were presented continuously at 1/second rather than in a series of 16 stimuli with an inter-trial interval. The computer was programmed to collect the evoked potenitals as if there were a series of 16 stimuli repeated over and over; AEPs were formed for each of the 16 stimuli. The sequence used in rat #5 (right column, Fig. 1) was: (1) 100 'trials' of 16 light flash stimuli, a total of 1600 flashes; (2) an identical n u m b e r o f paw stimuli; (3) 100 trials of the stimulus change paradigm, with paw stimuli for the background stimulus train and light flashes substituted for every 16 stimuli. As for the first rat, a very large P300 wave was found in the light flash evoked potential from the stimulus change paradigm. In this case the wave was a biphasic negative-positive potential, with the peak of the positive wave occurring at 300 msec latency. When the stimulus change paradigm was repeated over and over without a preceding light control and paw alone train, the P300 wave became smaller and smaller and finally disappeared. In general, this required about 100 presentations of the novel stimulus. Figure 2 shows two examples that exhibited less habituation than usual. The left column shows sequential 64 trial AEPs to light flash. The top AEP is the control response and this is followed by 192 novel light flashes introduced into a background train of paw stimuli (1 light flash per 15 paw stimuli). There is still a fairly substantial P300 in the bottom 64 trial AEP. The right column in Figure 2 shows a similar sequence of responses to paw stimulation. The top 64 trial AEP is the control response, and then the paw stimuli are introduced into a background train of light flashes. A small residual P300
/lPI' "~1
Novel
I
I
I
0
768m$
768ms
FIG. 2. Effect of repetition of stimulus change paradigm Top traces, control responses from repetitive tram. Lower 3 traces, consecutive 64 trial AEPs from stimulus change paradigm. Left column, paw background train, light flash novel. Right column, hght background train, paw stimulus novel. Note habituation of P300 component
may be seen in the bottom 64 trial AEP. The example of responses to paw stimulation also shows a number of new response waves to the novel paw stimulus. This was always observed for novel paw responses in a background train of light flashes, whereas the novel light response in a background train of paw stimuli was primarily just the P300. After the novel P300 response had habituated, it was usually possible to reinstate the wave by presenting a long series of the background stimulus by itself (1,000--2,000 stimuli). When the novel stimulus was now once again introduced into the train, a P300 was produced for about 50-100 stimulus presentations. The wave habituated faster than in the original series. On rare occasions this procedure could be repeated a third time to obtain the P300 wave. Since no calibration was included when averaging the evoked potentials, amplitudes can only be reported in arbitrary units. However, a comparison of measures for both the short-latency evoked potential and the P300 wave provides a meaningful evaluation of the magnitude of the P300 evoked potential. A P300 wave to light flash was obtained in 8 rats, and the following means and standard deviations are based on this N of 8 (the remaining 4 rats were examined with other types of stimulus paradigms). The peak amplitude was 124___47for the short-latency wave, and 112_ + 55 for the P300 wave. The area under the curve was 71___48 for the short-latency wave and 146---107 for the P300 wave. The standard deviations for the peak and area measures are not very meaningful since the amplifier settings varied considerably among rats and both large and small AEPs were collected. An alternative way to evaluate peak amplitude is to obtain a difference score for each animal of the short-latency minus P300. The mean
P300 WAVE
713
difference was 12 and the standard deviation 61. On the average the peak amplitudes of the short-latency and P300 waves were about the same, but there was considerable variability among animals as to which peak was greater and the magnitude of this difference. The latency to the peak of the P300 wave was 315+_25 msec. DISCUSSION The P300 wave observed in these experiments was extremely robust and easily obtained if the appropriate stimulus sequence was presented. Although the successful stimulus sequence is fairly simple, the recipe is in most cases critical. In two rats an attempt was made to obtainthe P300 wave to light by presenting the stimulus change paradigm (no preceding paw alone sequence) as the first sequence in the animal, and for one rat the P300 was observed but not for the second. Evidently the paw alone sequence is important before introducing the infrequent light stimulus. From examination of a number of stimulus sequences in the present study, expectation or predictability appears to be the critical variable. If a large number of stimuli in one modality are repetitively presented and then a stimulus in a different mo-
dality is infrequently substituted for a background stimulus, the P300 wave is elicited by the infrequent stimulus. To obtain the P300 it is apparently necessary to establish a set or expectation for a particular stimulus and then introduce an unexpected (novel) stimulus. In a recent sutdy by Wilder et al. [12] a similar P300 wave was observed in a classical pupillary conditioning task in cats. The P300 wave was present only when the evoking stimulus was relevant to the task, and the amplitude of the component varied inversely with stimulus probability and was independent of stimulus modality. This wave, therefore, behaved essentially like the P300 component recorded from humans. The results of this and the present study indicate that it should be possible to determine the neural basis of the P300 wave in animal studies, and that this information could be applicable to the P300 wave observed in human cognitive studies.
