Brain Research, 96 (1975) 103-107 © Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
103
Noxious effects of excessive currents used for intracortical microstimulation
HIROSHI ASANUMA ANDARTHUR P. ARNOLD The Rockefeller University, New York, N.Y. 10021 (U.S.A.)
(Accepted June 3rd, 1975)
It has been reported by Asanuma and his co-workers that there are small areas within the gray matter of the m o t o r cortex in the catS, 7 and the monkey 8 which upon stimulation can produce contraction of particular muscles. Some of these cortical efferent zones are relatively widespread, having a horizontal diameter of a few millimeters within the cortex, but others are confined to a small volume of the cortex which extends along the direction of the radial fibers having a diameter, in cross-section, of the order of 1.0 m m L Each efferent zone has a sharp boundary, but the fringe frequently overlaps with the fringes of other efferent zones and the zones as a whole form an overlapping mosaic within the m o t o r cortex 3,5. Recently, Andersen et al. 1 have reinvestigated the effects of intracortical microstimulation using the Old World primate Papio (baboon). They confirmed the existence of relatively widespread efferent areas and rediscovered the overlap of these areas which had been reported previously 3. However, they could not find efferent zones of the order of 1.0 sq. m m which had been shown to exist in baboon 1°,11 and Cebus~. They also failed to observe radial spread of low threshold areas within the gray matter s and reported that all low threshold areas are located in the deep layers 1. They discussed the possibility that 'Asanuma and Rosdn's narrower efferent zones and our broader aggregations m a r k a genuine difference between Cebus and Papio - - N e w World and Old World primates.' They also discussed that the discrepancy
in results might have been derived from their use of stronger currents instead of 10 #A used by Asanuma and Ros6n~ and suggested repeating the experiments with stronger currents using Cebus. We have repeated these experiments with stronger currents usingcats, instead of Cebus, because it is known that the Old World primate baboon 1°, the New World primate Cebus 3 and the cat 5 are similar in that they all possess confined efferent foci in addition to larger efferent areas. During the course of their study, Asanuma and Ward 7 reported that repeated intracortical microstimulation (ICMS) of 20 #A (150 pulses of 0.2 msec duration, 3.0 msec interval) delivered to the same position caused deterioration of the responses. They attributed these noxious effects to the bubbling from the tip of the electrode which they observed in saline under the microscope. Andersen et al. 1 used short train I C M S of 80 /~A (6 pulses of 0.2 msec duration, 2.0 msec interval) through silver
104 microelectrode with exposed tip of 15 /zm in diameter and 30 /zm in length. We started the experiments by examining whether the kind of electrode and stimulus parameters they used produce bubbles or not. The electrode was immersed into saline and the tip was observed under the microscope. Both silver and tungsten electrodes of various sizes were examined. The characteristics of silver and tungsten electrodes for bubble production were similar. The threshold for bubbling was dependent on the size of exposed tip and electrodes of 15 # m × 30 # m started producing bubbles with currents of around 60 #A (6 pulses of 0.2 msec duration). The next experiments were carried out with cats under Nembutal anesthesia (35 mg/kg i.p.). Silver or tungsten electrodes of various sizes (from 10 #m x 10/~m to 12 #m × 50 #m) were inserted into the motor cortex while stimulating the medullary pyramid with strong currents. When isolated unitary spikes (/> 150 /~V) of short fixed latency (antidromic) or long variable latency (orthodromic) were recorded through the microelectrode in response to pyramidal stimulation, ICMS of various intensities was delivered through the same cortical electrode. In all the cases, single train ICMS of 80 #A (6 pulses of 0.2 msec duration at 2 msec interval) immediately abolished the unitary spikes of both fixed and variable latencies. Altogether, more than 20 neurons from 2 cats were examined in this way and it was noted that when the spike height was sizable (more than 200/~V), ICMS of 40/~A started abolishing the spikes. Fig. 1 shows an example of the results. As shown in the second line, the antidromic spike disappeared after a single train ICMS of 40 #A. The disappearance of the spikes was unlikely to have resulted from distortion of brain tissue caused by bubbles because in several trials, the electrode was moved around the original position, but the spikes of the same cells could not be found. Furthermore, ICMS of 4 0 / z A usually did not produce bubbles in saline. The results altogether indicated that bubbles are not the only cause of noxious effects produced by excessive currents. The disappearance, however, was not permanent. A small and distorted spike usually started appearing again several to ten minutes after ICMS, depending on the intensity of stimulus, and could recover to the original shape and size a considerable time later. The next step taken was to examine the effectiveness of intracortical stimulation with strong current in producing muscle contractions. The experiments were perform-
200,uV
I
I
I
I
I
0.5 m s e c
Fig. 1. Effect of strong current to a PT cell. Upper line: antidromic spike of a PT cell. Lower line: disappearance of the spike after delivering ICMS of 40/~A (6 pulses of 0.2 msec duration, at 2.0 msec interval) through the same electrode. The electrode used was a silver wire whose exposed tip was 12 /~m × 32/~m. Negativity upward.
