Brain Research, 85 (1975) 403-422 ~
403
Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
M O D U L A T I O N OF C O R T I C A L A N D P Y R A M I D A L T R A C T I N D U C E D MOT O R RESPONSES BY E L E C T R I C A L S T I M U L A T I O N OF T H E BASAL GANGLIA
ROBERTA A. NEWTON AND DONALD D. PRICE
Department of Physical Therapy, Medical College of Virginia, Virginia Commonwealth University~ Richmond, Va. 23298 and National Institute of Dental Research, NIH, Bethesda, Aid. 20014 (U.S.A.) (Accepted October 14th, 1974)
SUMMARY
Two general mechanisms based on anatomical studies are possible for modulation of motor activity by the caudate nucleus and globus pallidus. These mechanisms are: (i) modulation of the output of cortical neurons that exert motor influences; and (2) modulation of subcortical neurons that exert motor influences. Differentiation between these two mechanisms was accomplished in the present study by two experimental approaches, both of which employed the conditioning-test paradigm. The first approach was an investigation of caudate nucleus or globus pallidus modulation (conditioning stimulus) of flexor responses of the anterior tibialis muscle elicited by electrical stimulation of the sensorimotor cortex (test stimulus) or pyramidal tract (test stimulus). These investigations were carried out in the intact and in decorticate cats. The second approach was an analysis of modulation of cortically induced pyramidal tract responses (direct and indirect, D - I potentials) by conditioning shock trains delivered to various loci within the caudate nucleus or globus pallidus. Both approaches were designed to determine which inhibitory and facilitatory motor influences of the basal ganglia occurred at a cortical or subcortical level. Simultaneous stimulation of a locus within the caudate nucleus and the sensorimotor cortex evoked either an enhancement, reduction or no alteration of the cortically induced increase in flexor responses (measured by Ia afferent activity, EMG, myogram). In contrast, no inhibitory influences occurred from caudate nucleus stimulation upon pyramidal tract induced flexor responses in either the intact or decorticate preparation. Inhibitory loci were distributed toward the rostral portion of the caudate nucleus, whereas facilitatory loci were distributed throughout; this distribution was statistically significant (42; P < 0.01). Only enhancement or no influence upon cortical induced or pyramidal tract induced responses were obtained by conditioning stimuli to the globus pallidus.
404 In the unanesthetized but immobilized cat, trains of shocks delivered to the caudate nucleus enhanced, reduced or had no influence upon the cortically evoked direct (D) and indirect (l) potentials recorded in the bulbar pyramidal tract. The distribution of facilitatory and inhibitory loci was organized in a similar t=ashion as in the anesthetized preparation. From these observations, a model was proposed in which the output of the caudate nucleus exerts both facilitatory or inhibitory modulation ot: the tonically active globus pallidus cells. The latter in turn predominantly or exclusively facilitate output of pyramidal tract neurons as welt as the output of subcortical structures; both effects facilitate motor responses at the spinal level.
INTRODUCTION
The basal ganglia have been shown to exert inhibitory and facilitatory influences on m o t o r activity 6,11,2~,2s. In particular. Liles and Davis have demonstrated that the anteroventral and the dorsal posterior portions of the caudate nucleus have respective inhibitory and facilitatory influences on cortically induced flexor responses 20.21. Furthermore. Granit and K a a d a have demonstrated basal ganglia facilitatory influences upon g a m m a motoneuron activity 7. However. these studies have not determined the brain areas at which these modulating influences are integrated, Therefore, physiological mechanisms underlying basal ganglia influences on motor activity are difficult to assess, especially since these structures are many synapses removed from sensory input and from lower motoneurons 12.13. Two general mechanisms based predominantly on anatomical considerations are possible for modulation of motor activity by the basal ganglia. Modulation o f the output of cortical motoneurons could occur via a well defined pathway from basal ganglia structures to VA and VL thalamic nuclei and from the latter to the sensorim o t o r cortex 15,24. Modulating influence could also occur via globus paltidus projections