ACKNOWLEDGEMENT This work was supported by a research grant from the Whitehall Foundation.
REFERENCES
1. Donchin, E., P. Tueting, W. Ritter, M. Kutas and E. Heffiey On the independence of the CNV and the P300 components of the human averaged evoked potential. Electroenceph chn. Neurophystol. 38: 449--461, 1975. 2 Hillyard, S. A., K. C Sqmres, J. W. Bauer and P. H. Lindsay. Evoked potential correlates of auditory signal detection. Science 172: 1357-1360, 1971. 3. Johnson, R. Jr. and E. Donchin. P300 and stimulus categorization: Two plus one is not so different from one plus one. Psychophyslology 17: 167-178, 1980. 4. Parasuraman, R. and J. Beatty. Brain events underlying detection and recognition of weak sensory signals. Science 210: 80-83, 1980. 5 Paul, D. and S. Sutton. Evoked potential correlates of response criterion in auditory signal detection. Science 177: 362-364, 1972. 6. Rltter, W. and H. G Vaughan, Jr. Averaged evoked responses in vigilance and discrimination: A reassessment. Scwnce 164: 326--328, 1969.
7. Simson, R., H. G. Vaughan, Jr. and W. Ritter. The scalp topography of potentials in auditory and visual GO/NOGO tasks. Electroenceph. Neurophy~tol. 43: 864-875, 1977. 8. Squires, N. K., E. Donchin, K. C. Squires and S Grossberg. Bisensory stimulation: Inferring decision related processes from the P300 component. J. exp. Psychol.. Human Percept Perform. 3: 299-315, 1977. 9. Squires, N. K., K. C. Squires and S. A. Hfllyard. Two varieties of long-latency posiUve waves evoked by unpredictable auditory stimuli in man. Electroenceph. clin. Neurophystol 38: 387-401, 1975. 10. Tueting, P., S. Sutton and J Zugin. Quanutative evoked potential correlates of the pro.bability of events. Psychophyslology 7: 385-394, 1971. 11. Vaughan, H. G. Jr. and W. Rltter. The sources of auditory evoked responses recorded from the human scalp. Electroenceph, clin. Neurophysiol. 28" 360-367, 1970. 12 Wilder, M. B G. R. Farley and A. Starr. Endogenous late positive component of the evoked potential in cats corresponding to P300 in humans. Scwnce 211: 605-607, 1981.
