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A comparative analysis of short-latency somatosensory evoked potentials in man, monkey, cat, and rat
EXPERIMENTAL
NEUROLOGY
72, 592-611 (1981)
A Comparative Analysis of Short-Latency Somatosensory Evoked Potentials in Man, Monkey, Cat, and Rat TRUETT ALLISON
AND ANN L. HUME’
Neuropsychology Laboratory, Veterans Administration Medical Center, West Haven, Connecticut 06516, and Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510 Received
September
16, 1980; revision
received
November
19. 1980
The spatial and temporal properties of the early portion of the somatosensory evoked potential (SEP) were assessed in normal human subjects and in monkeys, cats, and rats. When recorded from comparable loci, the SEP evoked by median nerve stimulation was similar in waveform and topography in all species, suggesting direct correspondences between human and animal components. To assessthe neural origins of this activity, simultaneous surface and depth recordings were obtained from cats and monkeys, and the effects of lethal doses of sodium pentobarbital were studied in all animals. Components identifiable in most humans and in the animals tested, and the structures thought to be their primary generators, are: NIO, peripheral nerve at the level of the brachial plexus; N 12a and N 12b, primary afferent fibers at caudal and rostra1 levels of the cervical cord; Nl3a, dorsal horn; Nl3b, cuneate nucleus; N14, medial lemniscus; PI 5, n. ventralis posterolateralis; PI6 and PI 8, uncertain; N20 or P20, primary somatosensory cortex.
INTRODUCTION Short-latency somatosensory evoked potentials (SEPs) generated in afferent pathways and somatosensory cortex can be recorded from surface Abbreviations: SEP-somatosensory evoked potential, CN+uneate nucleus, ML-medial lemniscus, VPL-ventral posterolateral nucleus, PS-primary spike, EMG&electromyographic, IP-initial positivity, A-afferent spike. ’ This work was supported by the Medical Research Service of the Veterans Administration and by the National Institute of Mental Health grant MH-05286. Dr. Hume was supported by the Auckland Medical Research Foundation, the Auckland Hospital Board, a Fulbright Travel Grant, and the Hackett Memorial Trust. Dr. Hume’s current address is the Department of Clinical Neurophysiology, Auckland Hospital, Auckland, New Zealand. We thank R. Bartozzi, C. Gaff, J. Jasiorkowski. and M. Reisenauer for assistance, and G. H. Glaser, W. R. Goff, and C. C. Wood for helpful discussion. 592 0014-4886/81/060592-20$02.00/O Copyright 0 1981 by Academic Press. Inc. All rights of reproduction in any form reserved
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electrodes and are used increasingly in the evaluation of neurological disorders (9, 18, 24). The specificity with which inferences as to the locus of a lesion can be made depends on the degree to which each component of the surface-recorded SEP can be ascribed to neuronal activity in a particular structure or level of the neuraxis. In human recordings analysis of latency and topography, recovery functions, pathophysiological correlates, and other techniques have been used to infer neural origins (1, 9, 10, 1315, 18, 20-23, 29). Progress has been made, but much disagreement remains. Studies in animals have addressed this question by correlating surfacerecorded activity with evoked potentials or multiple-unit activity recorded locally from various portions of the somatosensory system (6, 19, 28). However, animal SEP components have thus far been difficult to relate to those commonly recorded in humans, largely because of differences in surface-recording derivations. The animal studies typically recorded from the surface of the brain. In contrast, topographic studies in humans showed that greater differentiation of SEP components can be achieved using several derivations from the head, neck, and shoulder (1, 9, 14, 18, 20, 22, 24, 29). In this paper we show that, when recorded from similar electrode derivations, short-latency SEPs in the four species studied are remarkably similar in morphology and surface topography. In addition, the pattern of alteration of SEP components in the nonhuman species after barbiturate overdose was highly similar for the species studied. These two types of comparative evidence support the working hypothesis of correspondence between human and animal short-latency SEP components when recorded from the derivations used here. This hypothesis, in turn, provides a basis for using simultaneous surface and intracranial recordings in the nonhuman species as evidence bearing on the neural origins of SEPs in humans. METHODS Studies were made of 20 humans without history of neurological disease ( 10 males and 10 females, aged 10 to 76 years), two monkeys (one Mucaca mulatta, one iU. fascicularis), five cats, and six rats. Stimulating and recording conditions in all species were similar to those used previously in humans (1, 18). Stimuli were 0.5 ms duration, five/s constant-current shocks to the median nerve at the wrist at an intensity producing a detectable twitch of the first digit. Surface electrodes were comparably placed in all species, except that in humans F, was used as a reference for neck and shoulder recordings whereas in animals a screw electrode in frontal bone (Fp,) was used. After preamplification (system gain 25,000) with
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filter settings of 0.03 and 3 kHz (-3 dB points), SEPs were digitized (80 ps/point) and averaged (N = 512 in man, 128 or 256 in animals) by a Fabri-Tek Model 1074 four-channel averager and transferred to a LINC computer for further analysis. The animals were initially anesthetized with 30 to 45 mg/kg sodium pentobarbital and maintained under light anesthesia by supplemental doses as required. Body temperature was maintained at 37 + 1°C. After reflection of the scalp, small stainless-steel screw electrodes were placed in bone overlying cat and rat somatosensory cortex (SI), and over monkey parietal area contralateral to the nerve stimulated (P,) at loci comparable to the P3 or P4 loci used in humans. Subcutaneous needle electrodes were used to record at other surface loci. Recordings from multielectrode depth probes were made as the probe was advanced stereotactically toward and through the target structures. The deepest recording site was subsequently marked by passage of current, and recording sites were reconstructed from cell body and myelin stains of histologic sections. Coaxial electromyographic (EMG) electrodes were placed in or near the cord dorsum for recording spinal SEPs; their positions were determined from postmortem radiographs of the cervical spine. RESULTS Comparison of Somatosensory Evoked Potentials in Man and Animals. Due to the complexity of the potential fields generated by activation of the somatosensory system, and the variable manner in which they have been recorded, there is as yet little consensus regarding short-latency component identification and nomenclature. We use the “polarity-peak latency” nomenclature; human latency values are for a young adult normal population. To avoid prejudging the correspondence of surface- and depth-recorded activity, this nomenclature will be used only for surface-recorded activity. The choice of a polarity label and recording convention is arbitrary for most subcortical components because they may be “dipolar” and appear to be recorded as negativities from neck and shoulder loci and as positivities from scalp sites including the frontal “reference” lead (I, 10, 20, 29). To be consistent with previous human studies in which shoulder and neck recordings were made with reference to frontal scalp (9, 14, 18, 20, 24) relative negativity at the nonscalp lead (relative positivity at the scalp lead) was displayed upward, and upward peaks were given a negative label. To be consistent with previous animal and human studies in which recordings from scalp or cortical surface were made with reference to ears or a noncephalic site ( 1, 2, 6, 9, 10, 19, 21, 28), relative scalp or skull positivity was displayed upward, and upward peaks were given a positive label.
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somatosensory evoked potentials to median nerve stimulation in human (upper left), monkey (lower left), cat (lower right), and rat (upper right). Simultaneous recordings from shoulder (Si. midway along the clavicle of the ipsilateral shoulder), neck (CT), and contralateral parietal area (P,) or somatosensory cortex (SI) referred to linked-ear (A,A2) or midfrontal (F, or Fp,) electrodes. In this and the following figures, polarity at electrode locus specified first is noted on the vertical calibration (5 pV unless noted otherwise). FIG. 1. Short-l8tenCy
Figure 1 (upper left) shows a typical short-latency human SEP as recorded under these experimental conditions. The three traces were obtained simultaneously. The top trace shows the median nerve volley (N 10) re-
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corded from the ipsilateral shoulder (Si). The middle trace shows the N12N13-N14 complex (2, 9, 18, 20, 22, 24, 29) recorded from an electrode over the seventh cervical spinous process (C7). This complex is preceded by an upward deflection which peaks slightly before NIO and reflects median nerve activity (9, 10,20,2 1,293, and is followed by an uncharacterized downward deflection which will not be considered further. The lower trace begins with a scalp-positive amalgam of potentials corresponding in latency with the N12-N14 components as recorded in the C7 derivation, and terminating in a small peak or inflection labeled PI 5. PI5 is followed by a scalp-negative potential typically interrupted by two inflections labeled P 16 and P18 and terminating in N20, which reflects initial activity of somatosensory cortex (2, 6, 7, 18). SEPs recorded from similar montages are also shown for monkey, cat, and rat in Fig. 1. The results to be reported strongly suggest that corresponding components can be identified in all species. For this reason, and to avoid a confusion of nomenclatures, animal components are labeled according to their probable human counterparts. Comparison of recordings for the species tested shows that the waveforms were similar, with one major difference: The initial activity of somatosensory cortex in man and monkey was recorded as a negativity (N20), whereas in cat and rat it was recorded as a positivity [also see ( 19, 28)] and for convenience is labeled P20. This difference in polarity results from the different geometry of the somatosensory cortex hand area in primates and nonprimates (2, 7). Components are labeled in the derivation in which they were typically best observed; most components were also identifiable in other derivations (see below). Peak latencies are summarized in Table 1. Latencies provide another source of information for assessing possible correspondence of components. Absolute latencies cannot be compared directly because they decrease with decreasing body size and reflect corresponding decrease in length of the conduction pathway. However, relative latencies can be compared if the peripheral nerve volley (NlO) and initial activity of somatosensory cortex (N20/P20) are used as benchmarks; a detailed analysis will appear elsewhere (3). To summarize, relative latencies were similar for the species tested and deviated less than 10% from expected values if monkey, cat, and rat somatosensory systems are assumed to be linearly compressed versions of the human system. The discrepancies appeared to result from changes in length of portions of the somatosensory pathway and from anesthetic effects in the animals. Comparison of Surface and Depth Recordings. Simultaneous surface and depth recordings were made in cats and monkeys. The results in Fig. 2 are representative of those obtained in all animals. Proceeding centrally
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SEPs IN MAN AND ANIMALS TABLE
1
Peak Latency of Bomatosensory Evoked Potential Components’
NlO
N12a
N12b
N13a
N13b
N14
P15
P16
P18
N20/ P20
Human
10.1 8.0 13.2
11.6 9.4 14.1
12.3 9.9 15.3
13.5 10.3 16.0
13.9 10.7 16.6
14.5 11.8 17.4
15.1 12.4 17.6
16.6 13.8 19.0
18.2 15.4 20.2
19.2 16.2 21.8
Monkey
4.4 4.1 4.8
5.0 5.0 5.1
5.7 5.4 5.9
6.5 6.4 6.7
7.0 6.9 7.1
7.8 7.6 8.0
8.2 7.9 8.5
9.2 9.2 9.3
10.1 10.0 10.1
10.5 10.4 10.6
Cat
2.8 2.1 3.2
3.6 3.1 4.2
4.3 3.7 5.0
5.4 4.9 6.1
5.9 5.6 6.4
6.5 6.1 7.3
7.6 7.2 8.4
9.1 8.5 9.7
10.3 9.5 11.2
11.4 10.8 12.1
Rat
1.5 1.3 1.6
1.7 1.5 1.9
2.5 2.3 3.0
3.0 2.4 3.2
3.5 3.3 3.8
4.0 3.1 4.5
4.8 4.2 5.6
5.6 4.9 6.3
6.7 6.0 7.3
7.5 7.0 8.1
’ For each species, the top row is mean peak latency, and the middle and bottom rows are lower and upper ranges of latency.
