Stimulus-induced tremor in chronic monkeys

Journal of the neurological Sciences

555

Elsevier Publishing Company, Amsterdam-Printed in The Netherlands

Stimulus-induced J. C. DE VILLIERS,

Tremor in Chronic Monkeys T. W. LANGFITT,

AND S.

Department

of Neurosurgery,

M. PEACOCK,

S. Y. GHOSTINE JR.

Pennsylvania Hospital, Philadelphia, Pa. (U.S.A.)

(Received 19 January 1967)

INTRODUCTION

Motor responses to stimulation of the basal ganglia have occupied the interest of numerous investigators since the earliest days of electrophysiology. The results have varied considerably, but in most of the original studies stimulation of such structures as the caudate nucleus, globus pallidus, putamen and thalamus produced a paucity of movement. Turning of the head and body were described, but movement of the limbs, in particular, was rarely found. Furthermore, there has always been the issue as to whether the results are due to stimulation of the target structures or are caused by spread of current to adjacent corticospinal pathways. In more recent times reinvestigation of subcortical nuclei, including studies in man during stereotaxic surgery, have demonstrated both tonic and phasic movement of the limbs from widely distributed subcortical regions. However, a consensus of opinion on the responses obtained from many structures is still lacking. The original impetus for the present study was the observation that stimulation of certain portions of the brain stem at low intensities produces a tremor or phasic motion which does not follow the frequency of stimulation and which therefore might be related

to the spontaneous

tremor

of Parkinsonism.

Thus, by studying

monkeys

with chronically-implanted electrodes at numerous sessions over a period of several months, we hoped to determine whether stimulus-induced tremor was a unique property of the dorsal brain stem and also to define better the motor properties of subcortical nuclei. Many kinds of movement were observed, but the present report will This paper was presented at the Symposium on Neurophysiological Basis of Normal and Abnormal Motor Activities, New York, December 1966. J. C. DE VILLIERS:Chief of Neurosurgery, University of Cape Town, Cape Town (South Africa). T. W. LANGETIT:Head, Department of Neurosurgery, Pennsylvania Hospital Associate Professor of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, Pa. (U.S.A.). S. Y. GHOSTINE: Neurosurgeon, Beirut (Libanon).

S. M. PEACOCK, JR.: Senior Medical Research Scientist, Eastern PennsylvaniaPsychiatric Institute, Assistant Professor of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pa. (U.S.A.). J. neural. Sci.

(1967) 5 : 555-574

556

.I. C. DE VILLIERS,T. W. LANGFITT, S. Y. GHOSTINE, S. M. PEACOCK,JR.

be confined

to an analysis

of phasic motion.

by stimulation of sensorimotor ponses and will be described.

In addition,

phasic movement

cortex has been compared

produced

with the subcortical

res-

MATERIALSAND METHODS Mature

rhesus monkeys

with pentobarbital

weighing

sodium,

5-7 kg were used. The animals

were anesthetized

and the head was held rigidly in a stereotaxic

Stimulation was performed with bipolar, concentric, tips were bared for 0.5 mm with a 1 mm interelectrode

instrument.

stainless steel electrodes. The distance. The electrodes were

directed toward the right caudate nucleus, ventrolateral nucleus of the thalamus, globus pallidus, and mesencephalic reticular formation in each animal (SNIDER AND LEE 1961). In the first two preparations electrodes were inserted in the vertical stereotaxic plane, in the usual manner, and both monkeys developed mild weakness of the contralateral upper extremity. Therefore, in subsequent experiments the electrodes were inserted at acute angles to the vertical axis in order to avoid the more important motor pathways. Insulated silver wires were soldered at right angles to each electrode at the estimated position of the skull surface, and the electrodes were implanted through small drill holes in the skull. The wires were soldered to an amphenol connector which was fixed to the skull with screws and acrylic. In 10 animals a craniectomy was performed over the right Rolandic fissure. An array of 9 electrodes in the form of a Greek cross was placed in the extradural space and fixed to the skull with screws and acrylic. The central electrode was placed on the anterior bank of the Rolandic fissure, as visualized through the intact dura, at the estimated position of the hand area. The leads from the cortical electrodes were soldered to a second amphenol connector. The animals were studied in numerous stimulus-recording sessions for 3-24 months following surgery. Stimulation was performed with a Grass stimulator and isolation unit, and current was monitored with a previously calibrated oscilloscope. Stimulus parameters were: pulse repetition rate l-200 pps; pulse duration 0.5-2 msec; pulse amplitude 0.4-5 mA; and the train duration was variable depending on the character of the response. Phasic motion was recorded with piezoelectric stereophonograph cartridges secured to the limbs with a plastic band. The cartridge was angled 45” to the surface so that only the stylus made contact with the skin. Movement of the skin produced by motion of the hand at the wrist displaced the stylus. Cartridges were frequently applied to both wrists and occasionally to the proximal upper extremity or the dorsal surface of the ankle. The output of each cartridge was recorded on two channels of an 8-channel inkwriting oscillograph. A third channel was used to record stimulus artifact. The cartridge is sensitive to acceleration as well as to changes in amplitude. In an attempt to establish the relative contribution of these two variables to a given deflection on the writer, a cartridge was applied to the wrist of one of the investigators who performed voluntary movements of the hand and submitted to stimulation of the ulnar nerve at the elbow. A very rapid short extension of the wrist produced the same deflection as a slow, high amplitude movement. Despite these limitations direct J. neural. Sci. (1967) 5: 555-574

