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Human pulvinar units, spontaneous activity and sensory-motor influences
388
Electroencephalography and clinical Neurophysiology, 1982, 54:388-398 Elsevier Scientific Publishers I r e ~ Ltd.
HUMAN PULVINAR UNITS, SPONTANEOUS ACTIVITY AND S E N S O R Y - M O T O R INFLUENCES l J.G. MARTIN-RODRIGUEZ 2, W. BUNO, Jr. 3 and E. GARCIA-AUSTT 3
Centro "Rambn y Cajal" Madrid 34 (Spain) (Accepted for publication: May 13, 1982)
Visual, auditory and somesthetic potentials have been evoked in the human pulvinar nucleus (Pu) (Cooper et al. 1974). In the cat, sensory evoked potentials of different modalities have been recorded at specific Pu sites (Kreindler et al. 1968). Substantial evidence exists concerning Pu unitary responses evoked by visual stimulation (e.g., Veraart et al. 1972; Gattas et al. 1978) as well as by auditory and somatosensory inputs (Avanzini et al. 1980). The projection of Pu upon oculomotor neurons has been demonstrated electrophysiologically (Wilson and Goldberg 1980). In a preliminary report Magarifios Ascone et al. (1981) demonstrated that, in the awake monkey, some Pu units fire in relation with movements and also in response to auditory or photic stimulation. Furthermore, the same Pu sites project widely to homo- and heterolateral neocortical primary or associative areas (Kreindler et al. 1968). Although controversial, stereotaxic lesions in the human Pu have been proposed to provide relief of chronic pain (Kudo et al. 1966; Richardson 1967) and to decrease spasticity and abnormal involuntary movements (Cooper 1971; Cooper et al. 1974; Martin-Rodriguez and Obrador 1975). The reported clinical and experimental data suggest an involvement of Pu in sensory-motor integrative mechanisms, in which convergence from other CNS regions may be important. However, the participation of Pu in voluntary movements, as well as the I This work was supported in part by the Fundacibn Rodriguez Pascual, Spain, and with Grant 831 from the Fondo de Investigaciones Sanitarias (RAPEL). 2 Departamento de Neurocirugia. 3 Departamento de Investigacibn.
demonstration of converging sensory-motor influences upon the same Pu units, which would lend strong support to the above proposed integrative role of the nucleus, have not been demonstrated except for the report of Magarifios Ascone et al. (1981). Most of the above-mentioned studies have been performed on anesthetized animals, an unfavorable situation to investigate small effects conveyed through multisynaptic connections, as is the case with Pu. The purpose of this study was to analyze Pu unit activity in the unanesthetized man during a spontaneous condition, voluntary and involuntary movements, and auditory, visual and somesthetic stimulation. The clarification of the above points may provide guides for thalamic locations and thus correction for anatomical variations during surgery. Moreover, they may provide information on the functional significance of this nucleus in man where it has attained its highest philogenetic development. Microelectrode recording has been systematically performed during stereotaxic surgery in awake man to correct for anatomical variability within the thalamic nuclei (Guiot et al. 1962; Gaze et al. 1964; Jasper and Bertrand 1964; Kalyanaraman 1964; Jasper 1966; Bates 1971). The Pu is generally in the path of the microelectrode track to the specific 'target' in somatosensory nuclei; thus its unitary activity could be explored during therapeutic surgery. The techniques used for microelectrode recording in man and some characteristics of the discharge patterns of Pu units have been described elsewhere (Bufio et al. 1977).
0013-4649/82/0000-0000/$02.75 © 1982 Elsevier Scientific Publishers Ireland, Ltd.
SENSORY-MOTOR INFLUENCES UPON P U L V I N A R UNITS
389
Methods
Seventy-four units were recorded in 7 male patients undergoing l0 stereotaxic operations for various neurological problems requiring placement of a lesion in the thalamus (nuclei ventralis oralis, posterior-ventralis intermedium, centralis medialis, parafascicularis, or Pu). Three patients were operated on for otherwise intractable bilateral parkinsonian tremor, allowing 3-5 months to elapse after each thalamotomy. For practical purposes they were considered as 6 separate operations. Two patients were operated on to treat intention tremor (unilateral thalamotomy), 1 patient had spasmodic torticollis (bilateral pulvinectomy in one surgical session) and 1 patient suffered from chronic intractable pain (bilateral medialis-parafascicularis complex lesions in one surgical session). Operations were performed under local anesthesia, using current stereotaxic techniques and a Leksell (1949) apparatus. All surgical and experimental procedures were carefully explained beforehand to the patients and informed consent was obtained. They were familiarized with the equipment including the pressing handle, earphones, flash and pin-point skin stimulators, and were instructed to squeeze the handle upon request. Tungsten microelectrodes (Hubel 1957) inside an uninsulated protective cannula, were inserted through a posterior parietal burrhole by means of a specially designed carrier fitted to the Leksell frame. The microelectrode was introduced with a micrometer drive attached to the carrier. Up to 30 m m were explored in each track. The cannula was used as a grounded shield and a stainless steel clip attached to the scalp incision was used as reference electrode. Potentials were fed to a high input impedance preamplifier, and then through two bandpass filter amplifiers, one set as a high-pass and the other as a low-pass with 1-50 Hz and 0.1-10 kHz cut-offs, respectively, to separate electrographic (EEG) - - which will also be called gross - - and unitary activities (i.e., spikes; Fig. 1). Spikes were also acoustically monitored with a loudspeaker. A specially designed pressing handle, which produced an electrical signal when squeezed, was attached to the contra- or ipsilateral hand. It pro-
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Fig. 1. Gross and unit activity recorded with the microelectrode (A). High-pass (B) and low-pass (C) filtering separates unit spikes and EEG, respectively. Calibrations, 500 ~tV and 20 msec.
vided a time reference for voluntary movements. In these conditions the hand and pressing handle were hidden from the patient's view. The same signal was also used to time voluntary movements of the jaw and passive finger movements. A minute microphone (Fox-2212) was taped to the contralateral thumb to record tremor after convenient amplification and filtering. Photic, auditory and tactile stimulation were performed with a photostimulator, an ear-phone fed with rectangular pulses and a pin-point microswitch, respectively. This last instrument was included in an electrical circuit which generated a signal when the skin was mechanically stimulated. Signals were monitored in a four-channel storage oscilloscope and recorded on magnetic tape together with a voice protocol. 'Spontaneous' activity was recorded for 1-3 min. The influence of voluntary movements of the contra- and ipsilateral hands, involuntary movements of contralateral fingers, photic and auditory stimulation, and tactile stimulation of the contralateral arm, were then studied during similar time periods. Data were processed off-line, playing back the tapes in a PDP-12 computer, by means of specially developed software. When two spikes of different amplitudes were clearly observed in the raw data, a window discriminator circuit was used to separate these events, which could be processed simultaneously by the computer. The following statistical functions were estimated: interspike in-
390 terval histogram, autocorrelation histograms of spikes, cross-correlation histograms between spikes of a pair, peristimulus time histograms of unit firing probabilities, autocorrelation functions and averages of gross activity, preceding and following voluntary handle squeezing, voluntary movements of the jaw, passive movements of fingers, clicks, flashes, or skin stimulation. Finally, E E G averages were calculated, taking the spikes as reference; spike-triggered E E G averages will be called cross-correlation functions. The above statistical techniques were necessary for an accurate description of the spontaneous unitary discharge patterns, their temporal relationships with the EEG, voluntary movements and sensory inputs. They also permitted the demonstration of small effects which were not clear in the raw electrical records because of the unit's varying ongoing activity. All functions were calculated with 4 msec bins or sampling intervals. Mean firing rates for the 1 rain observation periods were also calculated. Units were selected for processing according to the following criteria: (1) signal-to-noise ratios greater than 5; (2) pairs with at least a 2 to 1 amplitude ratio; (3) stable amplitude and spike wave form; (4) maintained discharge without marked sustained variations of the firing rate; and (5) data with the above characteristics, lasting for at least 1 min. Twelve pairs and 12 isolated units (n = 36) fulfilled these criteria. Stereotaxic targets were calculated for the rostro-ventral aspect of the Pu because this region is near the somatosensory nuclei, which was the surgical 'target' in most cases. Fig. 2 shows the projections of the 24 positions recorded on two superimposed sagittal planes of the Van Buren and Borke atlas (1972), at 9 and 12 m m from the midline. The position of each point was corrected for individual variations according to the data of Van Buren and Borke (1972) and Andrew and Watkins (1969). In all cases except one, in which the Pu itself was the stereotaxic 'target,' after recording from the Pu the electrode was advanced (following the same track) toward the sensory nuclei. Unit responses to tactile contralateral stimulation of the face or hand were then explored. These nuclei generally lay more ventrally and rostrally than the Pu region studied.
