Somatosensory evoked potentials (SEPs) and cortical single unit responses elicited by mechanical tactile stimuli in awake monkeys

Electroencephalograpt~v and clinical Neurophysiologv, 1984, 58:537 552 Elsevier Scientific Publishers Ireland, Ltd.

537

S O M A T O S E N S O R Y EVOKED P O T E N T I A L S (SEPs) AND C O R T I C A L S I N G L E UNIT R E S P O N S E S E L I C I T E D BY M E C H A N I C A L T A C T I L E S T I M U L I IN AWAKE M O N K E Y S ESTHER P. G A R D N E R 1,2 HEIKK1 A. HfitM,~L,~INEN, SUSAN WARREN, JANE DAVIS and WISE Y O U N G

Department of Physiology and Biophysics and Department of Neurosurgery, New York University School of Medicine, 550 First Avenue, New York, N Y 10016 (U.S.A.)

(Accepted for publication: June 6, 1984)

Somatosensory evoked potentials (SEPs) are widely used as a diagnostic procedure for evaluating the integrity of somatosensory pathways and cortical receiving areas in humans. However, correlations of SEP recordings from the scalp with intracranial recordings in the same subject have been rare, and limited to measuring field potentials (Celesia 1979; Woolsey et al. 1979; Allison et al. 1980; Papakostopoulos and Crow 1980). Direct analysis of the physiological bases of SEPs therefore requires appropriate animal models. Rhesus monkeys seem to provide an excellent preparation for analyzing physiological mechanisms underlying evoked potentials. The anatomical organization of somatosensory and motor cortices is similar in humans and rhesus monkeys. SEPs recorded in awake monkeys resemble the early components of human SEPs (Arezzo et al. 1979, 1981; Allison and Hume 1981; Kulics 1982). Furthermore, the alert monkey has been widely used for single unit recordings of cortical somatosensory activity. Such studies have delineated single cell responses to a variety of controlled tactile and kinesthetic stimuli (Sakata et al. 1973; Mountcastle et al. 1975; Hyvarinen and Poranen 1978a,b; Iwamura and Tanaka 1978; Costanzo and Gardner 1980; Gardner and Costanzo 1980a,b, 1981). Cellular cytoarchitecture, microcircuitry and somatotopic organization of primary somatosensory

1 This research was supported by United States Public Health Service Research Grant NS 11862 from NINCDS. 2 Send correspondenceto: Dr. Esther P. Gardner, Department of Physiologyand Biophysics, New York University Medical Center, 550 First Avenue, New York, NY 10016, U.S.A.

cortex have also been well defined in these monkeys (Nelson et al. 1980; Jones 1981; McKenna et al. 1982). In this study, we have used controlled mechanical stimulation of the skin to compare the timing of single unit responses in primary somatosensory (SI) cortex of alert monkeys to that of SEPs elicited in the same monkeys, and to correlate cortical neuronal excitation and inhibition with the surface recorded positive and negative components. We also demonstrate the relationship of SEP amplitude to the intensity of tactile stimulation, and to the skin areas represented in the underlying cortex. SEPs and single unit activity were elicited using puffs of air delivered to the skin of the hand and arm. These mechanical stimuli evoke a more physiological distribution of activity in cutaneous nerves than do the electric shocks to whole nerves usually employed to elicit SEPs. Airpuffs provide reproducible tap-like stimuli without steady pressure or direct contact on the skin. They permit stimulation of a restricted area of skin in a variety of spatial and temporal patterns, and activate selectively rapidly adapting cutaneous mechanoreceptors. We have previously described the electrophysiological responses of cortical neurons in alert monkeys to airpuffs (Gardner and Costanzo 1980a,b), and measured behavioral indices of the sensations evoked by airpuffs in psychophysical experiments on both humans and monkeys (Gardner and Tast 1981). We now extend this work by relating cortical SEPs and unit recordings produced by the same airpuff stimulus. A preliminary report of these findings has been presented (H~imalainen et al. 1983).

0013-4649/84/$03.00 © 1984 Elsevier Scientific Publishers Ireland, Ltd.