along the afferent pathway, the top trace, left column, shows the median nerve afferent volley, N 10. The next pair of traces illustrates SEPs recorded from C7 (hereafter referred to as “surface C7”) and from an electrode inserted into the C6-C7 intervertebral space (“deep C7”) and slowly advanced until large focal potentials were recorded. The latter electrode recorded a biphasic positive-negative spike followed by a larger negativity and positivity. ,The spike potential reflects the incoming afferent volley. Following Gelfan and Tarlov (16), its positive and negative phases are labeled the initial positivity (IP) and intramedullary primary afferent spike (A). The slower negative and positive potentials are the N and P waves described in many previous recordings from the cord dorsum [e.g., (8, 11, 12, 16)]. That these potentials were locally generated was demonstrated by the strong dependence of their amplitude on electrode placement, and by the polarity inversion of the N wave as the electrode was advanced deeper into the cord. The N wave reflects depolarization of neurons in the dorsal horn by the afferent volley, and its polarity-inverted counterpart ventral to the dorsal horn reflects positive source potentials in axons of the dorsal horn neurons (8, 11, 12, 16). During this study it became clear that the surface-recorded N12 could often be divided into subcomponents, labeled Nl2a, and Nl2b in Fig 2.
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N12a, best recorded at C7, was synchronous with the A spike. Two fractions of N13 were also apparent in most recordings. The first of these, N13a, coincided with the peak of the cord dorsum N wave (Fig. 2, cf. surface and deep C7 traces). It has been noted that the human N 13 is also often “bifid” or “bilobed” (9, 10, 20, 22). Recordings from an electrode advanced into the C2-C3 intervertebral space (“deep C2”) were similar to those recorded from deep C7 except that the initial diphasic spike was approximately 0.5 ms later than the IP
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and A spikes recorded at the C7 level. The negative phase of the spike potential at the C2 level was coincident with the surface-recorded N12b (Fig. 2). Recordings from the region of the cuneate nucleus (CN) were similar in some respects to those from the cord dorsum. From loci dorsal to the CN, the first local activity recorded was a negative spike 0.3 ms later than N12b (Fig. 2, CN A). Therman (26) labeled this potential the primary spike (PS), and he and others (5) showed that it reflects the ascending afferent volley into the cuneate nucleus. In the recordings of Fig. 2, the PS had no surface counterpart; in some recordings it coincided with a slight inflection on the rising phase of N13. The PS was followed by a slow negative potential upon which several negative spike discharges were superimposed. By analogy with the cord dorsum N wave, Andersen et al. (5) labeled this slow negativity the N wave and ascribed it to depolarization of cuneate neurons by the ascending volley. Ventral to the CN, large potentials of similar waveform but inverted in polarity were recorded (Fig. 2, CN B). This region of positivity is thought to reflect current sources in the ventrally directed axons of CN neurons (5). The first large positive spike to follow the PS was coincident with the first peak of the N wave recorded dorsally and with the later of the N13 fractions, N13b. At the mesencephalic level of the medial lemniscus (ML) a large, predominantly positive spike potential was recorded with a latency 0.6 ms greater than that of N13b. This potential was coincident with the surfacerecorded N 14. In the caudal pole of n. ventralis posterolateralis (Fig. 2, VPL B) a positive spike potential of similar latency was followed by a slower negativity upon which several spike discharges were superimposed. Again by analogy with the N wave of the cord dorsum and the CN, this local negativity was labeled the N wave and ascribed to depolarization of VPL neurons by the lemniscal volley (4). Dorsal to the VPL (Fig. 2, VPL A) a complex waveform began with a large positive spike coincident with the lemniscal volley. The N wave showed a slight polarity inversion, and similarly most of the negative spikes recorded ventrally were recorded dorsally as positive potentials. The initial large spike of the series was coincident with the surface-recorded P15. The later spikes recorded dorsal to the VPL were roughly coincident with the surface-recorded P16-P18 complex, but the correspondence in latency either with the surface complex or with the later potentials at other VPL and ML sites was not close enough to suggest their precise origin. In this example, as often occurred in animal and human recordings, P16 consisted of two subcomponents. In some recordings even more wavelets were seen. Part of the P16-P18 complex may reflect burst discharges of CN and VPL neurons (4-6). Activity in thalamocortical fibers is also a
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FIG. 3. Somatosensory evoked potentials from surface C2 and C7 of a cat in which the spatial and temporal separation of N l2a and N12b was unusually clear.
likely source of activity in this latency range (1, 6, 19, 28). However, we did not record from the region of the internal capsule. The origin of the P16-P18 complex will not be considered further. The results in Figs. 3-6 further illustrate the relationship between surface- and depth-recorded potentials. Usually, N 12 was recorded from surface C7 as a single potential, as in the examples of Fig. 1, although occasionally, as in Fig. 2, two peaks were evident. The second, N12b, was more clearly differentiated in a surface C2 recording as shown in Fig. 2 N’Oy:
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FIG. 4. Topographic and temporal relations of N12 and N13 in man. Cursors mark the peak of Nl2a (peak latency = 12.2 ms) in the C7 trace and N12b (12.9 ms) in the C2 trace. Four other cursors set to the same latency on each trace mark N 13a (13.7 ms), N l3b (14.3). N14 (15.1). and PI5 (15.6). Left median nerve stimulation.
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and, for another animal, in Fig. 3. Figure 4 shows that similar differentiation could be obtained in humans. Although C2 also shows a deflection synchronous with N 12a and C7 shows a defection synchronous with N 12b, suggesting that the two peaks are of separate fixed origin, they could equally well reflect a single propagated potential which was recorded later at C2 than at C7. In some humans and animals tested, the N 12a and N12b peaks could not be distinguished. In the 20 human subjects (in whom recordings were made using both C7 and C2 derivations and left and right median nerve stimulation), N 12a and N12b could be distinguished in 32 of 40 cases. In the remainder the fractions merged into a single wave with similar peak latency at C7 and C2. Figure 5A shows another example of the relationship between the N 13 complex and depth-recorded activity. The cord dorsum N wave coincided with N 13a, and the initial spike discharge after the PS was coincident with N 13b. A less common result is seen in Fig. 5B; the initial spike after the PS was synchronous with an undifferentiated N13. The surface recordings of Figs. 4 and 5A illustrate a common topographic difference: at C7, N 13a was largest and N13b was seen as a later inflection, whereas at C2, N 13b was largest and N 13a was seen as an earlier inflection. N 13b was typically larger than N13a in the Si derivation as well (Fig. 4). In humans the N13a and Nl3b fractions could be differentiated in 27 of 40 cases; in the remaining 13 only a single peak could be distinguished. A
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FIG. 5. Topographic and temporal relations of N12 and N13 in cat somatosensory evoked potentials (SEPs). A-surface SEPs compared with recordings from deep C7 and from an electrode ventral to CN (for locus see Fig. 9D). lsolatency lines at 5.5 (Nl3a) and 6.0 ms (Nl3b). B-surface SEP compared with depth recordings from the CN (for locus see Fig. 9E). In this and the following figure positivity in brain stem and thalamic loci is displayed upward to facilitate comparison with the surface-recorded activity.
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FIG. 6. Surface somatosensory evoked potentials in cat compared with depth recordings in and dorsal to the medial lemniscus (ML, see Fig. 9F), and lateral to the ventral posterolateral nucleus (VPL, see Fig. 9G). The ML recordings were obtained 20 min after recordings from the VPL; no latency changes were observed during this interval. Note that N13a and Nl3b were unusually distinct; in this recording stimulus intensity was reduced well below that producing a forepaw twitch owing to the very large amplitude of the ML potential.