J.G. MARTIN-RODRIGUEZ ET AL.
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Results
Spontaneous dischargepatterns During recording, the operating lights were turned off and the other lights were dimmed. The surgeon and staff were quiet and out of the patient's visual field; ambient noise-level was reduced to a minimum by turning off all unnecessary equipment. In this 'spontaneous' condition the patient was instructed not to move. In the above conditions, mean firing rates varied between 1.8 and 29.0 i m p / s e c (IPS) (n---34; ~ = 9.8 IPS; median -- 9.1 IPS; S.E.= 6.5 IPS). Visual analysis of the raw data showed that 21 of 34 units (62%) tended to fire in bursts. The interspike interval distributions were either bimodal (n = 17 or 50%; Fig. 3Al) or monomodal ( n = 17 or 50%; Fig. 3A 2-4). Most monomodal interval histograms showed 'Poisson-like' distributions (Fig. 3A2), but lacked very short interspike intervals, probably because of refractoriness. 'Poisson-like' distributions indicate a random firing pattern. Bimodal distributions always showed a higher, narrower, short interval mode and a wider, lower mode corresponding to longer intervals (Fig. 3A1). Most autocorrelation histograms ( n = 2 6 or
S E N S O R Y - M O T O R I N F L U E N C E S U P O N P U L V I N A R UNITS
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Fig. 3. Interval histograms (A) and autocorrelation histograms (B) of different units. 1, rhythmic unit with bimodal interval and periodic autocorrelation histograms with a wide central peak, indicating periodic bursts. The shorter interval histogram mode corresponds to intraburst and the longer to interburst intervals. 2, non-rhythmic unit with 'Poisson-like' interval histograms and flat autocorrelation histograms with a wide central peak indicating bursts. 3 and 4, non-rhythmic units with unimodal interval with a small ' h u m p ' at long intervals during the exponential decay in A 3 and with a gradually rising mode in A 4, both with flat autocorrelation histograms (B 3 and B4). Calibrations, 50 counts for A, 100 for B l, B2 and B4, and 800 for B3; time in sec.
76%) showed a wide central peak (i.e., of more than one bin width) indicating that the firing rate was high before and after a spike and then decayed more or less rapidly. Central peaks of more than one bin width indicate a tendency to fire in bursts (Figs. 3Bland2, 4, 5A1.2 and B]). In some cases (n = 14 or 41%) autocorrelation histograms showed a wide central peak and other peaks at fixed intervals (i.e., they were periodic) at longer delays and advances from the zero reference, indicating a tendency to fire in rhythmic bursts (Figs.
391
3B~, 4A 2, 5A1 and2 )' In most cases peak amplitudes decayed gradually with the separation from the central peak. The 14 rhythmic units fired at mean bursting rates between 3.5 and 6.0 bursts/sec (BPS). Although most rhythmic units had bimodal interval histograms, some showed 'Poisson-like' distributions, but they all had periodic autocorrelation histograms with a wide central peak, indicating rhythmic spike bursts. Twelve of the 20 non-rhythmic units also presented a wide central peak in the autocorrelation histograms, indicating bursts (Figs. 3B2, 4B2, 5A, and B t). The gross activity or Pu lz•O recorded with the microelectrode was rhythmic in 14 of the 21 sites studied (67%). The average characteristics of the periodic EEG during the 1 min observation period were determined with the autocorrelation function (Fig. 4A l, B I and C1). In 13 records the periodic EEG waves were within the theta band (Fig. 4: 5.0 7.0 c/sec; X = 6.4 c/sec, S . E . - 0 . 2 6 c/sec), while in the other record the frequency was in the alpha band (10.5 c/sec). Rhythmic and nonrhythmic units were recorded either with or without a simultaneous rhythmic EEG. Seven rhythmic units were recorded during rhythmic theta activity. Six of these fired in rhythmic bursts with rates at half the frequency of the EEG rhythm (Fig. 4A: 3.5 BPS and 7.0 c/sec, respectively), while one fired in bursts at the EEG frequency (5.0 c/sec). The finding of units with rhythmic bursts at half the frequency of the periodic EEG waves is unusual because in other structures rhythmic cells fire in synchrony with periodic gross activity waves (e.g., Bufio et al. 1978). All (e.g., Fig. 4A) but one of the rhythmic units showed a periodic cross-correlation function with the EEG rhythm. An important finding was that 5 non-rhythmic units revealed a positive, rhythmic, cross-correlation function with the theta rhythm (Fig. 4C). The periodic cross-correlation function was at the same frequency as the EEG rhythm (Fig. 4C3), indicating a temporal relationship between spikes and gross activity. The other 7 non-rhythmic units recorded in the presence of a rhythmic EEG did not show a temporal relationship with the rhythm, and cross-correlation functions were flat (Fig. 4B 3). Cross-correlation functions between rhythmic or non-rhythmic units and non-rhythmic EEG were
392
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Fig. 4. Temporal relationships between spikes and Pu EEG. Autocorrelation function, autocorrelation histogram and cross-correlation function, 1, 2 and 3, respectively.A: rhythmic unit (2) with bursting rate at half (about 3.5 bursts/sec) the frequency of the EEG (1) waves (about 7.0 c/sec) with a phase relationship with the rhythmic EEG (3). B: non-rhythmic unit unrelated with the EEG. C: non-rhythmic unit related with the EEG rhythm (3). Calibrations, 15X 10 3 ~V for 1; 50, 200 and 100 counts for A2, B2 and C2, respectively; 150/zV for 3; time in sec.
always negative (i.e., they were flat). Twelve pairs of units were recorded (see Methods). In 11 pairs both units had similar discharge patterns, 6 pairs were rhythmic (Fig. 5A 1~nd2) and 5 pairs were non-rhythmic units (Fig. 5Bla,d2). In only one case was the pair composed of a rhythmic and a non-rhythmic unit. Cross-correlation histograms between both units of a pair were always positive (Fig. 5A3, An, B3 and B4). In the 6 rhythmic pairs, cross-correlation histograms were rhythmic with peaks at the same frequency as the unit's bursting rate (Fig. 5A3). Cross-correlation histograms indicated that both units tended to fire in synchrony (i.e., the functions had a clear central peak) or with a phase difference (i.e., the peak was close to but displaced either to the left or right of the zero reference; Fig. 5A3and4). An important observation was that the cross-correlation histograms of the rhythmic non-rhythmic pair were also periodic, with peaks at the bursting rate of the rhythmic unit (see Bufio et al. 1977). Cross-corre-
lation histograms of pairs composed of nonrhythmic units were aperiodic and either showed a decrease in rate after the zero reference (3 pairs) or a symmetric rate increase on either side of the reference (2 pairs; Fig. 5B3and4). In 3 units out of 5 in which the spontaneous activity of the same unit was studied in different observation periods, but under the same spontaneous condition, the discharge pattern did not change between observations. The other two units changed from rhythmic to non-rhythmic and one lost its positive cross-correlation function with the Pu E E G rhythm. In 4 units the effect of voluntary closing and opening the eyes was studied and no sustained modifications of the unit's firing patterns were observed. Activity
modifications
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movements
Thirteen out of 28 units (46%) showed firing rate modifications during voluntary handle pressings performed with the contralateral hand.