538 Methods

Recording techniques SEPs and single unit responses were recorded from the cerebral cortex of 4 alert macaque monkeys prepared for chronic single unit recording (2 Macaca mulatta, weight 10 kg (Monk 171) and 3 kg (Monk 318), and 2 Macaca fascicularis, (Monks 602 and 604, weight 3 - 4 kg). Sterile surgical procedures were performed under halothane anesthesia. A sterile stainless steel chamber was permanently implanted over a 20 mm diameter opening in the skull centered over the hand area of the left postcentral gyrus. Recordings were made in fully alert, unanesthetized monkeys, from primary somatosensory cortex (areas 3b, 1 and 2), and from portions of motor cortex (area 4), and posterior parietal cortex (areas 5 and 7). A calibrated micropositioner, fitted to the chamber opening, was used to locate precisely the point of entry of microelectrodes into the cortex, and to place SEP electrodes on the dural surface. Extracellular single unit responses were recorded with tungsten microelectrodes as described previously (Gardner and Costanzo 1980a). SEPs were recorded epidurally from the left cortex with a sterile, 2 mm diameter, chlorided silver ball electrode referenced to the frontal pole (SI-Fz), and occipital pole (SI-Oz). In 2 monkeys, SEPs were also recorded from the right cortex (ipsilateral to the stimulated arm) with a vitallium screw inserted in the skull approximately over the arm area of the postcentral gyrus, and referenced to the occipital site. SEP components were labeled ' N ' or 'P' for negative or positive polarities, followed by a number indicating the peak latency in milliseconds measured from the onset of the airpuff stimulus. Vitallium screws placed in the skull served as reference electrodes in monkeys 318, 602 and 604. Screws were soldered to ceramic-insulated stainless steel wires led under the scalp to a plastic connector cemented on the posterior skull. In monkey 171, a silver cup electrode filled with conductive paste, and taped to the shaved skin over the frontal pole, and a steel screw embedded in dental acrylic over the occipital skull served as reference electrodes. Screw reference electrodes gave much

E.P. GARDNER ET AL. less noisy recordings than the scalp electrodes. This cephalic electrode placement precluded the recording of far-field potentials. Non-cephalic reference sites were not employed because the monkey's spontaneous and evoked motor behavior generated too much noise, obscuring SEPs. SEPs were amplified at gains of 100,000 (Grass P511 AC preamplifiers), filtered (bandpass 10 Hz-1 kHz), and sampled, together with stimulus monitor displays, at 5 kHz with a PDP-11/10 computer over a 102.4 msec stimulus epoch. Each sample was initiated 10-15 msec before delivery of the airpuff, to provide a prestimulus baseline. Traces with extraneous noise amplitude > +4.5 V, generated by the monkey chewing, vocalizing or emitting other unwanted behavior, were automatically rejected by the computer. Averages of 100 trials of each stimulus were computed on-line and stored, together with the individual responses, in digital form.

Stimulation techniques The monkey was seated in a primate chair during recording sessions with his right arm restrained. Airpuffs were delivered to the volar or dorsal surface of the hand or forearm through an array of plastic nozzles held in a micromanipulator secured to the chair. The airpuff tactile stimulator has been previously described (Gardner and Costanzo 1980a). It consists of a solenoid valve which controls the flow of air from a regulated air supply through a series of tubes. The valve is opened by a voltage pulse, whose duration controls both the pressure and duration of air flow through the tubes. Individual airpuffs, or groups of 3 airpuffs, 15 mm apart, were activated simultaneously under computer control. Airpuffs lasted 10 msec, and applied a peak pressure to the skin of approximately 1.24 × 105 d y n e / c m 2. Airpuff force was measured throughout the experiment with a pressure sensitive transistor (PITRAN model PT-H2, Stow Laboratories). Examples of the monitored wave forms are shown with each of the SEP traces. In the single unit experiments, airpuffs were presented once or twice per second for 20-25 trials at each stimulus location. In SEP studies, airpuffs were delivered at random intervals over a 0.5-4

T A C T I L E SEPs IN A W A K E M O N K E Y S

539

sec period for a minimum of 100 trials. Airpuffs were also activated sequentially at short intervals (typically 20-40 msec), allowing us to test various frequencies of stimulation. Most of the stimulus trials for monkey 171 were initiated by the animal pressing a response lever; the airpuff was delivered after a randomly chosen foreperiod, and the monkey was reinforced to release the lever within 400 msec of stimulus delivery. In studies of the other monkeys, the computer initiated each trial, and the animals were not required to respond.

Recording localization Recordings were made over a period of 3-14 months. At the end of the study the monkeys were sacrificed by an overdose of barbiturate anesthetic,

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and the brains fixed by intracardiac perfusion. Reference marks denoting the location of the recording chamber were made by advancing stainless steel tubes dipped in india ink into the brain ( + , Fig. 1). Photographs of the brain were used to locate the sites of microelectrode penetrations and SEP recordings with respect to the reference marks. Nissl stained frozen sections were examined histologically to confirm unit recording sites. It was not possible to precisely locate the exact layer within the cortex where all single units were recorded, because microlesions disappeared after a few weeks. Depth with respect to the white matter and surface was measured on each penetration; most unit recordings were judged to be made from neurons in layers I I I - V I .

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540

E.P. G A R D N E R ET AL.

