Short latency somatosensory evoked potentials recorded around the human upper brain-stem

Electroencephalography and clinicalNeurophysiology, 88 (1993) 92-104 © 1993 Elsevier Scientific Publishers Ireland, Ltd. 0168-5597/93/$06.00

92

EVOPOT 92130

Short latency somatosensory evoked potentials recorded around the human upper brain-stem Eiichirou Urasaki a, Sumio U e m a t s u

a

and Ronald P. Lesser a,b

a Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD (USA), and b Department of Neurology, Johns Hopkins University School of Medicine and Zanvyl Krieger Mind ~Brain Institute, Johns Hopkins University, Baltimore, MD (USA)

(Accepted for publication: 14 October 1992)

Summary We analyzed the intracranial spatiotemporal distributions of the N18 component of short latency median nerve somatosensory evoked potentials (SSEPs) in 3 patients with epilepsy. In these patients, depth electrodes were implanted bilaterally into the frontal and temporal lobes, with targets including the amygdalaand hippocampus, the latter two targets are close to the upper pons and midbrain. In this study N18 was divided into the initial negative peak (N18a) and the followingprolonged negativity(N18b). Mapping around the upper pons and midbrain showed that: (1) the amplitude of the first negativity,which coincidedwith scalp N18a, was larger contralateral to the side of stimulation, but showed no polarity change around the upper brain-stem; and (2) the second negativity,whichwas similar to scalp N18b, did show an amplitude difference or a polarity change. This wave appeared to reflect a positive-negative dipole directed in a dorso-ventral as well as dorso-lateral direction from the midbrain, where positivity arises from the dorsum of the midbrain, contralateral to the side of the stimulation. Recordings from depth electrode derivations oriented in a caudo-rostral direction suggest that N18a and N18b may in part reflect neural activity originating from the upper pons to midbrain region which projects to the rostral subcortical white matter of the frontal lobe as stationary peaks. Keywords: Somatosensoryevoked potentials; Median nerve stimulation; Depth recordings; N18 component

Non-cephalic reference recording of short latency median nerve somatosensory evoked potentials (SSEPs) has disclosed a long-lasting slow negativity, designated as N18, distributed widely over the scalp (Desmedt and Cheron 1981; Desmedt and Nguyen 1984; Hashimoto 1984; Desmedt and Bourguet 1985; De Weerd et al. 1985; Urasaki et al. 1985a,b, 1990a; Tsuji and Murai 1986; Iwayama et al. 1988; Tsuji et al. 1988; Maugui~re and Desmedt 1989; Sonoo et al. 1991). Several subpeaks on the prolonged N18 event are known to exist. These appear to be divided into at least 2 components: a first N18 peak that is identified on almost all scalp recordings (Desmedt and Cheron 1981; Desmedt and Nguyen 1984; Hashimoto 1984; De Weerd et al. 1985; Urasaki et al. 1985a,b, 1990a; Tsuji and Murai 1986; Iwayama et al. 1988; Tsuji et al. 1988; Maugui~re and Desmedt 1989), and a subsequent prolonged N18 event that is often obscured by cortical components (Desmedt and Cheron 1981; Maugui~re et al. 1983;

Correspondence to: Ronald P. Lesser, Department of Neurology and Neurosurgery, Meyer 2-147, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287-7247(USA). Tel.: (410) 955-1270; Fax: (410) 955-0751.

Desmedt and Nguyen 1984; Desmedt and Bourguet 1985; Maugui~re and Desmedt 1989; Sonoo et al. 1991). Recently, Tomberg et al. (1991), using a nasopharyngeal electrode, demonstrated that at least a part of N18 originated in the medulla oblongata. However, controversy remains as to whether N18 reflects activities originating in the pons and midbrain (Maugui~re et al. 1983; Suzuki et al. 1988; Urasaki et al. 1985a,b, 1990a, 1992b; Maugui~re and Desmedt 1989; Sonoo et al. 1991). Detailed analysis of SSEP activities around the upper pons and midbrain is required to resolve this issue. Comparison between deep SSEPs and the ipsilateral parietal response has also been suggested, since parietal leads can accurately record the shape of N18 (Desmedt and Cheron 1981; Maugui~re et al. 1983; Desmedt and Bourguet 1985; Maugui~re and Desmedt 1989). We recorded SSEPs from depth electrodes implanted during the evaluation of patients with intractable seizures who were candidates for epilepsy surgery. An inspection of the relationship of the amygdala and hippocampus to the brain-stem demonstrates that these structures are quite near the upper pons and midbrain. Depth electrodes in these structures should

U P P E R B R A I N - S T E M SSEPs B Y M N S T I M U L A T I O N

therefore be able to record near-field potentials during evoked potential studies that activate ponto-mesencephalic structures. In this article, we report the spatiotemporal distributions of upper brain-stem median nerve SSEPs and suggest that the scalp N18 component appears to reflect several activities in the ports and midbrain as well in more caudal structures such as the medulla oblongata.