to lower brain stem structures which in turn affect spinal m o t o r mechanisms. The present study was designed to determine which of these two mechanisms could account for the inhibitory and facilitator~, influences exerted on m o t o r activity by the caudate nucleus and globus pallidus. Differential analysis of these two mechanisms was accomplished in the present study by two experimental approaches. In the first approach, anterior tibialis l ankle flexor) g a m m a and alpha motoneurons were driven by stimulation of the sensorim o t o r cortex or pyramidal tract in anesthetized cats. The modulating influences of the caudate nucleus and globus pallidus on these pathways were determined. To further specify the pathways by which the basal ganglia exert their influences, studies were also done in decorticate preparations. I n the second approach, experiments were performed on unanesthetized animals. In these preparations, the modulatory effect of localized stimulation m areas of the caudate nucleus and globus pallidus upon cortically evoked pyramidal tract discharges was studied. In both types of experiments, a major hypothesis tested was
405 whether the rostral and caudal regions of the caudate respectively exerted inhibitory and facilitatory motor influences. A second purpose of the study was to determine the central nervous system levels at which the inhibitory and facilitatory influences were integrated. METHODS
Anesthetized preparations Thirty-five cats weighing between 2.7 and 4.2 kg were used. These were maintained under light sodium pentobarbital anesthesia (flexion reflex present) during the surgical preparation and during the period of data collection. Four of these cats were decorticated. A tracheal cannula and a femoral venous cannula were inserted into each animal. The animal was then placed in a stereotaxic and spinal frame and the right sensorimotor cortex and the bulbar pyramidal tract were exposed, the latter by a ventral approach. All dorsal surgical wounds were filled with mineral oil and maintained at 37 °C. The body temperature of the preparation was maintained between 35 and 37 °C by a water filled heating pad in contact with the ventral surface of the animak E K G monitored in all preparations indicated normal heart rate (HR -- 130150 beats/rain) and electrical activity. The left hind limb was denervated except for the nerve to the anterior tibialis muscle. The anterior tibialis muscle was dissected free from surrounding tissue and the tendon was attached to a Grass FTO3 force-displacement transducer. An E M G needle electrode was inserted into the belly of the muscle. A laminectomy was performed from spinal segments L3 to S~ and the exposed spinal cord was covered by a pool of mineral oil at 37 °C. A thin filament from the sixth lumbar dorsal root was cut centrally and placed over a silver bipolar recording electrode. The filament was repeatedly divided until, with the aid of audio and visual monitoring, a single spindle afferent from the anterior tibialis was identified. Three criteria were used to identify Ia spindle afferents from the anterior tibialis. (a) These afferents were excited by weak stretches of only the anterior tibialis. (b) They exhibited silent periods during the rising phase of a twitch contractionS, 22. (c) Conduction velocities of these afferents were measured and were greater than 80 m/sec. These Ia afferents increased their firing frequency during electrical stimulation of the sensorimotor cortex and of the bulbar pyramidal tract. Since these increases occurred without concomitant changes in anterior tibia[is myogram or E M G , they therefore served as indications of g a m m a motoneuron activation. Signals from the spindle afferents, myogram, and E M G were amplified, monitored on a Tektronix 502 oscilloscope, and recorded on magnetic tape by means of an 8 track Ampex tape recorder. Bipolar ball-tipped stainless steel electrodes were used to stimulate the leg area of the contralateral sensorimotor cortex. Location of the leg area was obtained by stimulation of the cortex at various locations until an increase in the rate of the anterior tibialis spindle afferent discharge occurred. A similar procedure was used for the contralateral pyramidal tract. Five type G0 stainless steel insect pins insulated to within 0.5 mm from their tips were separated at 1 mm intervals into an array or ' c o m b '
406 o f electrodes. This ' c o m b ' o f electrodes was stereotaxically placed within either the c a u d a t e nucleus o r globus pallidus.