Results The locations of single unit microelectrode penetrations and SEP epidural recording sites on the surface of the brains of the 4 animals studied are indicated in Fig. 1. SEPs were recorded during 270 sessions at 42 cortical locations, primarily over area 1 and the crown of the postcentral gyrus at the 3b-1 border, and at scattered locations over areas 4, 2, 5 and 7. Most single unit recordings were made from the hand and arm regions of cytoarchitectonic areas 1 and 2. Microelectrode tracks were also placed in the posterior bank of the central sulcus in area 3b, and in motor and posterior parietal cortex.

following the airpuff onset. The early positive complex is seen with both frontal (SI-Fz) and occipital (SI-Oz) references, but the individual

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Characteristics of SEPs generated by airpuffs Typical epidural SEPs recorded from awake monkeys are illustrated in Fig. 2. The earliest responses consist of a positive complex beginning 8 - 1 0 msec after the onset of the airpuff, and lasting approximately 25 msec. The early positivity rises slowly from the baseline, with an initial small peak or inflection at about 11 msec. This is followed by a large sharply rising positive potential which peaks about 15 msec after airpuff onset (P15). P15 is succeeded by another prominent positive potential (P25). The P15 and P25 potentials are the most salient features of the early positive complex. One or more additional small positive wavelets are often observed 30-40 msec

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TACTILE SEPs IN AWAKE MONKEYS

541

components show varying strengths with the two montages. P15 often appears larger in the SI-Fz records, while P25 is usually higher in the SI-Oz trace. The early positive complex appears to be superimposed upon a longer lasting, slower negativity,

with a poorly defined onset latency, and a broad peak typically occurring at 43-45 msec. This negativity, which we call N43, can be seen with both frontal and occipital electrodes. N43 is terminated after about 30 msec by a broad positivity, peaking in these records at 70 msec. P70 varies in shape,

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+[ 10 uV "11000 dyn 10 ms Fig. 4. Short latency SEPs are seen only when the stimulus is delivered to the contralateral arm. Recordings from epidural electrodes over left SI cortex (center of the postcentral gyrus (area 1), and central sulcus at the 3b-1 border (area 3b)), and from a screw electrode placed in the skull above the right SI cortex, and referenced to the occiput. Three airpuffs delivered to right arm; 1 airpuff delivered to left arm. Monkey 602, sessions 32-34, location 13; sessions 49, 52, and 53, location 23.

542

latency and duration within the 102 msec time epoch sampled. Although there was some variability in peak amplitude and time of occurrence among animals, SEPs recorded in each monkey showed a consistent positive-negative-positive wave form (Fig. 3). In monkeys 602 and 318, P15 decayed rapidly due to the onset of an early negative potential (N20); in the others N20 was relatively weak, providing only a brief interruption of the early positivity. A positive potential at 30 msec was quite pronounced only in monkey 318; it appeared relatively weak and was superimposed on the large N43 negativity in the others. SEPs were slightly longer in latency in monkey 171, which probably reflects his much larger size. SEP wave forms recorded from individual monkeys were remarkably reproducible from session to session, over a period of one to several months. Compare the responses in Figs. 2 - 4 and 9-10 from monkey 602 which were recorded with different electrodes on different days at a variety of positions in the hand and forearm area, and the responses of monkey 318 illustrated in Figs. 3 and 5-8. These potentials appear to be specific to tactile stimulation of the contralateral limb, and are greatly reduced or absent if the airpuff is placed on the limb ipsilateral to the recording electrode. Fig. 4 shows recordings from epidural electrodes placed over the left SI cortex, and a screw electrode in the skull above the right SI cortex. Stimulating the right arm produced large SEPs over the left cortex, but evoked almost no response in the right cortex. Similarly, when the left arm was stimulated, the right cortex was responsive, whereas relatively little activity was seen over the left cortex. Bilateral stimulation produced responses on both sides. Potentials recorded with the screw electrode were somewhat smaller than those recorded directly from the cortical surface. These results rule out the possibility that the evoked potentials are elicited by non-tactile stimuli.

Comparison of single unit responses and SEPs Responses of 30 neurons in SI cortex were evaluated with airpuffs; 92 additional neurons were studied quantitatively with other types of tactile a n d / o r kinesthetic stimuli, and 847 cells were used

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Fig. 6. PSTHs of unit responses to airpuffs from 8 different cortical neurons. Same c o n v e n t i o n s as in Fig. 5A. A: m o n k e y 318, spike d a t a s a m p l e d at 5 kHz, U n i t 30-9: area 1; receptive field ( R F ) on dorsal radial forearm and wrist; m e a n n u m b e r of impulses per r e s p o n s e ( I / R ) , 4.6_+ 1.9 spikes. U n i t 35-7: area 3b, R F on dorsal fingers; l / R , 4.4 +_ 1.8 spikes. U n i t 35-9: area 3b; R F on dorsal p a l m ; I / R , 2.7 + 1.5 spikes. U n i t 29-11 : area 3b; R F on glabrous p a l m ; I / R , 1.9 _+ 1.4 spikes. SEPs from 3b-1 b o r d e r of wrist-forearm area shown above PSTHs. Session 2, location 12. B: m o n k e y 171, spike d a t a s a m p l e d at 1 kHz. U n i t 54-2: area 1; R F on volar forearm, ulnar margin; I / R , 4.1 ± 0.9 spike~. U n i t 38°6: area 1; R F on ulnar m a r g i n of volar forearm, wrist and palm; l / R , 3.8 ± 1.5 spikes. Unit 18-5: area 3b; R F on p r o x i m a l volar forearm; I / R , 5 . 3 ± 1 . 1 spikes. U n i t 7-2: area 3b; R F on dorsal fingers; I / R , 7.0 ± 3.4 spikes. SEPs from center of area 1 wrist-forearm area d i s p l a y e d above PSTHs. Session 57, location 80.

