Pain - Session II Chairmen: B. S. N ashold, Durham, N. C., W. U mbach, Berlin Proc. 6th Symp. Int. Soc. Res. Stereoencephalotomy, Tokyo 1973, part II Confinia neurol. 37: 99-106 (1975)
Nociceptive Neurons in the Human Thalamus B uichi I shijima , N orio Y oshimasu, T akanori F ukushima, T omokatsu H ori, H iroaki Sekino and K eiji Sano Department of Neurosurgery, Tokyo Metropolitan Police Hospital, Department of Neurosurgery, Jichi Medical School, Tochigi Pref., and Department of Neurosurgery, Faculty of Medicine, University of Tokyo, Tokyo
The intralaminar nuclei or centrum median and parafascicular com plex (CM-Pf complex) have often been a favorite target point for intract able pain. The functional properties of these structures in terms of pain, however, still remain to be clarified especially in the human thalamus. The purpose of the present study is to see whether neurons exist in the CM-Pf complex which respond to peripheral noxious natural stimulation and, if they do exist, what are their physiological characteristics from the viewpoint of pain perception mechanisms at the thalamic level.
Materials and Method
Downloaded by: MacQuarie University 137.111.162.20 - 1/20/2020 3:21:06 PM
The recording was done in 11 stereotaxic operations in 7 cases. Four cases out of 7 were intractable pain, 2 were spasmodic torticollis and one was abnormal eye movement, seesaw nystagmus [8]. The target was the CM-Pf complex for pain and the pretectal area including interstitial nucleus of Cajal for the others. In all cases electrodes passed through the medial aspect of the intralaminar nuclei. All the oper ations were done under local anesthesia. The microclectrode was made of tungsten wire of 200 /tm in diameter and sev eral millimeters in length, and was fixed in the small stainless steel tube. The resist ance was 5-10 Mi2. It was driven by a small screw micromanipulator which was situated on the stereotaxic apparatus. Signals were displayed on the cathode ray os cilloscope via the cathode follower, and recorded on the magnetic tape at the same time as the time mark of the stimulation.
100
Ishijima/Y oshimasu/F ukushima/H ori/S ekino/S ano
(260 )
Noxious stimulation was provided by a needle held on a small switching device which would close the circuit for the electrical time mark when the needle was pushed to the skin. For heat stimulation, a test tube filled with hot water (60-70 °C) was used.
Results
Downloaded by: MacQuarie University 137.111.162.20 - 1/20/2020 3:21:06 PM
The neurons successfully recorded in the thalamus and in the pretectal area were 190 in total. 75 neurons were picked up in the dorsomedial nu cleus, 80 in the CM-Pf complex and 35 in the pretectal area. Out of 80 neurons in the CM-Pf complex, 20 responded to pin prick at the body surface, 2 of which responded to the heat as well. No nociceptive neuron was found in the dorsomedial nucleus or pretectal area. None responded to the stimulation of lemniscal modalities except for one neuron in the CM-Pf complex which was activated by finger movement of the contralat eral hand. 20 nociceptive neurons in the CM-Pf complex may be divided into 2 groups, according to their response. The neurons of one group (type A) responded with short latency and duration. Another group (type B) had long and fluctuating response. Figure 1 is a typical example of a type-A neuron. It responds to the stimulation of the contralateral half and ipsilateral upper half of the body. Its response latency varies from 30 to 90 msec, depending upon the dis tance of stimulation points from the thalamus. But it is almost constant, if the stimuli are given to the same point repeatedly. Thus, it is possible to calculate the conduction velocity of the system which mediates the impul ses to this neuron. It was roughly calculated as 16-20 m/sec for this sys tem as a whole which includes both peripheral and central nervous sys tems. The response duration is 150-300 msec. Again, it tends to be long er at the more remote stimulation points. In ipsilateral stimulation, the duration is longer and the response intensity is weaker than in stimulation of the contralateral side. Here, the response intensity is regarded as stronger when the neuron responded with more spikes with shorter inter spike intervals. Eleven neurons out of 20 were found to be of such a type. They were mainly distributed in the medial and basal area of the Pf nu cleus (fig. 2). Figure 3 illustrates an example of a type-B neuron. This response is not as clear as that of type-A, although an apparent increase of discharges is observed 100-500 msec after the stimulation. Its latency is variable
(261)
Nociceptive Neurons in the Human Thalamus
101
Contra. Cheek
Forearm
Thigh Lower leg
Ipsi. Cheek
Hand
500 msec Fig.l. Typical example of type-A response of a neuron in the Pf. The bar with arrow means the length of time of stimulating the skin with the needle. Activities of three neurons are being recorded simultaneously. The largest and smallest ones show a response of the same pattern. Middle-sized spikes seem to be entirely indif ferent. Upward is positive in figures 1, 3 and 4. The number at each trace shows the position of the stimulation in the body. The shaded portion of the body is the recep tive field. Contra. = Contralateral: Ipsi. = Ipsilateral.