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Fig. 5. Temporal relationships between units of a pair. A 1 and A 2: autocorrelation histograms of the components of a rhythmic pair. A3: cross-correlation histograms of the pair taking as reference the unit corresponding to A~; the histogram is periodic at the same frequency of the bursts in both units. A4: same as A 3 but with expanded time-base to show that the central peak is displaced to the right, indicating that one unit discharged preferently after the one taken as zero reference. B~ and B3: autocorrelation histograms of a pair of non-rhythmic units. B3: cross-correlation histogram of the pair showing an increase followed by a decrease of discharge probability around the reference. B4: same as B3 with expanded time-base. Calibrations: 50, 100, 50 and 50 counts for AI_4, respectively; 200, 50, 50 and 50 counts for BI_4, respectively; time in sec.
Pressings were always rhythmic at frequencies between 1.0 and 1.2/sec, although patients were not instructed to press periodically. Peristimulus time histograms, calculated taking the instants of handle pressings as a zero reference, were periodic at the same or double the frequency of pressings in the 13 units. In 9 of these units a rate increase was observed after pressings (Figs. 6B and 8A~); peristimulus time histogram peak latencies were between 100 and 400 msec (× = 271
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Fig. 6. Firing rate modulation during voluntary" handle pressings. A and B: cross-correlation histograms between firings and handle pressings of two units recorded with the same microelectrode. C: average of handle pressings; all pressings (64) occurred at the 0 time reference. The average shows that pressings (downward) and releases (upward) were rhythmic with a cycle duration of about 0.8 sec. Unit B shows a firing rate increase immediately after pressings which peaks at about 200 msec. Unit A although close to the other unit was apparently unrelated with movements. Calibrations, 3 counts and in sec.
msec, S.E.---- 34.5 msec). In 2 units equivalent rate increases were recorded in relation with both pressings and releases of the handle; they were periodic at double the frequency of pressings (Fig. 7 A 2 a n d 3 ) . In 2 other units a rate decrease was related to pressings. Three units which did not respond to pressings were tested for releases (i.e., the releases were taken as the zero reference in the peristimulus time histograms) and were also found to be negative. Movement-related units were similar in their spontaneous discharge characteristics to the other group of cells. In 4 units activated during voluntary hand movements, the effects of passive contralateral finger flexions and extensions were tested. One unit which increased its firing rate during both voluntary handle pressings and releases showed a firing rate decrease during passive flexions and an
394
J.G. M A R T i N - R O D R I G U E Z ET AL.
increase with extensions of the thumb (Fig. 7A2, 3 and B2.3). Thus, during voluntary movements the discharge rate modulation was at double the frequency of movement while during similar passive movements discharge modulation was at the frequency of the movement (Fig. 7A and B, respectively). A response to flexion was also observed in the other fingers explored (index and
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fifth; Fig. 7C2. 3 and D2,3, respectively). In 3 cases the effects of voluntary opening and closing of the mouth were studied. Two units were found which responded phasically to opening of the mouth. These two cells also responded to handle pressings (Fig. 8mland2, Bland2). They were characterized as phasic because their firing rates decayed rapidly (within 500-800 msec) to spontaneous rates when the patient was asked to hold his mouth open at a fixed position.
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Fig. 7. Effects of voluntary handle pressing and passive mobilization Of the fingers upon the firing rate of the same unit. A: voluntary handle pressing. B - D : passive movement of the thumb, index and fifth finger, respectively. 1, autocorrelation histograms during movements; 2, cross-correlation histograms between unit activity and movements; 3, averages of movements (pressings-down), which were rhythmic in all circumstances. Two increases in firing rate per voluntary movement cycle were observed (A), but only one during passive movements of the thumb, index and fifth fingers (B, C and D, respectively). Calibrations, 100 counts for A - D 1, 20 counts for A 2 and 10 counts for B-D2; time in sec.
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Fig. 8. Effects of voluntary hand and jaw movements, and photic stimulation, upon two units recorded simultaneously. A and B: cross-correlation histograms of the two units refer to handle pressings (1), opening of the jaw (2), both occurring at the zero reference, and peristimulus time histograms during flashes with relative intensity (in the Grass-PS22) of 4 (3) and 16 (4). Stimulation was at about l/sec, thus two responses per histogram were evoked; one of the two stimuli which occurred per analysis interval was at the zero reference. The impulse rate of unit A increases after handle pressings and openings of the jaw (peaking at about 150 msec), and with low and high intensity flashes (peaking at about 250 msec). Unit B shows an increased discharge after pressings. The same unit decreased and increased its impulse rate before and after jaw openings, respectively. A response of this unit is observed to high intensity flashes (B4) but is not clear at low intensity (B3). Calibrations, 3 counts and in sec.
395
SENSORY-MOTOR INFLUENCES UPON PULVINAR UNITS
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Fig. 9. Effects of handle pressings (A), clicks (B), and flashes (C) upon the firing rate of the same unit. 1, cross-correlation (A) and peristimulus time histograms (B and C); 2, averages of Pu EEG. The firing rate increased after handle pressings (A l), auditory (B I) and visual stimulation (C0, which occurred at the zero reference; as in previous figure, stimulation was at about 1/sec. Evoked EEG responses were elicited by sensory stimulation but not by movements. Calibrations, 3 counts for 1 and 150/iV for 2: time in sec.
In 4 patients with tremor, 11 units were tested for a relationship with the rhythmic involuntary movement, and in none of them were cross-correlation functions between tremor and discharges positive.
Tactile stimulation of the contralateral limbs and face was ineffective in the 5 units in which it was investigated.
Discussion Sensory
responses
Of the 12 units studied during photic stimulation 6 responded with excitation at delays between 70 and 140 msec which peaked at about 2 0 0 - 5 0 0 msec (Figs. 8A3,4, B4 and 9C1), while the other units were unresponsive. In all, except one, electrode positions studied, an evoked potential was recorded in the Pu E E G which began with a negative deflection at about 140-200 msec (Fig. 9C2). Five of the 6 responsive cells were also correlated with voluntary h a n d movements (Fig. 9A~ and C1) and two also with voluntary movements of the jaw. In 3 units the effects of auditory stimulation were investigated. Only one of these cells increased its firing rate in response to clicks; however, an evoked potential was recorded at 2 of the 3 sites (Fig. 9B). The responsive unit was also activated by photic stimulation and was related to voluntary h a n d movements (Fig. 9).