105 ed on 2 cats sedated with Nembutal (10 mg/kg). The procedure was exactly the same as that previously described ~. Several penetrations passed through low threshold areas (efferent zones) for various muscles but because of the convexity of the pericruciate gyrus, only 2 passed through cortical areas which elicited contraction of a given muscle and extended more than 1.0 mm along the direction of penetrations. Comparison of the effects of weak and strong ICMS was made utilizing these 2 penetrations and the results of both penetrations were similar. The effects of ICMS were first examined limiting the stimulus current to 15 #A (17 pulses of 0.2 msec duration at 2.5 msec intervals) to avoid possible damage to the cortex. From previous studiesa, 5, it is known that these stimulus parameters are optimal for eliciting muscle contractions and that the threshold increases rapidly when train duration is decreased. It is also known that the effects of ICMS remain unchanged even after repeated penetrations as long as stimulus intensity is limited to this range. In the example shown in Fig. 2, the low threshold area extended along the penetration from layer II to V. The electrode was then withdrawn close to the surface (layer 1) and short train ICMS (6 pulses of 0.2 msec duration at 2.0 msec interval) of 80/zA or less was delivered during the second penetration. During the threshold determination, an important procedure is to manipulate the limb so that the animal is kept alert and
10 o.1 0.3 0.5
Threshold Ipa] 20 30 40 ', ,
/,
o i
i
i
}-
0.7
/;
"...:
ff ~9 1.1 1.3 1.5 1.7 1.9
o
/
.iT \!
, \i o
\o
Fig. 2. Depth-threshold curves for eliciting contraction of m. ext. digit, communis (wrist flexor). Inset figurine shows electrode track and the sites of stimulation. Open squares: thresholds for weak intracortical microstimulation (ICMS). Open and filled circles: thresholds for stronger but shorter ICMS with and without manipulation of the target muscle respectively. Filled squares: thresholds for weak ICMS after delivering strong ICMS. Further details are in the text.
106 stretch-evoked E M G discharges can easily be elicited in the muscles undergoing examination as has been described elsewhere 6. Since Andersen et al. 1 did not describe whether they manipulated the limb during their threshold determination, we determined the threshold with and without manipulation of the limb to allow better comparison between short and long ICMS. As shown in Fig. 2, the threshold for short train without manipulation was very high, the minimum threshold obtained was 70 # A as compared to 3/~A obtained by ICMS of long train. With manipulation, the threshold was lower, but the effect appeared only from deep layers and, in agreement with Andersen et al. 1, 80/~A stimuli in the superficial layers did not elicit muscle contractions. To examine possible brain damage produced by strong currents, ICMS of long train was delivered again l0 min after the strong intracortical stimulation, limiting the intensity to 15 #A. The low threshold contractions from the superficial layers observed in the initial trial could not be reproduced and the effects could be elicited only from the deep layers, but the threshold was higher than the control. The results altogether indicate that excessive currents delivered through metal microelectrodes produce noxious effects to the brain. |t has been shown (Fig. l) that | C M S with 80 #A blocks activity of neurons around the electrode. The damage, however, should be restricted to the immediate vicinity of the electrode and neurons located at the fringe of the effective current spread should be excited by the same stimuli. A question then arises of why activation of neurons in the contiguous area did not elicit muscle contraction when superficial layers were stimulatedL It should be noted that the threshold for producing motoneuron discharges s or movement a by cortical surface stimulation is known to be higher than the threshold for direct activation of PT cells, suggesting that direct activation of PT cells is necessary to activate motoneurons. This in turn indicates that subthreshold surface stimuli for PT cells which must activate a large number of cortical interneurons located in the superficial layers are ineffective in producing motoneuron discharges, hence likely to have failed activating PT cells synaptically. On the other hand, it has been shown that selective activation of a small number of neurons in the superficial