Subjects and methods The clinical histories and findings on 3 patients with intractable seizures are summarized in Table I. Neurological examination was normal except for case 3 (Table I). Three bilateral pairs of multi-electrode depth leads were implanted stereotaxically under CT guidance towards the right and left frontal base (RF, LF), amygdalar (RA, LA), and hippocampal (RH, LH) regions for the lateralization and search of the epileptogenic area (Fig. 1). The electrodes were placed through burr holes located in the frontal region 2.5 cm from the midline and 0-3 cm anterior to the coronal suture on each side. Because of the standard direction of implantation used at our institution, the deep leads are aligned parallel to the brain-stem (Fig. 1), with the deepest lead the most caudal with respect to the brain-stem. Their placement was such that 'the deep amygdalar

93

leads were ventral, and hippocampal leads were dorsal, to the midbrain and upper pons. Each lead was constructed of polyurethane tubing with 8 stainless steel electrodes connected by fine stainless steel wire to independent pins which were plugged into an electroencephalographic (EEG) "head box" at the leads' proximal end. For convenience, depth electrodes are numbered from 1 to 8, on each 6-electrode tress, with lead 1 as the deepest electrode. The depth electrodes were 2.5 mm long with an outer diameter of 1 ram, set at intervals of 2 mm for leads 1-5 or 4 mm for leads 6-8 of the amygdalar and hippocampal electrodes with an inter-electrode distance between numbers 5 and 6 of 36 mm. The inter-electrode distance between each pair of frontal depth electrodes was 4 mm. The electrode positions were confirmed by an intraoperative CT scan immediately after stereotaxic placement of the electrodes. A postoperative skull X-ray was routinely obtained to reassess the electrode position (Fig. 1). For example, in the patient (case 1) shown in Fig. 1, symmetric parallel placement of 6-electrode tresses is apparent in both axial CT scan and skull film. Although uniform curvature occurred in the deeper portion of the tresses, there was some discrepancy between the two sides in the depth of the electrodes: the right hemispheric tresses were about 10 mm deeper than the left. Curvature and depth discrepancies may occur because the flexible electrodes adapt to the texture of the surrounding brain tissue (which may

TABLE I S u m m a r y of the 3 patients with intractable seizures~ Case no.

Age/ sex

Diagnosis and history

Scalp E E G findings

Depth EEG findings

M R I findings

1. T L *

30 y M

CPS and GTCS for 19 y

Interictal: Bil T Sp Ictal: R T and L T rhy S L / S p

Interictal: Sp, Bil A Ictal: rhy Sp and EDA. R + L , F and T

Small lesion (? angioma) mesial R F

2. D P * *

45 y M

CPS and GTCS for 25 y

Interictal: Bii T SL burst no Sp Ictal:? L F T C SL

Interictal: Sp, R A, H and F Ictal: E D A and Sp, R A and H

Normal

3. MJ * * *

27 y M

Posttraumatic epilepsy, CPS and GTCS for 10 y

Interictal: L T Sp Ictal: L T and R T Sp LT and R C P T rhy SL

Interictal: L H Sp Ictal: Sp and EDA, LH

Encephalomalacia, L T

M ffi male, y = years, CPS ffi complex partial seizure, GTCS ffi generalized tonic clonic seizure, Bil = bilateral, R = right, L ffi left, rhy = rhythmic, SL =slow, S p = s p i k e s , E D A = e l e c t r o d e c r e m e n t a l activity, A = a m y g d a l a , H = hippocampus, F = frontal, C = c e n t r a l , P = parietal, T = temporal. * Normal neurological examination. ** Normal neurological examination, past history of C2 fracture due to traffic accident at 37 y. * * * H e a d trauma and right distal radial nerve injury (palsy) due to traffic accident at 16 y.

