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Distribution of nociceptive neurons in the ventrobasal complex of macaque thalamus
Neuroscience Research 31 (1998) 39 – 51
Distribution of nociceptive neurons in the ventrobasal complex of macaque thalamus Natsu Koyama a,*, Yasuo Nishikawa b, Toshikatsu Yokota a b
a Department of Physiology, Shiga Uni6ersity of Medical Science, Seta, Otsu 520 -2192, Japan Department of Physiology, Osaka Dental Uni6ersity, 8 -1, Kuzuhahanazono-cho, Hirakata-shi, Osaka 573 -1121, Japan
Received 2 September 1997; accepted 28 February 1998
Abstract In urethane–chloralose anesthetized Japanese macaques, the distribution of nociceptive neurons within the thalamic ventrobasal (VB) complex was studied. Nociceptive specific (NS) and wide dynamic range (WDR) neurons were found in the periphery of the contralateral integument compartment of the VB complex. Thus, they formed a shell at the perimeter of this compartment with a somatotopic organization. The compartment consisted of large parts of nucleus ventralis posteromedialis (VPM) and nucleus ventralis posterolateralis, pars caudalis (VPLc). NS neurons were located more caudally than WDR neurons. In the NS zone of VPM, the forehead was represented caudally, and oral structures rostrally. In the ventral NS zone of VPM, there was a sequential representation of the tongue, gum and mandibular skin from the medial to the lateral edge. The hand was represented medially in the NS zone of VPLc, and its representation dominated in the rostral NS zone. There was a sequential representation of the cervical, thoracic, lumbar, sacral and caudal segments mediolaterally along the dorsal VPLc. In the medial half of ventral NS zone of VPLc, the upper body half was represented, and in the lateral half, the lower body half. The foot was represented at or near the medial edge of lateral half. In the rostral WDR zone, the trunk and peripheral face were represented. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Thalamus; Nociception; Ventrobasal complex; Monkey
1. Introduction The nucleus ventralis posterior (VP) of the monkey’s thalamus consists of four parts: nucleus ventralis posteromedialis (VPM), nucleus ventralis posteromedialis parvocellularis (VPMpc), nucleus ventralis posterolateralis (VPL) and nucleus ventralis posterior inferior (VPI). The VPL is further subdivided into pars oralis (VPLo) and pars caudalis (VPLc) (Olszewski, 1952; Jones, 1985). The ventrobasal (VB) complex of the thalamus comprises somatosensory parts of the nucleus ventralis posterior. In the monkey, it is coextensive with VPM and VPLc, exclusive of the VPMpc and VPLo (Olszewski, 1952; Jones, 1985). * Corresponding author. Tel.: + 81 775 2147; fax.: + 81 775 2146; e-mail: [email protected]
It is widely accepted that there are nociceptive specific (NS) and wide dynamic range (WDR) neurons in the VB complex of mammalian thalamus (Kenshalo et al., 1980; Guilbaud et al., 1980; Casey and Morrow, 1983; Honda et al., 1983; Kniffki and Mizumura, 1983; Albe-Fessard et al., 1985; Yokota et al., 1985, 1986, 1988a,b; Chung et al., 1986; Bushnell and Duncan, 1987; Zagami and Lambert, 1990; Chandler et al., 1992; Hutchison et al., 1992; Morrow and Casey, 1992; Berkley et al., 1993; Bushnell et al., 1993; Simone et al., 1993; Apkarian and Shi, 1994). Previously we reported that both NS and WDR neurons in the cat are somatotopically distributed in the periphery of VB complex, thus forming a shell at the perimeter of this complex (Yokota et al., 1985, 1988b). The detailed pattern of nociceptive representation within the primate VB complex is still unknown. The present study was undertaken to clarify this problem.