Experimental format A c o n d i t i o n i n g - t e s t p a r a d i g m was used. A test train o f constant current pulses with a pulse d u r a t i o n o f 1.0 msec. a frequency o f 60 Hz and a train d u r a t i o n o f 500 o r 1000 msec was delivered to the cortex. The intensity was a d j u s t e d until a m i n i m a l increase in d o r s a l r o o t discharge was detected. The c o n d i t i o n i n g t r a i n to c a u d a t e nucleus or globus pallidus consisted o f 1130 H z square wave pulses, with a pulse d u r a tion o f 0.5 msec, a n d a train d u r a t i o n o f 5130 or 113130msec. Stimulus intensity within the c a u d a t e nucleus ranged from 2.0 to 2.5 m A , a current strength well below that which w o u l d by itself m o d i f y Ia spindle afferent discharge. Each electrode pair o f the c o m b was used to deliver c o n d i t i o n i n g shocks in a stimulating sequence corn posed o f a m i n i m u m o f one cortical test train, and 5 s i m u l t a n e o u s l y delivered c o n d i t i o n i n g a n d test trains. This f o r m a t was then repeated, with the test stimuli to the cortex replaced by a 1 sec d u r a t i o n train o f 0.5 msec square wave pulses at 1130 H z delivered to the p y r a m i d a l tract. As before, the intensity o f the test train was adjusted until a m i n i m a l increase in spindle afferent discharge occurred. These c o n d i t i o n i n g - t e s t procedures were a p p l i e d using each pair o f electrodes within the ' c o m b ' . Each locus within the c a u d a t e nucleus o r globus pallidus was m a r k e d by an electrolytic lesion. The c o m b of electrodes was lowered 1 m m a n d the e x p e r i m e n t a l f o r m a t was repeated, The same e x p e r i m e n t a l f o r m a t was used in the decorticate p r e p a r a t i o n .
Data analysis The r e c o r d e d d a t a were filmed on L i n o g r a p h p a p e r with a G r a s s K y m o g r a p h camera. Changes in m y o g r a m tension, E M G activity, and frequency of spindle afferent activity were m e a s u r e d for the d u r a t i o n o f the shock trains. If the p a i r e d c o n d i t i o n i n g ,, or m o r e test trains elicited an increase in spindle afferent discharge that was 40 °/ a b o v e the average test response in at least 4 o f the 5 trials, a "~' ' was recorded on the a p p r o p r i a t e sagittal m a p o f the c a u d a t e nucleus or globus pallidus. Similarly, if the c o n d i t i o n i n g - t e s t trains resulted in a decrease in la spindle discharge that was 40°/o or m o r e below the average test response m 4 o f the 5 trials, a ' - ' was recorded. The s t a n d a r d d e v i a t i o n o f the c o n t r o l responses was in each case less than 15 ~!~,. These criteria were sufficient to conclude that responses at each ' ~ ' and ' ' locus were significantly different from the cortical o r p y r a m i d a l tract elicited c o n t r o l responses ( W i l c o x o n sign P
403
Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
M O D U L A T I O N OF C O R T I C A L A N D P Y R A M I D A L T R A C T I N D U C E D MOT O R RESPONSES BY E L E C T R I C A L S T I M U L A T I O N OF T H E BASAL GANGLIA
ROBERTA A. NEWTON AND DONALD D. PRICE
Department of Physical Therapy, Medical College of Virginia, Virginia Commonwealth University~ Richmond, Va. 23298 and National Institute of Dental Research, NIH, Bethesda, Aid. 20014 (U.S.A.) (Accepted October 14th, 1974)
SUMMARY
Two general mechanisms based on anatomical studies are possible for modulation of motor activity by the caudate nucleus and globus pallidus. These mechanisms are: (i) modulation of the output of cortical neurons that exert motor influences; and (2) modulation of subcortical neurons that exert motor influences. Differentiation between these two mechanisms was accomplished in the present study by two experimental approaches, both of which employed the conditioning-test paradigm. The first approach was an investigation of caudate nucleus or globus pallidus modulation (conditioning stimulus) of flexor responses of the anterior tibialis muscle elicited by electrical stimulation of the sensorimotor cortex (test stimulus) or pyramidal tract (test stimulus). These investigations were carried out in the intact and in decorticate cats. The second approach was an analysis of modulation of cortically induced pyramidal tract responses (direct and indirect, D - I potentials) by conditioning shock trains delivered to various loci within the caudate nucleus or globus pallidus. Both approaches were designed to determine which inhibitory and facilitatory motor influences of the basal ganglia occurred at a cortical or subcortical level. Simultaneous stimulation of a locus within the caudate nucleus and the sensorimotor cortex evoked either an enhancement, reduction or no alteration of the cortically induced increase in flexor responses (measured by Ia afferent activity, EMG, myogram). In contrast, no inhibitory influences occurred from caudate nucleus stimulation upon pyramidal tract induced flexor responses in either the intact or decorticate preparation. Inhibitory loci were distributed toward the rostral portion of the caudate nucleus, whereas facilitatory loci were distributed throughout; this distribution was statistically significant (42; P < 0.01). Only enhancement or no influence upon cortical induced or pyramidal tract induced responses were obtained by conditioning stimuli to the globus pallidus.