Two findings with important functional implications which to our knowledge had not been reported previously will be discussed first. (1) The m o d u l a t i o n of discharge rates in relation with voluntary movements, found in a great proportion of PU units and predominantly excitatory. In one case it was evident that the m o t o r response was influenced by peripheral feedback because it also appeared with passive movements. The differences between the firing rate modulation in that unit during voluntary and passive finger movements (see description of Fig. 7 in Results) suggests that the cell received converging influences from m o t o r o u t p u t generators and peripheral feedback. It should be emphasized that independent of the origin of the m o t o r 'response' there was a great convergence of movement-related influences because in a given unit they were elicited not only from 3 fingers such as the thumb, index and fifth,
396 but also from such distant regions as the hand and the jaw. The above findings suggest that Pu is not involved in the generation of 'specific' movements but that it may underly more general phenomena related to a general preparation or correction of movement. (2) The existence of convergence of sensory and motor influences upon individual Pu units. Sensory convergence has been demonstrated in Pu units (Avanzini et al. 1980) but the modulation of discharge rates of the same cell by sensory input and movements, which is suggestive of a sensory-motor integrative function of the nucleus, had not been reported previously except for the preliminary report of Magarifios Ascone et al. (1981). In agreement with other reports, most of the units studied responded with excitation to visual stimuli (Veraart et al. 1972; Gattas et al. 1978). Responses were in many cases small and evoked at long latencies, which can only be explained by multisynaptic pathways. A novel finding was that most of the units that responded to light also responded to movements. Thus, this convergence is frequent in Pu. However, there are not enough data to confirm that the same is true for auditory stimulation, although the identification of a unit which responded to visual and auditory stimulation and to movement points in that direction. The convergence may be the basic mechanism of a sensory-motor integrative function which is still of unknown nature. The lack of correlation between unit activity and tremor is in agreement with other studies in which tremorogenic and tremorophasic units in Pu were not detected (Albe-Fessard et al. 1962, 1966, 1967). N o correlation was found between discharge patterns and the neurological disorders of the patients, although the important proportion of bursting units suggested a possible pathological cause for this discharge pattern; however, they appeared in all 7 cases in similar proportions. Furthermore, in normal monkeys under similar experimental conditions a comparable proportion of bursting Pu units has been found (Magarifios Ascone, Bufio, Martin-Rodriguez and Garcia Austt, in preparation), suggesting that in healthy man they may be present in identical numbers. The spontaneous discharge patterns of Pu units,
J.G. MARTIN-RODRIGUEZ ET AL. as established by the statistical procedures, showed similarities with those described for other structures such as the hippocampus (Bufio et al. 1978; Garcia-Sfinchez et al. 1978). Discharges with or without bursts, and rhythmic or non-rhythmic, did not reveal any significant dominance. In general, these data are in agreement with those reported by Albe-Fessard et al. (1962) based on the analysis of the raw records obtained from the same nucleus in humans. Non-rhythmic units cross-correlated with the rhythmic Pu EEG and the non-rhythmic cell with a periodic cross-correlation with a rhythmic bursting unit, which have similar meanings, were also found in the rat hippocampus in the presence of theta rhythm (Garcia-S/mchez et al. 1978; Garcia Austt et al. 1977). This type of periodic cross-correlation indicates that the cell, although non-rhythmic, tends to fire at a preferred phase of the EEG rhythm and of rhythmic unit bursts (Fuentes et al. 1981). This type of functional relationship may be determined by the converging influences of rhythmic and random presynaptic inputs (Fuentes et al. 1981). This kind of discharge may be important functionally because in a 'hidden' way, it carries information about the rhythmic activity. The different firing patterns which may be present in the same unit under similar conditions reveal transitory, non-stable functional states. No significant correlation was found between the rhythmic or non-rhythmic unit types and their capacity to respond to either voluntary movements or sensory stimulation, indicating that synaptic influences determining 'spontaneous' discharges are probably independent of those responsible for the evoked activity. Although the present data provide information about firing patterns and input-output relations of Pu units they are insufficient to be used as a guide for thalamic target location both because of the small number of recorded cells and because similar firing patterns and responses may be found in structures close by (see above).
Summary Unit activity was recorded from the pulvinar nucleus (Pu) in human patients undergoing stereo-
SENSORY-MOTOR INFLUENCES UPON PULVINAR UNITS
taxic surgery. Thirty-six units (12 isolated and 12 pairs recorded with the same microelectrode) with a signal-to-noise ratio > 5, a stable amplitude, and a sustained discharge rate for more than 1 rain, were selected for processing. The following functions were calculated with a digital computer to characterize discharge patterns: interval, autocorrelation and peristimulus time histograms for spikes, cross-correlation histograms between spikes of a pair, and autocorrelation functions and averages of the EEG. In spontaneous conditions, about half of the units fired in rhythmic bursts at the same or half the frequency of the Pu EEG. Most non-rhythmic units showed a 'Poisson-like' interval histogram indicating a random firing pattern. Some nonrhythmic units revealed a periodic cross-correlation with the rhythmic Pu EEG, indicating that spikes tend to fire at a preferred phase of the rhythm. About half of the units showed phasic firing rate changes during voluntary movements. In most cells a discharge rate increase was observed. One unit also responded to passive movements of the fingers. Of the neurons tested, 2 out of 3 showed firing rate modulation during voluntary movements of the jaw as well as of the contralateral hand. The above units also increased the impulse rate after visual stimulation. Convergence of the effects of voluntary movements, and visual and auditory stimulation, was demonstrated in one unit. These results indicate the participation of the Pu in sensory-motor integrative functions.
Resume
397
d6charge, on a calcul6 avec un ordinateur digital les fonctions suivantes: histogrammes d'intervalles, d'auto-corr~lation, de d61ais p6ristimutus, de corr6lation crois6e entre les spikes d'une paire d'unit6s, fonction d'auto-corr61ation et moyennage de I'EEG. En activit6 spontan6e environ la moiti6 des unit6s d6chargeait en bursts rythmiques /l la fr6quence ou /l la moiti6 de la fr6quence du trac6 global du Pu. La plupart des unit6s non-rythmiques pr6sentait un histogramme d'intervalles de type Poisson, indiquant une configuration de d6charge al6atoire. Chez quelques unit~s nonrythmiques s'est r6v616e une corr61ation crois6e p6riodique avec le trac6 global rythmique du Pu, indiquant que les spikes tendent h survenir lors d'une phase pr6f6rentielle du rythme. Environ la moiti6 des unit6s montrait des modifications phasiques de leur taux de d6charge pendant les mouvements volontaires, dans le sens d'une augmentation pour la plupart des cellules. Une unit6 r6pondait aussi aux mouvements passifs des doigts. Parmi les neurones testbs, 2 sur 3 pr6sentaient une modulation de leur d6charge pendant les mouvements volontaires de la m~choire aussi bien que de la main contralat6rale. Ces unit6s augmentaient 6galement leur taux de d6charge apr6s stimulation visuelle. On a mis en 6vidence pour 1 unit6 la convergence des effets des mouvements volontaires et des stimulations visuelle et auditive. Ces r6sultats indiquent la participation du Pu /t des fonctions d'int6gration sensori-motrice. Many thanks are due to Mrs. C. Delgado for the correction of the manuscript.
Unitbs du pulvinar chez l'homme. Activitb spontanke et influences sensori-motrices
References
On a enregistr6 l'activit+ unitaire du pulvinar (Pu) chez des patients au cours des interventions st6r6otaxiques. On a retenu, pour les analyser, 36 unit6s (12 isol6es et 12 paires enregistrbes avec la mame micro-61ectrode) qui pr6sentaient un quotient signal/bruit sup6rieur h 5, une amplitude stable et un taux de dbcharge soutenue pendant plus d'l min. Pour caract6riser les patterns de
Albe-Fessard, D., Arfel, G., Guiot, G., Hardy, J., Vourc'h, G., Aleonard, P. et Derome, P. D6rivations d'activit6s spontan6es et evoqu6es dans les structures c6r6brales profondes de l'homme. Rev. neurol., 1962, 106: 89-105. Albe-Fessard, D., Guiot, G., Lamarre, Y. and Arfel, G. Activation of thalamocortical projections related to tremorogenic processes. In: D.P. Purpura and M.D. Yahr (Eds.), The Thalamus. Columbia University Press, New York, 1966: 237-253.