P300 Wave Elicited by a Stimulus-Change Paradigm in Acutely Prepared Rats JAMES H. O'BRIEN
Department of Medical Psychology, The Oregon Health Sciences University, Portland, OR 97201 R e c e i v e d 3 A u g u s t 1981 O'BRIEN, JAMES H. P300 wave elicited by a sttmulus-change paradigm in acutely prepared rats. PHYSIOL. BEHAV. 28(4) 711-713, 1982.--Presentation of a long sequence of stimuli in one modality followed by infrequent substitution of stimuli in a different modality produced a very large P300 wave in the evoked potential to the infrequent stimulus. The P300 wave was never observed in a repetitive train of stimuli in one modality or to the background stimuli during the stimuluschange procedure. This phenomenon was observed in cortical recordings from anesthetized rats. This P300 wave corresponds in latency to that observed in human cognitive studies, and the use of this paradigm in animal studies could greatly facilitate work to determine the neural basis of the P300 wave. P300 wave
Event-related potentials
Cognition
D U R I N G the last few years there has been increasing interest in relating measures of brain activity to cognitive function in humans. The most common measure is that referred to as event-related potentials, particularly the contingent negative variation and P300 wave o f sensory evoked activity. The objective has been to relate the brain measure to some particular type of cognitive function. The studies have been primarily with humans, and a stimulus-change paradigm is the procedure most often employed. A stimulus in a different sensory modality, or a qualitative or quantitative change in the stimulus being presented, is introduced irregularly and infrequently into a repetitive background train of stimuli [6, 8, 9,]. The P300 wave is elicited by the unpredictable stimuli, but not by the repetitive stimuli. A number of signal detection studies have also been performed, and stimulus-change and unpredictability are features of the designs [1, 2, 3, 4, 5, 7, 10]. The P300 wave has been observed to the stimulus requiring a response in all o f these studies. Even a simple paradigm, with the stimulus presented irregularly at an average 45 sec interval, produces the P300 wave [11]. The purpose of this report is to describe a P300 wave elicited by a stimulus-change paradigm used with acutely prepared rats. METHOD
Experiments were performed on 12 Long-Evans rats anesthetized with Nembutal (50 mg/kg IP). Most experiments were completed with the initial dose of Nembutal and in no case were the animals allowed to become light enough for spontaneous or elicited movement. Different sequences of stimuli were examined in different animals, and the P300 wave described in this report was observed both soon and a few hours after a single anesthetic dose. All experiments were performed in an IAC sound-proof chamber. Recordings were taken from the bregma association area (1 mm caudal to bregma, 1 mm lateral of midline) through a
Evoked potential
0.01 inch stainless steel wire (0.5 mm tip bared) placed on the surface of the dura through a small Burr hole; all recordings were monopolar referenced to a hemostat on the temporal muscle. The signals were amplified and led to an A/D converter on a PDP-12 computer. The somatic stimulus was three 0.1 msec pulses at 250 Hz and 5 volts (50/xA) presented through subcutaneous hypodermic needles inserted on the two sides of the hindpaw contralaterai to the cortical recording electrode. This stimulus intensity was just subthreshold for producing muscle movement. The visual stimulus was a flash from a Grass photo-stimulator set at intensity 8. Atropine was placed on the cornea every 4 hours. RESULTS
A large number of stimulus sequences were examined, including the omitted stimulus and stimulus change paradigms. The successful procedure was found to be to present a large number of repetitive stimuli in one modality and then to substitute a stimulus in a different modality infrequently into the background train. A modality change of 1 out o f every 16 stimuli was used in the experiments reported here. F o r the first rat, trains of 16 stimuli were presented at a frequency of one/second with a one minute inter-train intervai. The sequence was: (1) 24 trains of light alone to form a control AEP; (2) 24 trains of paw-alone; (3) 24 trains of paw background with a light flash substituted for every 16th stimulus. The results with this sequence are shown in the left column of Fig. 1 ; the responses are 24 trial average evoked potentials. The top A E P is from the repetitive light sequence, the middle A E P is from the stimulus change sequence and the lower A E P is the somatic background response in the stimulus change paradigm. There is no evidence for a P300 wave in the control light response or in the somatic response, whereas the light response from the
C o p y r i g h t © 1982 B r a i n R e s e a r c h P u b l i c a t i o n s Inc.--0031-9384/82/040711-04503.00/0
712
O'BRIEN ASSOCIATION CORTEX AEP Ret#l
ASSOCIATION CORTEX AEP LRh! FIosh Paw Shin Rot d~7 Rot #11
Rat #5
Light Flesh
i' IJ ~00ms
l \//
,
Novel ~
II
'v ,illj,,I 3(X) ml
Stlm Re~ltlh~ l ~ ' ~ , ~ . ~ .
300~
/
I1'~
/
'!'