Downloaded by: MacQuarie University 137.111.162.20 - 1/20/2020 3:21:06 PM
from time to time. Its duration is usually 1-2 sec or more. The threshold is higher; in other words, stronger pin prick is necessary to produce a re sponse. Moreover, it shows rapid adaptation. It responds only at the ini tial two or three stimuli, and about a minute is necessary to regain the ini tial responsiveness. The receptive field is wide. too. This particular neu ron in figure 3 responded to the finger movement of the contralateral hand. Nine neurons showed such a type of response. They were found to be scattered in the CM and in the dorsal part of Pf nucleus (fig. 2). Duali ty of the response, as A l b e - F e s s a r d et al. [1 ] observed in the CM neu rons of cats, was not seen in the human thalamus.
102
Ishijima/Y oshimasu/F ukushima/H ori/S ekino /S ano
(262 )
Fig. 2. Recorded neurons are schematically plotted on the Schaltenbrand and Bailey [9] Atlas, a Sagittal section at 5.0 mm lateral from the midline, b Frontal
Downloaded by: MacQuarie University 137.111.162.20 - 1/20/2020 3:21:06 PM
section at 6.5 mm posterior to the midpoint of the AC-PC line. Right and left of the maps is reversed from the originals. Each mark represents some group of neurons. Black circles are nociceptive neurons. Simple black circles are type-A and black circle with a dot represent type-B. White circles are neurons entirely indifferent to any kind of stimulation. Other marks are not related to pain. Ce, Centrum median; Edy, n. endymalis; Gr.ce.mes, griseum centrale mesencephali; Hb, n. habenularis; iLa, n. intralamellaris; Lim, n. limitans thalami; M, n. dorsomedialis; Pf, n. parafascicularis; PC, commissura posterior; R, n. ruber; T.t.c., tractus tegmentalis cen tralis; V.c., n. ventrocaudalis, V.im, n. ventrointermedius, Z.i.dc, n. zonae incertae dorsocaudalis.
( 263)
Nociceptive Neurons in the Human Thalamus
103
K.S., U.5 Hancj3 iMwi1** I
Ipsi. jaw
1
li,i|
2
m 4y»U » * » ) >■.!.». Jfaj Jfa fa.fa I .kl| itm, i., l u f .., 3
Thigh
U « fa U
Contra., finger movement
500 msec
Fig. 3. Example of type-B response of a neuron in the CM. The bottom trace shows the concurrent increase of discharge with the finger movement of the contra lateral hand.