The relationship between surface-recorded N14 and P15 and activity in deep structures is further illustrated in Fig. 6. The large potential recorded from the ML (Fig. 6, ML B) was synchronous with N14. This large positive potential and the large positive spikes recorded from the ML and caudal thalamus (Fig. 2, ML and VPL A) are attributable to injury (“killed end” recording) of some of the lemniscal fibers (4). As in all such recordings from deep structures, the ML potential was highly focal; dorsal to the ML (Fig. 6, ML A) it was smaller by an order of magnitude than at locus B but roughly four times larger than the surface-recorded N14. At a locus lateral to the VPL the lemniscal volley was followed 1.3 ms later by a positive spike which was synchronous with P15. This spike coincided with the peak of the local N wave (not shown) recorded ventral to the VPL. It was followed by later spikes which had no clear surface counterparts. Effects of Terminal Anesthesia. After the studies described above, recordings were made after administration of a lethal dosage of sodium pentobarbital. The sequence of SEP changes in these recordings was similar in all animals tested. Figure 7 shows representative results for each of the species tested. Activity of somatosensory cortex (N20 or P20) was consistently the first to be abolished, approximately at the time of cessation of breathing. Components PlS-PI 8 were abolished before activity in the N 13-N14 range. For example in Fig. 7 (upper right, rat), P 16 was abolished after P20 but before N13a. (In general, however, it was difficult to
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quantify changes in the N 13b-P18 sequence because these components were small and often appeared to be superimposed on larger potentials.) Within 3 min of cessation of breathing, all surface components later than N12b were usually abolished although in some cases remnants of activity in the N13-N 14 latency range were observed for several more minutes (Fig. 7, lower left, monkey). In contrast, at the time when later components were first abolished, N 10 and N 12 (a or b) frequently showed an increase in amplitude. N12 then disappeared at a time when NlO was still normal or supernormal in amplitude, and finally N 10 was abolished. The sensitivity of cortical neural activity to oxygen lack is well known (17), and the lesser sensitivity of the afferent pathway is not surprising because there is evidence that cerebral ischemia produces a gradient of decreasing injury from cerebral cortex to brainstem (25). However, one aspect of these results seemed paradoxical. The cord dorsum recordings suggested that N 12a and N 12b reflect the intramedullary primary afferent volley. If so, one would expect the volley to be equally robust whether recorded centrally (as N12a or N 12b) or more peripherally (as N 10). Figure 7 shows, however, that NlO was consistently abolished later than N12a or N12b. To explore this question, in some cats we recorded the afferent volley at the elbow, shoulder, cervical cord, and CN. The later components were also recorded. Figure 8 shows representative results. At 8 min (1 min after cessation of breathing), P 15 and later components were abolished. The N wave of the cord dorsum and postsynaptic activity in the CN were reduced in amplitude, whereas both A and PS were larger than their baseline amplitudes. At 12 min all postsynaptic activity was abolished (with the possible exception of a remnant of activity after the PS) whereas the increased amplitude of PS is evident; the same phenomenon was seen in all animals in which the PS and postsynaptic activity in the CN were recorded. At 20 min the PS was abolished, followed by abolition of A at 24 min, NlO at 30 min, and E at 40 min. Similar results from another animal are summarized in Fig. 7, lower right. Because the median nerve afferent volley is clearly abolished at the shoulder earlier than at the elbow, the sequential abolition of the PS, N 12b, and N 12a (or A) appears to reflect in the central projections of these fibers the same gradient of susceptibility to the effects of asphyxia that is apparent peripherally. The recordings of Fig. 7, lower right are pertinent to another issue. If a surface-recorded potential is indeed the counterpart of a particular depthrecorded potential, any experimental manipulation should produce similar changes in both potentials. Few comparisons of this sort were made due to channel limitations. However, note in Fig. 7, lower right that A and N12a showed a parallel decrease in amplitude, as did the cord dorsum N
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wave and N13a. Although these and similar observations in other animals do not prove the correspondence of the surface- and depth-recorded potentials, a dissociation would disprove their correspondence. DISCUSSION The objective of studies such as this is to infer the neural origins of potentials recorded from the surface of humans after a somatosensory stimulus. Only in certain types of neurosurgical procedures is it possible to obtain local recordings from some somatosensory structures, and then only in a manner dictated by clinical goals. More systematic recordings
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can be obtained from animals, but their relationship to human recordings must be demonstrated. Thus, the conclusions we wish to draw from this study require evidence bearing on two types of correspondence. (i) Correspondence of surface- and depth-recorded components: Demonstration that a surface-recorded potential is the volume-conducted counterpart of a locally recorded deep potential requires: (a) Simultaneity of latency. We accepted as “simultaneous,” components differing in peak latency by less than 0.2 ms, which approached the limit of temporal resolution of the recording system. (b) Parallel changes effected by experimental manipulation. The terminal recordings (e.g., Fig. 7) allowed some preliminary observations which showed closely parallel changes in amplitude and latency of presumptively corresponding components, but additional observations of this sort are needed. (c) Evidence that other concurrent neural activity does not contribute significantly to a surface component. Our recordings were restricted to regions in or near structures of the lemniscal pathway and its primary cortical termination. Further work is needed to determine the degree of spatiotemporal overlap of activity within the lemniscal system itself, and to determine the extent to which other structures conveying somatosensory input [e.g., cerebellar pathways and cortex ( 19)] contribute to surface-recorded activity. (ii) Correspondence of components for different species: Having located in animals the probable structures which generate surface-recorded activity, it is then necessary to infer correspondences among animal and human components. As the architecture and function of somatosensory afferent pathways in mammals are similar, one might expect to record similar evoked activity in different species. These recordings show that, when comparable stimulating and recording methods are used, the waveform topography, and relative latency of the surface-recorded SEPs are indeed highly similar. Moreover, in monkey, cat, and rat the differential effects of terminal barbiturate anesthesia on components are similar. These observations suggest that comparable components reflect similar neural events in the four species, although the possibility that a component with similar characteristics in different species might reflect activity in different neural structures cannot be excluded. That NlO reflects the median nerve volley at the level of the brachial plexus is accepted by all workers and requires no comment. We found that N12 is composed of two fractions which can be ascribed to the volley in primary afferent fibers at caudal (Nl2a)and rostra1 (Nl2b) levels of the cervical dorsal column. During terminal recordings these potentials, as well as the PS, were consistently normal or supernormal in amplitude at a stage when later activity was reduced or abolished. Previous recordings from the cord dorsum have shown that the A spike was supernormal when postsynaptic activity (the N wave) was initially abolished (8, 12, 16). Similarly,
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C
n LGN
FIG. 9. Locations of electrodes in the A-P dimension as noted. nucleus, CP-cerebral peduncle, cuneate nucleus, HN-hypoglossal geniculate nucleus, ML-medial TN-trochlear nucleus, VPL-n. dialis.