94 contain some sclerotic tissue) and because of technical problems inherent in the stereotaxic implantation of the flexible tress. ~ Nevertheless, this variability of the electrode position did not interfere with the clinical depth E E G studies or with the evoked potential analysis reported here. Separate consent was obtained for this study, using procedures approved by our Institutional Review Board. SSEPs by median nerve stimulation were recorded several days after implantation of depth electrodes. Silver-silver chloride disks 0.7 cm in diameter were placed over the ipsilateral mid-clavicular (MCL) point, at the back of the neck over the fifth cervical spinous process, at Fpz (international 10-20 system), and at contralateral and ipsilateral parietal points located 7 cm lateral and 2 cm posterior to the vertex. All electrode impedances were maintained below 5000 O. SSEPs were obtained by the use of 0.2 msec square wave electrical stimuli at 5 . 1 / s e c delivered transcutaneously to the median nerve at the wrist via bipolar electrodes, with the cathode 3 cm proximal to the anode. Stimulus intensity was adjusted to produce a brisk twitch of the thumb. The evoked activity was amplified at a filter setting of 5-3000 Hz ( - 3 dB), and 1000-3000 trials were averaged by a Nicolet Compact Four system. The period of analysis was 50-70 msec with a 10% pre-stimulus time (512 points). A handmade connector board allowed us to study the SSEPs at the same time as the continuous E E G monitoring. At least two recordings of the responses were made with each montage, all the data being stored on floppy disks and printed separately. M C L point contralateral to the side of stimulation was used as reference. Negativity in grid 1 of the recording electrodes registered upward in all the recordings. Ground electrodes were at the ipsilateral earlobe.

I The electrode was implanted by a CT-guided stereotaxic technique using a CRW frame (Radionics Inc., Burlington, MA). The flexible electrode (Ad-Tech Med Instrument Co. Racine WS) is inserted with aid of the 16-gauge solid guiding needle, which is advanced into the targets, namely orbital cortex, amygdala, and posterior hippocampus. The target areas, particularly for the latter two, are located at the plane of the circle of Willis. Because we wish to place some leads into the parahippocampal gyrus, the flexible tress is advanced alone 10 mm further toward the base of the skull, while the solid guiding needle is kept in the amygdala and hippocampus. A further advance of the metallic guiding needle, beyond the level of the circle of Willis, has the potential risk of traumatizing nearby vessels. Because of the flexibility of the tress, as it advances beyond the tip of the guiding needle, the electrode may take a curved course or vary in its penetration as it adapts to the texture (e.g., sclerotic, non-sclerotic) of the brain tissue. Moreover, as the guiding needle is withdrawn, the flexible electrode tress may either be slightly pulled back together with the guiding needle, or slightly advanced by the maneuvering required to keep the tress at the fixed position.

E. URASAKI ET AL. Because the number of recording channels was limited to 4, the reproducibility, stability, and inter-relationships of the wave forms was confirmed by recording scalp and M C L potentials along with the depth recordings at several different times during the test session. N18a was defined as the first peak after the trough of the preceding P14, and N18b as a major negative p e a k following N18a in the parietal scalp recording ipsilateral to the side of stimulation. Identification of frontal P20-N30, recorded anterior to the central sulcus, parietal N20-P30, recorded posterior to central sulcus, and central P25, recorded near the central sulcus, followed the method of Allison et al. (1989). These potentials were reported to be recorded only contralateral to the side of the stimulated median nerve (Allison et al. 1989). In the present article, the terms ipsilateral and contralateral are used to indicate the sites of recordings relative to the side of the stimulation.

Results Fig. 1 shows the location of depth electrodes in case 1. R A 1 - 5 , R H 1 - 5 , L A 1 - 3 and L H 1 - 3 were located adjacent to the upper pons and midbrain. L A 4 - 5 and L H 4 - 5 were almost at the level of the thalamus. The hippocampal tresses passed near the thalamus, but did not enter the thalamic nucleus itself. All other electrodes (electrodes 6 - 8 in RA, LA, RH, and LH, and 1 - 8 in R F and LF) were located in the frontal subcortex (Fig. 1). Two scalp recordings at different times, at the beginning and the end of the test session in case 1, are shown in Fig. 2. There was good reproducibility and stability of the wave forms. The ipsilateral parietal response revealed the N18 component. In all 3 cases, we distinguished an initial N18a with peak latencies of 18-23 msec from a subsequent N18b with peak latencies of 21-27 msec (Figs. 2-7). After electronic subtraction of ipsilateral parietal responses from those at Fpz or at the contralateral parietal recording sites, the frontal P20 and parietal N20 components, located between the N18a and N18b peaks, could be seen clearly (Fig. 2). Even after subtraction, central P25, frontal N30 and parietal P30 (Allison et al. 1989) were not clearly identified on the scalp recordings in this case (Fig. 2). Fig. 3 shows the intracranial SSEPs recorded from bilateral amygdalar and hippocampal electrodes in case 1. In all electrodes, P9, P l l and P14 components were recorded with stationary peaks (Fig. 3 A - D ) . Two negative peaks that coincided in latency with scalp N18a and N18b were readily identified in the deepest tips of each depth electrode (RA1, LA1, RH1, and LH1). In

