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A special role of the parvocellular red nucleus in lesion-induced spontaneous tremor in monkeys
241
Behavioural Brain Research, 28 (1988) 241-243 Elsevier BBR 00751
A special role of the parvocellular red nucleus in lesion-induced spontaneous tremor in monkeys C. Ohye, T. Shibazaki, T. Hirai, H. Wada, Y. Kawashima, M. Hirato and
M. Matsumura Department of Neurosurgery, Gunma University School of Medicine, Maebashi, Gunma (Japan) (Received 16 March 1987) (Revised version received 7 August 1987) (Accepted 13 August 1987)
Key words: Experimental tremor; Mosaic lesion; Parvocellular division of red nucleus; Stereotaxy; Monkey
The neural mechanisms underlying spontaneous tremor were investigated in monkeys. Tremor-producing ventromedial tegmental (VMT) lesions involve at least three major neural elements. (1)ParvoceUular division of the red nucleus (RNpc); (2) cerebellothalamic fibers passing through the red nucleus, and, (3) nigrostriatal fibers. These three elements were destroyed stereotaxically in areas remote from the VMT area separately and/or in various combinations, and correlation between the site of lesions and tremor was made. Lesion-induced tremor appeared only when the three elements were destroyed. A possible, particular role of the RNpc in the production of the spontaneous tremor is discussed.
Using small monkeys (Macaca irus, BW = 2-3 kg), we studied the neural mechanisms underlying the resting, lesion-induced spontaneous tremor. It is now well established that a mesencephalic ventromedial tegrnental (VMT) lesion may induce sustained tremor of a parkinsonian type, the latter appearing to be superimposed on the flexed posture in the contralateral limbs 5"6"~°. Generally speaking, the tremor develops gradually over a period of 10-14 days after the operation, and once present, it continues for several months (for 7 years according to our longest record). The clinicopathological correlative studies revealed that for tremor production, the VMT lesion should destroy directly the red nucleus parvocellular division (RNpc), cerebellothalamic fibers crossing the RN and the nigrostriatal dopaminergic fibers coursing through the
reticular formation just ventral to the R N 4A3. In a quantitative assessment of the amount of involvement of neural elements destroyed in VMT tremor-producing lesions has shown that at least 75~o of the damage in the RNpc and 75~o of the cell loss in the substantia nigra might represent the essential features to induce sustained tremor 4. It is noteworthy to mention that the magnocellular division of the RN (RNmc) or its crossed efferent, rubrospinal tract were not involved in the tremorproducing lesions. To elucidate further the role of the RNpc in tremor production, we used 5 monkeys (Table I; in this table one monkey with a standard VMT lesion was added for comparison). We produced stereotaxically mosaic lesions involving the above-mentioned neural elements separately in other brainstem areas than the VMT itself2,3,14.
Correspondence: C. Ohye, Department of Neurosurgery, Gunma University School of Medicine, 3-39-22, Showa-machi, Maebashi-shi, Gunma-ken, 371, Japan. 0166-4328/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)
242
Oz
RN f Pc Passin 9 fiber (Cerebellot hal
(!) RN
RN
-H-
"
"
QClC
"
~) DPCS
@ deep VMT
Spontaneous tremor
'
® DPCMZ~I
SN
+
D~, ¢Kainlc x ®""' acid'
3M I
0 DPCS ~ )
VMT
Harmaline induced tremor
J3
+
® deep VMT @deep VMT
4-
+
+
+
~) deep vivlT
+
I
i
+
J I
_
i 4+
I:>75°to :effect
Selective stereotaxic lesions were produced 6 by using Leksell's shortest coagulating needles ( = 2 mm) for human stereotactic surgery and a radiofrequency coagulator, one coagulation involving brain tissue of about 2 x 2 x 1.5 mm 3 (length x interval of two needles x outer diameter of the needle). Lesions were placed after radiological and neurophysiological controls 1'6. For example, the location of several specific deep structures were determined precisely referring to the posterior commissure visualized on ventriculography with a radio-opaque substance, and prior to coagulation, using a bipolar concentric needle electrode, RNpc and