404 In the unanesthetized but immobilized cat, trains of shocks delivered to the caudate nucleus enhanced, reduced or had no influence upon the cortically evoked direct (D) and indirect (l) potentials recorded in the bulbar pyramidal tract. The distribution of facilitatory and inhibitory loci was organized in a similar t=ashion as in the anesthetized preparation. From these observations, a model was proposed in which the output of the caudate nucleus exerts both facilitatory or inhibitory modulation ot: the tonically active globus pallidus cells. The latter in turn predominantly or exclusively facilitate output of pyramidal tract neurons as welt as the output of subcortical structures; both effects facilitate motor responses at the spinal level.
INTRODUCTION
The basal ganglia have been shown to exert inhibitory and facilitatory influences on m o t o r activity 6,11,2~,2s. In particular. Liles and Davis have demonstrated that the anteroventral and the dorsal posterior portions of the caudate nucleus have respective inhibitory and facilitatory influences on cortically induced flexor responses 20.21. Furthermore. Granit and K a a d a have demonstrated basal ganglia facilitatory influences upon g a m m a motoneuron activity 7. However. these studies have not determined the brain areas at which these modulating influences are integrated, Therefore, physiological mechanisms underlying basal ganglia influences on motor activity are difficult to assess, especially since these structures are many synapses removed from sensory input and from lower motoneurons 12.13. Two general mechanisms based predominantly on anatomical considerations are possible for modulation of motor activity by the basal ganglia. Modulation o f the output of cortical motoneurons could occur via a well defined pathway from basal ganglia structures to VA and VL thalamic nuclei and from the latter to the sensorim o t o r cortex 15,24. Modulating influence could also occur via globus paltidus projections to lower brain stem structures which in turn affect spinal m o t o r mechanisms. The present study was designed to determine which of these two mechanisms could account for the inhibitory and facilitator~, influences exerted on m o t o r activity by the caudate nucleus and globus pallidus. Differential analysis of these two mechanisms was accomplished in the present study by two experimental approaches. In the first approach, anterior tibialis l ankle flexor) g a m m a and alpha motoneurons were driven by stimulation of the sensorim o t o r cortex or pyramidal tract in anesthetized cats. The modulating influences of the caudate nucleus and globus pallidus on these pathways were determined. To further specify the pathways by which the basal ganglia exert their influences, studies were also done in decorticate preparations. I n the second approach, experiments were performed on unanesthetized animals. In these preparations, the modulatory effect of localized stimulation m areas of the caudate nucleus and globus pallidus upon cortically evoked pyramidal tract discharges was studied. In both types of experiments, a major hypothesis tested was
405 whether the rostral and caudal regions of the caudate respectively exerted inhibitory and facilitatory motor influences. A second purpose of the study was to determine the central nervous system levels at which the inhibitory and facilitatory influences were integrated. METHODS
Anesthetized preparations Thirty-five cats weighing between 2.7 and 4.2 kg were used. These were maintained under light sodium pentobarbital anesthesia (flexion reflex present) during the surgical preparation and during the period of data collection. Four of these cats were decorticated. A tracheal cannula and a femoral venous cannula were inserted into each animal. The animal was then placed in a stereotaxic and spinal frame and the right sensorimotor cortex and the bulbar pyramidal tract were exposed, the latter by a ventral approach. All dorsal surgical wounds were filled with mineral oil and maintained at 37 °C. The body temperature of the preparation was maintained between 35 and 37 °C by a water filled heating pad in contact with the ventral surface of the animak E K G monitored in all preparations indicated normal heart rate (HR -- 130150 beats/rain) and electrical activity. The left hind limb was denervated except for the nerve to the anterior tibialis muscle. The anterior tibialis muscle was dissected free from surrounding tissue and the tendon was attached to a Grass FTO3 force-displacement transducer. An E M G needle electrode was inserted into the belly of the muscle. A laminectomy was performed from spinal segments L3 to S~ and the exposed spinal cord was covered by a pool of