398 Albe-Fessard, D., Arfel, G., Guiot, G., Derome, P. and Guilbaud, G. Thalamic unit activity in man. Electroenceph. clin. Neurophysiol., 1967, Suppl. 25: 132-142. Andrew, J. and Watkins, E.S. A Stereotaxic Atlas of the Human Thalamus and Adjacent Structures. Williams and Wilkins, Baltimore, Md., 1969. Avanzini, G., Broggi, G., Francheschetti, S. and Spreafico, R. Multisensory convergence and interaction on the pulvinarlateralis complex of the cat's thalamus. Neurosci. Lett., 1980, 19: 27-32. Bates, J.A.V. Electrical recording from the thalamus in human subjects. In: A. Iggo (Ed.), Handbook of Sensory Physiology, Vol. II, Somatosensory System. Springer, Berlin, 1971: 278-561. Bufio, Jr., W., Martin-Rodriguez, J.G., Garcia Austt, E. and Obrador, S. Electrophysiological set-up for data acquisition and processing during stereotaxic surgery: demonstration on pulvinar units. Acta neurochir. (Wien), 1977, 24 (Suppl.): 109-119. Bufio, Jr., W., Garcia-Shnchez, J.L. and Garcia Austt, E. Reset of hippocampal rhythmical activities by afferent stimulation. Brain Res. Bull., 1978, 3: 21-28. Cooper, I.S. Pulvinectomy: a preliminary report. J. Amer. Geriat. Soc., 1971, 19: 553-554. Cooper, I.S., Riklan, M. and Rakic, P. (Eds,) The Pulvinar-LP Complex. Thomas, Springfield, II1., 1974. Fuentes, J., Bufio, Jr., W. and Garcia Austt, E. Simulation of post-synaptic activities in hippocampal cells during theta rhythm. Brain Res. Bull., 1981, 7: 157-162. Garcia Austt, E., Bufio, Jr., W. and Garcia-S~achez, J.L. Analysis of unit pairs in the hippocampus. Acta neurol, lat.-amer., 1977, 23: 141-153. Garcia-Shnchez, J.L., Bufio, Jr., W., Fuentes, J. and Garcia Austt, E. Non-rhythmical hippocampal units, theta rhythm and afferent stimulation. Brain Res. Bull., 1978, 3: 213-219. Gattas, R., Oswaldo-Cruz, E. and Sousa, A.P.B. Visuotopic organization of the cebus pulvinar: a double representation of the contralateral hemifield. Brain Res., 1978, 152: 1-16. Gaze, R.M., Gillingham, F.J., Kalyanaraman, S., Porter, R.W., Donaldson, A.A. and Donaldson, I.M.L. Microelectrode recordings from the human thalamus. Brain, 1964, 87: 691-706.
J.G. MARTIN-RODRIGUEZ ET AL. Guiot, G., Hardy, J. et Albe-Fessard, D. Drlimitation precise des structures sous°corticales et identification des noyaux thalamiques chez l'homme par l'61ectrophysiologie strreotaxique. Neurochirurgia (Stuttg.), 1962, 5: 1-19. Hubel, D.H. Tungsten microelectrodes for recordings from single units. Science, 1957, 125: 549-550. Jasper, H. Recording from microelectrodes in stereotactic surgery for Parkinson's disease. J. Neurosurg., 1966, 24: 219-221. Jasper, H. and Bertrand, G. Exploration of the human thalamus with microelectrodes. Physiologist, 1964, 7: 167-176. Kalyanaraman, S. Anatomical and Physiological Studies of the Internal Capsule and Adjacent Structures in the Human during Stereotaxic Surgery. Ph.D. Thesis, Edinburgh. 1964. Kreindler, A., Crighel, E. and Marinchescu, C. Integrative activity of the thalarnic pulvinar-lateralis posterior complex and interrelations with the neocortex. Exp. Neurol., 1968, 22: 423-435. Kudo, T., Yoshii, N., Shimizu, S., Aikawa, S. and Nakehama, H. Effects of stereotoaxic thalamotomy on intractable pain and numbness. Keio J. Med., 1966, 15: 191-194. Leksell, L. A stereotaxic apparatus for intracerebral surgery. Acta chir. scand., 1949, 99: 229-233. Magarifaos Ascone, C., Martin-Rodriguez, J.G., Bufio, Jr., W. and Garcia Austt, E. Sensory-motor convergence upon pulvinar neurons. Neurosci. Lett., 1981, 7 (Suppl.): $217. Martin-Rodriguez, J.G. and Obrador, S. Evaluation of stereotaxic pulvinar lesions. Confin. neurol. (Basel), 1975, 37: 56-62. Richardson, D.E. Thalamotomy for intractable pain. Confin. neurol. (Basel), 1967, 29: 139. Van Buren, J.M. and Borke, R.C. Variations and Connections of the Human Thalamus. Springer, Berlin, 1972. Veraart, C., Meulders, M. and Godfraind, J.M. Visual properties of neurons in pulvinar, nucleus lateralis posterior and nucleus suprageniculatus thalami in the cat. II. Quantitative investigation. Brain Res., 1972, 44: 527-545. Wilson, J.S. and Goldberg, S.J. Inputs to the pulvinar and lateral posterior nucleus into the abducens nucleus of the cat. Exp. Neurol., 1980, 68: 72-86.
Electroencephalography and clinical Neurophysiology, 1982, 54:388-398 Elsevier Scientific Publishers I r e ~ Ltd.
HUMAN PULVINAR UNITS, SPONTANEOUS ACTIVITY AND S E N S O R Y - M O T O R INFLUENCES l J.G. MARTIN-RODRIGUEZ 2, W. BUNO, Jr. 3 and E. GARCIA-AUSTT 3
Centro "Rambn y Cajal" Madrid 34 (Spain) (Accepted for publication: May 13, 1982)
Visual, auditory and somesthetic potentials have been evoked in the human pulvinar nucleus (Pu) (Cooper et al. 1974). In the cat, sensory evoked potentials of different modalities have been recorded at specific Pu sites (Kreindler et al. 1968). Substantial evidence exists concerning Pu unitary responses evoked by visual stimulation (e.g., Veraart et al. 1972; Gattas et al. 1978) as well as by auditory and somatosensory inputs (Avanzini et al. 1980). The projection of Pu upon oculomotor neurons has been demonstrated electrophysiologically (Wilson and Goldberg 1980). In a preliminary report Magarifios Ascone et al. (1981) demonstrated that, in the awake monkey, some Pu units fire in relation with movements and also in response to auditory or photic stimulation. Furthermore, the same Pu sites project widely to homo- and heterolateral neocortical primary or associative areas (Kreindler et al. 1968). Although controversial, stereotaxic lesions in the human Pu have been proposed to provide relief of chronic pain (Kudo et al. 1966; Richardson 1967) and to decrease spasticity and abnormal involuntary movements (Cooper 1971; Cooper et al. 1974; Martin-Rodriguez and Obrador 1975). The reported clinical and experimental data suggest an involvement of Pu in sensory-motor integrative mechanisms, in which convergence from other CNS regions may be important. However, the participation of Pu in voluntary movements, as well as the I This work was supported in part by the Fundacibn Rodriguez Pascual, Spain, and with Grant 831 from the Fondo de Investigaciones Sanitarias (RAPEL). 2 Departamento de Neurocirugia. 3 Departamento de Investigacibn.
demonstration of converging sensory-motor influences upon the same Pu units, which would lend strong support to the above proposed integrative role of the nucleus, have not been demonstrated except for the report of Magarifios Ascone et al. (1981). Most of the above-mentioned studies have been performed on anesthetized animals, an unfavorable situation to investigate small effects conveyed through multisynaptic connections, as is the case with Pu. The purpose of this study was to analyze Pu unit activity in the unanesthetized man during a spontaneous condition, voluntary and involuntary movements, and auditory, visual and somesthetic stimulation. The clarification of the above points may provide guides for thalamic locations and thus correction for anatomical variations during surgery. Moreover, they may provide information on the functional significance of this nucleus in man where it has attained its highest philogenetic development. Microelectrode recording has been systematically performed during stereotaxic surgery in awake man to correct for anatomical variability within the thalamic nuclei (Guiot et al. 1962; Gaze et al. 1964; Jasper and Bertrand 1964; Kalyanaraman 1964; Jasper 1966; Bates 1971). The Pu is generally in the path of the microelectrode track to the specific 'target' in somatosensory nuclei; thus its unitary activity could be explored during therapeutic surgery. The techniques used for microelectrode recording in man and some characteristics of the discharge patterns of Pu units have been described elsewhere (Bufio et al. 1977).
0013-4649/82/0000-0000/$02.75 © 1982 Elsevier Scientific Publishers Ireland, Ltd.