0168-0102/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0168-0102(98)00021-2
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2. Materials and methods A total of 53 Japanese macaques (Macaca fuscata) weighing 4.3–9.4 kg, were used. They were supplied by the Laboratory Animal Institute of our university and the protocol was approved by our Animal Care and Use Committee. The animals were pretreated with intramuscular ketamine (20 mg/kg) and were then anesthetized with intravenous administration of 3.5 ml/kg of urethane–chloralose solution (urethane 125 mg/ml and chloralose 10 mg/ml). Supplementary doses of urethane–chloralose solution were administered as required. Anesthesia was considered sufficiently deep when the pupils were small, and when no pupillary dilatation or blood pressure changes occurred on noxious heating or mechanical stimulation of the integument. In addition, animals were routinely allowed to recover from paralysis during the course of experiment, and the flexion–withdrawal reflexes were checked. In rare cases in which any motor or autonomic reflexes occurred, urethane– chloralose solution was infused. Body temperature was monitored with an esophageal probe and was maintained at 3791°C. Acraniotomy was performed on the right side to allow introduction of a recording microelectrode into the thalamus. During exploration, muscle paralysis was maintained with pancuronium bromide (2 – 4 mg kg − 1
h − 1). The animal was artificially ventilated with room air, and end-tidal CO was maintained between 3.5 and 4.5%. Glass capillary microelectrodes filled with 4% pontamine sky blue in 0.5 M sodium acetate were used to record single unit activity in the thalamus. The thalamus was explored by making rows of microelectrode penetrations in Horsley-Clarke frontal planes. In most experiments, these penetrations were made 0.5 mm apart in the mediolateral direction, but in others at 0.25-mm intervals. Single unit potentials were amplified and fed into a window discriminator. The output pulses of the window discriminator were used by a spike counter to compile peristimulus time histograms. Once well-isolated unitary activity had been recorded from the thalamus, the somatic receptive field of the unit was examined and mapped using mechanical stimuli. The mechanical stimuli included displacement of hairs, stroking and probing the skin, firm but innocuous pressure exerted by picking up a fold of skin with flattened forceps or an arterial clip, and noxious pinch with small serrated forceps or an alligator clip. For thalamic units that responded to mechanical stimuli in the noxious range, a graded radiant heat stimulus was, if accessible, applied to the skin near the center of the receptive field as determined by mechanical stimulation.
Fig. 1. Responses of a trigeminal NS unit exclusively driven by noxious stimulation. (A) Receptive field in the forehead (black area). (B) Responses to graded mechanical stimuli. Upper trace illustrates peristimulus time histogram. Bin width is 1 s. Histogram calibration shows number of spike discharges/s. Lower trace illustrates spike discharges. (C) Responses to heat stimuli graded in temperature. Upper trace shows peristimulus time histogram, whereas lower trace shows skin temperature. Both mechanical and heat stimuli were applied to the black area in (A).
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Fig. 2. Recording sites of NS and LTM units and their receptive fields. Observations were made during three microelectrode penetrations through caudal VB complex. Filled circles, open circles, filled squares and open squares along vertical lines indicate positions at which trigeminal NS, trigeminal LTM, spinal NS and spinal LTM units were identified, respectively. Corresponding receptive fields are shown in figurines.
Precisely controlled local skin temperatures were obtained using a servo-controlled thermostimulator, coupled with a quartz halogen lamp. The lamp was focused onto the skin through a condenser lens. The current to the lamp was controlled by feedback from a thermister in contact with the skin. The duration of heat stimuli was preset at 20 s. The skin temperature was adapted to 35°C for 3 min before each heat stimulus. After concluding an observation of interest, the recording site was marked with pontamine sky blue, extruded from the tip of the microelectrode by passing a current of 5 mA (electrode negative) through it for 10 min. At the termination of each experiment, the brain
was cleared of blood and fixed in situ by perfusing 1000 ml of normal saline through the beating heart, followed by 3000 ml of 10% formalin–saline. After postfixation for at least 1 week, the brain was frozen, cut into 50-mm coronal sections, and stained with cresyl violet. Dye marks were identified in the stained sections, and these were photographed. Abbreviations used in photomicrographs are as follows: CL, nucleus centralis lateralis; CM, nucleus centrum medianum; GL, corpus geniculatum laterale; GM, corpus geniculatum mediale; LP, nucleus lateralis posterior; MD, nucleus medialis dorsalis; PuO, nucleus pulvinaris oralis; R, nucleus reticularis thalami; Ret,
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formatio reticularis; VPI, nucleus ventralis posterior inferior; VPLc, nucleus ventralis posterolateralis, pars caudalis; VPM, nucleus ventralis posteromedialis.