layers can produce discharges of PT cells ~ and also motoneurons 7. The neuronal mechanisms for the above phenomena may partly be explained by the observation that the spread to inhibitory effect from a given site in the superficial layers is wider than the spread of excitatory effects 4. Given a stronger stimulus, the inhibitory effects should summate more than the excitatory effects in the contiguous area and at the same time the stimulus current damages the neurons around the electrode. This might have resulted in a failure in el|citing motor effects from the superficial layers as reported by Andersen et al. 1. On the other hand, stimulation at the deeper layer can activate corticofugal neurons directly, hence the stronger the current, the more PT cells (or fibers) are activated. The stronger current at the deep layer, therefore might activate a given motoneuron even from an area where the neuronal density projecting to that motoneuron is sparse. In the present experiments, it is shown that noxious effects are produced when excessive currents are used. These noxious effects can partially be prevented by superimposing weak currents of opposite direction during train stimulation 7 or delivering
107 a short current pulse of opposite direction immediately after each stimulus curren#, 4 as has been r e p o r t e d . This c u r r e n t also prevents the electrode p o l a r i z a t i o n a n d stabilizes c u r r e n t intensity d u r i n g a t r a i n o f stimuli. This cancellation current, however, is effective only within a l i m i t e d c u r r e n t range a n d the p a r a m e t e r s for m i c r o s t i m u l a t i o n , i.e., the frequency a n d the n u m b e r o f pulses, have to be chosen carefully to p r o d u c e the effect w i t h m i n i m u m current. W h e n these p a r a m e t e r s are correct, it is possible to d e m o n s t r a t e the existence o f discrete c o r t i c a l efferent zones where the p o p u l a t i o n density o f n e u r o n s d e s t i n e d for given m o t o n e u r o n p o o l s is the highest. L o w t h r e s h o l d p o i n t s in each efferent zone are a r r a n g e d in a r a d i a l d i r e c t i o n a n d the fringes o f the zones overlap3, 5. This m i g h t be likened to A l p i n e m o u n t a i n s in t h a t each p e a k is discrete, b u t the skirts overlap. T o o b t a i n a clear view o f A l p i n e m o u n t a i n s , however, one has to c h o o s e the c o r r e c t angle a n d a clear sky.
This research was supported by the NIH Grant NS-10705. Dr. A. Arnold was the recipient of the NIH Fellowship 1-S22-MH 00559.
1 ANDERSON,P., HAGAN, P. J., PHILLIPS, C. G., AND POWELL,T. P. S., Mapping by microstimulation of overlapping projections from area 4 to motor units of the baboon's hand, Proc. roy. Soc. B, 188 (1975) 31-60. 2 ASANUMA,H., AND HUNSPERGER,R. W., Functional significance of projection from the cerebellar nuclei to the motor cortex in the cat, Brain Research, in press. 3 ASANUMA,H., AND ROSI~N,I., Topographical organization of cortical efferent zones projecting to distal forelimb muscles in the monkey, Exp. Brain Res., 14 (1972) 243-256. 4 ASANUMA,H., AND ROSEN, I., Spread of mono- and polysynaptic connections within cat's motor cortex, Exp. Brain Res., 16 (1973) 507-520. 5 ASANUMA,S., AND SAKATA,H., Functional organization of a cortical efferent system examined with focal depth stimulation in cats, J. Neurophysiol., 30 (1967) 35-54. 6 ASANUMA,H., STONEY,S. n . , JR., AND ABZUG, C., Relationship between afferent input and motor outflow in cat motorsensory cortex, J. Neurophysiol., 31 (1968) 670-681. 7 ASANUMA,H., AND WARD, J. E., Patterns of contraction of distal forelimb muscles produced by intracortical stimulation in cats, Brain Research, 27 (1971) 97-109. 8 BERNHARD, C. G., AND BOHM, E., Cortical representation and functional significance of the corticomotoneuronal system, Arch. Neurol. Psychiat. (Chic.), 72 (1954) 473-502. 9 HERN, J. E. C., PHILLIPS, C. G., AND PORTER, R., Electrical thresholds of unimpaled corticospinal cells in the cat, Quart. J. exp. Physiol., 47 (1962) 134-140. 10 LANDGREN, S., PHILLIPS, C. G., AND PORTER, R., Cortical fields of origin of the monosynaptic pyramidal pathways to some alpha motoneurons of the baboon's hand and forearm, J, Physiol. (Lond.), 161 (1962) 112-125. 11 PORTER, R., Functions of the mammalian cerebral cortex in movement. In G. A. KERKUT AND J. W. PHILLIS(Eds.), Progress in Neurobiology, Pergamon, Oxford, 1973, p. 1.