STIMULUS-INDUCED TREMOR IN CHRONIC MONKEYS

557

observation and analysis of movie film showed a good correlation between the amplitude of the movement and the amplitude of the tremorogram. Prior to sacrifice an electrolytic lesion was made at the tip of each electrode, and the brain was fixed in 10% formalin. The electrode tracks were identified in serial sections, and alternate sections were stained with Luxol-blue and the Weil stain.

Fig. 1. Location of electrode tips directed at mesencephalic reticular formation (above) and thalamus (below). The number of each animal is indicated. Squares are positive and circles negative points for phasic motion. The AP stereotaxic plane is indicated for each section. J. neural. Sci. (1967) 5: 555-574

558

J. C. DE VILLIERS, T. W. LANGFITT, S. Y. GHOSTINE, S. M. PEACOCK, JR. RESULTS

Eighteen

animals

of 3 to 22 months.

were submitted

to multiple

The tip of the mesencephalic

stimulus-recording reticular

formation

sessions for periods (RF) electrode was

identified in 17 preparations (Fig. 1). Phasic motion was obtained from stimulation of the mesencephalic tegmentum, posterior thalamic nuclei, such as nucleus parafascicularis, the periaqueductal the mesencephalic electrode

gray, and even the pulvinar.

reticular

was identified

formation

did not produce

in 16 of 18 animals,

Stimulation

of one electrode

phasic motion.

but stimulation

in

The thalamic

of this electrode produced

phasic motion in only 5 monkeys (Fig. 1). The positive electrode placements were in nucleus ventralis lateralis, nucleus ventralis postero-medialis, the mesencephalic reticular formation, nucleus paracentralis, and the globus pallidus (GP). Only 9 of the GP electrode placements were identified histologically, and these were widely distributed (Fig. 2). Phasic motion was obtained from the globus pallidus, putamen, and nucleus paracentralis of the thalamus. The tip of the caudate electrode was identified in 14 animals, and all placements were in the head of the caudate nucleus or in the internal capsule adjacent to the caudate (Fig. 2). Phasic motion was never observed from stimulation of these electrodes. Initially the phasic motion induced by subcortical stimulation was studied at low

Fig. 2. Location of electrode tips directed at globus pallidus (above) and caudate nucleus (below). J. neurol. Sci. (1967) 5: 555-574

STIMULUS-INDUCED TREMOR IN CHRONIC MONKEYS

559

stimulus frequencies. The threshold response consisted of movement of the hand or one of the digits. During continuous threshold stimulation at 2-5/set occasional low amplitude extension of the wrist occurred, and as the intensity was gradually increased a response was obtained for each stimulus (Fig. 3). With a further increase in intensity the amplitude of the movements became more uniform. As long as the animal re-

Fig. 3. Phasic motion from stimulation of mesencephalic reticular formation. In this and subsequent illustrations the top two channels are the tremorogram (Tr), and the third channel is the stimulus artifact (Stint).

Fig. 4. Development of non-following phasic motion from thalamic stimulation during increase in pulse repetition rate from 2.5 to 16. Frequency of phasic motion remained constant as the frequency of stimulation was increased from 24 to 50. J. neural. Sci. (1967) 5: 555-514