for recordings of Figs. 2-8, with approximate coordinates Schematic drawings are not to same scale. CN-cuneate DN-dorsal motor nucleus of the vagus, ECN-external nucleus, LGN-lateral geniculate nucleus, MGN-medial lemniscus, ON-oculomotor nucleus, RN-red nucleus, ventralis postereolateralis, VPM-n. ventralis posterome-
the PS was supernormal during an early stage of asphyxia when all postsynaptic activity in the CN was abolished (26). Our results further demonstrate a gradient of susceptibility along the primary afferent fibers, the central terminals being most sensitive and the more peripheral portions progressively less so [also see (16)]. In animals N12a is synchronous with A, and in humans its onset latency is similar to the estimated time of arrival (10 to 11.5 ms) of the median nerve volley in the spinal cord to
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stimulation at the wrist (13, 29). Its latency is also similar to that of the initial potential recorded near the human cord dorsum to stimulation of the ulnar nerve at the wrist (23) or to stimulation at the elbow (15) if allowance is made for wrist-to-elbow conduction time. Although various postsynaptic origins for the human N12 have been suggested (10, 14, 21), our results support previous opinion that it reflects activity in primary afferent fibers (18, 20, 22, 29). Similarly, N12 in our monkey, cat, and rat recordings appears to correspond, respectively, to potentials recorded from the skull of monkey [P3.8 (6)], cat [component I (19)], and rat [component 1(28)], and ascribed to activity in primary afferent fibers of the dorsal column. The first peak of the N 13 complex, N13a, appears to be the surface counterpart of the cord dorsum N wave and hence reflects the initial activation of dorsal horn neurons. Several lines of evidence indicate that N13b reflects the postsynaptic discharge of CN neurons: (i) the PS is a recording of the afferent volley as it enters the CN, and precedes spike discharges by about 1.O ms [ (5, 26); Figs. 2,5, 81. (ii) The N wave recorded from the dorsal aspect of the CN reflects the depolarization of CN neurons in response to the PS (5) and thus provides another estimate of the interval during which postsynaptic discharges can be expected to occur. (iii) The polarity inversion of the N wave and superimposed spikes as a recording electrode passes through the CN (5) was consistently seen (e.g., Fig. 2) and verifies the local origin of the activity. Although a good case can be made that the N13a and N13b peaks provide temporal markers of the modal time of discharge of dorsal horn and CN neurons, several facts suggest that activity in both structures contributes to the overall amplitude or area under the curve of these components. First, we recorded only from the rostra1 pole of the CN; neurons in the caudal pole may discharge slightly earlier. Moreover, the cord dorsum and CN N waves are rather broad potentials which overlap considerably in time. These considerations suggest that, in the humans and animals tested in whom N 13a and N 13b were not separable, the modal discharge of dorsal horn and CN neurons was nearly simultaneous. For purposes of amplitude quantification of N 13a in Fig. 7 we assumed that the C7 derivation primarily records cord dorsum activity; this remains to be determined. Because the N13b-P18 sequence of potentials generally appeared to ride on slower activity of possibly different origin, their “true” amplitude was difficult to determine with any assurance. In contrast, the peak latencies of all components did not appear to be affected by neighboring activity. Numerous structures extending from peripheral nerve to thalamus have been proposed as generators of the human N 13 complex ( 1, 10,20-22,29); our conclusions support recent patho-
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physiological studies (9, 18) suggesting that this activity is generated caudal to the thalamus. The largest spike recorded from electrodes in or near the ML was coincident with the surface-recorded N14 (Figs. 2, 6). In monkey a surface-recorded P6.2, perhaps corresponding to N14, was synchronous with the lemniscal volley as determined by multiunit studies (6). P 15 appears to be the surface reflection of initial postsynaptic activity in the VPL. As in the CN, the latencies of the presynaptic spike and the locally recorded N wave allow estimation of the timing of postsynaptic discharge of VPL neurons. In all recordings the initial large spike so identified was synchronous with the surface-recorded P15. In cat and rat a potential (component III) of similar relative latency was ascribed partly to activity in the VPL (19, 28). However, in monkey Arezzo et al. (6) were unable to identify in surface recordings activity corresponding to postsynaptic activity in the VPL. They suggested that the cellular geometry of the VPL leads to the generation of a closed potential field such that postsynaptic potentials are not recordable at a distance. In both their recordings and ours the potential fields in the region of the thalamus are complex, but both show local depolarizing sinks in the VPL and positive source potentials dorsal and lateral to it (e.g., Fig. 2), suggesting that the potential field is at least partially an open field and hence may be recorded at a distance. In our human and monkey recordings, P15 in parietal derivations was a small but identifiable peak or inflection at the end of the scalppositive potentials which were synchronous with N 13 and N 14. Another problem regarding the origin of P15 is that in human and monkey the difference in latency of about 0.5 ms between N14 and P15 would not appear to be large enough for the synaptic delay in the VPL required by our interpretation. More detailed surface and depth recordings of thalamic activity are needed to resolve these questions. We conclude that, with the exception of P16 and PI 8, the primary sources of these surface-recorded potentials can be identified tentatively. Excepting N 13a, generation of all subcortical components is attributed to the initial, synchronous discharge in fiber tracts and nuclei of the dorsal column-medial lemniscal system. In recordings from the CN and VPL only the initial postsynaptic spikes were consistently associated with discrete surface components. These observations are consistent with evidence that NlO and N12 reflect the afferent volley in rapidly conducting cutaneous and proprioceptive fibers ( 1, 13, 14,20,22,29), that the PS reflects activity in rapidly conducting cuneate tract fibers (26), and that these fibers terminate on rapidly conducting CN neurons which in turn project to rapidly conducting VPL neurons (27). It is not necessary to postulate additional sources of activi$y to account for each peak of the surface recorded activity,
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but future recordings may of course reveal contributions from other afferent pathways and nuclear structures which convey somatosensory information. REFERENCES T., W. R. GOFF AND C. C. WOOD. 1979. Auditory, somatosensory and visual evoked potentials in the diagnosis of neuropathology: recording considerations and normative data. Pages l-16 in D. LEHMANN AND E. CALLAWAY, Eds., Human Evoked Potentials. Plenum, New York. ALLISON, T., W. R. GOFF, P. D. WILLAMSON, AND J. C. VANGILDER. 1980. On the neural origin of early components of the human somatosensory evoked potential. Pages 51-68 in J. E. DESMEDT, Ed., Clinical Uses of Cerebral, Brainstem and Spinal Somatosensory Evoked Potentials. Karger, Basel. ALLISON, T., C. C. WOOD, G. MCCARTHY, A. L. HUME, AND W. R. GOFF. in press. Short-latency somatosensory evoked potentials in man, monkey, cat and rat: comparative latency analysis. Proceedings of the Symposium on Clinical Applications of Evoked Potentials in Neurology, Lyon, 1980. Raven Press, New York. ANDERSEN, P., C. M. BROOKS, J C. ECCLES, AND T. A. SEARS. 1964. The ventro-basal nucleus of the thalamus: potential fields, synaptic transmission and excitability of both presynaptic and postsynaptic components. J. Physiol. (London) 174: 348-369. ANDERSEN. P., J. C. ECCLES, R. F. SCHMIDT, AND T. YOKOTA. 1964. Slow potential wave produced in the cuneate nucleus by cutaneous volleys and by cortical stimulation. J. Neurophysiol. 27: 78-9 1. AREZZO, J., A. D. LEGATT, AND H. G. VAUGHAN, JR. 1979. Topography and intracranial sources of somatosensory evoked potentials in the monkey, I. early components. Electroenceph. Clin. Neurophysiol46: 155-I 72. AREZZO, J. C., H. C. VAUGHAN, JR., AND A. D. LEGATT. 1981. Topography and intracranial sources of somatosensory evoked potentials in the monkey. II. Cortical components. Electroenceph. Clin. Neurophysiol 51: l-l 8. AUSTIN, G. M., AND G. P. MCCOUCH. 1955. Presynaptic component of intermediary cord potential. J. Neurophysiol. 18: 441-451. CHIAPPA, K. H., S. K. CHOI, AND R. R. YOUNG. 1980. Short-latency somatosensory evoked potentials following median nerve stimulation in patients with neurological lesions. Pages 264-281 in J. E. DESMEDT, Ed., Clinical Uses ofCerebral. Bruinstem and Spinal Somatosensory Evoked Potentials. Karger, Base]. CRACCO, R. Q.. AND J. B. CRACCO. 1976. Somatosensory evoked potential in man: far field potentials. Electroenceph. Clin. Neurophysiol. 41: 460-466. ECCLES, J. C., P. G. KOSTYUK, AND R. F. SCHMIDT. 1962. Central pathways responsible for depolarization of primary afferent fibers. J. Physiol. (London) 161: 237-257. ECCLES, R. M., Y. LOYNING, AND T. OSHIMA. 1966. Effects of hypoxia on the monosynaptic reflex pathway in the cat spinal cord. J. Neurophysiol. 29: 315-332. EISEN, A., AND K. NUDLEMAN. 1978. F-wave and cervical somatosensory response conduction from the seventh cervical spinous process to cortex in multiple sclerosis. J. Can. Sci. Neurol. 5: 289-295. EL-NEGAMY, E., AND E. M. SEDGEWICK. 1978. Properties of a spinal somatosensory evoked potential recording in man. J. Neurol. Neurosurg. Psychiat. 41: 762-768. ERTEKIN, C. 1976. Studies on the human evoked electrospinogram. I. The origin of the segmental evoked potentials. Acta Neurol. Stand. 53: 3-20. GELFAN, S, AND 1. M. TARLOV. 1955. Differential vulnerability of spinal cord structures to anoxia. J. Neurophysiol. 18: 170-188.
1. ALLISON,
2.
3.
4. 5. 6. 7. 8. 9.
10. 11. 12. 13. 14. 15. 16.
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17. HEYMANS, C. 1950. Survival and revival of nervous tissues after arrest of circulation. Physiol. Rev. 30: 375-392. 18. HUME, A. L., AND B. R. CANT. 1978. Conduction time in central somatosensory pathways in man. Electroenceph. Clin. Neurophysiol. 45: 361-375. 19. IRAGUI-MADOZ, V. J., AND W. C. WIEDERHOLT. 1977. Far-field somatosensory evoked potentials in the cat: Correlation with depth recording. Ann. Neural. 1: 569-574. 20. JONES, S. J. 1977. Short latency potentials recorded from the neck and scalp following median nerve stimulation in man. Electroenceph. Clin. Neurophysiol. 43: 853-863. 21. KRITCHEVSKY, M., AND W. C. WIEDERHOLT. 1978. Short-latency somatosensory evoked potentials. Arch. Neural. 35: 706-711. 22. MATTHEWS, W. B., M. BEAUCHAMP, AND D. G. SMALL. 1974. Cervical somatosensory evoked responses in man. Nature (London) 252: 230-232. 23. SHIMOJI, K., M. MATSUKI, AND H. SHIMIZU. 1977. Wave-form characteristics and spatial distribution of evoked spinal electrogram in man. J. Neurosurg. 46: 304-313. 24. SMALL, D. G., W. B. MATTHEWS, AND M. SMALL. 1978. The cervical somatosensory evoked potential (SEP) in the diagnosis of multiple sclerosis. J. Neurol. Sci. 35: 21 l224. 25. STEEGMAN, A. T. 1969. The neuropathology of cardiac arrest. Pages 1005-1017 in J. MINCKLER. Ed., Pathology o/the Nervous System. McGraw-Hill, New York. 26. THERMAN, P. 0. 1941. Transmission of impulses through the Burdach nucleus. J. Neurophysiol. 4: 153-166. 27. TSUMOTO, T. 1974. Characteristics of the thalamic ventrobasal relay neurons as a function of conduction velocities of medial lemniscal fibers. Exp. Brain Res. 21: 21 l-224. 28. WIEDERHOLT, W. C., AND V. J. IRAGUI-MADOZ. 1977. Far-field somatosensory potentials in the rat. Electroenceph. Ciin. Neurophysiol. 42: 456-465. 29. YAMADA, T., J. KIMURA, AND D. M. NITZ. 1980. Short latency somatosensory evoked potentials following median nerve stimulation in man. Efectroenceph. C/in. Neum physiol. 48: 367-376.