RNmc were identified by the characteristic spontaneous electrical activity proper to either RN parts. Thus, three types of lesions were made (1)by coagulation or by local injection of kainic acid (for instance, 1.6 ng was injected by a nanoliter pump, to destroy the cellular elements) in the RNpc, (2) at the level of decussation of the brachium conjunctivum (DPCS) for severing cerebeUothalamic fibers, and (3)at the base of the VMT, not impinging on the RN to interrupt nigrostriatal fibers. These lesions were made in several combinations, in random order, with certain intervals of weeks (W) or months (M) (Table I). An operated monkey was kept in a special cage in a c o m -
•
+
~):<75°/o @:not enough e s t i m a t e d by cell loss in SN
fortable condition, and its movement (especially tremor) was observed at least once a day for 2-3 weeks, and thereafter once a week. If tremor was observed during inspection, a mark ( + ) was given, and a mark ( + + ) denoted virtually continuous tremor (see Table I). Histological examinations verified mostly the intended lesions at the conclusion of each experiment. A coagulation lesion confmed to the RNpc did not induce drug-free tremor (K 7 in Table I). The monkey apparently did not show any abnormal movement. Monkey P3 had an initial lesion at DPCS (destroying only a dorsal part of the decussation) and another lesion at deep VMT one month later. This monkey with an intact RN did not develop tremor and failed to respond to hatmaline. Monkey 07 had a RNpc lesion followed by a DPCS lesion 3 months later and a deep VMT lesion after another month. Resting tremor developed only after the third lesion. Monkey J3 had first a deep VMT lesion. A DPCS lesion added 10 months later did not produce tremor. Then a third lesion was placed by injecting kainic acid into the RNpc. Resting tremor appeared only after the third lesion. Monkey P6 had a DPCS lesion Fn'st and a deep VMT lesion two weeks later, without producing any tremor. But after adding a third lesion by kainic acid injection into
243 the R N p c , resting tremor developed. In both cases, cell loss in the R N p c was almost complete. Harmaline-induced tremor was observed when the cerebellar efferents were damaged ~2. H o w ever, m o n k e y P3, in which the D P C S lesion was not properly placed, did not show tremor after harmaline. In this respect, harmaline may be used as an indicator o f damage to certain cerebellar components. The present observations, although more tissue damaging procedures were used than a single lesion, confirm that in order to produce resting drug-free tremor, at least 3 major neural elements, the R N p c , cerebellothalamic fibers and nigrostriatal fibers must be simultaneously involved. A m o n g them, the R N p c seems to be o f particular interest because phylogenetically the R N p c is hyperdeveloped only in the higher primates, including human, and the primate is the only experimental animal in which the parkinsonian type o f tremor has been produced. However, unfortunately, the R N p c has been scarcely investigated and its functional role in the nervous system is still poorly understood. It has already been suggested that damage o f nigrostriatal fibers by a V M T lesion leads to a cell loss in the substantia nigra pars c o m p a c t a associated with dopamine deficiency in the striatum TM. This in turn produces a postural change 8. This postural change may play an important preparatory role in the production o f 'spontaneous' or resting tremor, as the latter is always superimposed to the former, in the flexed limb. In the m o n k e y with sustained tremor, recording experiments were c o n d u c t e d to find out the tremor-mediating pathway in the spinal cord and in the lower brainstem. In the light of a series of experiments, we are tempted to suggest that rhythmic grouped discharges initiated at the level o f the pontine reticular formation, descend ipsilaterally by way of the reticulospinal tract 7,9. Therefore, the next question to be answered might be to establish the possible relationship between the neural elements involved in V M T lesions (as described above) and the pontine reticular formation.