103
Noxious effects of excessive currents used for intracortical microstimulation
HIROSHI ASANUMA ANDARTHUR P. ARNOLD The Rockefeller University, New York, N.Y. 10021 (U.S.A.)
(Accepted June 3rd, 1975)
It has been reported by Asanuma and his co-workers that there are small areas within the gray matter of the m o t o r cortex in the catS, 7 and the monkey 8 which upon stimulation can produce contraction of particular muscles. Some of these cortical efferent zones are relatively widespread, having a horizontal diameter of a few millimeters within the cortex, but others are confined to a small volume of the cortex which extends along the direction of the radial fibers having a diameter, in cross-section, of the order of 1.0 m m L Each efferent zone has a sharp boundary, but the fringe frequently overlaps with the fringes of other efferent zones and the zones as a whole form an overlapping mosaic within the m o t o r cortex 3,5. Recently, Andersen et al. 1 have reinvestigated the effects of intracortical microstimulation using the Old World primate Papio (baboon). They confirmed the existence of relatively widespread efferent areas and rediscovered the overlap of these areas which had been reported previously 3. However, they could not find efferent zones of the order of 1.0 sq. m m which had been shown to exist in baboon 1°,11 and Cebus~. They also failed to observe radial spread of low threshold areas within the gray matter s and reported that all low threshold areas are located in the deep layers 1. They discussed the possibility that 'Asanuma and Rosdn's narrower efferent zones and our broader aggregations m a r k a genuine difference between Cebus and Papio - - N e w World and Old World primates.' They also discussed that the discrepancy
in results might have been derived from their use of stronger currents instead of 10 #A used by Asanuma and Ros6n~ and suggested repeating the experiments with stronger currents using Cebus. We have repeated these experiments with stronger currents usingcats, instead of Cebus, because it is known that the Old World primate baboon 1°, the New World primate Cebus 3 and the cat 5 are similar in that they all possess confined efferent foci in addition to larger efferent areas. During the course of their study, Asanuma and Ward 7 reported that repeated intracortical microstimulation (ICMS) of 20 #A (150 pulses of 0.2 msec duration, 3.0 msec interval) delivered to the same position caused deterioration of the responses. They attributed these noxious effects to the bubbling from the tip of the electrode which they observed in saline under the microscope. Andersen et al. 1 used short train I C M S of 80 /~A (6 pulses of 0.2 msec duration, 2.0 msec interval) through silver
104 microelectrode with exposed tip of 15 /zm in diameter and 30 /zm in length. We started the experiments by examining whether the kind of electrode and stimulus parameters they used produce bubbles or not. The electrode was immersed into saline and the tip was observed under the microscope. Both silver and tungsten electrodes of various sizes were examined. The characteristics of silver and tungsten electrodes for bubble production were similar. The threshold for bubbling was dependent on the size of exposed tip and electrodes of 15 # m × 30 # m started producing bubbles with currents of around 60 #A (6 pulses of 0.2 msec duration). The next experiments were carried out with cats under Nembutal anesthesia (35 mg/kg i.p.). Silver or tungsten electrodes of various sizes (from 10 #m x 10/~m to 12 #m × 50 #m) were inserted into the motor cortex while stimulating the medullary pyramid with strong currents. When isolated unitary spikes (/> 150 /~V) of short fixed latency (antidromic) or long variable latency (orthodromic) were recorded through the microelectrode in response to pyramidal stimulation, ICMS of various intensities was delivered through the same cortical electrode. In all the cases, single train ICMS of 80 #A (6 pulses of 0.2 msec duration at 2 msec interval) immediately abolished the unitary spikes of both fixed and variable latencies. Altogether, more than 20 neurons from 2 cats were examined in this way and it was noted that when the spike height was sizable (more than 200/~V), ICMS of 40/~A started abolishing the spikes. Fig. 1 shows an example of the results. As shown in the second line, the antidromic spike disappeared after a single train ICMS of 40 #A. The disappearance of the spikes was unlikely to have resulted from distortion of brain tissue caused by bubbles because in several trials, the electrode was moved around the original position, but the spikes of the same cells could not be found. Furthermore, ICMS of 4 0 / z A usually did not produce bubbles in saline. The results altogether indicated that bubbles are not the only cause of noxious effects produced by excessive currents. The disappearance, however, was not permanent. A small and distorted spike usually started appearing again several to ten minutes after ICMS, depending on the intensity of stimulus, and could recover to the original shape and size a considerable time later. The next step taken was to examine the effectiveness of intracortical stimulation with strong current in producing muscle contractions. The experiments were perform-
200,uV
I
I
I
I
I
0.5 m s e c
Fig. 1. Effect of strong current to a PT cell. Upper line: antidromic spike of a PT cell. Lower line: disappearance of the spike after delivering ICMS of 40/~A (6 pulses of 0.2 msec duration, at 2.0 msec interval) through the same electrode. The electrode used was a silver wire whose exposed tip was 12 /~m × 32/~m. Negativity upward.