Two neurons were activated by heat as well as by pin prick. One of them was type-A and another was a type-B neuron. It is of interest that the response modes of both neurons look alike. They resemble that of type-B response to the pin prick. Figure 4 is a response of a type-A neu ron to heat. It has a long latency and its duration is also very long. The inhibitory influence of the lemniscal system on the activity of the nociceptive neurons was not demonstrated. Discussion Discrepancy between the Anatomical and Physiological Findings There has been a controversy in the anatomical field as to whether or not the spinothalamic tract terminates in the CM-Pf complex. However, by the recent studies made by Mehter et al., on monkey [5] and man Downloaded by: MacQuarie University 137.111.162.20 - 1/20/2020 3:21:06 PM
Thigh
» « » »Mu. fa
104
ISHIJIMA/YOSHIMASU/FUKUSHIMA/HORl/SEKrNO/SANO
(264 )
200 msec
Fig. 4. Response to heat stimulation of a neuron in the Pf. A test tube filled with hot water was touched to the contralateral thigh for the period shown by the bar under the trace. This neuron belongs to the type-A group.
Downloaded by: MacQuarie University 137.111.162.20 - 1/20/2020 3:21:06 PM
[6], a direct termination is almost excluded. According to M eh ler , only a small part of the spinothalamic fibers ‘pass through’ the CM as far as nu cleus centralis lateralis. This finding is, however, not compatible with the clinical results of stimulation and destruction of the CM-Pf complex [7]. The stimulation of this area in man produces burning pain in a wide area of the body contralaterally, or sometimes even bilaterally [7]. The result of destruction is well known to all neurosurgeons who perform stereotaxic surgery. Phy siological data from the experiments also indicate that this thalamic struc ture is closely related to the noxious sensation which is considered to be carried by the A.6 and C-fibers in the peripheral nervous system [2, 4]. The results of our study give support to the concept that, at least from the physiological point of view, noxious sensation is mediated via the CM-Pf complex, provided that those response discharges are not the ac tion potentials of fibers which are ‘passing through’ this nuclei complex. There is no direct evidence that they are the action potentials of somadendrites of the neurons. However, the following facts might strongly sug gest that this is the case: (1) The deflection of the spike is initially posi tive-negative and dien the positive component becomes dominant as the electrode is drawn nearer. Finally, the spikes become completely positive just before injury. (2) On some occasion, the amplitude of spikes sudden ly becomes tremendously large in the positive direction at the time of in jury, suggesting that the tip of the electrode is in the cell body. (3) Injury discharge usually persists long, showing the waxing and waning corre sponding to the pulse. (4) The potential is usually recorded in a long range along the electrode track (60-100 /
Nociceptive Neurons in the Human Thalamus B uichi I shijima , N orio Y oshimasu, T akanori F ukushima, T omokatsu H ori, H iroaki Sekino and K eiji Sano Department of Neurosurgery, Tokyo Metropolitan Police Hospital, Department of Neurosurgery, Jichi Medical School, Tochigi Pref., and Department of Neurosurgery, Faculty of Medicine, University of Tokyo, Tokyo
The intralaminar nuclei or centrum median and parafascicular com plex (CM-Pf complex) have often been a favorite target point for intract able pain. The functional properties of these structures in terms of pain, however, still remain to be clarified especially in the human thalamus. The purpose of the present study is to see whether neurons exist in the CM-Pf complex which respond to peripheral noxious natural stimulation and, if they do exist, what are their physiological characteristics from the viewpoint of pain perception mechanisms at the thalamic level.
Materials and Method
Downloaded by: MacQuarie University 137.111.162.20 - 1/20/2020 3:21:06 PM
The recording was done in 11 stereotaxic operations in 7 cases. Four cases out of 7 were intractable pain, 2 were spasmodic torticollis and one was abnormal eye movement, seesaw nystagmus [8]. The target was the CM-Pf complex for pain and the pretectal area including interstitial nucleus of Cajal for the others. In all cases electrodes passed through the medial aspect of the intralaminar nuclei. All the oper ations were done under local anesthesia. The microclectrode was made of tungsten wire of 200 /tm in diameter and sev eral millimeters in length, and was fixed in the small stainless steel tube. The resist ance was 5-10 Mi2. It was driven by a small screw micromanipulator which was situated on the stereotaxic apparatus. Signals were displayed on the cathode ray os cilloscope via the cathode follower, and recorded on the magnetic tape at the same time as the time mark of the stimulation.