SENSORY-MOTOR INFLUENCES UPON P U L V I N A R UNITS
389
Methods
Seventy-four units were recorded in 7 male patients undergoing l0 stereotaxic operations for various neurological problems requiring placement of a lesion in the thalamus (nuclei ventralis oralis, posterior-ventralis intermedium, centralis medialis, parafascicularis, or Pu). Three patients were operated on for otherwise intractable bilateral parkinsonian tremor, allowing 3-5 months to elapse after each thalamotomy. For practical purposes they were considered as 6 separate operations. Two patients were operated on to treat intention tremor (unilateral thalamotomy), 1 patient had spasmodic torticollis (bilateral pulvinectomy in one surgical session) and 1 patient suffered from chronic intractable pain (bilateral medialis-parafascicularis complex lesions in one surgical session). Operations were performed under local anesthesia, using current stereotaxic techniques and a Leksell (1949) apparatus. All surgical and experimental procedures were carefully explained beforehand to the patients and informed consent was obtained. They were familiarized with the equipment including the pressing handle, earphones, flash and pin-point skin stimulators, and were instructed to squeeze the handle upon request. Tungsten microelectrodes (Hubel 1957) inside an uninsulated protective cannula, were inserted through a posterior parietal burrhole by means of a specially designed carrier fitted to the Leksell frame. The microelectrode was introduced with a micrometer drive attached to the carrier. Up to 30 m m were explored in each track. The cannula was used as a grounded shield and a stainless steel clip attached to the scalp incision was used as reference electrode. Potentials were fed to a high input impedance preamplifier, and then through two bandpass filter amplifiers, one set as a high-pass and the other as a low-pass with 1-50 Hz and 0.1-10 kHz cut-offs, respectively, to separate electrographic (EEG) - - which will also be called gross - - and unitary activities (i.e., spikes; Fig. 1). Spikes were also acoustically monitored with a loudspeaker. A specially designed pressing handle, which produced an electrical signal when squeezed, was attached to the contra- or ipsilateral hand. It pro-
B
I
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Fig. 1. Gross and unit activity recorded with the microelectrode (A). High-pass (B) and low-pass (C) filtering separates unit spikes and EEG, respectively. Calibrations, 500 ~tV and 20 msec.
vided a time reference for voluntary movements. In these conditions the hand and pressing handle were hidden from the patient's view. The same signal was also used to time voluntary movements of the jaw and passive finger movements. A minute microphone (Fox-2212) was taped to the contralateral thumb to record tremor after convenient amplification and filtering. Photic, auditory and tactile stimulation were performed with a photostimulator, an ear-phone fed with rectangular pulses and a pin-point microswitch, respectively. This last instrument was included in an electrical circuit which generated a signal when the skin was mechanically stimulated. Signals were monitored in a four-channel storage oscilloscope and recorded on magnetic tape together with a voice protocol. 'Spontaneous' activity was recorded for 1-3 min. The influence of voluntary movements of the contra- and ipsilateral hands, involuntary movements of contralateral fingers, photic and auditory stimulation, and tactile stimulation of the contralateral arm, were then studied during similar time periods. Data were processed off-line, playing back the tapes in a PDP-12 computer, by means of specially developed software. When two spikes of different amplitudes were clearly observed in the raw data, a window discriminator circuit was used to separate these events, which could be processed simultaneously by the computer. The following statistical functions were estimated: interspike in-
390 terval histogram, autocorrelation histograms of spikes, cross-correlation histograms between spikes of a pair, peristimulus time histograms of unit firing probabilities, autocorrelation functions and averages of gross activity, preceding and following voluntary handle squeezing, voluntary movements of the jaw, passive movements of fingers, clicks, flashes, or skin stimulation. Finally, E E G averages were calculated, taking the spikes as reference; spike-triggered E E G averages will be called cross-correlation functions. The above statistical techniques were necessary for an accurate description of the spontaneous unitary discharge patterns, their temporal relationships with the EEG, voluntary movements and sensory inputs. They also permitted the demonstration of small effects which were not clear in the raw electrical records because of the unit's varying ongoing activity. All functions were calculated with 4 msec bins or sampling intervals. Mean firing rates for the 1 rain observation periods were also calculated. Units were selected for processing according to the following criteria: (1) signal-to-noise ratios greater than 5; (2) pairs with at least a 2 to 1 amplitude ratio; (3) stable amplitude and spike wave form; (4) maintained discharge without marked sustained variations of the firing rate; and (5) data with the above characteristics, lasting for at least 1 min. Twelve pairs and 12 isolated units (n = 36) fulfilled these criteria. Stereotaxic targets were calculated for the rostro-ventral aspect of the Pu because this region is near the somatosensory nuclei, which was the surgical 'target' in most cases. Fig. 2 shows the projections of the 24 positions recorded on two superimposed sagittal planes of the Van Buren and Borke atlas (1972), at 9 and 12 m m from the midline. The position of each point was corrected for individual variations according to the data of Van Buren and Borke (1972) and Andrew and Watkins (1969). In all cases except one, in which the Pu itself was the stereotaxic 'target,' after recording from the Pu the electrode was advanced (following the same track) toward the sensory nuclei. Unit responses to tactile contralateral stimulation of the face or hand were then explored. These nuclei generally lay more ventrally and rostrally than the Pu region studied.
J.G. MARTIN-RODRIGUEZ ET AL.
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Results
Spontaneous dischargepatterns During recording, the operating lights were turned off and the other lights were dimmed. The surgeon and staff were quiet and out of the patient's visual field; ambient noise-level was reduced to a minimum by turning off all unnecessary equipment. In this 'spontaneous' condition the patient was instructed not to move. In the above conditions, mean firing rates varied between 1.8 and 29.0 i m p / s e c (IPS) (n---34; ~ = 9.8 IPS; median -- 9.1 IPS; S.E.= 6.5 IPS). Visual analysis of the raw data showed that 21 of 34 units (62%) tended to fire in bursts. The interspike interval distributions were either bimodal (n = 17 or 50%; Fig. 3Al) or monomodal ( n = 17 or 50%; Fig. 3A 2-4). Most monomodal interval histograms showed 'Poisson-like' distributions (Fig. 3A2), but lacked very short interspike intervals, probably because of refractoriness. 'Poisson-like' distributions indicate a random firing pattern. Bimodal distributions always showed a higher, narrower, short interval mode and a wider, lower mode corresponding to longer intervals (Fig. 3A1). Most autocorrelation histograms ( n = 2 6 or
S E N S O R Y - M O T O R I N F L U E N C E S U P O N P U L V I N A R UNITS
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Fig. 3. Interval histograms (A) and autocorrelation histograms (B) of different units. 1, rhythmic unit with bimodal interval and periodic autocorrelation histograms with a wide central peak, indicating periodic bursts. The shorter interval histogram mode corresponds to intraburst and the longer to interburst intervals. 2, non-rhythmic unit with 'Poisson-like' interval histograms and flat autocorrelation histograms with a wide central peak indicating bursts. 3 and 4, non-rhythmic units with unimodal interval with a small ' h u m p ' at long intervals during the exponential decay in A 3 and with a gradually rising mode in A 4, both with flat autocorrelation histograms (B 3 and B4). Calibrations, 50 counts for A, 100 for B l, B2 and B4, and 800 for B3; time in sec.
76%) showed a wide central peak (i.e., of more than one bin width) indicating that the firing rate was high before and after a spike and then decayed more or less rapidly. Central peaks of more than one bin width indicate a tendency to fire in bursts (Figs. 3Bland2, 4, 5A1.2 and B]). In some cases (n = 14 or 41%) autocorrelation histograms showed a wide central peak and other peaks at fixed intervals (i.e., they were periodic) at longer delays and advances from the zero reference, indicating a tendency to fire in rhythmic bursts (Figs.