1 Feger, J., Ohye, C., Gallouin, F. and Albe-Fessard, D., Stereotaxic technique for stimulation and recording in non-anesthetized monkeys: application to the determination of connections between caudate nucleus and substantia nigra. In B.S. Meldrum and C.D. Marsden (Eds.), Advances in Neurology, Vol. 10, Raven, New York, 1975, pp. 35-45. 2 Larochelle, L., Bedard, P., Boucher, R. and Poirier, L.J., The rubro-olivo-cerebello-rubral loop and postural tremor in the monkey, J. Neurol. Sci., 11 (1970) 53-64. 3 Nagaseki, S., Hirai, T., Imai, S., Miyazaki, M., Tsukahara, Y., Ohye, C., Experimental tremor in monkeys. Studies in the selective small lesions in the midbrain, Clin. Neurol., 21 (1981) 1117. 40hye, C., Pathophysiology of experimental tremor in monkeys, Adv. Neurol. Sci., 22 (1978) 765-767. 50hye, C., Primate model of Parkinsonian motor symptoms, Adv. Neurol. Sci., 23 (1979) 949-955. 60hye, C., Imai, S., Nakajima, H., Shibazaki, T. and Hirai, T., Experimental study of spontaneous postural tremor induced by a more successful tremor-producing procedure in the monkey. In L.J. Poirier, T.L. Sourkes and P.J. Bedard (Eds.), Advances in Neurology, Vol. 24, Raven, New York, 1979, pp. 83-91. 70hye, C., Shibazaki, T., Hirai, T., Nagaseki, K., Wada, H., Kawashima, Y. and Hirato, M. Possible descending pathways mediating spontaneous tremor in monkeys. In Advances in Neurology, Vol. 40, Raven, New York, 1984, pp. 181-188. 80hye, C., Shibazaki, T., Hirai, T., Nagaseki, Y., Hirato, M., Wada, H. and Kawashima, Y., Postural and behavioral changes related to the nigral cell loss in monkeys. In J.S. McKenzie, R.E. Kemm, L.N. Wilcock (Eds.), The Basal Ganglia - - Structure and Function, Plenum, New York, 1984, pp. 393-404. 90hye, C., Neurons of the thalamic ventralis intermedius nucleus - - their special reference to tremor, Adv. Neurol. Sci., 29 (1985) 222-231. 10 Poirier, L.J., Experimental and histological study of midbrain dyskinesias, J. Neurophysiol., 23 (1960) 534-551. 11 Poirier, L.J. and Sourkes, T.L., Influence of the substantia nigra on the catecholamine content of the striatum, Brain, 88 (1965) 181-192. 12 Poirier, L.J. and Sourkes, T.L., Bouvier, G., Boucher, R. and Carabin, S., Striatal amines, experimental tremor and the effect of harmaline in the monkey, Brain, 89 (1966) 37-52. 13 Poirier, L.J., Bouvier, G., Bedard, P., Boucher, R., Larochelle, L., et al., Essai sur les circuits neuronaux impliques dans le tremblement postural et l'hypokinesie, Rev. Neurol., 120 (1969) 12-40. 14 Wada, H., Hirai, T., Kawashima, Y., Hirato, M., Shibazaki, T., Ohye, C., Experimental tremor in monkey - - role of the parvocellular part of the red nucleus, Clin. Neurol., 22 (1982) 1207.
Behavioural Brain Research, 28 (1988) 241-243 Elsevier BBR 00751
A special role of the parvocellular red nucleus in lesion-induced spontaneous tremor in monkeys C. Ohye, T. Shibazaki, T. Hirai, H. Wada, Y. Kawashima, M. Hirato and
M. Matsumura Department of Neurosurgery, Gunma University School of Medicine, Maebashi, Gunma (Japan) (Received 16 March 1987) (Revised version received 7 August 1987) (Accepted 13 August 1987)
Key words: Experimental tremor; Mosaic lesion; Parvocellular division of red nucleus; Stereotaxy; Monkey
The neural mechanisms underlying spontaneous tremor were investigated in monkeys. Tremor-producing ventromedial tegmental (VMT) lesions involve at least three major neural elements. (1)ParvoceUular division of the red nucleus (RNpc); (2) cerebellothalamic fibers passing through the red nucleus, and, (3) nigrostriatal fibers. These three elements were destroyed stereotaxically in areas remote from the VMT area separately and/or in various combinations, and correlation between the site of lesions and tremor was made. Lesion-induced tremor appeared only when the three elements were destroyed. A possible, particular role of the RNpc in the production of the spontaneous tremor is discussed.
Using small monkeys (Macaca irus, BW = 2-3 kg), we studied the neural mechanisms underlying the resting, lesion-induced spontaneous tremor. It is now well established that a mesencephalic ventromedial tegrnental (VMT) lesion may induce sustained tremor of a parkinsonian type, the latter appearing to be superimposed on the flexed posture in the contralateral limbs 5"6"~°. Generally speaking, the tremor develops gradually over a period of 10-14 days after the operation, and once present, it continues for several months (for 7 years according to our longest record). The clinicopathological correlative studies revealed that for tremor production, the VMT lesion should destroy directly the red nucleus parvocellular division (RNpc), cerebellothalamic fibers crossing the RN and the nigrostriatal dopaminergic fibers coursing through the
reticular formation just ventral to the R N 4A3. In a quantitative assessment of the amount of involvement of neural elements destroyed in VMT tremor-producing lesions has shown that at least 75~o of the damage in the RNpc and 75~o of the cell loss in the substantia nigra might represent the essential features to induce sustained tremor 4. It is noteworthy to mention that the magnocellular division of the RN (RNmc) or its crossed efferent, rubrospinal tract were not involved in the tremorproducing lesions. To elucidate further the role of the RNpc in tremor production, we used 5 monkeys (Table I; in this table one monkey with a standard VMT lesion was added for comparison). We produced stereotaxically mosaic lesions involving the above-mentioned neural elements separately in other brainstem areas than the VMT itself2,3,14.