544 trials and peristimulus time histograms (PSTHs) averaging responses from 25 trials. The burst of impulses in this cell began 12 msec after the airpuff and lasted 15-20 msec. The initial impulses were highly synchronous, but later discharges were more variable in time of occurrence. PSTHs reflect this synchrony of impulses as a sharp increase in firing probability followed by a slow decay with multiple smaller peaks. PSTHs from 8 representative neurons in areas 3b or 1 are illustrated in Fig. 6. These are typical of neuronal responses to airpuff stimuli, seen not only in 30 neurons studied in this report, but also in the population of 150 neurons previously described by Gardner and Costanzo (1980a,b) using this same stimulator. SI neurons usually had an initial response latency of 11 12 msec, and showed peak responses 1-3 msec later. Thus airpuffs applied to the hand or forearm evoke maximum unit activity in SI cortex 12-15 msec after the stimulus onset. No significant difference was observed in the latency of responses of neurons in areas 3b and 1. Most airpuff elicited spike activity in areas 3b and 1 was terminated 30 msec after stimulus onset. Single unit action potentials coincided with the initial SEP positivity (Figs. 5B and 6). Usually the single unit responses occurred simultaneously with the peak of the P15 potential. SI neurons continued firing during much of the early positive complex, but spike frequency diminished while SEPs rose in amplitude. Most airpuff evoked unit activity in SI terminated before or in parallel with the early positive complex. Several neurons responded with onset latencies as brief as 9 msec, preceding the onset of the P15 potential (unit 18-5, Fig. 6). However, such neurons had receptive fields on the upper arm, whereas the SEPs illustrated were elicited by stimulating hairy skin at the wrist. We attribute the brief latency of the unit response to the shorter conduction distance. Similarly, SI neurons with receptive fields on the digits showed slightly longer response latencies, and began firing only 15-18 msec after the stimulus (units 29-11 and 7-2, Fig. 6). Units with glabrous skin receptive fields (unit 29-11) displayed weaker and shorter duration responses than hairy skin neurons. Finally, about 20% of the

E.P. GARDNER ET AL. entire population of 180 neurons showed prolonged responses to airpuffs lasting 40-80 msec (unit 7-2, Fig. 6). Response onset latency in these cells was more variable from trial to trial, their PSTHs lacked a well defined peak, and the total number of spikes in the response was higher than that of the synchronously activated, short latency burst neurons. After the initial excitation, cortical unit responses became depressed. This is clearly demonstrated by. repetitive stimulation of the receptive field using a conditioning test (CT) paradigm. In Fig. 7, airpuffs were presented at 2 different skin locations within the receptive field (C and T). Each stimulus alone evoked a strong response from the cells. When they were paired (C + T), with T following C by 27 msec, the neuron's response to the T airpuff was reduced. The mean number of impulses in the T response of cell 35-9 fell to 59% of control value, while the T response of cell 30-9 was entirely abolished. This suppression of the T response was not a generalized change in neuronal excitability, because the response to the preceding C stimulus was essentially unchanged. This suppression of paired responses has been called 'in-field inhibition,' and shown to be maximum 20-40 msec after the C airpuff onset, with diminishing effectiveness over a 60-100 msec period (Laskin and Spencer 1979b; Gardner and Costanzo 1980b). SEPs recorded from the cortex directly over unit 35-9, and 0.5 mm anterior to the penetration containing unit 30-9 are displayed above the PSTHs. Peak unit firing coincided with P15, and decayed during P25. Test response suppression coincided with the maximum N43 negativity, suggesting that the N43 wave may reflect in-field inhibition of SI unit responses. A similar suppression of SEPs was observed using repetitive stimulation of the skin. Fig. 8 shows SEPs recorded at a slightly more posterior location. Both the C and T airpuffs elicited strong, clearly defined SEPs when presented separately to the skin (top row). When C and T airpuffs were paired (C + T), with the T airpuff delayed by 29 msec, the SEP elicited by the T airpuff was markedly reduced. This can be seen more clearly in the lower right panel ((C + T) - C), in which the

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Time After C Airpuff Fig. 7. In-field inhibition of single unit responses. PSTHs of unit responses to 3 airpuffs delivered 9 msec (A) or 11 msec (B) after sample onset (C stimulus), and 1 airpuff delivered 36 or 37 msec after sample start (T stimulus). When C and T stimuli are paired (bottom panels), the response to the T stimulus is significantly reduced. Top panels: mean response to C stimulus; A: 3.5 + 1.8 s p i k e s / s t i m u l u s ; B: 3.34-2.0 spikes/stimulus. Middle panels: mean response to T stimulus; A: 3.4 4-1.7 s pi ke s / s t i mul us ; B: 2.4 + 1.4 spikes/stimulus. Bottom panels: mean response to C stimulus; A: 3.5_+ 1.6 s pi ke s / s t i mul us ; B: 3.24-1.7 spikes/stimulus; mean response to T stimulus; A: 2.0 4-1.7 spikes/stimulus; B: 0.4_+ 0.64 spikes/stimulus. SEPs recorded from the dura above unit 35-9 and 0.5 m m anterior to unit 30-9 are shown above the PSTHs. Note that T response suppression in the PSTHs occurs simultaneously with m aximum N43 negativity. Session 56, location 33.