NEUROLOGY
72, 592-611 (1981)
A Comparative Analysis of Short-Latency Somatosensory Evoked Potentials in Man, Monkey, Cat, and Rat TRUETT ALLISON
AND ANN L. HUME’
Neuropsychology Laboratory, Veterans Administration Medical Center, West Haven, Connecticut 06516, and Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510 Received
September
16, 1980; revision
received
November
19. 1980
The spatial and temporal properties of the early portion of the somatosensory evoked potential (SEP) were assessed in normal human subjects and in monkeys, cats, and rats. When recorded from comparable loci, the SEP evoked by median nerve stimulation was similar in waveform and topography in all species, suggesting direct correspondences between human and animal components. To assessthe neural origins of this activity, simultaneous surface and depth recordings were obtained from cats and monkeys, and the effects of lethal doses of sodium pentobarbital were studied in all animals. Components identifiable in most humans and in the animals tested, and the structures thought to be their primary generators, are: NIO, peripheral nerve at the level of the brachial plexus; N 12a and N 12b, primary afferent fibers at caudal and rostra1 levels of the cervical cord; Nl3a, dorsal horn; Nl3b, cuneate nucleus; N14, medial lemniscus; PI 5, n. ventralis posterolateralis; PI6 and PI 8, uncertain; N20 or P20, primary somatosensory cortex.
INTRODUCTION Short-latency somatosensory evoked potentials (SEPs) generated in afferent pathways and somatosensory cortex can be recorded from surface Abbreviations: SEP-somatosensory evoked potential, CN+uneate nucleus, ML-medial lemniscus, VPL-ventral posterolateral nucleus, PS-primary spike, EMG&electromyographic, IP-initial positivity, A-afferent spike. ’ This work was supported by the Medical Research Service of the Veterans Administration and by the National Institute of Mental Health grant MH-05286. Dr. Hume was supported by the Auckland Medical Research Foundation, the Auckland Hospital Board, a Fulbright Travel Grant, and the Hackett Memorial Trust. Dr. Hume’s current address is the Department of Clinical Neurophysiology, Auckland Hospital, Auckland, New Zealand. We thank R. Bartozzi, C. Gaff, J. Jasiorkowski. and M. Reisenauer for assistance, and G. H. Glaser, W. R. Goff, and C. C. Wood for helpful discussion. 592 0014-4886/81/060592-20$02.00/O Copyright 0 1981 by Academic Press. Inc. All rights of reproduction in any form reserved
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electrodes and are used increasingly in the evaluation of neurological disorders (9, 18, 24). The specificity with which inferences as to the locus of a lesion can be made depends on the degree to which each component of the surface-recorded SEP can be ascribed to neuronal activity in a particular structure or level of the neuraxis. In human recordings analysis of latency and topography, recovery functions, pathophysiological correlates, and other techniques have been used to infer neural origins (1, 9, 10, 1315, 18, 20-23, 29). Progress has been made, but much disagreement remains. Studies in animals have addressed this question by correlating surfacerecorded activity with evoked potentials or multiple-unit activity recorded locally from various portions of the somatosensory system (6, 19, 28). However, animal SEP components have thus far been difficult to relate to those commonly recorded in humans, largely because of differences in surface-recording derivations. The animal studies typically recorded from the surface of the brain. In contrast, topographic studies in humans showed that greater differentiation of SEP components can be achieved using several derivations from the head, neck, and shoulder (1, 9, 14, 18, 20, 22, 24, 29). In this paper we show that, when recorded from similar electrode derivations, short-latency SEPs in the four species studied are remarkably similar in morphology and surface topography. In addition, the pattern of alteration of SEP components in the nonhuman species after barbiturate overdose was highly similar for the species studied. These two types of comparative evidence support the working hypothesis of correspondence between human and animal short-latency SEP components when recorded from the derivations used here. This hypothesis, in turn, provides a basis for using simultaneous surface and intracranial recordings in the nonhuman species as evidence bearing on the neural origins of SEPs in humans. METHODS Studies were made of 20 humans without history of neurological disease ( 10 males and 10 females, aged 10 to 76 years), two monkeys (one Mucaca mulatta, one iU. fascicularis), five cats, and six rats. Stimulating and recording conditions in all species were similar to those used previously in humans (1, 18). Stimuli were 0.5 ms duration, five/s constant-current shocks to the median nerve at the wrist at an intensity producing a detectable twitch of the first digit. Surface electrodes were comparably placed in all species, except that in humans F, was used as a reference for neck and shoulder recordings whereas in animals a screw electrode in frontal bone (Fp,) was used. After preamplification (system gain 25,000) with
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filter settings of 0.03 and 3 kHz (-3 dB points), SEPs were digitized (80 ps/point) and averaged (N = 512 in man, 128 or 256 in animals) by a Fabri-Tek Model 1074 four-channel averager and transferred to a LINC computer for further analysis. The animals were initially anesthetized with 30 to 45 mg/kg sodium pentobarbital and maintained under light anesthesia by supplemental doses as required. Body temperature was maintained at 37 + 1°C. After reflection of the scalp, small stainless-steel screw electrodes were placed in bone overlying cat and rat somatosensory cortex (SI), and over monkey parietal area contralateral to the nerve stimulated (P,) at loci comparable to the P3 or P4 loci used in humans. Subcutaneous needle electrodes were used to record at other surface loci. Recordings from multielectrode depth probes were made as the probe was advanced stereotactically toward and through the target structures. The deepest recording site was subsequently marked by passage of current, and recording sites were reconstructed from cell body and myelin stains of histologic sections. Coaxial electromyographic (EMG) electrodes were placed in or near the cord dorsum for recording spinal SEPs; their positions were determined from postmortem radiographs of the cervical spine. RESULTS Comparison of Somatosensory Evoked Potentials in Man and Animals. Due to the complexity of the potential fields generated by activation of the somatosensory system, and the variable manner in which they have been recorded, there is as yet little consensus regarding short-latency component identification and nomenclature. We use the “polarity-peak latency” nomenclature; human latency values are for a young adult normal population. To avoid prejudging the correspondence of surface- and depth-recorded activity, this nomenclature will be used only for surface-recorded activity. The choice of a polarity label and recording convention is arbitrary for most subcortical components because they may be “dipolar” and appear to be recorded as negativities from neck and shoulder loci and as positivities from scalp sites including the frontal “reference” lead (I, 10, 20, 29). To be consistent with previous human studies in which shoulder and neck recordings were made with reference to frontal scalp (9, 14, 18, 20, 24) relative negativity at the nonscalp lead (relative positivity at the scalp lead) was displayed upward, and upward peaks were given a negative label. To be consistent with previous animal and human studies in which recordings from scalp or cortical surface were made with reference to ears or a noncephalic site ( 1, 2, 6, 9, 10, 19, 21, 28), relative scalp or skull positivity was displayed upward, and upward peaks were given a positive label.