UPPER BRAIN-STEM SSEPs BY MN STIMULATION

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RA and RH electrode arrays (ipsilateral to the side of the stimulation), the peaks of intracranial N18a and N18b were almost the same in all recording sites (RA1-8, RH1-4 in Fig. 3A and C). In contrast, in LA and LH electrode arrays (contralateral to the stimulated side), although the peaks were similar, the centers of the peaks, representing the negative traveling potentials, appeared to be overlaid on the stable intracranial N18a peak and gradually increased in latency rostrally. This is clearly seen when the peaks of intracranial first negativity between LA1 and LA5, and between LH1 and LH5, are compared (Fig. 3B and D). Through LH6 to LH8 of the subfrontal cortex, a

large negative portion was identified around the peak of scalp N18b (Fig. 3D), which could be related to the well localized frontal N30 component that has been found contralateral to the side of stimulation (Allison et al. 1989). However, this frontal N30 was not clearly produced by the scalp electrodes in this case (Fig. 2). Between the N18a and N18b peaks, there was a clear positivity, showing almost the same peak latency as parietal N20 and frontal P20 (Fig. 2), at LH6-8 as well as LA6-8 ~ (contralateral to the side of stimulation; Fig. 3B and D), which could represent an intracranial P20. This positivity was not well delineated at the ipsilateral RA and RH electrodes (Fig. 3A and C). We did not

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Fig. l. The locations of depth electrodes in case 1 are mapped on the lateral view of the X-ray and indicated numerically in this and succeeding figures. RA, right amygdala; LA, left amygdala; RH, right hippocampns; LH, left hippocampus; RF, right frontal; LF, left frontal. Note the discrepancy in the depth of the tress. The right hemispheric tresses are deeper than the left (frontal and amygdalar tresses, right side 2 leads deeper; hippocampal tresses, right side 3 leads deeper). Leads I.A2, RA4, LH1, and RH3 were situated at midbrain axial level. Axial CT scan at the level of upper pons (CT1) shows only the array of right amygdala electrode between RA1 and RA2. C-q'2 indicates the locations of electrodes in both left and right amygdala and hippocampus, around the midbrain. CT3 and CT4 demonstrate the thalamus and subcortical levels, respectively. RA1-5, RH1-5, LA1-3, and LH1-3 are located adjacent to the upper pons and midbrain. LA4-5 and LH4-5 are almost at the level of the thalamus. Note that the LH4 and LH5 electrodes are located outside of the thalamic nucleus. All other electrodes (6-8 in RA, LA, RH, and LH) are located in the frontal subcortex.

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right median nerve stimulation in case 1, recorded at the beginning (first set, 4 channels) and the ending (third set, 3 channels) stage of the test session. Notice the good reproducibility and stability of the wave forms at all recordings. The reference (Lt. MCL) is the midclavicular point contralateral to the side of stimulation in each case. The middle set (two traces) shows bipolar recordings calculated by electronic subtraction of the third set. MN, median nerve; Lt., left; Rt., right; Par., parietal scalp; Cv5, spinous process of the fifth cervical vertebra; Ref, reference; MCL, mid-clavicular point; Fpz, fronto-polar point according to international 10/20 system. The two vertical dotted lines indicate the respective peak latencies of scalp N18a and N18b at the parietal scalp ipsilateral to the stimulation. Shadowed areas represent the N18 component. Subtraction study shows frontal P20 and parietal N20. However, frontal N30, parietal P30 and central P25 are not clearly identified on these scalp recordings. The unlabeled arrow head in the left parietal scalp (Lt. Par.) non-cephalic derivation shows where N20 should be. No peak actually occurs in this case in the distant reference recording, but it can be seen in Lt. Par.-Rt. Par. (channel 6).

see a clear central P25 (Allison et al. 1989; Vanderzant et al. 1991), perhaps because P25 was obscured at the scalp electrodes (Figs. 2 and 3).