560

J. C. DE VILLIERS, T. W. LANGFITT, S. Y. GHOSTINE, S. M. PEACOCK, JR.

mained quiet, suprathreshold stimulation produced a 1:l response of fairly uniform amplitude for as long as several minutes. However, at stimulus rates above S/set a change in the following frequency of the phasic motion occurred in several animals, and initially the response rate dropped to one-half the stimulus rate. This is illustrated in Fig. 4 during stimulation of the ventrolateral thalamus. The following frequency of the phasic motion as the stimulus frequency was gradually increased is also shown. At 12/set the response was still 1: 2, but at a stimulus rate of 15/set it dropped to 1: 3. When the stimulus rate was increased beyond 20/set the response remained slow with a dominant frequency of 8-lO/sec, but the record became more disorganized. However, this basic response rate was maintained to a stimulus frequency of 50/set. In order to quantitate the frequency of phasic motion in terms of the stimulus frequency, the latter was increased at increments of 5-20, and the average number of responses per second was determined for several lo-set recording periods. Analysis was made of responses obtained from stimulation of an effective area at different recording sessions, with stimulus intensities from threshold to a maximum of 5 mA, and with the animal awake and lightly anesthetized (pentobarbital sodium 15-20 mg/kg). Although the phasic motion failed to follow at stimulus frequencies as low as S/set, and following frequencies to 50/set also occurred, these were exceptional observations. In the majority of animals phasic movement followed the stimulus frequency to 20-30/set and remained between 20 and 30/set as the stimulus frequency was increased to lOO/sec. Fig. 5 illustrates random examples obtained from 64 recording sessions in 6 animals. Phasic motion of the hand ipsilateral to the RF electrode was obtained within the 5 mA upper limit of stimulus intensity in most preparations. When the electrode was O-0 ll/l6/65 O-O A-A A-d

5moAw

O-0

PUT8/12/65

5maAw

ll/l6/65 5/V/65

3ma Aw 3maAs

0-O

X12/14/65

4maAw

A-4

5h1/65

2maAs

RF12/14/65 RF8/12/65

, A-A

5maAs PmaAs

100. QO80G =

70-

2 2 ii.

60-

z 0

50-

t

40-

; z30ii 20-

I

0

I

10

20

30 PHASIC

0 MOTION

10

20

30

Fig. 5. Phasic motion produced by progressive increase in the frequency of stimulation of the putamen

(left) and of the mesencephalic reticular formation, ventrolateral nucleus of the thalamus, and putamen (rig/zt). The date of the trial and the intensity of stimulation are indicated; the animals were awake (Aw) or lightly anesthetized

with pentobarbital

sodium (As).

All data are from animal E25. .r. neural. Sci. (1967) 5: 555-574

STIMULUS-INDUCED TREMOR IN CHRONIC MONKEYS

561

located posteriorly and near the midline differences in threshold as low as 0.2 mA were recorded for contralateral and ipsilateral movement. The frequency of the ipsilateral phasic motion bore no consistent relationship to the contralateral movement. At low frequencies and suprathreshold intensity a 1 :l response was obtained bilaterally, but as the stimulus frequency was increased the break in the response frequency was independent in the two hands. Fig. 6 illustrates a 1 :l response contralateral to the electrode and a 1: 2 response of slightly less amplitude in the ipsilateral hand.

Fig. 6. Bilateral phasic motion produced by stimulation of mesencephalic reticular formation near the midline. The response in the left hand follows the frequency of stimulation. The response in the right hand is one-half the stimulus frequency.

The frequency response of cortically-induced phasic motion was indistinguishable from subcortically induced movement. However, analysis of stimulus frequencyresponse curves was limited for fear of producing a seizure. In each animal the cortex was stimulated sequentially with multiple combinations of electrodes, and the most consistent response with the lowest threshold was then further evaluated. Fig. 7 illustrates a follwing response to stimulation at S/set, then an alternating 5 and lO/sec response to stimulation at lO/sec. The amplitude of the response was augmented by an increase in intensity. At a stimulus rate of 15/set and 3 mA the response alternated between a high amplitude S/set phasic motion and a barely detectable movement at the frequency of stimulation. At an intensity of 4 mA the phasic motion followed 1: 1 gradually increasing in amplitude and was followed by a generalized seizure. Fig. 8 illustrates cortical stimulus frequency-response curves from two animals in which phasic motion did not exceed IO/set. J. neurol. Sci. (1967) 5: 555-574

562

J. C. DE VILLIERS, T. W. LANGFITT, S. Y. GHOSTINE, S. M. PEACOCK, JR.

One monkey in which subcortical electrodes were implanted in the usual manner developed generalized seizures beginning in the right upper extremity on the day following surgery.