100
Ishijima/Y oshimasu/F ukushima/H ori/S ekino/S ano
(260 )
Noxious stimulation was provided by a needle held on a small switching device which would close the circuit for the electrical time mark when the needle was pushed to the skin. For heat stimulation, a test tube filled with hot water (60-70 °C) was used.
Results
Downloaded by: MacQuarie University 137.111.162.20 - 1/20/2020 3:21:06 PM
The neurons successfully recorded in the thalamus and in the pretectal area were 190 in total. 75 neurons were picked up in the dorsomedial nu cleus, 80 in the CM-Pf complex and 35 in the pretectal area. Out of 80 neurons in the CM-Pf complex, 20 responded to pin prick at the body surface, 2 of which responded to the heat as well. No nociceptive neuron was found in the dorsomedial nucleus or pretectal area. None responded to the stimulation of lemniscal modalities except for one neuron in the CM-Pf complex which was activated by finger movement of the contralat eral hand. 20 nociceptive neurons in the CM-Pf complex may be divided into 2 groups, according to their response. The neurons of one group (type A) responded with short latency and duration. Another group (type B) had long and fluctuating response. Figure 1 is a typical example of a type-A neuron. It responds to the stimulation of the contralateral half and ipsilateral upper half of the body. Its response latency varies from 30 to 90 msec, depending upon the dis tance of stimulation points from the thalamus. But it is almost constant, if the stimuli are given to the same point repeatedly. Thus, it is possible to calculate the conduction velocity of the system which mediates the impul ses to this neuron. It was roughly calculated as 16-20 m/sec for this sys tem as a whole which includes both peripheral and central nervous sys tems. The response duration is 150-300 msec. Again, it tends to be long er at the more remote stimulation points. In ipsilateral stimulation, the duration is longer and the response intensity is weaker than in stimulation of the contralateral side. Here, the response intensity is regarded as stronger when the neuron responded with more spikes with shorter inter spike intervals. Eleven neurons out of 20 were found to be of such a type. They were mainly distributed in the medial and basal area of the Pf nu cleus (fig. 2). Figure 3 illustrates an example of a type-B neuron. This response is not as clear as that of type-A, although an apparent increase of discharges is observed 100-500 msec after the stimulation. Its latency is variable
(261)
Nociceptive Neurons in the Human Thalamus
101
Contra. Cheek
Forearm
Thigh Lower leg
Ipsi. Cheek
Hand
500 msec Fig.l. Typical example of type-A response of a neuron in the Pf. The bar with arrow means the length of time of stimulating the skin with the needle. Activities of three neurons are being recorded simultaneously. The largest and smallest ones show a response of the same pattern. Middle-sized spikes seem to be entirely indif ferent. Upward is positive in figures 1, 3 and 4. The number at each trace shows the position of the stimulation in the body. The shaded portion of the body is the recep tive field. Contra. = Contralateral: Ipsi. = Ipsilateral.
Downloaded by: MacQuarie University 137.111.162.20 - 1/20/2020 3:21:06 PM
from time to time. Its duration is usually 1-2 sec or more. The threshold is higher; in other words, stronger pin prick is necessary to produce a re sponse. Moreover, it shows rapid adaptation. It responds only at the ini tial two or three stimuli, and about a minute is necessary to regain the ini tial responsiveness. The receptive field is wide. too. This particular neu ron in figure 3 responded to the finger movement of the contralateral hand. Nine neurons showed such a type of response. They were found to be scattered in the CM and in the dorsal part of Pf nucleus (fig. 2). Duali ty of the response, as A l b e - F e s s a r d et al. [1 ] observed in the CM neu rons of cats, was not seen in the human thalamus.