Dorso-ventral wave form distribution SSEPs around the midbrain in case 1 are shown in Fig. 4 (tracings 10-13, with superimposition (sup) on tracing 9). Bipolar recordings in left-right, antero-posterior, and oblique directions around the midbrain were created by electronic subtraction (Fig. 4, tracings 3-8). The results of subtraction around the midbrain

clarify the sites where individual waves are relatively more or less negative, or more or less positive. A wave with a latency similar to scalp N18a was more negative contralaterally than ipsilaterally ( L H 1 - R H 3 and L A 2 RA4), and equipotential or slightly more negative ventrally than dorsally ( L A 2 - L H 1 and R A 4 - R H 3 ) . These results suggest that the depth electrodes recorded either the negative part of a dipole oriented in the ventro-dorsal direction or an ascending negative wave form in or near the contralateral medial lemniscus, or both. Following the intracranial N18a, the subtraction studies show a potential which is downward in the L H 1 - R H 3 derivation, and generally upward in the L A 2 - L H 1 and R A 4 - L H 1 recordings. A likely explanation for this is that an intracranial N18b was the least negative at the dorsum of midbrain contralateral to the side of stimulation (LH1). The original wave form at LH1 referred to M C L (tracing 12, Fig. 4) also showed the same tendency, although less dearly than in the subtraction study (tracing 8, Fig. 4). Similar findings occurred in case 2 (Fig. 5). In this case, the RA1, LA3, RH1 and LH2 electrodes were located at the almost same level at the ponto-mesencephalic junction. The negative wave that resulted from left median nerve stimulation and that coincided in latency to scalp N18a was larger contralaterally than ipsilaterally. The dipole in the dorso-ventral direction which coincided with scalp N18b was seen more clearly than in case 1. The original wave form at RH1 referenced to M C L showed, at the time of p e a k latency of N18b at the scalp (see Fpz, Lt. Par. in Fig. 5), a low amplitude positivity following N18a. A clearer downward potential was revealed by the R H 1 - L H 2 subtraction study (Fig. 5). The amplitude of the upward potential, which coincided with this downward wave, appeared to be approximately equal on both sides of the ventral u p p e r brain-stem, resulting in an almost flat response in the R A I - I . A 3 recording. In contrast, there was a small but clear upward deflection in I . A 3 - L H 2 and a larger one at R A 1 - R H 1 . T h e r e were also upward potentials at L A 3 - R H 1 and R A 1 - L H 2 . These findings might indicate a dipole with a ventral negativity (LA3, RA1) and contralateral dorsal positivity (RH1). In the subtraction study of case 2, there is a b r o a d upward potential at R H 1 - L H 2 and downward potentials at R A 1 - R H 1 and L A 3 - R H 1 with peak latency about 40 msec in (Fig. 5). It is possible that there were widespread negativities with maximal negativity at the contralateral dorsal upper brain-stem near the site of electrode RH1. Alternatively, based on analysis of the "bipolar" recordings, in Fig. 5, this negativity might also have been part of a dipole with a phase-reversed positivity at the veritral upper brain-stem bilaterally and the ipsilateral dorsal u p p e r brain-stem. In this

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study, no scalp components could be correlated with this potential. Caudo-rostral distribution Fig. 6 shows the wave forms (of case 1) produced by electronic subtraction. On the side ipsilateral to stimulation, there was no difference in electrical activity between the upper edge of the ventral midbrain (RA5)

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clearly, especially the second negative deflection that coincided with N18b. This finding might suggest that intracranial N18b, and possibly N18a, is mainly produced between RA4 and RA5, at the level of the quadrigeminal plate (Fig. 1). The similarity of the wave forms in the RA8-RA1 and RA5-RA1 derivations and the isopotentiality indicated by the RA8-RA5 recording are noted and discussed below. These two negative deflections also occur at electrodes recording from the ipsilateral dorsal aspect of the upper pons to midbrain, as shown by the RH4-RH1 derivation (Fig. 6). The SSEPs recorded from the leads contralateral to stimulation were rather more complex (Fig. 6) than those from the ipsilateral array, because there were traveling waves and much greater contamination from cortical potentials (Fig. 3). Between the midbrain and thalamic levels (Fig. 6: LA4-LA1, LA5-LA1, LH4LH1, and LH5-LH1), one positive and two negative deflections occur. However, the peak latencies of the positive and first negative deflection were later than those of the scalp P14 and N18a components (Fig. 6). The wave form of first negative deflection has a longer duration than does the ipsilateral wave form at this latency, possibly because a traveling wave is superimposed upon a stationary potential (Figs. 3 and 6). Subtraction recordings of LA8-LA5, located at the frontal subcortex and the thalamic level, respectively, revealed no clear negative inflection at the time of N18a. However, when the reference (grid 2) was "moved" caudally to LA1 by the subtraction method, the negative deflection that coincided with the N18a peak became clear (LA8-LA1 in Fig. 6). This result was the same as that obtained from the ipsilateral leads. Because of the influence of a large localized negativity (frontal N30), the second negative deflection seen in LA4-LA1 and LA5-LA1 was obscured at LA8-LA1 (Fig. 6). Fig. 7 shows the SSEPs obtained from the LH array contralateral to the stimulated side in case 3. The LH5 electrode, the only one in this study located within the thalamus, showed a remarkably complex wave with large amplitude. Notably, SSEPs from the other leads, including those 2 mm below (LH4) and 36 mm above (LH6) LH5, showed wave forms similar to one another and different from that at LH5, suggesting that thalamic activity itself did not contribute to either the rostral or caudal SSEPs owing to its closed field (Fig. 7).