105 ed on 2 cats sedated with Nembutal (10 mg/kg). The procedure was exactly the same as that previously described ~. Several penetrations passed through low threshold areas (efferent zones) for various muscles but because of the convexity of the pericruciate gyrus, only 2 passed through cortical areas which elicited contraction of a given muscle and extended more than 1.0 mm along the direction of penetrations. Comparison of the effects of weak and strong ICMS was made utilizing these 2 penetrations and the results of both penetrations were similar. The effects of ICMS were first examined limiting the stimulus current to 15 #A (17 pulses of 0.2 msec duration at 2.5 msec intervals) to avoid possible damage to the cortex. From previous studiesa, 5, it is known that these stimulus parameters are optimal for eliciting muscle contractions and that the threshold increases rapidly when train duration is decreased. It is also known that the effects of ICMS remain unchanged even after repeated penetrations as long as stimulus intensity is limited to this range. In the example shown in Fig. 2, the low threshold area extended along the penetration from layer II to V. The electrode was then withdrawn close to the surface (layer 1) and short train ICMS (6 pulses of 0.2 msec duration at 2.0 msec interval) of 80/zA or less was delivered during the second penetration. During the threshold determination, an important procedure is to manipulate the limb so that the animal is kept alert and
10 o.1 0.3 0.5
Threshold Ipa] 20 30 40 ', ,
/,
o i
i
i
}-
0.7
/;
"...:
ff ~9 1.1 1.3 1.5 1.7 1.9
o
/
.iT \!
, \i o
\o
Fig. 2. Depth-threshold curves for eliciting contraction of m. ext. digit, communis (wrist flexor). Inset figurine shows electrode track and the sites of stimulation. Open squares: thresholds for weak intracortical microstimulation (ICMS). Open and filled circles: thresholds for stronger but shorter ICMS with and without manipulation of the target muscle respectively. Filled squares: thresholds for weak ICMS after delivering strong ICMS. Further details are in the text.
106 stretch-evoked E M G discharges can easily be elicited in the muscles undergoing examination as has been described elsewhere 6. Since Andersen et al. 1 did not describe whether they manipulated the limb during their threshold determination, we determined the threshold with and without manipulation of the limb to allow better comparison between short and long ICMS. As shown in Fig. 2, the threshold for short train without manipulation was very high, the minimum threshold obtained was 70 # A as compared to 3/~A obtained by ICMS of long train. With manipulation, the threshold was lower, but the effect appeared only from deep layers and, in agreement with Andersen et al. 1, 80/~A stimuli in the superficial layers did not elicit muscle contractions. To examine possible brain damage produced by strong currents, ICMS of long train was delivered again l0 min after the strong intracortical stimulation, limiting the intensity to 15 #A. The low threshold contractions from the superficial layers observed in the initial trial could not be reproduced and the effects could be elicited only from the deep layers, but the threshold was higher than the control. The results altogether indicate that excessive currents delivered through metal microelectrodes produce noxious effects to the brain. |t has been shown (Fig. l) that | C M S with 80 #A blocks activity of neurons around the electrode. The damage, however, should be restricted to the immediate vicinity of the electrode and neurons located at the fringe of the effective current spread should be excited by the same stimuli. A question then arises of why activation of neurons in the contiguous area did not elicit muscle contraction when superficial layers were stimulatedL It should be noted that the threshold for producing motoneuron discharges s or movement a by cortical surface stimulation is known to be higher than the threshold for direct activation of PT cells, suggesting that direct activation of PT cells is necessary to activate motoneurons. This in turn indicates that subthreshold surface stimuli for PT cells which must activate a large number of cortical interneurons located in the superficial layers are ineffective in producing motoneuron discharges, hence likely to have failed activating PT cells synaptically. On the other hand, it has been shown that selective activation of a small number of neurons in the superficial