/i;
I,
~90ms SOOmi 1
l
"-~ ~VI /
Novel
//i Ij,
t
0
I
k
768ml 0
4
768ms
FIG. 1. Cortical average evoked potentmls (AEPs) to a repetmve hght flash (top row), a light flash interspersed in a background repetitive train of paw stimuli (middle row), and a repetitive paw stimulus (bottom row). Left column, 24 trial AEPs; fight column, 100 trial AEPs. Stimulus occurrence at t~me zero, total time base of 768 msec AEPs plotted positive up
stimulus change paradigm has a very large P300 wave. In this rat the 'P300' wave was negative, but it should be noted that the electrode was introduced 1 mm into the cortex and it was not a surface recording. In all of the remaining rats the recording electrode was placed on the surface of the cortex, and the P300 wave was always positive. For the remaining rats, stimuli were presented continuously at 1/second rather than in a series of 16 stimuli with an inter-trial interval. The computer was programmed to collect the evoked potenitals as if there were a series of 16 stimuli repeated over and over; AEPs were formed for each of the 16 stimuli. The sequence used in rat #5 (right column, Fig. 1) was: (1) 100 'trials' of 16 light flash stimuli, a total of 1600 flashes; (2) an identical n u m b e r o f paw stimuli; (3) 100 trials of the stimulus change paradigm, with paw stimuli for the background stimulus train and light flashes substituted for every 16 stimuli. As for the first rat, a very large P300 wave was found in the light flash evoked potential from the stimulus change paradigm. In this case the wave was a biphasic negative-positive potential, with the peak of the positive wave occurring at 300 msec latency. When the stimulus change paradigm was repeated over and over without a preceding light control and paw alone train, the P300 wave became smaller and smaller and finally disappeared. In general, this required about 100 presentations of the novel stimulus. Figure 2 shows two examples that exhibited less habituation than usual. The left column shows sequential 64 trial AEPs to light flash. The top AEP is the control response and this is followed by 192 novel light flashes introduced into a background train of paw stimuli (1 light flash per 15 paw stimuli). There is still a fairly substantial P300 in the bottom 64 trial AEP. The right column in Figure 2 shows a similar sequence of responses to paw stimulation. The top 64 trial AEP is the control response, and then the paw stimuli are introduced into a background train of light flashes. A small residual P300
/lPI' "~1
Novel
I
I
I
0
768m$
768ms
FIG. 2. Effect of repetition of stimulus change paradigm Top traces, control responses from repetitive tram. Lower 3 traces, consecutive 64 trial AEPs from stimulus change paradigm. Left column, paw background train, light flash novel. Right column, hght background train, paw stimulus novel. Note habituation of P300 component
may be seen in the bottom 64 trial AEP. The example of responses to paw stimulation also shows a number of new response waves to the novel paw stimulus. This was always observed for novel paw responses in a background train of light flashes, whereas the novel light response in a background train of paw stimuli was primarily just the P300. After the novel P300 response had habituated, it was usually possible to reinstate the wave by presenting a long series of the background stimulus by itself (1,000--2,000 stimuli). When the novel stimulus was now once again introduced into the train, a P300 was produced for about 50-100 stimulus presentations. The wave habituated faster than in the original series. On rare occasions this procedure could be repeated a third time to obtain the P300 wave. Since no calibration was included when averaging the evoked potentials, amplitudes can only be reported in arbitrary units. However, a comparison of measures for both the short-latency evoked potential and the P300 wave provides a meaningful evaluation of the magnitude of the P300 evoked potential. A P300 wave to light flash was obtained in 8 rats, and the following means and standard deviations are based on this N of 8 (the remaining 4 rats were examined with other types of stimulus paradigms). The peak amplitude was 124___47for the short-latency wave, and 112_ + 55 for the P300 wave. The area under the curve was 71___48 for the short-latency wave and 146---107 for the P300 wave. The standard deviations for the peak and area measures are not very meaningful since the amplifier settings varied considerably among rats and both large and small AEPs were collected. An alternative way to evaluate peak amplitude is to obtain a difference score for each animal of the short-latency minus P300. The mean