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response to the C stimulus was digitally subtracted from the paired response. Both the early positive complex a n d N43 wave are still present in the records, b u t their a m p l i t u d e is sharply attenuated. The area u n d e r the early positive complex was reduced to 58% of control, while the integrated N43 wave was d i m i n i s h e d still further, to 14% of the u n c o n d i t i o n e d value. The degree of T response suppression was f o u n d to be a f u n c t i o n of the c o n d i t i o n i n g test interval a n d the intensity of the c o n d i t i o n i n g stimulus. Thus SEP suppression closely parallels in-field i n h i b i t i o n of unit activity.

Specificity of airpuff elicited SEPs In a d d i t i o n to the temporal c o r r e s p o n d e n c e between SEPs a n d single unit responses, we f o u n d

that SEP a m p l i t u d e could be altered by the same experimental variables which affected unit firing rates. Like single unit responses ( G a r d n e r a n d Costanzo 1980a), SEP amplitudes were d e p e n d e n t o n both recording location a n d extent of skin area stimulated. Fig. 9 illustrates representative SEPs recorded at different cortical sites to s t i m u l a t i o n of the right wrist. The early positive complex was largest over area 1 in the region c o n t a i n i n g neurons with receptive fields centered at the wrist (C). Surprisingly, large SEPs were also observed more posteriorly, near the intraparietal sulcus (E). SEPs were clearly weaker near the central sulcus at the 3b-1 border (A), a n d in the elbow (B) or p a l m (D) regions of area 1. SEPs from the intraparietal sulcus face area (F), a n d motor cortex h a n d area

TACTILE SEPs IN AWAKE MONKEYS

547

A

÷ 10 uV ~1000 dyn 10 ms

Fig. 9. Change in SEP amplitude with recording location on the dural surface. Three airpuffs delivered to the volar wrist of the right hand. Recordings made from: A: central sulcus at border between areas 1 and 3b; B: elbow region of area 1; C: wrist region of area 1; D: palm region at border between areas 3b and 1; E: posterior parietal cortex (area 5) arm area; F: intraparietal sulcus face area; G: motor cortex hand area. Shading on the postcentral gyrus indicates cortical columns with receptive fields centered at the right wrist as observed in single neuron recordings. The early positive complex is largest at location C in the center of the wrist region of area l. Monkey 602, sessions 65, 66, 15, 57, 64, 63, 62. SEPs in A-B and E - G were recorded on the same day with the same epidural electrode shifted to different cortical locations.

(G), were further attenuated, and the component p e a k s w e r e less d i s t i n c t . T h e r e w a s n o r e v e r s a l o f the polarity of the wave forms anterior to the central sulcus; the responses simply decremented in amplitude. Weaker responses to airpuffs over motor cortex than sensory cortex, and lack of polarity reversal of any of the SEP components w e r e c o n s i s t e n t l y o b s e r v e d i n t h e s e e p i d u r a l recordings. SEP amplitude also depended on the number of

p o i n t s s t i m u l a t e d o n t h e skin. S E P s w e r e l a r g e r when 3 points were stimulated simultaneously, t h a n w h e n a n y o n e of t h e m w a s s t i m u l a t e d a l o n e ( F i g . 10). T h i s c o r r e l a t e s w i t h p r e v i o u s s i n g l e u n i t studies demonstrating facilitation or summation of a c t i v i t y i n SI c o r t e x w i t h m u l t i p l e p o i n t a r r a y s ( G a r d n e r a n d C o s t a n z o 1 9 8 0 a ) , as well as p s y c h o physical demonstrations of enhanced sensation m a g n i t u d e ( G a r d n e r a n d T a s t 1981). T h u s o n e c a n improve the signal strength of mechanically elicited

548

E.P. GARDNER ET AL. Airpuffs 1 2 3

I

Airpuff 1

?

l

Airpuff 2

Airpuff 3 "-x,

/

jr\ ~,%

Alrpuffs 1 2 3

--

+[ 10 uV _~ 1 0 0 0 dyn 10 ms

Fig. 10. Effect of number of stimulus points on SEP amplitude. Figurine shows stimulus locations on the forearm. SEPS are largest when 3 points are stimulated simultaneously (airpuffs 123), than when any one of them is stimulated alone. SI-Oz records• Monkey 602, sessions 3-6, 8, location 10.