With treatment

the seizure activity

subsided

within a few hours, and

examination at that time showed paralysis of the right upper extremity. Recovery of function began in 3 weeks, and 2 months following electrode implantation a sponta-

Fig. 7. Non-following

motion from stimulation of sensorimotor cortex. Stimulation duced a generalized seizure.

ultimately pro-

80 *Et9 OE19

70

1

OE28

Fig. 8. Stimulus frequency-response graphs from stimulation of sensorimotor cortex in three animals. The tremor frequency or phasic motion does not exceed 1I/set.

neous tremor of the right hand and fingers was noted for the first time (Fig. 9A). extremity was still paretic, but the animal was able to use it for protection in climbing. The tremor was consistent at 6-lO/sec throughout many months observation. It was present at rest and at various times either disappeared or enhanced by movement of the extremity. Emotional excitement always increased J. new-o/. Sci.

The and of was the

(1967) 5: 555-574

STIMULUS-INDUCED

TREMOR IN CHRONIC

MONKEYS

563

amplitude of the tremor but did not alter the frequency, Threshold stimulation of the RF electrode increased the amplitude of the tremor at its spontaneous frequency (Fig. 9B), but when the stimulus intensity was increased further the phasic motion of the right hand followed the frequency of stimulation 1: 1, then immediately dropped to a high amplitude response at the spontaneous frequency following cessation of stimulation (Fig. 9C). Three months following the beginning of the experiment and 1 month after the tremor was first observed, the upper extremity portion of right precentral motor cortex was removed, as part of the original experimental design. This resulted in paralysis of the left upper extremity and no change in the tremor of the right hand. At the time of sacrifice 22 months following electrode implantation, mild residual weakness was

Fig. 9. Spontaneous tremor in right hand (A). When the tremor was absent it could be elicited by threshold stimulation of the mesencephalic reticular formation (B), and at a higher intensity of stimulation the tremor followed the frequency of stimulation, then reverted to the spontaneous tremor frequency following cessation of stimulation (C).

Fig. 10. Facilitation of phasic motion by simultaneous stimulation of the putamen and mesencephalic reticular formation. J. neural. Sci. (1967) 5: 555-574

564

J. C. DE VILLIERS, T. W. LANGFITT, S. Y. GHOSTINE, S. M. PEACOCK, JR.

present

in the right hand. This had not changed

had there been any change had returned

to normal

in the tremor

significantly

for several months

nor

in the right hand. The left upper extremity

except for some residual

dysfunction

in fine movements

of the

fingers. At post-mortem examination the dura was densely adherent to the cortex surrounding the cortical ablation and at the site of the electrode implantations, but the cortex was otherwise electrode

intact.

On section the only gross subcortical

lesions were related to the

tracts.

In several

animals

two

electrodes

were

stimulated

simultaneously

at various

frequencies in an attempt to obtain facilitation or inhibition of phasic motion and also as a potential means of influencing the response rate. In Fig. 10 high-frequency stimulation of the putamen and the mesencephalic reticular formation separately produced low amplitude irregular responses at threshold. The amplitude of the response was enhanced by simultaneous stimulation. Distinct inhibition was seen occasionally on stimulation of the caudate nucleus (Fig. 11A and B), but facilitation of phasic motion by caudate stimulation was also observed in one animal (Fig. 1lC). In those preparations in which stimulus-response curves were obtained for stimulation of a given area, graphs were also constructed for simultaneous stimulation of two structures. One of the stimulus frequencies was kept constant at 20, 50 or lOO/sec while the frequency of stimulation of the second electrode was gradually increased.

Fig. 1I. Inhibition of reticular formation phasic motion by simultaneous stimulation of the caudate nucleus (A and B). Facilitation of threshold movement produced by motor cortex stimulation, by simultaneous stimulation of the caudate nucleus (C). Facilitation of reticular formation phasic motion by simultaneous stimulation of ventrolateral thalamus (B). J. tieurol. Sci. (1967) 5: 555-574

565

STIMULUS-INDUCED TREMOR IN CHRONIC MONKEYS

d0

60

30

2C

10

/-

RF 20

10

0

lOOh,

PHASIC

L"

10

30

MOTION

PHASK

MOTION

Fig. 12. Subthreshold stimulation of the mesencephalic reticular formation was kept constant at lOO/ set, and the frequency of phasic motion was measured as the frequency of stimulation of the thalamus (leji) and putamen (right) was increased to lOO/sec. Results are similar to those illustrated in Fig. 5.