102
Ishijima/Y oshimasu/F ukushima/H ori/S ekino /S ano
(262 )
Fig. 2. Recorded neurons are schematically plotted on the Schaltenbrand and Bailey [9] Atlas, a Sagittal section at 5.0 mm lateral from the midline, b Frontal
Downloaded by: MacQuarie University 137.111.162.20 - 1/20/2020 3:21:06 PM
section at 6.5 mm posterior to the midpoint of the AC-PC line. Right and left of the maps is reversed from the originals. Each mark represents some group of neurons. Black circles are nociceptive neurons. Simple black circles are type-A and black circle with a dot represent type-B. White circles are neurons entirely indifferent to any kind of stimulation. Other marks are not related to pain. Ce, Centrum median; Edy, n. endymalis; Gr.ce.mes, griseum centrale mesencephali; Hb, n. habenularis; iLa, n. intralamellaris; Lim, n. limitans thalami; M, n. dorsomedialis; Pf, n. parafascicularis; PC, commissura posterior; R, n. ruber; T.t.c., tractus tegmentalis cen tralis; V.c., n. ventrocaudalis, V.im, n. ventrointermedius, Z.i.dc, n. zonae incertae dorsocaudalis.
( 263)
Nociceptive Neurons in the Human Thalamus
103
K.S., U.5 Hancj3 iMwi1** I
Ipsi. jaw
1
li,i|
2
m 4y»U » * » ) >■.!.». Jfaj Jfa fa.fa I .kl| itm, i., l u f .., 3
Thigh
U « fa U
Contra., finger movement
500 msec
Fig. 3. Example of type-B response of a neuron in the CM. The bottom trace shows the concurrent increase of discharge with the finger movement of the contra lateral hand.
Two neurons were activated by heat as well as by pin prick. One of them was type-A and another was a type-B neuron. It is of interest that the response modes of both neurons look alike. They resemble that of type-B response to the pin prick. Figure 4 is a response of a type-A neu ron to heat. It has a long latency and its duration is also very long. The inhibitory influence of the lemniscal system on the activity of the nociceptive neurons was not demonstrated. Discussion Discrepancy between the Anatomical and Physiological Findings There has been a controversy in the anatomical field as to whether or not the spinothalamic tract terminates in the CM-Pf complex. However, by the recent studies made by Mehter et al., on monkey [5] and man Downloaded by: MacQuarie University 137.111.162.20 - 1/20/2020 3:21:06 PM
Thigh
» « » »Mu. fa
104
ISHIJIMA/YOSHIMASU/FUKUSHIMA/HORl/SEKrNO/SANO
(264 )
200 msec
Fig. 4. Response to heat stimulation of a neuron in the Pf. A test tube filled with hot water was touched to the contralateral thigh for the period shown by the bar under the trace. This neuron belongs to the type-A group.
Downloaded by: MacQuarie University 137.111.162.20 - 1/20/2020 3:21:06 PM
[6], a direct termination is almost excluded. According to M eh ler , only a small part of the spinothalamic fibers ‘pass through’ the CM as far as nu cleus centralis lateralis. This finding is, however, not compatible with the clinical results of stimulation and destruction of the CM-Pf complex [7]. The stimulation of this area in man produces burning pain in a wide area of the body contralaterally, or sometimes even bilaterally [7]. The result of destruction is well known to all neurosurgeons who perform stereotaxic surgery. Phy siological data from the experiments also indicate that this thalamic struc ture is closely related to the noxious sensation which is considered to be carried by the A.6 and C-fibers in the peripheral nervous system [2, 4]. The results of our study give support to the concept that, at least from the physiological point of view, noxious sensation is mediated via the CM-Pf complex, provided that those response discharges are not the ac tion potentials of fibers which are ‘passing through’ this nuclei complex. There is no direct evidence that they are the action potentials of somadendrites of the neurons. However, the following facts might strongly sug gest that this is the case: (1) The deflection of the spike is initially posi tive-negative and dien the positive component becomes dominant as the electrode is drawn nearer. Finally, the spikes become completely positive just before injury. (2) On some occasion, the amplitude of spikes sudden ly becomes tremendously large in the positive direction at the time of in jury, suggesting that the tip of the electrode is in the cell body. (3) Injury discharge usually persists long, showing the waxing and waning corre sponding to the pulse. (4) The potential is usually recorded in a long range along the electrode track (60-100 /