Discussion

All depth electrodes in this study presented stationary positivities that coincided with respective scalp P9, P l l and P14 components (Fig. 3), as shown previously

U P P E R B R A I N - S T E M SSEPs BY M N S T I M U L A T I O N

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(Hashimoto 1984; Allison et al. 1989; Urasaki et al. 1990a; Vanderzant et al. 1991). P9 and P l l were canceled out when the recordings from the leads around the upper brain-stem were subtracted from one an-

other (Figs. 4-6), indicating that the P9 and P l l peaks reflected volume-conducted far-field activity recorded at the upper brain-stem, but that they originated caudally, i.e., from the brachial plexus and dorsal column

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Fig. 7. Intracranial SSEPs recorded along the array of left hippocampal (LH) electrodes in case 3. T h e right median nerve is stimulated. CT scan shows the location of LH5 electrode, which entered the postero-lateral portion of the left thalamus. Note that the voltage calibration differs from that in the previous figures. SSEPs of LH5 demonstrate complex wave forms with large amplitude, while SSEPs at other locations are similar to one another and much lower in amplitude.

UPPER BRAIN-STEMSSEPs BY MN STIMULATION of the lower cervical cord, respectively (Jones 1979; Anziska and Cracco 1980, 1981; Desmedt and Cheron 1981; Synek and Cowan 1982; Lueders et al. 1983b; Nakanishi et al. 1983; Desmedt and Nguyen 1984; Emerson et al. 1984; Urasaki et al. 1985a, 1990a,c, 1992a). Hashimoto (1984) reported a similar result for intracranial P l l (cf., Urasaki et al. 1990a; Tomberg et al. 1991; Wagner 1991). Previous suggested origins for P14 have included the medial lemniscus (Liberson et al. 1970; Anziska and Cracco 1980, 1981; Desmedt and Cheron 1981; Desmedt and Nguyen 1984; Hashimoto 1984; Suzuki and Mayanagi 1984; Maugui~re and Desmedt 1989), medulla oblongata including the cuneate nucleus (Lueders et al. 1983b; Suzuki and Mayanagi 1984; M~ller et al. 1986; Gu6rit et al. 1990; Urasaki et al. 1990a,c; Morioka et al. 1991a). P14 The P14 potential showed an increased amplitude when recorded at the upper brain-stem, strongly suggesting that P14 is not a solely far-field potential at that level (Figs. 3 and 6). Electronic subtraction demonstrated an amplitude increase of intracranial P14 along the rostro-caudal direction at the upper brain-stem both ipsilateral and contralateral to the side of stimulation (Fig. 6). At the most caudal sites of each depth electrode, there was a stationary positivity coinciding with scalp P14 (Fig. 3). These data indicate that at the time of peak latency of scalp P14, several activities originate in the upper brain-stem as well as in more caudal structures. N18a Analysis of the SSEPs recorded from depth electrodes clearly demonstrated localized upper brain-stem activities that coincided in latency with scalp N18a and N18b (Figs. 4-6) with durations of about 7-8 msec and 10 msec respectively. There appeared to be a stationary potential caudally, because the deepest electrodes showed stationary peaks (Fig. 3). The amplitude of N18a and N18b, however, became higher in both the ipsilateral and contralateral rostral leads (e.g., RA5RA1, LA5-LA1 and LA4-LA1 in Fig. 6). These suggested that N18a and N18b have both near-field components from upper brain-stem structures, and volumeconducted "far-field" responses from more caudal structures including the medulla oblongata (Sonoo et al. 1991; Tomberg et al. 1991). Intracranial negativity similar to scalp N18a have been reported by several investigators who made direct recordings from the brain-stem (Hashimoto 1984; Suzuki and Mayanagi 1984; Urasaki et al. 1985a, 1990a; Morioka et al. 1991a,b). This stationary negativity might be a counterpart of the early phase of the P wave originating in the cuneate nucleus (Andersen et al. 1964a,b).