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somatosensory evoked potentials to median nerve stimulation in human (upper left), monkey (lower left), cat (lower right), and rat (upper right). Simultaneous recordings from shoulder (Si. midway along the clavicle of the ipsilateral shoulder), neck (CT), and contralateral parietal area (P,) or somatosensory cortex (SI) referred to linked-ear (A,A2) or midfrontal (F, or Fp,) electrodes. In this and the following figures, polarity at electrode locus specified first is noted on the vertical calibration (5 pV unless noted otherwise). FIG. 1. Short-l8tenCy
Figure 1 (upper left) shows a typical short-latency human SEP as recorded under these experimental conditions. The three traces were obtained simultaneously. The top trace shows the median nerve volley (N 10) re-
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corded from the ipsilateral shoulder (Si). The middle trace shows the N12N13-N14 complex (2, 9, 18, 20, 22, 24, 29) recorded from an electrode over the seventh cervical spinous process (C7). This complex is preceded by an upward deflection which peaks slightly before NIO and reflects median nerve activity (9, 10,20,2 1,293, and is followed by an uncharacterized downward deflection which will not be considered further. The lower trace begins with a scalp-positive amalgam of potentials corresponding in latency with the N12-N14 components as recorded in the C7 derivation, and terminating in a small peak or inflection labeled PI 5. PI5 is followed by a scalp-negative potential typically interrupted by two inflections labeled P 16 and P18 and terminating in N20, which reflects initial activity of somatosensory cortex (2, 6, 7, 18). SEPs recorded from similar montages are also shown for monkey, cat, and rat in Fig. 1. The results to be reported strongly suggest that corresponding components can be identified in all species. For this reason, and to avoid a confusion of nomenclatures, animal components are labeled according to their probable human counterparts. Comparison of recordings for the species tested shows that the waveforms were similar, with one major difference: The initial activity of somatosensory cortex in man and monkey was recorded as a negativity (N20), whereas in cat and rat it was recorded as a positivity [also see ( 19, 28)] and for convenience is labeled P20. This difference in polarity results from the different geometry of the somatosensory cortex hand area in primates and nonprimates (2, 7). Components are labeled in the derivation in which they were typically best observed; most components were also identifiable in other derivations (see below). Peak latencies are summarized in Table 1. Latencies provide another source of information for assessing possible correspondence of components. Absolute latencies cannot be compared directly because they decrease with decreasing body size and reflect corresponding decrease in length of the conduction pathway. However, relative latencies can be compared if the peripheral nerve volley (NlO) and initial activity of somatosensory cortex (N20/P20) are used as benchmarks; a detailed analysis will appear elsewhere (3). To summarize, relative latencies were similar for the species tested and deviated less than 10% from expected values if monkey, cat, and rat somatosensory systems are assumed to be linearly compressed versions of the human system. The discrepancies appeared to result from changes in length of portions of the somatosensory pathway and from anesthetic effects in the animals. Comparison of Surface and Depth Recordings. Simultaneous surface and depth recordings were made in cats and monkeys. The results in Fig. 2 are representative of those obtained in all animals. Proceeding centrally
597
SEPs IN MAN AND ANIMALS TABLE
1
Peak Latency of Bomatosensory Evoked Potential Components’
NlO
N12a
N12b
N13a
N13b
N14
P15
P16
P18
N20/ P20
Human
10.1 8.0 13.2
11.6 9.4 14.1
12.3 9.9 15.3
13.5 10.3 16.0
13.9 10.7 16.6
14.5 11.8 17.4
15.1 12.4 17.6
16.6 13.8 19.0
18.2 15.4 20.2
19.2 16.2 21.8
Monkey
4.4 4.1 4.8
5.0 5.0 5.1
5.7 5.4 5.9
6.5 6.4 6.7
7.0 6.9 7.1
7.8 7.6 8.0
8.2 7.9 8.5
9.2 9.2 9.3
10.1 10.0 10.1
10.5 10.4 10.6
Cat
2.8 2.1 3.2
3.6 3.1 4.2
4.3 3.7 5.0
5.4 4.9 6.1
5.9 5.6 6.4
6.5 6.1 7.3
7.6 7.2 8.4
9.1 8.5 9.7
10.3 9.5 11.2
11.4 10.8 12.1
Rat
1.5 1.3 1.6
1.7 1.5 1.9
2.5 2.3 3.0
3.0 2.4 3.2
3.5 3.3 3.8
4.0 3.1 4.5
4.8 4.2 5.6
5.6 4.9 6.3
6.7 6.0 7.3
7.5 7.0 8.1
’ For each species, the top row is mean peak latency, and the middle and bottom rows are lower and upper ranges of latency.
along the afferent pathway, the top trace, left column, shows the median nerve afferent volley, N 10. The next pair of traces illustrates SEPs recorded from C7 (hereafter referred to as “surface C7”) and from an electrode inserted into the C6-C7 intervertebral space (“deep C7”) and slowly advanced until large focal potentials were recorded. The latter electrode recorded a biphasic positive-negative spike followed by a larger negativity and positivity. ,The spike potential reflects the incoming afferent volley. Following Gelfan and Tarlov (16), its positive and negative phases are labeled the initial positivity (IP) and intramedullary primary afferent spike (A). The slower negative and positive potentials are the N and P waves described in many previous recordings from the cord dorsum [e.g., (8, 11, 12, 16)]. That these potentials were locally generated was demonstrated by the strong dependence of their amplitude on electrode placement, and by the polarity inversion of the N wave as the electrode was advanced deeper into the cord. The N wave reflects depolarization of neurons in the dorsal horn by the afferent volley, and its polarity-inverted counterpart ventral to the dorsal horn reflects positive source potentials in axons of the dorsal horn neurons (8, 11, 12, 16). During this study it became clear that the surface-recorded N12 could often be divided into subcomponents, labeled Nl2a, and Nl2b in Fig 2.
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N12a, best recorded at C7, was synchronous with the A spike. Two fractions of N13 were also apparent in most recordings. The first of these, N13a, coincided with the peak of the cord dorsum N wave (Fig. 2, cf. surface and deep C7 traces). It has been noted that the human N 13 is also often “bifid” or “bilobed” (9, 10, 20, 22). Recordings from an electrode advanced into the C2-C3 intervertebral space (“deep C2”) were similar to those recorded from deep C7 except that the initial diphasic spike was approximately 0.5 ms later than the IP
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and A spikes recorded at the C7 level. The negative phase of the spike potential at the C2 level was coincident with the surface-recorded N12b (Fig. 2). Recordings from the region of the cuneate nucleus (CN) were similar in some respects to those from the cord dorsum. From loci dorsal to the CN, the first local activity recorded was a negative spike 0.3 ms later than N12b (Fig. 2, CN A). Therman (26) labeled this potential the primary spike (PS), and he and others (5) showed that it reflects the ascending afferent volley into the cuneate nucleus. In the recordings of Fig. 2, the PS had no surface counterpart; in some recordings it coincided with a slight inflection on the rising phase of N13. The PS was followed by a slow negative potential upon which several negative spike discharges were superimposed. By analogy with the cord dorsum N wave, Andersen et al. (5) labeled this slow negativity the N wave and ascribed it to depolarization of cuneate neurons by the ascending volley. Ventral to the CN, large potentials of similar waveform but inverted in polarity were recorded (Fig. 2, CN B). This region of positivity is thought to reflect current sources in the ventrally directed axons of CN neurons (5). The first large positive spike to follow the PS was coincident with the first peak of the N wave recorded dorsally and with the later of the N13 fractions, N13b. At the mesencephalic level of the medial lemniscus (ML) a large, predominantly positive spike potential was recorded with a latency 0.6 ms greater than that of N13b. This potential was coincident with the surfacerecorded N 14. In the caudal pole of n. ventralis posterolateralis (Fig. 2, VPL B) a positive spike potential of similar latency was followed by a slower negativity upon which several spike discharges were superimposed. Again by analogy with the N wave of the cord dorsum and the CN, this local negativity was labeled the N wave and ascribed to depolarization of VPL neurons by the lemniscal volley (4). Dorsal to the VPL (Fig. 2, VPL A) a complex waveform began with a large positive spike coincident with the lemniscal volley. The N wave showed a slight polarity inversion, and similarly most of the negative spikes recorded ventrally were recorded dorsally as positive potentials. The initial large spike of the series was coincident with the surface-recorded P15. The later spikes recorded dorsal to the VPL were roughly coincident with the surface-recorded P16-P18 complex, but the correspondence in latency either with the surface complex or with the later potentials at other VPL and ML sites was not close enough to suggest their precise origin. In this example, as often occurred in animal and human recordings, P16 consisted of two subcomponents. In some recordings even more wavelets were seen. Part of the P16-P18 complex may reflect burst discharges of CN and VPL neurons (4-6). Activity in thalamocortical fibers is also a
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FIG. 3. Somatosensory evoked potentials from surface C2 and C7 of a cat in which the spatial and temporal separation of N l2a and N12b was unusually clear.
likely source of activity in this latency range (1, 6, 19, 28). However, we did not record from the region of the internal capsule. The origin of the P16-P18 complex will not be considered further. The results in Figs. 3-6 further illustrate the relationship between surface- and depth-recorded potentials. Usually, N 12 was recorded from surface C7 as a single potential, as in the examples of Fig. 1, although occasionally, as in Fig. 2, two peaks were evident. The second, N12b, was more clearly differentiated in a surface C2 recording as shown in Fig. 2 N’Oy:
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FIG. 4. Topographic and temporal relations of N12 and N13 in man. Cursors mark the peak of Nl2a (peak latency = 12.2 ms) in the C7 trace and N12b (12.9 ms) in the C2 trace. Four other cursors set to the same latency on each trace mark N 13a (13.7 ms), N l3b (14.3). N14 (15.1). and PI5 (15.6). Left median nerve stimulation.
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and, for another animal, in Fig. 3. Figure 4 shows that similar differentiation could be obtained in humans. Although C2 also shows a deflection synchronous with N 12a and C7 shows a defection synchronous with N 12b, suggesting that the two peaks are of separate fixed origin, they could equally well reflect a single propagated potential which was recorded later at C2 than at C7. In some humans and animals tested, the N 12a and N12b peaks could not be distinguished. In the 20 human subjects (in whom recordings were made using both C7 and C2 derivations and left and right median nerve stimulation), N 12a and N12b could be distinguished in 32 of 40 cases. In the remainder the fractions merged into a single wave with similar peak latency at C7 and C2. Figure 5A shows another example of the relationship between the N 13 complex and depth-recorded activity. The cord dorsum N wave coincided with N 13a, and the initial spike discharge after the PS was coincident with N 13b. A less common result is seen in Fig. 5B; the initial spike after the PS was synchronous with an undifferentiated N13. The surface recordings of Figs. 4 and 5A illustrate a common topographic difference: at C7, N 13a was largest and N13b was seen as a later inflection, whereas at C2, N 13b was largest and N 13a was seen as an earlier inflection. N 13b was typically larger than N13a in the Si derivation as well (Fig. 4). In humans the N13a and Nl3b fractions could be differentiated in 27 of 40 cases; in the remaining 13 only a single peak could be distinguished. A
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FIG. 6. Surface somatosensory evoked potentials in cat compared with depth recordings in and dorsal to the medial lemniscus (ML, see Fig. 9F), and lateral to the ventral posterolateral nucleus (VPL, see Fig. 9G). The ML recordings were obtained 20 min after recordings from the VPL; no latency changes were observed during this interval. Note that N13a and Nl3b were unusually distinct; in this recording stimulus intensity was reduced well below that producing a forepaw twitch owing to the very large amplitude of the ML potential.