SEPs by s i m u l t a n e o u s l y s t i m u l a t i n g several p o i n t s on the skin.

Discussion

W e have shown that m e c h a n i c a l tactile stimuli elicit r e p r o d u c i b l e SEPs of specific wave form in monkeys. These SEPs consist of: (a) an early positive c o m p l e x with two i d e n t i f i a b l e p e a k s (P15, P25) i n t e r r u p t e d b y a small negative wave (N20), (b) a large negative potential, N43, lasting a b o u t 30 msec, a n d (c) a late slow positivity, P70, of v a r i a b l e onset, d u r a t i o n a n d p e a k location. These wave forms closely r e s e m b l e those previously described by A r e z z o a n d c o w o r k e r s (1981) a n d b y K u l i c s (1982) using electrical s t i m u l a t i o n of whole

nerves or the skin in alert monkeys. T h e P15-P25 c o m p l e x elicited b y airpuffs is similar in configuration to the P12-P20 c o m p l e x in the A r e z z o g r o u p ' s study, a n d to the P1 wave in Kulics" report. The longer latencies of a i r p u f f SEPs are p r o b a b l y due to the process of r e c e p t o r transduction, a n d to the slower c o n d u c t i o n velocities of c u t a n e o u s afferents (Arezzo et al. 1981; Burke et al. 1981). The early positive complex of airpuff SEPs has a longer d u r a t i o n than that of electrically elicited SEPs, but a i r p u f f SEPs are only a b o u t o n e - f o u r t h the amp l i t u d e of those illustrated b y Arezzo a n d coworkers (1981). N e i t h e r Arezzo a n d coworkers nor Kulics labeled the early negative wave which we call N20, b u t such small negative p o t e n t i a l s are clearly visible in the records of b o t h investigators. A r e z z o and coworkers' N45 complex, a n d Kulics' N1 p o t e n t i a l occur at the same time as our N43 wave. Similarly the A r e z z o g r o u p ' s P l 1 0 a n d Kulics' P2 (latency 1 1 0 - 1 3 0 msec) p r o b a b l y represent the same p o t e n t i a l we describe as P70; the latency difference m a y reflect the fact that our s a m p l e was t e r m i n a t e d at 102 msec. Clear similarities are also seen between the early phases of the SEPs we observed in monkeys, a n d the d o u b l e h u m p e d early positivity seen in h u m a n SEPs elicited by m e c h a n i c a l s t i m u l a t i o n of the skin ( N a k a n i s h i et al. 1974; Pratt et al. 1980). However, we d i d not record an initial negative wave in the m o n k e y SEP c o r r e s p o n d i n g to the h u m a n N20 potential. This seems surprising to us since Allison a n d colleagues (1980) have p r o p o s e d that N20 is generated by a h o r i z o n t a l l y oriented d i p o l e l o c a t e d in the p o s t e r i o r wall of the central sulcus ( p r e s u m a b l y in area 3b). Their hypothesis w o u l d predict an initial negative p o t e n t i a l in the m o n k e y SEP c o r r e s p o n d i n g to activation of neurons in area 3b when mechanical tactile stimuli are used, but this p o t e n t i a l was not present in our records. T h e m e c h a n i c a l stimuli we e m p l o y e d in this s t u d y have the great a d v a n t a g e over electrical shocks that the user can specify the type a n d s p a t i a l location of receptors activated in the skin. Electric shocks p r o v i d e an abnormal spatial pattern b y s y n c h r o n o u s l y activating multiple r e c e p t o r types, and b y s i m u l t a n e o u s l y exciting n e u r o n s innervating wide regions of skin, muscle a n d joints.

TACTILE SEPs IN AWAKE MONKEYS In addition, electrical stimuli produce an abnormal temporal pattern of single impulses in many fibers, rather than the physiological pattern of multiple discharges in selected neurons demonstrated here with airpuffs.

Electrophysiological sources of the early positive complex We have shown in this and previous studies (Gardner and Costanzo 1980a) that neurons in areas 3b and 1 of SI cortex respond to airpuffs with a repetitive train of impulses lasting 15-30 msec, followed by a period of inhibition of 60-100 msec duration. Units respond specifically to inputs from rapidly adapting cutaneous mechanoreceptors in particular patches of skin. Neuronal firing rates are dependent upon stimulus location within the receptive field, stimulus intensity, and total number of points stimulated on the skin (Gardner and Costanzo 1980a). The maximum firing of neurons in areas 3b and 1 coincides with the P15 wave. SI neurons continue to fire for 15-30 msec, and undoubtedly contribute to the currents recorded later in the early positive complex. The earliest positive deflection in the SEP occurs slightly before cortical spike activity begins, and may be due, in part, to the thalamo-cortical input, or to dendritic EPSPs which precede spike activity in cortical neurons. P25 and subsequent small positive deflections may reflect the activation of new populations of neurons in more posterior parietal areas, as well as repetitive activity of neurons in areas 3b and 1. Neurons responding to tactile stimulation have been identified in areas 2 and 5, but these cells usually require more complex stimuli than simple punctate airpuffs (Sakata et al. 1973; Mountcastle et al. 1975; Hyvarinen and Poranen 1978a,b; Iwamura and Tanaka 1978; Costanzo and Gardner 1980). Neurons in area 7b require even more specialized stimuli, usually with clear behavioral relevance for the animal (Hyv~rinen 1982). Activity in SII cortex on the superior bank of the lateral fissure, and the retroinsular cortex may also contribute to the later portions of the SEP (Whitsel et al. 1969; Robinson and Burton 1980a,b). Activity in motor cortex may provide only a minor contribution to the early components of