mineral oil at 37 °C. A thin filament from the sixth lumbar dorsal root was cut centrally and placed over a silver bipolar recording electrode. The filament was repeatedly divided until, with the aid of audio and visual monitoring, a single spindle afferent from the anterior tibialis was identified. Three criteria were used to identify Ia spindle afferents from the anterior tibialis. (a) These afferents were excited by weak stretches of only the anterior tibialis. (b) They exhibited silent periods during the rising phase of a twitch contractionS, 22. (c) Conduction velocities of these afferents were measured and were greater than 80 m/sec. These Ia afferents increased their firing frequency during electrical stimulation of the sensorimotor cortex and of the bulbar pyramidal tract. Since these increases occurred without concomitant changes in anterior tibia[is myogram or E M G , they therefore served as indications of g a m m a motoneuron activation. Signals from the spindle afferents, myogram, and E M G were amplified, monitored on a Tektronix 502 oscilloscope, and recorded on magnetic tape by means of an 8 track Ampex tape recorder. Bipolar ball-tipped stainless steel electrodes were used to stimulate the leg area of the contralateral sensorimotor cortex. Location of the leg area was obtained by stimulation of the cortex at various locations until an increase in the rate of the anterior tibialis spindle afferent discharge occurred. A similar procedure was used for the contralateral pyramidal tract. Five type G0 stainless steel insect pins insulated to within 0.5 mm from their tips were separated at 1 mm intervals into an array or ' c o m b '
406 o f electrodes. This ' c o m b ' o f electrodes was stereotaxically placed within either the c a u d a t e nucleus o r globus pallidus.
Experimental format A c o n d i t i o n i n g - t e s t p a r a d i g m was used. A test train o f constant current pulses with a pulse d u r a t i o n o f 1.0 msec. a frequency o f 60 Hz and a train d u r a t i o n o f 500 o r 1000 msec was delivered to the cortex. The intensity was a d j u s t e d until a m i n i m a l increase in d o r s a l r o o t discharge was detected. The c o n d i t i o n i n g t r a i n to c a u d a t e nucleus or globus pallidus consisted o f 1130 H z square wave pulses, with a pulse d u r a tion o f 0.5 msec, a n d a train d u r a t i o n o f 5130 or 113130msec. Stimulus intensity within the c a u d a t e nucleus ranged from 2.0 to 2.5 m A , a current strength well below that which w o u l d by itself m o d i f y Ia spindle afferent discharge. Each electrode pair o f the c o m b was used to deliver c o n d i t i o n i n g shocks in a stimulating sequence corn posed o f a m i n i m u m o f one cortical test train, and 5 s i m u l t a n e o u s l y delivered c o n d i t i o n i n g a n d test trains. This f o r m a t was then repeated, with the test stimuli to the cortex replaced by a 1 sec d u r a t i o n train o f 0.5 msec square wave pulses at 1130 H z delivered to the p y r a m i d a l tract. As before, the intensity o f the test train was adjusted until a m i n i m a l increase in spindle afferent discharge occurred. These c o n d i t i o n i n g - t e s t procedures were a p p l i e d using each pair o f electrodes within the ' c o m b ' . Each locus within the c a u d a t e nucleus o r globus pallidus was m a r k e d by an electrolytic lesion. The c o m b of electrodes was lowered 1 m m a n d the e x p e r i m e n t a l f o r m a t was repeated, The same e x p e r i m e n t a l f o r m a t was used in the decorticate p r e p a r a t i o n .
Data analysis The r e c o r d e d d a t a were filmed on L i n o g r a p h p a p e r with a G r a s s K y m o g r a p h camera. Changes in m y o g r a m tension, E M G activity, and frequency of spindle afferent activity were m e a s u r e d for the d u r a t i o n o f the shock trains. If the p a i r e d c o n d i t i o n i n g ,, or m o r e test trains elicited an increase in spindle afferent discharge that was 40 °/ a b o v e the average test response in at least 4 o f the 5 trials, a "~' ' was recorded on the a p p r o p r i a t e sagittal m a p o f the c a u d a t e nucleus or globus pallidus. Similarly, if the c o n d i t i o n i n g - t e s t trains resulted in a decrease in la spindle discharge that was 40°/o or m o r e below the average test response m 4 o f the 5 trials, a ' - ' was recorded. The s t a n d a r d d e v i a t i o n o f the c o n t r o l responses was in each case less than 15 ~!~,. These criteria were sufficient to conclude that responses at each ' ~ ' and ' ' locus were significantly different from the cortical o r p y r a m i d a l tract elicited c o n t r o l responses ( W i l c o x o n sign P