P300 WAVE
713
difference was 12 and the standard deviation 61. On the average the peak amplitudes of the short-latency and P300 waves were about the same, but there was considerable variability among animals as to which peak was greater and the magnitude of this difference. The latency to the peak of the P300 wave was 315+_25 msec. DISCUSSION The P300 wave observed in these experiments was extremely robust and easily obtained if the appropriate stimulus sequence was presented. Although the successful stimulus sequence is fairly simple, the recipe is in most cases critical. In two rats an attempt was made to obtainthe P300 wave to light by presenting the stimulus change paradigm (no preceding paw alone sequence) as the first sequence in the animal, and for one rat the P300 was observed but not for the second. Evidently the paw alone sequence is important before introducing the infrequent light stimulus. From examination of a number of stimulus sequences in the present study, expectation or predictability appears to be the critical variable. If a large number of stimuli in one modality are repetitively presented and then a stimulus in a different mo-
dality is infrequently substituted for a background stimulus, the P300 wave is elicited by the infrequent stimulus. To obtain the P300 it is apparently necessary to establish a set or expectation for a particular stimulus and then introduce an unexpected (novel) stimulus. In a recent sutdy by Wilder et al. [12] a similar P300 wave was observed in a classical pupillary conditioning task in cats. The P300 wave was present only when the evoking stimulus was relevant to the task, and the amplitude of the component varied inversely with stimulus probability and was independent of stimulus modality. This wave, therefore, behaved essentially like the P300 component recorded from humans. The results of this and the present study indicate that it should be possible to determine the neural basis of the P300 wave in animal studies, and that this information could be applicable to the P300 wave observed in human cognitive studies.
ACKNOWLEDGEMENT This work was supported by a research grant from the Whitehall Foundation.
REFERENCES
1. Donchin, E., P. Tueting, W. Ritter, M. Kutas and E. Heffiey On the independence of the CNV and the P300 components of the human averaged evoked potential. Electroenceph chn. Neurophystol. 38: 449--461, 1975. 2 Hillyard, S. A., K. C Sqmres, J. W. Bauer and P. H. Lindsay. Evoked potential correlates of auditory signal detection. Science 172: 1357-1360, 1971. 3. Johnson, R. Jr. and E. Donchin. P300 and stimulus categorization: Two plus one is not so different from one plus one. Psychophyslology 17: 167-178, 1980. 4. Parasuraman, R. and J. Beatty. Brain events underlying detection and recognition of weak sensory signals. Science 210: 80-83, 1980. 5 Paul, D. and S. Sutton. Evoked potential correlates of response criterion in auditory signal detection. Science 177: 362-364, 1972. 6. Rltter, W. and H. G Vaughan, Jr. Averaged evoked responses in vigilance and discrimination: A reassessment. Scwnce 164: 326--328, 1969.
7. Simson, R., H. G. Vaughan, Jr. and W. Ritter. The scalp topography of potentials in auditory and visual GO/NOGO tasks. Electroenceph. Neurophy~tol. 43: 864-875, 1977. 8. Squires, N. K., E. Donchin, K. C. Squires and S Grossberg. Bisensory stimulation: Inferring decision related processes from the P300 component. J. exp. Psychol.. Human Percept Perform. 3: 299-315, 1977. 9. Squires, N. K., K. C. Squires and S. A. Hfllyard. Two varieties of long-latency posiUve waves evoked by unpredictable auditory stimuli in man. Electroenceph. clin. Neurophystol 38: 387-401, 1975. 10. Tueting, P., S. Sutton and J Zugin. Quanutative evoked potential correlates of the pro.bability of events. Psychophyslology 7: 385-394, 1971. 11. Vaughan, H. G. Jr. and W. Rltter. The sources of auditory evoked responses recorded from the human scalp. Electroenceph, clin. Neurophysiol. 28" 360-367, 1970. 12 Wilder, M. B G. R. Farley and A. Starr. Endogenous late positive component of the evoked potential in cats corresponding to P300 in humans. Scwnce 211: 605-607, 1981.