layers can produce discharges of PT cells ~ and also motoneurons 7. The neuronal mechanisms for the above phenomena may partly be explained by the observation that the spread to inhibitory effect from a given site in the superficial layers is wider than the spread of excitatory effects 4. Given a stronger stimulus, the inhibitory effects should summate more than the excitatory effects in the contiguous area and at the same time the stimulus current damages the neurons around the electrode. This might have resulted in a failure in el|citing motor effects from the superficial layers as reported by Andersen et al. 1. On the other hand, stimulation at the deeper layer can activate corticofugal neurons directly, hence the stronger the current, the more PT cells (or fibers) are activated. The stronger current at the deep layer, therefore might activate a given motoneuron even from an area where the neuronal density projecting to that motoneuron is sparse. In the present experiments, it is shown that noxious effects are produced when excessive currents are used. These noxious effects can partially be prevented by superimposing weak currents of opposite direction during train stimulation 7 or delivering
107 a short current pulse of opposite direction immediately after each stimulus curren#, 4 as has been r e p o r t e d . This c u r r e n t also prevents the electrode p o l a r i z a t i o n a n d stabilizes c u r r e n t intensity d u r i n g a t r a i n o f stimuli. This cancellation current, however, is effective only within a l i m i t e d c u r r e n t range a n d the p a r a m e t e r s for m i c r o s t i m u l a t i o n , i.e., the frequency a n d the n u m b e r o f pulses, have to be chosen carefully to p r o d u c e the effect w i t h m i n i m u m current. W h e n these p a r a m e t e r s are correct, it is possible to d e m o n s t r a t e the existence o f discrete c o r t i c a l efferent zones where the p o p u l a t i o n density o f n e u r o n s d e s t i n e d for given m o t o n e u r o n p o o l s is the highest. L o w t h r e s h o l d p o i n t s in each efferent zone are a r r a n g e d in a r a d i a l d i r e c t i o n a n d the fringes o f the zones overlap3, 5. This m i g h t be likened to A l p i n e m o u n t a i n s in t h a t each p e a k is discrete, b u t the skirts overlap. T o o b t a i n a clear view o f A l p i n e m o u n t a i n s , however, one has to c h o o s e the c o r r e c t angle a n d a clear sky.
This research was supported by the NIH Grant NS-10705. Dr. A. Arnold was the recipient of the NIH Fellowship 1-S22-MH 00559.
1 ANDERSON,P., HAGAN, P. J., PHILLIPS, C. G., AND POWELL,T. P. S., Mapping by microstimulation of overlapping projections from area 4 to motor units of the baboon's hand, Proc. roy. Soc. B, 188 (1975) 31-60. 2 ASANUMA,H., AND HUNSPERGER,R. W., Functional significance of projection from the cerebellar nuclei to the motor cortex in the cat, Brain Research, in press. 3 ASANUMA,H., AND ROSI~N,I., Topographical organization of cortical efferent zones projecting to distal forelimb muscles in the monkey, Exp. Brain Res., 14 (1972) 243-256. 4 ASANUMA,H., AND ROSEN, I., Spread of mono- and polysynaptic connections within cat's motor cortex, Exp. Brain Res., 16 (1973) 507-520. 5 ASANUMA,S., AND SAKATA,H., Functional organization of a cortical efferent system examined with focal depth stimulation in cats, J. Neurophysiol., 30 (1967) 35-54. 6 ASANUMA,H., STONEY,S. n . , JR., AND ABZUG, C., Relationship between afferent input and motor outflow in cat motorsensory cortex, J. Neurophysiol., 31 (1968) 670-681. 7 ASANUMA,H., AND WARD, J. E., Patterns of contraction of distal forelimb muscles produced by intracortical stimulation in cats, Brain Research, 27 (1971) 97-109. 8 BERNHARD, C. G., AND BOHM, E., Cortical representation and functional significance of the corticomotoneuronal system, Arch. Neurol. Psychiat. (Chic.), 72 (1954) 473-502. 9 HERN, J. E. C., PHILLIPS, C. G., AND PORTER, R., Electrical thresholds of unimpaled corticospinal cells in the cat, Quart. J. exp. Physiol., 47 (1962) 134-140. 10 LANDGREN, S., PHILLIPS, C. G., AND PORTER, R., Cortical fields of origin of the monosynaptic pyramidal pathways to some alpha motoneurons of the baboon's hand and forearm, J, Physiol. (Lond.), 161 (1962) 112-125. 11 PORTER, R., Functions of the mammalian cerebral cortex in movement. In G. A. KERKUT AND J. W. PHILLIS(Eds.), Progress in Neurobiology, Pergamon, Oxford, 1973, p. 1.