549 airpuff elicited SEPs. Precentral SEPs were found to have the same polarity as postcentral SEPs, with a smaller amplitude early positive complex. Few neurons in area 4 could be activated with airpuffs; most activity was related to manipulation of muscles and joints (Gardner and Costanzo 1980a). Responses to tactile stimulation of the hand and forearm seem to be confined to a small region of motor cortex, buried deep in the anterior wall of the central sulcus (Strick and Preston 1978). Further information concerning the specific sites of origin of cortical excitatory activity can be derived from metabolic maps of local cerebral glucose utilization made using the 2-deoxyglucose (2-DG) technique. 2-DG mapping was performed in 3 of the monkeys reported in this study. Preliminary data support the electrophysiological findings presented here (Hand and Gardner unpublished). The most intense metabolic activity elicited by airpuffs occurred at the crown and anterior one-third of the postcentral gyrus in area 1, and on the posterior wall of the central sulcus in area 3b. Very strong metabolic activity was also observed in SII cortex, and in the retroinsular area. Weaker 2-DG labeling was seen in areas 2 and 5, and only background level metabolism was found in areas 4 and 7b. Similar patterns of 2-DG labeling have been reported by Juliano and coworkers (1981, 1983) using other types of mechanical tactile stimuli.

Electrophysiological sources of the primary negative potential The early positive complex is terminated by a large, relatively long-lasting negative potential with a poorly defined peak (N43). N43 begins about 30 msec after the airpuff onset, and lasts approximately 30 msec. Most airpuff driven unit activity in SI cortex has ceased by the time N43 begins, and is replaced by a period of inhibition of the same neurons which were initially excited by the tactile stimulus (Laskin and Spencer 1979b; Gardner and Costanzo 1980b). This in-field inhibition depresses excitatory unit responses to test airpuffs delivered within 60-100 msec of a conditioning stimulus. Intracellularly recorded IPSPs of 60-100 msec duration, which may underlie in-field inhibition, have been observed in S! cortical neu-

550 rons following EPSPs evoked by peripheral stimulation (Whitehorn and Towe 1968; Innocenti and Manzoni 1972). In-field inhibition is strongest at the center of the receptive field, where excitation is most powerful, and decays, in parallel with excitation, in the periphery and field surround zone (Laskin and Spencer 1979b; Gardner and Costanzo 1980b). A similar poststimulus depression of SEP positivity was observed when airpuffs were presented sequentially at brief intervals. When stimulated with a 25-40 msec conditioning test interval, the early positive complex normally elicited by the test airpuff was severely attenuated. Similar reductions in the size of the N19 and P23 waves of the human SEP have been reported by Wiederholt and coworkers (1982), using pairs of shocks to the median nerve, and by Pratt et al. (1980) using trains of electrical or mechanical skin stimuli. In addition to the reductions in unit responses and the early cortical components of the SEP, the perceived intensity of a test airpuff is markedly diminished (Laskin and Spencer 1979a). Thus the attenuation of electrophysiological activity by in-field inhibition is correlated with depressed sensation magnitude. Towe (1966), in a theoretical analysis of the origin of the primary evoked response in anesthetized animals, proposed that the primary negativity was generated by cortical IPSPs in the neurons initially depolarized by the afferent volley in peripheral nerves. Our data suggest that this same mechanism may underlie the longer duration N43 negativity seen in alert animals tested with mechanical stimuli. This poststimulus inhibition of cortical neurons may explain why large SEPs are not observed at stimulus rates greater than 8/sec (Pratt et al. 1980; Wiederholt et al. 1982). The N43 complex is succeeded by a slow positivity (P70). We were unable to find any airpuff evoked electrophysiological activity in SI cortex which might correspond to this wave. No cells began firing during this period, and, on the contrary, most S I n e u r o n s still showed evidence of response depression 60-100 msec following an airpuff. P70 is related in some manner to tactile stimulation, and has been seen only when airpuffs were presented to the contralateral limb; it does

E.P. GARDNER ET AL. not appear to be an artifact of weak auditory stimuli associated with the airpuff, or other nontactile stimuli. It seems likely that P70 is generated in some other cortical area, such as SII cortex, insula a n d / o r retroinsular cortex.