The relationship between surface-recorded N14 and P15 and activity in deep structures is further illustrated in Fig. 6. The large potential recorded from the ML (Fig. 6, ML B) was synchronous with N14. This large positive potential and the large positive spikes recorded from the ML and caudal thalamus (Fig. 2, ML and VPL A) are attributable to injury (“killed end” recording) of some of the lemniscal fibers (4). As in all such recordings from deep structures, the ML potential was highly focal; dorsal to the ML (Fig. 6, ML A) it was smaller by an order of magnitude than at locus B but roughly four times larger than the surface-recorded N14. At a locus lateral to the VPL the lemniscal volley was followed 1.3 ms later by a positive spike which was synchronous with P15. This spike coincided with the peak of the local N wave (not shown) recorded ventral to the VPL. It was followed by later spikes which had no clear surface counterparts. Effects of Terminal Anesthesia. After the studies described above, recordings were made after administration of a lethal dosage of sodium pentobarbital. The sequence of SEP changes in these recordings was similar in all animals tested. Figure 7 shows representative results for each of the species tested. Activity of somatosensory cortex (N20 or P20) was consistently the first to be abolished, approximately at the time of cessation of breathing. Components PlS-PI 8 were abolished before activity in the N 13-N14 range. For example in Fig. 7 (upper right, rat), P 16 was abolished after P20 but before N13a. (In general, however, it was difficult to
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quantify changes in the N 13b-P18 sequence because these components were small and often appeared to be superimposed on larger potentials.) Within 3 min of cessation of breathing, all surface components later than N12b were usually abolished although in some cases remnants of activity in the N13-N 14 latency range were observed for several more minutes (Fig. 7, lower left, monkey). In contrast, at the time when later components were first abolished, N 10 and N 12 (a or b) frequently showed an increase in amplitude. N12 then disappeared at a time when NlO was still normal or supernormal in amplitude, and finally N 10 was abolished. The sensitivity of cortical neural activity to oxygen lack is well known (17), and the lesser sensitivity of the afferent pathway is not surprising because there is evidence that cerebral ischemia produces a gradient of decreasing injury from cerebral cortex to brainstem (25). However, one aspect of these results seemed paradoxical. The cord dorsum recordings suggested that N 12a and N 12b reflect the intramedullary primary afferent volley. If so, one would expect the volley to be equally robust whether recorded centrally (as N12a or N 12b) or more peripherally (as N 10). Figure 7 shows, however, that NlO was consistently abolished later than N12a or N12b. To explore this question, in some cats we recorded the afferent volley at the elbow, shoulder, cervical cord, and CN. The later components were also recorded. Figure 8 shows representative results. At 8 min (1 min after cessation of breathing), P 15 and later components were abolished. The N wave of the cord dorsum and postsynaptic activity in the CN were reduced in amplitude, whereas both A and PS were larger than their baseline amplitudes. At 12 min all postsynaptic activity was abolished (with the possible exception of a remnant of activity after the PS) whereas the increased amplitude of PS is evident; the same phenomenon was seen in all animals in which the PS and postsynaptic activity in the CN were recorded. At 20 min the PS was abolished, followed by abolition of A at 24 min, NlO at 30 min, and E at 40 min. Similar results from another animal are summarized in Fig. 7, lower right. Because the median nerve afferent volley is clearly abolished at the shoulder earlier than at the elbow, the sequential abolition of the PS, N 12b, and N 12a (or A) appears to reflect in the central projections of these fibers the same gradient of susceptibility to the effects of asphyxia that is apparent peripherally. The recordings of Fig. 7, lower right are pertinent to another issue. If a surface-recorded potential is indeed the counterpart of a particular depthrecorded potential, any experimental manipulation should produce similar changes in both potentials. Few comparisons of this sort were made due to channel limitations. However, note in Fig. 7, lower right that A and N12a showed a parallel decrease in amplitude, as did the cord dorsum N
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wave and N13a. Although these and similar observations in other animals do not prove the correspondence of the surface- and depth-recorded potentials, a dissociation would disprove their correspondence. DISCUSSION The objective of studies such as this is to infer the neural origins of potentials recorded from the surface of humans after a somatosensory stimulus. Only in certain types of neurosurgical procedures is it possible to obtain local recordings from some somatosensory structures, and then only in a manner dictated by clinical goals. More systematic recordings
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can be obtained from animals, but their relationship to human recordings must be demonstrated. Thus, the conclusions we wish to draw from this study require evidence bearing on two types of correspondence. (i) Correspondence of surface- and depth-recorded components: Demonstration that a surface-recorded potential is the volume-conducted counterpart of a locally recorded deep potential requires: (a) Simultaneity of latency. We accepted as “simultaneous,” components differing in peak latency by less than 0.2 ms, which approached the limit of temporal resolution of the recording system. (b) Parallel changes effected by experimental manipulation. The terminal recordings (e.g., Fig. 7) allowed some preliminary observations which showed closely parallel changes in amplitude and latency of presumptively corresponding components, but additional observations of this sort are needed. (c) Evidence that other concurrent neural activity does not contribute significantly to a surface component. Our recordings were restricted to regions in or near structures of the lemniscal pathway and its primary cortical termination. Further work is needed to determine the degree of spatiotemporal overlap of activity within the lemniscal system itself, and to determine the extent to which other structures conveying somatosensory input [e.g., cerebellar pathways and cortex ( 19)] contribute to surface-recorded activity. (ii) Correspondence of components for different species: Having located in animals the probable structures which generate surface-recorded activity, it is then necessary to infer correspondences among animal and human components. As the architecture and function of somatosensory afferent pathways in mammals are similar, one might expect to record similar evoked activity in different species. These recordings show that, when comparable stimulating and recording methods are used, the waveform topography, and relative latency of the surface-recorded SEPs are indeed highly similar. Moreover, in monkey, cat, and rat the differential effects of terminal barbiturate anesthesia on components are similar. These observations suggest that comparable components reflect similar neural events in the four species, although the possibility that a component with similar characteristics in different species might reflect activity in different neural structures cannot be excluded. That NlO reflects the median nerve volley at the level of the brachial plexus is accepted by all workers and requires no comment. We found that N12 is composed of two fractions which can be ascribed to the volley in primary afferent fibers at caudal (Nl2a)and rostra1 (Nl2b) levels of the cervical dorsal column. During terminal recordings these potentials, as well as the PS, were consistently normal or supernormal in amplitude at a stage when later activity was reduced or abolished. Previous recordings from the cord dorsum have shown that the A spike was supernormal when postsynaptic activity (the N wave) was initially abolished (8, 12, 16). Similarly,
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FIG. 9. Locations of electrodes in the A-P dimension as noted. nucleus, CP-cerebral peduncle, cuneate nucleus, HN-hypoglossal geniculate nucleus, ML-medial TN-trochlear nucleus, VPL-n. dialis.