Fig. 12 illustrates simultaneous stimulation of the reticular formation and the ventral thalamus, also the reticular formation and the putamen. In none of the animals was there a consistent difference between the responses to single and double stimulation. Also, within individual trials it was not possible to control the rate of the response by altering the frequency of stimulation of either structure except at very low stimulus rates. Thus, in this regard the double stimulation studies were indistinguishable from TABLE 1 SIMULTANEQUS

AnimalNo.VL/GP E24 E25 E28 E29 *E31 E32 -,

0 0 0

VL/RF 0 F F 0 0

RFjGP F F 0 F 0 0

RFjCAUD 0 0 0 FI 0

not studied; 0, no effect; F, facilitation;

STIMULATION

GP/CAUD 0 -

I, inhibition;

RFjCORT

CORTIVL

CORTIGP

CORTjCAUD

0 F F F F F

0 FI 0 0 -

F F F F 0 -

0 0 FI -

* histology not available. J. neural. Sci. (1967) 5 : 555-574

566

J. C. DE VILLIERS, T. W. LANGFITT, S. Y. GHOSTINE, S. M. PEACOCK, JR.

the results obtained with stimulation of a single structure. Table 1 summarizes the results obtained from stimulation of various electrode combinations in 6 animals. In previous illustrations emphasis has been placed on the high amplitude nonfollowing responses, whereas low amplitude phasic motion at the frequency of stimulation was often superimposed on the larger deflections. In fact, three simultaneous superimposed rhythms were seen occasionally. For example, the phasic responses to stimulation of the reticular formation at 30/set can consist of a barely detectable movement at the frequency of stimulation which resembles shivering. On to this is superimposed a higher amplitude movement at lO/sec. In turn the amplitude of the latter is modulated at a lower frequency, often 1 or 2/set (Fig. 13A). This waxing and

Fig. 13. Amplitude modulation

of phasic motion which is spontaneous tions in B.

in A and induced by respira-

waning in amplitude, or amplitude periodicity (BOSHES et al. 1960) was independent of the site, frequency, or intensity of stimulation. Even slower variations in amplitude were also observed and could be correlated with the respiratory cycle (Fig. 13B).

DISCUSSION

Stimulation of the corpus striatum has been performed in acute and chronic animals J. neural. Sci. (1967) 5: 555-574

STIMULUS-INDUCED TREMORIN CHRONICMONKEYS

561

and occasionally in man. In early studies spontaneous changes in behavior or motor activity were not seen (METTLERet al. 1939), but contraversive turning of the head and circling movements in chronic animals have been observed with electrical stimulation (HASSLER 1956; FORMANAND WARD 1957; SWEETet al. 1947) and by injection of acetylcholine into the head of the caudate nucleus (STEVENS et al. 1961). Phasic motion has also been described occasionally, and in studies in chronic cats FORMANAND WARD (1957) described repetitive movements of the contralateral extremities from stimulation of points in the head of the caudate nucleus remote from the internal capsule. Stimulation of the globus pallidus did not produce movement in the experiments of WILSON(1914), METTLERet al. (1939), and ARONSONet al. (1962), but rhythmic motion of the extremities was described as an occasional response by SPIEGELet al. (1961) and a frequent effect by SWEETet al. (1947) in acute cat preparations. BUCHWALDAND ERVIN(1947) routinely observed phasic motion of the contralateral limbs from stimulation of the globus pallidus in chronic cats. Stimulation of many regions in the thalamus and subthalamus has also produced contralateral phasic motion in cats (SWEETet al. 1947, SPIEGELet al. 1961, SPULERet al. 1962), and stimulation of the amygdala produces tremor in monkeys (ARONSONet al. 1962). Introduction of stereotaxic surgery has permitted exploration of the human brain stem and diencephalon, and although anatomical identification of stimulus sites is rarely possible, the techniques employed are sufficiently accurate to permit tentative conclusions. Stimulation of the globus pallidus in epileptics and in Parkinsonian patients without tremor has no observable effect on motor activity (SPIEGELet al. 1959; HASSLERet al. 1960). At a stimulus frequency above 25/set spontaneous tremor is abolished (HASSLERet al. 1960). The most extensive human studies have been carried out in the thalamus. Movement has been produced from stimulation of the ventrolateral thalamus (HASSLERet al. 1960; BERTRAND ANDMARTINEZ1961), and in general, HASSLERet al. (1960) found the thalamus to be more responsive to stimulation than the pallidum. The principal motor effect was turning of the head and eyes to the opposite side. Spontaneous tremor can be evoked (ADEYet al. 1960), and augmentation of tremor at its spontaneous rate is frequently observed (HOUSEPIANANDPURPURA 1963; HASSLERAND REICHERT1954; ALBERTSet al. 1961). At high frequencies of stimulation spontaneous tremor may be either increased or decreased (OHYE et al. JURKO et 1963), and according OHYE et al. (1964) the quality of the response depends upon the amplitude of the tremor. Thus, when spontaneous tremor is minimal it is enhanced by thalamic stimulation and high amplitude tremor is reduced or blocked by stimulation of the same point. The effect of thalamic stimulation on gamma motoneuron activity in the cat also depends in part on the level of spontaneous discharge at the time of stimulation (LANGFITTet al. 1963). JURKO et al. (1963) recorded tremor in Parkinsonian patients with piezoelectric cartridges similar to those used in the present study. Stimulation of the ventral thalamus and subthalamus resulted in amplitude changes, and occasionally an increase in the frequency of spontaneous tremor was also observed. This is the only measured change in frequency which we have found in the literature with the exception of the observations of LIN et al. (1961) that lesions in the pallidothalamic pathway decrease J. neurol.Sci. (1967)5: 555-574