Correspondence: C. Ohye, Department of Neurosurgery, Gunma University School of Medicine, 3-39-22, Showa-machi, Maebashi-shi, Gunma-ken, 371, Japan. 0166-4328/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)
242
Oz
RN f Pc Passin 9 fiber (Cerebellot hal
(!) RN
RN
-H-
"
"
QClC
"
~) DPCS
@ deep VMT
Spontaneous tremor
'
® DPCMZ~I
SN
+
D~, ¢Kainlc x ®""' acid'
3M I
0 DPCS ~ )
VMT
Harmaline induced tremor
J3
+
® deep VMT @deep VMT
4-
+
+
+
~) deep vivlT
+
I
i
+
J I
_
i 4+
I:>75°to :effect
Selective stereotaxic lesions were produced 6 by using Leksell's shortest coagulating needles ( = 2 mm) for human stereotactic surgery and a radiofrequency coagulator, one coagulation involving brain tissue of about 2 x 2 x 1.5 mm 3 (length x interval of two needles x outer diameter of the needle). Lesions were placed after radiological and neurophysiological controls 1'6. For example, the location of several specific deep structures were determined precisely referring to the posterior commissure visualized on ventriculography with a radio-opaque substance, and prior to coagulation, using a bipolar concentric needle electrode, RNpc and RNmc were identified by the characteristic spontaneous electrical activity proper to either RN parts. Thus, three types of lesions were made (1)by coagulation or by local injection of kainic acid (for instance, 1.6 ng was injected by a nanoliter pump, to destroy the cellular elements) in the RNpc, (2) at the level of decussation of the brachium conjunctivum (DPCS) for severing cerebeUothalamic fibers, and (3)at the base of the VMT, not impinging on the RN to interrupt nigrostriatal fibers. These lesions were made in several combinations, in random order, with certain intervals of weeks (W) or months (M) (Table I). An operated monkey was kept in a special cage in a c o m -
•
+
~):<75°/o @:not enough e s t i m a t e d by cell loss in SN
fortable condition, and its movement (especially tremor) was observed at least once a day for 2-3 weeks, and thereafter once a week. If tremor was observed during inspection, a mark ( + ) was given, and a mark ( + + ) denoted virtually continuous tremor (see Table I). Histological examinations verified mostly the intended lesions at the conclusion of each experiment. A coagulation lesion confmed to the RNpc did not induce drug-free tremor (K 7 in Table I). The monkey apparently did not show any abnormal movement. Monkey P3 had an initial lesion at DPCS (destroying only a dorsal part of the decussation) and another lesion at deep VMT one month later. This monkey with an intact RN did not develop tremor and failed to respond to hatmaline. Monkey 07 had a RNpc lesion followed by a DPCS lesion 3 months later and a deep VMT lesion after another month. Resting tremor developed only after the third lesion. Monkey J3 had first a deep VMT lesion. A DPCS lesion added 10 months later did not produce tremor. Then a third lesion was placed by injecting kainic acid into the RNpc. Resting tremor appeared only after the third lesion. Monkey P6 had a DPCS lesion Fn'st and a deep VMT lesion two weeks later, without producing any tremor. But after adding a third lesion by kainic acid injection into
243 the R N p c , resting tremor developed. In both cases, cell loss in the R N p c was almost complete. Harmaline-induced tremor was observed when the cerebellar efferents were damaged ~2. H o w ever, m o n k e y P3, in which the D P C S lesion was not properly placed, did not show tremor after harmaline. In this respect, harmaline may be used as an indicator o f damage to certain cerebellar components. The present observations, although more tissue damaging procedures were used than a single lesion, confirm that in order to produce resting drug-free tremor, at least 3 major neural elements, the R N p c , cerebellothalamic fibers and nigrostriatal fibers must be simultaneously involved. A m o n g them, the R N p c seems to be o f particular interest because phylogenetically the R N p c is hyperdeveloped only in the higher primates, including human, and the primate is the only experimental animal in which the parkinsonian type o f tremor has been produced. However, unfortunately, the R N p c has been scarcely investigated and its functional role in the nervous system is still poorly understood. It has already been suggested that damage o f nigrostriatal fibers by a V M T lesion leads to a cell loss in the substantia nigra pars c o m p a c t a associated with dopamine deficiency in the striatum TM. This in turn produces a postural change 8. This postural change may play an important preparatory role in the production o f 'spontaneous' or resting tremor, as the latter is always superimposed to the former, in the flexed limb. In the m o n k e y with sustained tremor, recording experiments were c o n d u c t e d to find out the tremor-mediating pathway in the spinal cord and in the lower brainstem. In the light of a series of experiments, we are tempted to suggest that rhythmic grouped discharges initiated at the level o f the pontine reticular formation, descend ipsilaterally by way of the reticulospinal tract 7,9. Therefore, the next question to be answered might be to establish the possible relationship between the neural elements involved in V M T lesions (as described above) and the pontine reticular formation.