101 This is the first report to analyze the spatiotemporal distribution around the midbrain by means of simultaneous recordings from multiple implanted electrodes in the same subject. We found that the amplitude of the intracranial N18a component was larger on the side contralateral to stimulation, suggesting that the main generator of N18a was located on the side contralateral to stimulation. Hashimoto (1984) noted the similarity of intracranial N18a to the N1 wave recorded from spinal cord. The N1 wave can be divided into two parts, an early traveling component, which reflects the action potential in the dorsal column, and a later component with relatively stable latency, which is a postsynaptic potential of the collateral branches in the dorsal horn (Lueders et al. 1983b; Urasaki et al. 1985a). In the present study, although intracranial wave forms corresponding to N18a were similar at the recording electrodes, there appeared to be a gradual shift in the "centers" of the upward going peaks of the recorded wave forms. We suggest that this occurred because a traveling negativity in the upper brain-stem contralateral to the side of stimulation possibly overlaid and washed a negativity with stable latency (Figs. 3 and 6). This stable negativity originating in the upper brain-stem was clearly revealed by the subtraction study (see LA8-LA1 in Fig. 6). Scalp N18a showed good correlation with the stable negativity with respect to peak latency, but the peak latency of the traveling negativity in the uppermost brain-stem contralateral to the side of stimulation was longer than that of scalp N18 (Figs. 3 and 6). Therefore, scalp N18a appears to reflect a stable negativity originating in the upper pons and midbrain. In this sense it is similar to the late component of the spinal N1 wave (Ertekin 1976; Shimoji et al. 1977; Desmedt and Cheron 1981; Urasaki et al. 1988, 1990b,d). Perhaps positive wave forms generated by the dipole source (or sources) of N18a project more caudally or become mixed with the P wave of the cuneate nucleus (Andersen et al. 1964a,b). The contralateral traveling negative peak might reflect the ascending axonal volley, because the peak seemed to be comparable to the early N1 component of the spinal potential (Lueders et al. 1983b; Urasaki et al. 1985a). A similar medial lemniscus traveling wave has been found previously in monkeys (Arezzo et al. 1979) and humans (Morioka et al. 1991b). Although the wave did not manifest volume conduction to rostral subfrontal regions in this study, restricted bandpass settings have disclosed several inflections on the scalp N18a wave form in the study of Maccabee et al. (1983). Ipsilateral to the side of stimulation, the amplitude increased between the upper pons and midbrain, similar to the responses contralateral to side of the stimulation. This localized ipsilateral activity could in part relate to volume conduction from the contralateral

102

activity. Alternatively a few fibers may actually cross (or have crossed) to the ipsilateral side. It is conceivable that volume conduction of a wave and direct fiber connections individually would be insufficient to provide a clear ipsilateral traveling wave, but would nevertheless be sufficient to provide a stationary wave form in the ipsilateral upper brain-stem. N18b The spatiotemporal distribution of the intracranial second negativity which coincided in latency to scalp N18b differed from that of intracranial N18a. Despite a progressive caudal-rostral amplitude increase (Figs. 3 and 6), there also was an amplitude difference of N18b in the horizontal plane around the midbrain (Figs. 4 and 5), which might indicate the existence of a dipole around the midbrain. In that case, the positive pole seemed to be located on the dorsolateral midbrain, contralateral to the side of stimulation. A recent anatomical study showed various fiber connections to the brain-stem nuclei from the dorsal column nuclei (Hand and Van Winkle 1977; Berkley and Hand 1978). In the midbrain, the quadrigeminal plate has been shown to receive many fiber projections from the contralateral dorsal column nucleus in several species (Baleydier and Maugui~re 1978; Bj6rklund and Boivie 1984), and several authors have demonstrated these connections physiologically (Gordon 1973; Nagata and Kruger 1979; RoBards 1979; Cooper and Dostrovsky 1985). Because the nerve input from the medial lemniscus to the quadrigeminal plate is oriented in the ventro-dorsal direction in the midbrain, a negative-positive dipole could be formed along that axis. This would be similar to the dipole formed by spinal N13 or N1 wave in the horizontal plane of the spinal cord resulting from the nerve input from dorsal column to ventral Rexed layers IV and V via collateral branches (Ertekin 1976; Shimoji et al. 1977; Desmedt and Cheron 1981; Urasaki et al. 1988, 1990b,d). The cup-like shape of the colliculi might be appropriate to project the negativity of the dipole to the ventral, medial, and rostral sides of the midbrain. Another possibility is that N18b might be a phasereversed component of a positivity originating in the contralateral dorsal brain-stem, similar to the P wave of the spinal cord and the cuneate nucleus (Anderson et al. 1964a,b; Beall et al. 1977; Shimoji et al. 1977; Emerson et al. 1984; Jeanmonod et al. 1989). Alternatively, the entire N18 complex could originate from multiple sites including multiple brain-stem nuclei (Gordon 1973; Hand and Van Winkle 1977; Berkley and Hand 1978; Nagata and Kruger 1979; RoBards 1979; Baleydier and Maugui~re 1978; Bj6rklund and Boivie 1984; Cooper and Dostrovsky 1985). The almost identical wave form amplitudes at the