568

J. C. DE VILLIERS, T. W. LANGFITT, S. Y. GHOSTINE,S. M. PEACOCK, JR.

tremor frequency. Thus, extensive studies in acute and chronic animal preparations and in man have demonstrated However,

a motor function for many subcortical structures.

a characteristic feature of these reports is a lack of consistency among

studies by different investigators, and in those investigations

in which the data are

presented in detail, inconsistencies among preparations. Slight differences in electrode placement would appear to be less important in explaining these discrepancies than changes in central excitatory A persistent problem, movement

from

state due to anesthesia and other unknown influences.

recognized

stimulation

by most investigators,

is the possibility

is due to spread of current to corticospinal

that fibers.

FORMAN AND WARD (1957) stated that the current spread from caudate electrodes in their cat experiments was probably no more than 2 mm, but this is difficult to quantitate. Another matter of interest is whether movement from stimulation of subcortical structures occurs by activation of descending pathways or through systems ascending to the motor cortex. Both of these issues have been investigated by acute and chronic decortication. SWEET et al. (1947) found that phasic motion produced by stimulation of caudate, putamen, and globus pallidus was not affected by acute destruction of the motor cortex, and in the experiments of FREEMANAND KRASNO (1940) the inhibitory function of caudate nucleus was not abolished by chronic decortication.

In contrast, PEACOCK

(1954) could no longer obtain inhibition of motor responses from caudate stimulation after chronic decortication.

SPIEGEL (1961) found that the motor effects of thalamic

stimulation persisted after chronic ablation of the motor cortex and cited anatomical evidence for a descending pathway from the thalamus to the brain stem (JOHNSON AND CLEMENTE 1959). Gamma motoneuron responses to thalamic stimulation are also unaffected by chronic decortication

(LANGFITT et al. 1963). Thus, the evidence indi-

cates that the motor effects produced by stimulation of some subcortical structures are both independent of cortical internal capsule. However,

mediation

and not due to current spread to the

it is difficult to eliminate the latter problem in any given

experiment. Most interest in phasic motion, or tremor, has centered on the brain stem tegmentum since the observations of JENKNER AND WARD (1953) in monkeys, and SPIEGEL and colleagues (SPIEGEL et al. 1953; FOLKERTSAND SPIEGEL 1953) in the cat, that repetitive stimulation

of the tegmentum produces phasic motion which does not follow

the

frequency of stimulation. In the monkey the most responsive areaincluded the reticular formation

from the red nucleus to the 6th nerve nucleus, and in the cat, the mesen-

cephalic tegmentum several millimeters dorsal to the corticospinal tract. The impetus for these investigations

was the observation

that lesions in the mesencephalic

teg-

mentum can produce spontaneous tremor which resembles the tremor of Parkinsonism (WARD et al. 1948; PETERSONet al. 1949; SCHREINERet al. 1958; POIRIER 1960). On the basis of the stimulation

and ablation experiments WARD AND JENKNER (1953)

advanced an hypothesis in which the mesencephalic important role in the pathophysiology As noted, previous investigations

reticular formation

plays an

of Parkinsonian tremor. of motor activity produced

by stimulation

of

subcortical structures have been marked by inconsistent responsesamongpreparations. Chronic monkeys were used in the present experiments and studied repeatedly for J. neural.Sci. (1967) 5: 555-574