391
3B~, 4A 2, 5A1 and2 )' In most cases peak amplitudes decayed gradually with the separation from the central peak. The 14 rhythmic units fired at mean bursting rates between 3.5 and 6.0 bursts/sec (BPS). Although most rhythmic units had bimodal interval histograms, some showed 'Poisson-like' distributions, but they all had periodic autocorrelation histograms with a wide central peak, indicating rhythmic spike bursts. Twelve of the 20 non-rhythmic units also presented a wide central peak in the autocorrelation histograms, indicating bursts (Figs. 3B2, 4B2, 5A, and B t). The gross activity or Pu lz•O recorded with the microelectrode was rhythmic in 14 of the 21 sites studied (67%). The average characteristics of the periodic EEG during the 1 min observation period were determined with the autocorrelation function (Fig. 4A l, B I and C1). In 13 records the periodic EEG waves were within the theta band (Fig. 4: 5.0 7.0 c/sec; X = 6.4 c/sec, S . E . - 0 . 2 6 c/sec), while in the other record the frequency was in the alpha band (10.5 c/sec). Rhythmic and nonrhythmic units were recorded either with or without a simultaneous rhythmic EEG. Seven rhythmic units were recorded during rhythmic theta activity. Six of these fired in rhythmic bursts with rates at half the frequency of the EEG rhythm (Fig. 4A: 3.5 BPS and 7.0 c/sec, respectively), while one fired in bursts at the EEG frequency (5.0 c/sec). The finding of units with rhythmic bursts at half the frequency of the periodic EEG waves is unusual because in other structures rhythmic cells fire in synchrony with periodic gross activity waves (e.g., Bufio et al. 1978). All (e.g., Fig. 4A) but one of the rhythmic units showed a periodic cross-correlation function with the EEG rhythm. An important finding was that 5 non-rhythmic units revealed a positive, rhythmic, cross-correlation function with the theta rhythm (Fig. 4C). The periodic cross-correlation function was at the same frequency as the EEG rhythm (Fig. 4C3), indicating a temporal relationship between spikes and gross activity. The other 7 non-rhythmic units recorded in the presence of a rhythmic EEG did not show a temporal relationship with the rhythm, and cross-correlation functions were flat (Fig. 4B 3). Cross-correlation functions between rhythmic or non-rhythmic units and non-rhythmic EEG were
392
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always negative (i.e., they were flat). Twelve pairs of units were recorded (see Methods). In 11 pairs both units had similar discharge patterns, 6 pairs were rhythmic (Fig. 5A 1~nd2) and 5 pairs were non-rhythmic units (Fig. 5Bla,d2). In only one case was the pair composed of a rhythmic and a non-rhythmic unit. Cross-correlation histograms between both units of a pair were always positive (Fig. 5A3, An, B3 and B4). In the 6 rhythmic pairs, cross-correlation histograms were rhythmic with peaks at the same frequency as the unit's bursting rate (Fig. 5A3). Cross-correlation histograms indicated that both units tended to fire in synchrony (i.e., the functions had a clear central peak) or with a phase difference (i.e., the peak was close to but displaced either to the left or right of the zero reference; Fig. 5A3and4). An important observation was that the cross-correlation histograms of the rhythmic non-rhythmic pair were also periodic, with peaks at the bursting rate of the rhythmic unit (see Bufio et al. 1977). Cross-corre-
lation histograms of pairs composed of nonrhythmic units were aperiodic and either showed a decrease in rate after the zero reference (3 pairs) or a symmetric rate increase on either side of the reference (2 pairs; Fig. 5B3and4). In 3 units out of 5 in which the spontaneous activity of the same unit was studied in different observation periods, but under the same spontaneous condition, the discharge pattern did not change between observations. The other two units changed from rhythmic to non-rhythmic and one lost its positive cross-correlation function with the Pu E E G rhythm. In 4 units the effect of voluntary closing and opening the eyes was studied and no sustained modifications of the unit's firing patterns were observed. Activity
modifications
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Thirteen out of 28 units (46%) showed firing rate modifications during voluntary handle pressings performed with the contralateral hand.
393
S E N S O R Y - M O T O R I N F L U E N C E S U P O N P U L V I N A R UNITS
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Pressings were always rhythmic at frequencies between 1.0 and 1.2/sec, although patients were not instructed to press periodically. Peristimulus time histograms, calculated taking the instants of handle pressings as a zero reference, were periodic at the same or double the frequency of pressings in the 13 units. In 9 of these units a rate increase was observed after pressings (Figs. 6B and 8A~); peristimulus time histogram peak latencies were between 100 and 400 msec (× = 271
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msec, S.E.---- 34.5 msec). In 2 units equivalent rate increases were recorded in relation with both pressings and releases of the handle; they were periodic at double the frequency of pressings (Fig. 7 A 2 a n d 3 ) . In 2 other units a rate decrease was related to pressings. Three units which did not respond to pressings were tested for releases (i.e., the releases were taken as the zero reference in the peristimulus time histograms) and were also found to be negative. Movement-related units were similar in their spontaneous discharge characteristics to the other group of cells. In 4 units activated during voluntary hand movements, the effects of passive contralateral finger flexions and extensions were tested. One unit which increased its firing rate during both voluntary handle pressings and releases showed a firing rate decrease during passive flexions and an
394
J.G. M A R T i N - R O D R I G U E Z ET AL.
increase with extensions of the thumb (Fig. 7A2, 3 and B2.3). Thus, during voluntary movements the discharge rate modulation was at double the frequency of movement while during similar passive movements discharge modulation was at the frequency of the movement (Fig. 7A and B, respectively). A response to flexion was also observed in the other fingers explored (index and
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fifth; Fig. 7C2. 3 and D2,3, respectively). In 3 cases the effects of voluntary opening and closing of the mouth were studied. Two units were found which responded phasically to opening of the mouth. These two cells also responded to handle pressings (Fig. 8mland2, Bland2). They were characterized as phasic because their firing rates decayed rapidly (within 500-800 msec) to spontaneous rates when the patient was asked to hold his mouth open at a fixed position.
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Fig. 8. Effects of voluntary hand and jaw movements, and photic stimulation, upon two units recorded simultaneously. A and B: cross-correlation histograms of the two units refer to handle pressings (1), opening of the jaw (2), both occurring at the zero reference, and peristimulus time histograms during flashes with relative intensity (in the Grass-PS22) of 4 (3) and 16 (4). Stimulation was at about l/sec, thus two responses per histogram were evoked; one of the two stimuli which occurred per analysis interval was at the zero reference. The impulse rate of unit A increases after handle pressings and openings of the jaw (peaking at about 150 msec), and with low and high intensity flashes (peaking at about 250 msec). Unit B shows an increased discharge after pressings. The same unit decreased and increased its impulse rate before and after jaw openings, respectively. A response of this unit is observed to high intensity flashes (B4) but is not clear at low intensity (B3). Calibrations, 3 counts and in sec.
395
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Fig. 9. Effects of handle pressings (A), clicks (B), and flashes (C) upon the firing rate of the same unit. 1, cross-correlation (A) and peristimulus time histograms (B and C); 2, averages of Pu EEG. The firing rate increased after handle pressings (A l), auditory (B I) and visual stimulation (C0, which occurred at the zero reference; as in previous figure, stimulation was at about 1/sec. Evoked EEG responses were elicited by sensory stimulation but not by movements. Calibrations, 3 counts for 1 and 150/iV for 2: time in sec.
In 4 patients with tremor, 11 units were tested for a relationship with the rhythmic involuntary movement, and in none of them were cross-correlation functions between tremor and discharges positive.
Tactile stimulation of the contralateral limbs and face was ineffective in the 5 units in which it was investigated.