1 Feger, J., Ohye, C., Gallouin, F. and Albe-Fessard, D., Stereotaxic technique for stimulation and recording in non-anesthetized monkeys: application to the determination of connections between caudate nucleus and substantia nigra. In B.S. Meldrum and C.D. Marsden (Eds.), Advances in Neurology, Vol. 10, Raven, New York, 1975, pp. 35-45. 2 Larochelle, L., Bedard, P., Boucher, R. and Poirier, L.J., The rubro-olivo-cerebello-rubral loop and postural tremor in the monkey, J. Neurol. Sci., 11 (1970) 53-64. 3 Nagaseki, S., Hirai, T., Imai, S., Miyazaki, M., Tsukahara, Y., Ohye, C., Experimental tremor in monkeys. Studies in the selective small lesions in the midbrain, Clin. Neurol., 21 (1981) 1117. 40hye, C., Pathophysiology of experimental tremor in monkeys, Adv. Neurol. Sci., 22 (1978) 765-767. 50hye, C., Primate model of Parkinsonian motor symptoms, Adv. Neurol. Sci., 23 (1979) 949-955. 60hye, C., Imai, S., Nakajima, H., Shibazaki, T. and Hirai, T., Experimental study of spontaneous postural tremor induced by a more successful tremor-producing procedure in the monkey. In L.J. Poirier, T.L. Sourkes and P.J. Bedard (Eds.), Advances in Neurology, Vol. 24, Raven, New York, 1979, pp. 83-91. 70hye, C., Shibazaki, T., Hirai, T., Nagaseki, K., Wada, H., Kawashima, Y. and Hirato, M. Possible descending pathways mediating spontaneous tremor in monkeys. In Advances in Neurology, Vol. 40, Raven, New York, 1984, pp. 181-188. 80hye, C., Shibazaki, T., Hirai, T., Nagaseki, Y., Hirato, M., Wada, H. and Kawashima, Y., Postural and behavioral changes related to the nigral cell loss in monkeys. In J.S. McKenzie, R.E. Kemm, L.N. Wilcock (Eds.), The Basal Ganglia - - Structure and Function, Plenum, New York, 1984, pp. 393-404. 90hye, C., Neurons of the thalamic ventralis intermedius nucleus - - their special reference to tremor, Adv. Neurol. Sci., 29 (1985) 222-231. 10 Poirier, L.J., Experimental and histological study of midbrain dyskinesias, J. Neurophysiol., 23 (1960) 534-551. 11 Poirier, L.J. and Sourkes, T.L., Influence of the substantia nigra on the catecholamine content of the striatum, Brain, 88 (1965) 181-192. 12 Poirier, L.J. and Sourkes, T.L., Bouvier, G., Boucher, R. and Carabin, S., Striatal amines, experimental tremor and the effect of harmaline in the monkey, Brain, 89 (1966) 37-52. 13 Poirier, L.J., Bouvier, G., Bedard, P., Boucher, R., Larochelle, L., et al., Essai sur les circuits neuronaux impliques dans le tremblement postural et l'hypokinesie, Rev. Neurol., 120 (1969) 12-40. 14 Wada, H., Hirai, T., Kawashima, Y., Hirato, M., Shibazaki, T., Ohye, C., Experimental tremor in monkey - - role of the parvocellular part of the red nucleus, Clin. Neurol., 22 (1982) 1207.