STIMULUS-INDUCED TREMORIN CHRONICMONKEYS

569

several months in an attempt to evaluate this variability. Responsive points were distributed throughout much of the diencephalon and dorsal brain stem, and we have not been able to explain the distribution of positive and negative points on the basis of known anatomical connections. Stimulation of essentially the same area in different animals, particularly in the thalamus and tegmentum, produced phasic activity in some and no response in others. In addition, stimulation of the pulvinar, a structure without apparent motor function, produced phasic motion with the same threshold and characteristics as that elicited from stimulationof themidbrainreticularformation. Thus, it has not been possible to speculate logically on the pathways mediating many of the effects, and factors other than the anatomy of the structure stimulated would appear to be equally important in determining whether or not a response was obtained. Another purpose of the studies was an attempt to define better the function of subcortical structures on the basis of stimulation and response characteristics. The principal criteria employed were stimulus thresholds and the frequency of phasic motion in terms of the frequency of stimulation. In none of the animals were consistent differences found among globus pallidus, thalamic and mesencephalic reticular formation electrode placements. An increase in the amplitude of phasic movement was produced by many electrode combinations, and reticular formation-cortex and globus pallidus-cortex appeared to be the most effective. Inhibition was observed rarely. Perhaps the most surprising finding was the frequent failure of phasic motion to follow motor cortex stimulation at fast stimulus frequencies. In 1878 FRANCOISFRANCKANDPITRES(cited by COOPERANDDENNY-BROWN1926) found that muscle contractions followed the frequency of cortical stimulation to 45/set, whereas HORSLEY AND SCHAFER(1886) concluded that a following frequency beyond lO/sec was rare. COOPERAND DENNY-BROWN(1926, 1928) observed that the EMG followed cortical stimulus frequency to 180/set, and some activity was seen in the mechanical myogram at following frequencies as high as 68/set. However, the latter was interspersed with rhythmic activity at lower non-following frequencies. In more recent studies of movement produced by cortical stimulation phasic motion has been mentioned infrequently. LILLY et al. (1952) described a phasic jerk of a portion of the limb with each pulse below lO/sec and smooth contraction with higher frequencies of stimulation. LIDDELLANDPHILLIPS(1950) described “flick-flexion” as a threshold movement of the thumb at low frequencies of stimulation, and above 1S/set the rhythmic motion of the thumb became irregular. At all stimulus frequencies below 30/set CUREANDRASMUSSEN (1954) found “a tremor which followed the frequency of stimulation as far as could be determined by visual observation”. Our findings are in agreement with HORSLEYANDSCHAFER(1886) in that high amplitude phasic motion with a response rate in excess of lO-15/set was rarely observed during cortical stimulation. However, low amplitude following responses to at least 40/set were also observed, confirming COOPERANDDENNY-BROWN (1926, 1928) and the frequency of clonic movement during the seizure illustrated in Fig. 7 is approximately 50/set. The mechanisms responsible for failure of the large amplitude phasic motion to follow the frequency of stimulation are not readily apparent. When bilateral phasic J. neural. Sci. (1967)5: 555-574

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J. C. DE VILLIERS,T. W. LANGFITT,S. Y. GHOSTINE,S. M. PEACOCK, JR.

movement was obtained from stimulation of the midbrain tegmentum, the frequency of phasic motion in the two hands was often different with one a subharmonic of the other. This could be explained by a difference in the “set” of anterior horn cells on opposite sides of the spinal cord which determines the frequency of the response. However, there are a multitude of afferent inputs to the mesencephalic tegmentum, and stimulation of the amygdala and pallidum produces a rhythmic modulation of mesencephalic reticular neurons (ADEY et al. 1959). In the pioneer experiments of HORSLEYANDSCHAFER(1886) stimulation of the corona radiata and the cut surface of the spinal cord produced lO/sec phasic motion, the same response as they observed during cortical stimulation. These observations and the fact that motor units can follow high frequency stimulation of both cortex (COOPERANDDENNY-BROWN 1928) and pyramidal tract (LANDAU1952) provide evidence that the failure of phasic motion to follow high frequency cortical stimulation in the present experiments is established in the spinal cord. Changes in tone, determined by passive movement of an extremity, were evaluated and recorded descriptively in each experiment. A decrease in tone was routinely observed during 20-30/set threshold stimulation of motor cortex, confirming previous observations (TOWER 1936; CLARKAND WARD 1948). This was not observed with stimulation of any subcortical structure. High frequency suprathreshold stimulation of the cortex produced tonic movement which was usually confined to a small portion of the limb. In contrast, suprathreshold stimulation of the tegmentum sufficient to produce tonic movement of the wrist, for example, also caused full elaboration of the tegmental response (HINSEYet al. 1930; INGRAMet al. 1932), including turning of the head and eyes, and tonic movement of the limbs. Thresholds for phasic motion and tonic movement varied greatly among the diencephalic structures stimulated but generally fell between the cortical and tegmental responses. Thus, the response to motor cortex stimulation could be distinguished, occasionally from stimulation of other structures by the failure of phasic motion to follow the frequency of stimulation beyond 10 pps. With higher stimulus frequencies the early development of the tegmental response from stimulation of the RF electrode was a constant distinguishing characteristic. Three distinct frequencies of phasic motion could be identified in the tremorograms. Frequently two were superimposed, and occasionally all three appeared in the same record. Fig. 14 illustrates frequency and amplitude modulation of the diaphragm of a loud speaker against which the stylus of the piezoelectric cartridge has been placed. This serves as a diagrammatic representation of the experimental data and in A shows 30 cycle sinewaves of uniform amplitude. The record corresponds to a fast I : 1 following frequency of phasic motion equivalent to repetitive activation of the same number of anterior horn cells at a constant frequency. This is the response which follows the stimulus to 20-30/set, and the amplitude is roughly proportional to the intensity of stimulation. Another oscillator was then added with twice the output and a frequency of lO/sec (Fig. 14B). This is equivalent to activation of a population of anterior horn cells which did not participate in A, and which are discharging at one-third the frequency of the motor neurons in A. Neither the amplitude nor frequency of this response could J. neural. Sci. (1967)5: 555-574