E. URASAKI ET AL.

RA5-RA1 and RA8-RA1 derivations in Fig. 6 are probably explained as follows. When the vertical segment of the dipole of intracranial N18 is stronger than the horizontal segment, a rostral electrode (e.g., RA8) would pick up this component of the dipole but its amplitude would be decreased according to the distance from generator. In contrast, an electrode located on the lateral side of the midbrain (e.g., RA5) would pick up the horizontal segment of the dipole which would be "weaker" than the vertical segment in this case, but the amplitude would not be markedly decreased as a result of the recording of a near-field potential. Another explanation is that the RA1 electrode picks up a near-field potential, the polarity of which is the reverse of that recorded more rostrally (RA5-8). In any case, our study strongly suggests the presence of a well localized upper brain-stem activity that contributed to the scalp N18 potential. By analyzing NP recordings, Tomberg et al. (1991) speculated that N18 is not generated more rostrally than the medulla oblongata. However, individual normal subjects in their study clearly showed upper brainstem contributions to N18a,b as well as to rostral P14 (Fig. 2 in Tomberg et al. 1991), The upper brain-stem N18a,b become obscured when they performed a grand average of SSEPs of all subjects, perhaps due to'interindividual variability of N18 (Tomberg et al. 1991). In the study of Tomberg et al. (1991, Fig. 5), a mesencephalic lesion resulted in a complete loss of upper brain-stern N18a and N18b during NP-scalp recording except for a residual rostral P14, the peak latency of which was delayed with respect to P14 in scalp-NC recording. Their result strongly suggests that the main generation site for the upper brain-stem N18a,b might be located at the uppermost level of the rostral medial lemniscus. As also suggested by our study (see RA4-RA1 and RA5-RA1 in Fig. 6), upper brain-stem N18a and N18b might be generated slightly more rostrally than the rostral P14. N18a,b is more likely to be disrupted by a mesencephalic lesion than is the rostral P14. Urasaki et al. (1992b) previously reported an amplitude decrease of scalp N18a in patients with midbrain-pontine lesions. One of the electrodes incidentally entered the lateral part of the thalamic nuclei (LH5 in Fig. 7), and recordings from this lead showed a completely different and larger amplitude wave form as compared to the extrathalamic electrodes. This was a finding in only one electrode and thus requires confirmation. If verified, this would provide evidence that the thalamic activity did not generate the wave forms recorded by the extrathalamic leads, most likely due to generation of a closed field. This conclusion also is supported by the absence of amplitude decrease of N18a in patients with thalamic lesions (Urasaki et al. 1992b).

UPPER BRAIN-STEM SSEPs BY MN STIMULATION

Influence from cortical components An amplitude difference between subfrontal electrodes contralateral to the side of stimulation (LA8LA5 in Fig. 6) is most likely due to the different distances of the two leads from the generators of cortical N20 and N30 potentials (Lueders et al. 1983a; Wood et al. 1988; Allison et al. 1989). In contrast, at the side ipsilateral to the stimulation, there was no amplitude difference between subfrontal electrodes (RA8-RA5, RA8-RA6 in Fig. 6) and no phase-reversed positivity of the contralateral N20 (Fig. 3), suggesting either no spreading of the contralateral cortical wave forms to the hemisphere ipsilateral to stimulation, or homogeneous spreading by means of volume conduction without amplitude differences, at least in the present case. Nevertheless, there is a well localized amplitude increase of N18b in the ipsilateral upper brain-stem, for example, at the level of the quadrigeminal plate (between RA4 and RA5 and at RH4 in Figs. 3 and 6). In summary, there is a difference in the spread of activities between the subfrontal electrodes as compared to the increases in amplitude of N18b in the electrodes recording from the upper brain-stem. Therefore, it seems unlikely that the amplitude increases of intracranial N18b through the upper brainstem are due to the different degrees of subcortical spreading of frontal N30 or parietal P30. The authors thank Robert W. McPherson (Department of Anesthesiology, Johns Hopkins University) for providing the evoked potential apparatus used in this study. The authors also express their appreciation to Pamela Talalay (Department of Neurology and Neurosurgery, Johns Hopkins University) for her editorial assistance. This study was supported by the Tanaka Kenji Memorial Scholarship provided by Mary Lorenc, Mrs. Tanaka, and in part by the McDonnell-Pew Program in Cognitive Neuroscience and the Educational Foundation of America.

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