Summary The origins of surface recorded evoked potentials have been investigated by combining recordings of single unit responses and somatosensory evoked potentials (SEPs) from the postcentral gyrus of 4 alert macaque monkeys. Responses were elicited by mechanical tactile stimuli (airpuffs) which selectively activate rapidly adapting cutaneous mechanoreceptors, and permit patterned stimulation of a restricted area of skin. Epidurally recorded SEPs consisted of an early positive complex, beginning 8-10 msec after airpuff onset, with two prominent positive peaks (P15 and P25), succeeded by a large negative potential (N43) lasting 30 msec, and a late slow positivity (P70). SEPs, while consistent in wave form, varied slightly between monkeys. The amplitude of the early positive complex was enhanced by increasing the number of stimulated points, or by placing the airpuffs in the receptive fields of cortical neurons located beneath the SEP recording electrode. SEP amplitude was depressed when preceded 20-40 msec earlier by a conditioning stimulus to the same skin area. Single unit responses in areas 3b and 1 of primary somatosensory (SI) cortex consisted of a burst of impulses, beginning 11 12 msec after the airpuff onset, and lasting another 15-20 msec. Peak unitary activity occurred at 12-15 msec, corresponding to the P15 wave in the SEP. No peak in SI unit responses occurred in conjunction with the P25 wave. Although SI neurons fired at lower rates during P25, the lack of any peak in SI unit responses suggests that activity in other cortical areas, such as SII cortex, contributes to this wave. Most unit activity in SI cortex ceased by the onset of N43, and was replaced by a period of profound response depression, in which unit responses to additional tactile stimuli were reduced. We propose that the N43 wave reflects IPSPs in

TACTILE SEPs 1N AWAKE MONKEYS

cortical neurons previously depolarized and excited by the airpuff stimulus. Late positive potentials (P70) in the SEP had no apparent counterpart in SI unit activity, suggesting generation at other cortical loci.

R6sume

Potentiels bvoqubs sornatosensoriels (PES) et rbponses corticales unitaires produites par stimulation tactile chez le singe Les origines des potentiels 6voqu6s enregistr6s en surface ont 6t6 recherch6es en combinant l'enregistrement de r6ponses neuronales unitaires et de potentiels 6voqu6s somatosensoriels (PES) au niveau du gyrus postcentral chez 4 singes macaques 6veill6s. Les r6ponses ont 6t6 provoqu6es par un stimulus tactile m6canique (bouff6es d'air) qui active s61ectivement les m6canor6cepteurs cutan6s h adaptation rapide, et permet une vari6t6 de patrons de stimulation sur une zone de peau restreinte. Les PES enregistr6s 6piduralement ont consist6s en un complexe positif pr6coce, commen~ant 8 /a 10 msec apr6s le d6but de la bouff6e d'air, pr6sentant deux pics positifs dominants (P15 et P25), suivis par un potentiel n6gatif large (N43) d'une dur6e de 30 msec, et d'une positivit6 lente et tardive (P70). Les PES, bien que stables darts leur forme, ont vari~ 16g6rement d'un singe ~ l'autre. L'amplitude du complexe positif pr6coce a 6t6 accrue en augmentant le nombre de points de stimulation, ou en pla~ant la bouff6e d'air dans le champ r6cepteur du neurone cortical iocalis6 audessous de l'61ectrode d'enregistrement du PES. L'amplitude du PES a diminu6 lorsqu'il 6tait pr6c6d6 de 20 ou 40 msec par un stimulus conditionnel appliqu6 dans la mEme aire cutan6e. Les r6ponses unitaires dans les aires 3b et 1 du cortex primaire somatosensoriel (SI) se sont pr6sent6es comme des groupes d'influx, comm e n , a n t 11 ~ 12 msec apr6s le d6but de la bouff6e d'air et durant 15 ~ 20 msec. Le pic de l'activit6 unitaire se situait entre 12 et 15 msec et correspondait ~ l'onde P15 du PES. Aucun pic dans les r6ponses des unit6s de SI n'est apparu en relation avec l'onde P25. Bien que les neurones de SI

551

d6chargent avec une fr6quence lente au cours de P25, l'absence de pic dans les r6ponses des neurones de SI sugg6re que l'activit6 d'une autre aire corticale comme le cortex SII, contribue ~ cette onde. L'activit6 unitaire dans le cortex SI a g6n~ralement cess6 avec le d6but de N43, e t a 6t6 remplac6e par une p6riode de forte d6pression de la r6ponse, au cours de laquelle les r6ponses unitaires h u n stimulus tactile additionnel 6taient r6duites. Nous proposons que l'onde N43 r6v61e la g6n~ration des IPSP par les neurones corticaux pr6c6demment d6polaris6s et excit6s par la bouff6e d'air. Les potentiels positifs tardifs (P70) du PES n'ont apparemment pas eu de correspondant dans l'activit6 unitaire de SI, sugg6rant ainsi que leur origine est dans d'autres aires corticales.

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