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Fig. 14. Representation of different frequencies of phasic motion. Traces were produced by frequency and amplitude modulation of the diaphragmof a loud speaker against which the stylus of thecartridge was placed. be controlled by varying the conditions of the experiment. Finally, in C, the amplitude of the lO/sec response is modulated to produce a waxing and waning phenomenon at l/set. The origin of this low frequency amplitude modulation is also unknown except when it is related to the respiratory cycle. We conclude that in the unanesthetized monkey, anterior horn cells can be driven at the frequency of stimulation of cortex and many subcortical structures. Perhaps the J. neural. Sci. (1967) 5 : 555-574

572

J. C. DE VILLIERS,

T. W. LANGFITT,

S. Y. GHOSTINE,

S. M. PEACOCK,

JR.

wide distribution of responsive areas in the diencephalon and brain stem is not surprising in light of the evidence that the entire cortex is “motor” (LILLY et al. 1956). Phasic motion which follows precisely the frequency of stimulation is best obtained by high intensity stimulation at frequencies less than lO/sec, but following responses to 30/set are observed commonly. At stimulus frequencies of 5-30/see high amplitude, phasic motion, non-following at a subharmonic of the stimulus frequency, may be the only detectable motor activity or may be superimposed on a fine movement which follows the frequency of stimulation. The amplitude of the phasic motion is influenced by several variables which may alter the excitability of either the cells stimulated or the anterior horn cells responsible for the movement. There is inconclusive evidence that the frequency of non-following phasic motion is established at the level of the final common pathway. In previous reports, one reason for designating the brain stem tegmentum a tremorogenic center was the ease with which phasic motion could be obtained with low threshold stimulation and frequent failure of the phasic motion to follow the stimulus frequency. On the basis of the present study, motor cortex and many additional subcortical structures have tremorogenic properties which are indistinguishable from the midbrain tegmentum. However, there still exists the well-documented observation that mesencephalic lesions can produce a spontaneous tremor which is similar to that seen in Parkinsonism. ACKNOWLEDGEMENTS

This work was supported by a grant from the John A. Hartford Foundation, Inc. The authors acknowledge the assistance in these experiments of Dr. Robert Meredith, Mr. Sherman Stein, Mr. Edward M. Sorr, and Mr. Richard T. Lachman. SUMMARY

Bipolar electrodes were chronically implanted in many subcortical structures and over the sensorimotor cortex in monkeys. Phasic motion was recorded with piezoelectric cartridges, strapped to the animals’ limbs, at numerous recording sessions for many months. The most common response observed was tremor which followed the frequency of stimulation to 20-30/set, then remained in that frequency range as the stimulus frequency was increased to lOO/sec. However, in all animals non-following tremor was also observed, and occasionally the response remained below lO/sec with stimulus frequencies to lOO/sec. The amplitude of both following and nonfollowing phasic motion was influenced by stimulus intensity, simultaneous stimulation of two electrodes, and barbiturate anesthesia. In contrast, the frequency of the non-following phasic motion was independent of all variables investigated. At high stimulus frequencies, high amplitude, non-following phasic motion was often superimposed on a low amplitude response at the frequency of stimulation. In addition, the amplitude of the non-following tremor was modulated at frequencies of I-2/set, and occasionally the modulation was related to the respiratory cycle. Evidence is presented that the frequency of the non-following phasic motion is established at the level of the spinal cord. J. rleurol. Sci. (1967) 5: 555-574

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573

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