Discussion Sensory
responses
Of the 12 units studied during photic stimulation 6 responded with excitation at delays between 70 and 140 msec which peaked at about 2 0 0 - 5 0 0 msec (Figs. 8A3,4, B4 and 9C1), while the other units were unresponsive. In all, except one, electrode positions studied, an evoked potential was recorded in the Pu E E G which began with a negative deflection at about 140-200 msec (Fig. 9C2). Five of the 6 responsive cells were also correlated with voluntary h a n d movements (Fig. 9A~ and C1) and two also with voluntary movements of the jaw. In 3 units the effects of auditory stimulation were investigated. Only one of these cells increased its firing rate in response to clicks; however, an evoked potential was recorded at 2 of the 3 sites (Fig. 9B). The responsive unit was also activated by photic stimulation and was related to voluntary h a n d movements (Fig. 9).
Two findings with important functional implications which to our knowledge had not been reported previously will be discussed first. (1) The m o d u l a t i o n of discharge rates in relation with voluntary movements, found in a great proportion of PU units and predominantly excitatory. In one case it was evident that the m o t o r response was influenced by peripheral feedback because it also appeared with passive movements. The differences between the firing rate modulation in that unit during voluntary and passive finger movements (see description of Fig. 7 in Results) suggests that the cell received converging influences from m o t o r o u t p u t generators and peripheral feedback. It should be emphasized that independent of the origin of the m o t o r 'response' there was a great convergence of movement-related influences because in a given unit they were elicited not only from 3 fingers such as the thumb, index and fifth,
396 but also from such distant regions as the hand and the jaw. The above findings suggest that Pu is not involved in the generation of 'specific' movements but that it may underly more general phenomena related to a general preparation or correction of movement. (2) The existence of convergence of sensory and motor influences upon individual Pu units. Sensory convergence has been demonstrated in Pu units (Avanzini et al. 1980) but the modulation of discharge rates of the same cell by sensory input and movements, which is suggestive of a sensory-motor integrative function of the nucleus, had not been reported previously except for the preliminary report of Magarifios Ascone et al. (1981). In agreement with other reports, most of the units studied responded with excitation to visual stimuli (Veraart et al. 1972; Gattas et al. 1978). Responses were in many cases small and evoked at long latencies, which can only be explained by multisynaptic pathways. A novel finding was that most of the units that responded to light also responded to movements. Thus, this convergence is frequent in Pu. However, there are not enough data to confirm that the same is true for auditory stimulation, although the identification of a unit which responded to visual and auditory stimulation and to movement points in that direction. The convergence may be the basic mechanism of a sensory-motor integrative function which is still of unknown nature. The lack of correlation between unit activity and tremor is in agreement with other studies in which tremorogenic and tremorophasic units in Pu were not detected (Albe-Fessard et al. 1962, 1966, 1967). N o correlation was found between discharge patterns and the neurological disorders of the patients, although the important proportion of bursting units suggested a possible pathological cause for this discharge pattern; however, they appeared in all 7 cases in similar proportions. Furthermore, in normal monkeys under similar experimental conditions a comparable proportion of bursting Pu units has been found (Magarifios Ascone, Bufio, Martin-Rodriguez and Garcia Austt, in preparation), suggesting that in healthy man they may be present in identical numbers. The spontaneous discharge patterns of Pu units,
J.G. MARTIN-RODRIGUEZ ET AL. as established by the statistical procedures, showed similarities with those described for other structures such as the hippocampus (Bufio et al. 1978; Garcia-Sfinchez et al. 1978). Discharges with or without bursts, and rhythmic or non-rhythmic, did not reveal any significant dominance. In general, these data are in agreement with those reported by Albe-Fessard et al. (1962) based on the analysis of the raw records obtained from the same nucleus in humans. Non-rhythmic units cross-correlated with the rhythmic Pu EEG and the non-rhythmic cell with a periodic cross-correlation with a rhythmic bursting unit, which have similar meanings, were also found in the rat hippocampus in the presence of theta rhythm (Garcia-S/mchez et al. 1978; Garcia Austt et al. 1977). This type of periodic cross-correlation indicates that the cell, although non-rhythmic, tends to fire at a preferred phase of the EEG rhythm and of rhythmic unit bursts (Fuentes et al. 1981). This type of functional relationship may be determined by the converging influences of rhythmic and random presynaptic inputs (Fuentes et al. 1981). This kind of discharge may be important functionally because in a 'hidden' way, it carries information about the rhythmic activity. The different firing patterns which may be present in the same unit under similar conditions reveal transitory, non-stable functional states. No significant correlation was found between the rhythmic or non-rhythmic unit types and their capacity to respond to either voluntary movements or sensory stimulation, indicating that synaptic influences determining 'spontaneous' discharges are probably independent of those responsible for the evoked activity. Although the present data provide information about firing patterns and input-output relations of Pu units they are insufficient to be used as a guide for thalamic target location both because of the small number of recorded cells and because similar firing patterns and responses may be found in structures close by (see above).
Summary Unit activity was recorded from the pulvinar nucleus (Pu) in human patients undergoing stereo-
SENSORY-MOTOR INFLUENCES UPON PULVINAR UNITS
taxic surgery. Thirty-six units (12 isolated and 12 pairs recorded with the same microelectrode) with a signal-to-noise ratio > 5, a stable amplitude, and a sustained discharge rate for more than 1 rain, were selected for processing. The following functions were calculated with a digital computer to characterize discharge patterns: interval, autocorrelation and peristimulus time histograms for spikes, cross-correlation histograms between spikes of a pair, and autocorrelation functions and averages of the EEG. In spontaneous conditions, about half of the units fired in rhythmic bursts at the same or half the frequency of the Pu EEG. Most non-rhythmic units showed a 'Poisson-like' interval histogram indicating a random firing pattern. Some nonrhythmic units revealed a periodic cross-correlation with the rhythmic Pu EEG, indicating that spikes tend to fire at a preferred phase of the rhythm. About half of the units showed phasic firing rate changes during voluntary movements. In most cells a discharge rate increase was observed. One unit also responded to passive movements of the fingers. Of the neurons tested, 2 out of 3 showed firing rate modulation during voluntary movements of the jaw as well as of the contralateral hand. The above units also increased the impulse rate after visual stimulation. Convergence of the effects of voluntary movements, and visual and auditory stimulation, was demonstrated in one unit. These results indicate the participation of the Pu in sensory-motor integrative functions.
Resume
397
d6charge, on a calcul6 avec un ordinateur digital les fonctions suivantes: histogrammes d'intervalles, d'auto-corr~lation, de d61ais p6ristimutus, de corr6lation crois6e entre les spikes d'une paire d'unit6s, fonction d'auto-corr61ation et moyennage de I'EEG. En activit6 spontan6e environ la moiti6 des unit6s d6chargeait en bursts rythmiques /l la fr6quence ou /l la moiti6 de la fr6quence du trac6 global du Pu. La plupart des unit6s non-rythmiques pr6sentait un histogramme d'intervalles de type Poisson, indiquant une configuration de d6charge al6atoire. Chez quelques unit~s nonrythmiques s'est r6v616e une corr61ation crois6e p6riodique avec le trac6 global rythmique du Pu, indiquant que les spikes tendent h survenir lors d'une phase pr6f6rentielle du rythme. Environ la moiti6 des unit6s montrait des modifications phasiques de leur taux de d6charge pendant les mouvements volontaires, dans le sens d'une augmentation pour la plupart des cellules. Une unit6 r6pondait aussi aux mouvements passifs des doigts. Parmi les neurones testbs, 2 sur 3 pr6sentaient une modulation de leur d6charge pendant les mouvements volontaires de la m~choire aussi bien que de la main contralat6rale. Ces unit6s augmentaient 6galement leur taux de d6charge apr6s stimulation visuelle. On a mis en 6vidence pour 1 unit6 la convergence des effets des mouvements volontaires et des stimulations visuelle et auditive. Ces r6sultats indiquent la participation du Pu /t des fonctions d'int6gration sensori-motrice. Many thanks are due to Mrs. C. Delgado for the correction of the manuscript.
Unitbs du pulvinar chez l'homme. Activitb spontanke et influences sensori-motrices
References
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