for recordings of Figs. 2-8, with approximate coordinates Schematic drawings are not to same scale. CN-cuneate DN-dorsal motor nucleus of the vagus, ECN-external nucleus, LGN-lateral geniculate nucleus, MGN-medial lemniscus, ON-oculomotor nucleus, RN-red nucleus, ventralis postereolateralis, VPM-n. ventralis posterome-
the PS was supernormal during an early stage of asphyxia when all postsynaptic activity in the CN was abolished (26). Our results further demonstrate a gradient of susceptibility along the primary afferent fibers, the central terminals being most sensitive and the more peripheral portions progressively less so [also see (16)]. In animals N12a is synchronous with A, and in humans its onset latency is similar to the estimated time of arrival (10 to 11.5 ms) of the median nerve volley in the spinal cord to
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stimulation at the wrist (13, 29). Its latency is also similar to that of the initial potential recorded near the human cord dorsum to stimulation of the ulnar nerve at the wrist (23) or to stimulation at the elbow (15) if allowance is made for wrist-to-elbow conduction time. Although various postsynaptic origins for the human N12 have been suggested (10, 14, 21), our results support previous opinion that it reflects activity in primary afferent fibers (18, 20, 22, 29). Similarly, N12 in our monkey, cat, and rat recordings appears to correspond, respectively, to potentials recorded from the skull of monkey [P3.8 (6)], cat [component I (19)], and rat [component 1(28)], and ascribed to activity in primary afferent fibers of the dorsal column. The first peak of the N 13 complex, N13a, appears to be the surface counterpart of the cord dorsum N wave and hence reflects the initial activation of dorsal horn neurons. Several lines of evidence indicate that N13b reflects the postsynaptic discharge of CN neurons: (i) the PS is a recording of the afferent volley as it enters the CN, and precedes spike discharges by about 1.O ms [ (5, 26); Figs. 2,5, 81. (ii) The N wave recorded from the dorsal aspect of the CN reflects the depolarization of CN neurons in response to the PS (5) and thus provides another estimate of the interval during which postsynaptic discharges can be expected to occur. (iii) The polarity inversion of the N wave and superimposed spikes as a recording electrode passes through the CN (5) was consistently seen (e.g., Fig. 2) and verifies the local origin of the activity. Although a good case can be made that the N13a and N13b peaks provide temporal markers of the modal time of discharge of dorsal horn and CN neurons, several facts suggest that activity in both structures contributes to the overall amplitude or area under the curve of these components. First, we recorded only from the rostra1 pole of the CN; neurons in the caudal pole may discharge slightly earlier. Moreover, the cord dorsum and CN N waves are rather broad potentials which overlap considerably in time. These considerations suggest that, in the humans and animals tested in whom N 13a and N 13b were not separable, the modal discharge of dorsal horn and CN neurons was nearly simultaneous. For purposes of amplitude quantification of N 13a in Fig. 7 we assumed that the C7 derivation primarily records cord dorsum activity; this remains to be determined. Because the N13b-P18 sequence of potentials generally appeared to ride on slower activity of possibly different origin, their “true” amplitude was difficult to determine with any assurance. In contrast, the peak latencies of all components did not appear to be affected by neighboring activity. Numerous structures extending from peripheral nerve to thalamus have been proposed as generators of the human N 13 complex ( 1, 10,20-22,29); our conclusions support recent patho-
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physiological studies (9, 18) suggesting that this activity is generated caudal to the thalamus. The largest spike recorded from electrodes in or near the ML was coincident with the surface-recorded N14 (Figs. 2, 6). In monkey a surface-recorded P6.2, perhaps corresponding to N14, was synchronous with the lemniscal volley as determined by multiunit studies (6). P 15 appears to be the surface reflection of initial postsynaptic activity in the VPL. As in the CN, the latencies of the presynaptic spike and the locally recorded N wave allow estimation of the timing of postsynaptic discharge of VPL neurons. In all recordings the initial large spike so identified was synchronous with the surface-recorded P15. In cat and rat a potential (component III) of similar relative latency was ascribed partly to activity in the VPL (19, 28). However, in monkey Arezzo et al. (6) were unable to identify in surface recordings activity corresponding to postsynaptic activity in the VPL. They suggested that the cellular geometry of the VPL leads to the generation of a closed potential field such that postsynaptic potentials are not recordable at a distance. In both their recordings and ours the potential fields in the region of the thalamus are complex, but both show local depolarizing sinks in the VPL and positive source potentials dorsal and lateral to it (e.g., Fig. 2), suggesting that the potential field is at least partially an open field and hence may be recorded at a distance. In our human and monkey recordings, P15 in parietal derivations was a small but identifiable peak or inflection at the end of the scalppositive potentials which were synchronous with N 13 and N 14. Another problem regarding the origin of P15 is that in human and monkey the difference in latency of about 0.5 ms between N14 and P15 would not appear to be large enough for the synaptic delay in the VPL required by our interpretation. More detailed surface and depth recordings of thalamic activity are needed to resolve these questions. We conclude that, with the exception of P16 and PI 8, the primary sources of these surface-recorded potentials can be identified tentatively. Excepting N 13a, generation of all subcortical components is attributed to the initial, synchronous discharge in fiber tracts and nuclei of the dorsal column-medial lemniscal system. In recordings from the CN and VPL only the initial postsynaptic spikes were consistently associated with discrete surface components. These observations are consistent with evidence that NlO and N12 reflect the afferent volley in rapidly conducting cutaneous and proprioceptive fibers ( 1, 13, 14,20,22,29), that the PS reflects activity in rapidly conducting cuneate tract fibers (26), and that these fibers terminate on rapidly conducting CN neurons which in turn project to rapidly conducting VPL neurons (27). It is not necessary to postulate additional sources of activi$y to account for each peak of the surface recorded activity,
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but future recordings may of course reveal contributions from other afferent pathways and nuclear structures which convey somatosensory information. REFERENCES T., W. R. GOFF AND C. C. WOOD. 1979. Auditory, somatosensory and visual evoked potentials in the diagnosis of neuropathology: recording considerations and normative data. Pages l-16 in D. LEHMANN AND E. CALLAWAY, Eds., Human Evoked Potentials. Plenum, New York. ALLISON, T., W. R. GOFF, P. D. WILLAMSON, AND J. C. VANGILDER. 1980. On the neural origin of early components of the human somatosensory evoked potential. Pages 51-68 in J. E. DESMEDT, Ed., Clinical Uses of Cerebral, Brainstem and Spinal Somatosensory Evoked Potentials. Karger, Basel. ALLISON, T., C. C. WOOD, G. MCCARTHY, A. L. HUME, AND W. R. GOFF. in press. Short-latency somatosensory evoked potentials in man, monkey, cat and rat: comparative latency analysis. Proceedings of the Symposium on Clinical Applications of Evoked Potentials in Neurology, Lyon, 1980. Raven Press, New York. ANDERSEN, P., C. M. BROOKS, J C. ECCLES, AND T. A. SEARS. 1964. The ventro-basal nucleus of the thalamus: potential fields, synaptic transmission and excitability of both presynaptic and postsynaptic components. J. Physiol. (London) 174: 348-369. ANDERSEN. P., J. C. ECCLES, R. F. SCHMIDT, AND T. YOKOTA. 1964. Slow potential wave produced in the cuneate nucleus by cutaneous volleys and by cortical stimulation. J. Neurophysiol. 27: 78-9 1. AREZZO, J., A. D. LEGATT, AND H. G. VAUGHAN, JR. 1979. Topography and intracranial sources of somatosensory evoked potentials in the monkey, I. early components. Electroenceph. Clin. Neurophysiol46: 155-I 72. AREZZO, J. C., H. C. VAUGHAN, JR., AND A. D. LEGATT. 1981. Topography and intracranial sources of somatosensory evoked potentials in the monkey. II. Cortical components. Electroenceph. Clin. Neurophysiol 51: l-l 8. AUSTIN, G. M., AND G. P. MCCOUCH. 1955. Presynaptic component of intermediary cord potential. J. Neurophysiol. 18: 441-451. CHIAPPA, K. H., S. K. CHOI, AND R. R. YOUNG. 1980. Short-latency somatosensory evoked potentials following median nerve stimulation in patients with neurological lesions. Pages 264-281 in J. E. DESMEDT, Ed., Clinical Uses ofCerebral. Bruinstem and Spinal Somatosensory Evoked Potentials. Karger, Base]. CRACCO, R. Q.. AND J. B. CRACCO. 1976. Somatosensory evoked potential in man: far field potentials. Electroenceph. Clin. Neurophysiol. 41: 460-466. ECCLES, J. C., P. G. KOSTYUK, AND R. F. SCHMIDT. 1962. Central pathways responsible for depolarization of primary afferent fibers. J. Physiol. (London) 161: 237-257. ECCLES, R. M., Y. LOYNING, AND T. OSHIMA. 1966. Effects of hypoxia on the monosynaptic reflex pathway in the cat spinal cord. J. Neurophysiol. 29: 315-332. EISEN, A., AND K. NUDLEMAN. 1978. F-wave and cervical somatosensory response conduction from the seventh cervical spinous process to cortex in multiple sclerosis. J. Can. Sci. Neurol. 5: 289-295. EL-NEGAMY, E., AND E. M. SEDGEWICK. 1978. Properties of a spinal somatosensory evoked potential recording in man. J. Neurol. Neurosurg. Psychiat. 41: 762-768. ERTEKIN, C. 1976. Studies on the human evoked electrospinogram. I. The origin of the segmental evoked potentials. Acta Neurol. Stand. 53: 3-20. GELFAN, S, AND 1. M. TARLOV. 1955. Differential vulnerability of spinal cord structures to anoxia. J. Neurophysiol. 18: 170-188.
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17. HEYMANS, C. 1950. Survival and revival of nervous tissues after arrest of circulation. Physiol. Rev. 30: 375-392. 18. HUME, A. L., AND B. R. CANT. 1978. Conduction time in central somatosensory pathways in man. Electroenceph. Clin. Neurophysiol. 45: 361-375. 19. IRAGUI-MADOZ, V. J., AND W. C. WIEDERHOLT. 1977. Far-field somatosensory evoked potentials in the cat: Correlation with depth recording. Ann. Neural. 1: 569-574. 20. JONES, S. J. 1977. Short latency potentials recorded from the neck and scalp following median nerve stimulation in man. Electroenceph. Clin. Neurophysiol. 43: 853-863. 21. KRITCHEVSKY, M., AND W. C. WIEDERHOLT. 1978. Short-latency somatosensory evoked potentials. Arch. Neural. 35: 706-711. 22. MATTHEWS, W. B., M. BEAUCHAMP, AND D. G. SMALL. 1974. Cervical somatosensory evoked responses in man. Nature (London) 252: 230-232. 23. SHIMOJI, K., M. MATSUKI, AND H. SHIMIZU. 1977. Wave-form characteristics and spatial distribution of evoked spinal electrogram in man. J. Neurosurg. 46: 304-313. 24. SMALL, D. G., W. B. MATTHEWS, AND M. SMALL. 1978. The cervical somatosensory evoked potential (SEP) in the diagnosis of multiple sclerosis. J. Neurol. Sci. 35: 21 l224. 25. STEEGMAN, A. T. 1969. The neuropathology of cardiac arrest. Pages 1005-1017 in J. MINCKLER. Ed., Pathology o/the Nervous System. McGraw-Hill, New York. 26. THERMAN, P. 0. 1941. Transmission of impulses through the Burdach nucleus. J. Neurophysiol. 4: 153-166. 27. TSUMOTO, T. 1974. Characteristics of the thalamic ventrobasal relay neurons as a function of conduction velocities of medial lemniscal fibers. Exp. Brain Res. 21: 21 l-224. 28. WIEDERHOLT, W. C., AND V. J. IRAGUI-MADOZ. 1977. Far-field somatosensory potentials in the rat. Electroenceph. Ciin. Neurophysiol. 42: 456-465. 29. YAMADA, T., J. KIMURA, AND D. M. NITZ. 1980. Short latency somatosensory evoked potentials following median nerve stimulation in man. Efectroenceph. C/in. Neum physiol. 48: 367-376.