3. Results Altogether 4483 units were studied. All units included in this report were located in the VB complex and had a receptive field on the contralateral integument. We did not systematically explore the ipsilateral compartment of VPM described by Jones et al. (1986). Of the neurons examined, 2416 were located in VPM, and the rest in VPLc. VPM units had a receptive field in the contralateral trigeminal nerve territory, whereas VPL units in the contralateral spinal nerve territory. Of VPM units, 2229 were trigeminal low-threshold mechanoreceptive (LTM) units, 174 were trigeminal NS units and 13 were trigeminal WDR units. Of VPL units, 1858 were spinal LTM units, 170 were spinal NS units and 39 were spinal WDR units.
3.1. Trigeminal NS units Trigeminal NS units had a circumscribed receptive field on the facial skin, oral mucosa or pinna. The great
majority of them responded exclusively to noxious mechanical stimuli with a maintained discharge (Fig. 1B). Some of them responded to innocuous pressure applied with flattened forceps or an arterial clip. They discharged, however, more vigorously, when a noxious pinch was applied. Some NS units responded to noxious heat stimulation of the same receptive field as previously defined by noxious mechanical stimulation. Fig. 1C illustrates responses evoked by graded radiant heat stimulation. All NS units studied showed a resting activity. The activity was suppressed when a supplementary dose of urethane–chloralose solution was administered. The administration also suppressed responses evoked by noxious mechanical stimulation, but the size of receptive field remained unchanged. Fig. 2 illustrates locations and receptive fields of trigeminal and spinal units recorded from a transverse plane of the caudal part of VB complex in one animal. The circles and squares placed along the tracks mark positions at which unit responses were obtained. The receptive fields of units obtained at these positions are presented in the form of figurine drawings. At this level, VPM is ventrally and laterally surrounded by VPLc. Two trigeminal NS units were isolated from the dorsal fringe of the VPM. The medial unit had a cutaneous
Fig. 3. Reconstruction of 10 microelectrode penetrations through VB complex. Observations were made in a transverse plane at a level rostral to the one illustrated in Fig. 2. Each figurine represents receptive field of corresponding trigeminal NS unit.
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Fig. 4. Reconstruction of three microelectrode penetrations through VPM, showing locations of NS and LTM units and receptive fields of NS units.
receptive field in the maxillary nerve territory, and the lateral unit in the ophthalmic nerve division. In the present experiments, altogether 10 trigeminal NS units were obtained at or near this transverse plane. All of them were located in the dorsal fringe of VPM. Of these, four were maxillary NS units, five were ophthalmic NS units and one NS unit had a receptive field in the pinna. Maxillary NS units were located more medially, and the pinna NS unit most laterally. None of them had a cutaneous receptive field in the mandibular nerve territory of facial skin or in the oral cavity. Fig. 3 illustrates an experiment which explored VPM at a level more rostral to the one illustrated in Fig. 2. The figure shows data obtained from 10 microelectrode penetrations 250 mm apart which passed through VPM and the adjacent VPLc. Of 168 units within the VB complex, 85 were trigeminal NS and LTM units activated by stimulation of the maxillary skin (12 units), mandibular skin (37 units), tongue (eight units) or the rest of oral mucosa (28 units). Receptive fields of facial units were mainly located in the perioral or paranasal area. The forehead was no longer represented at this
level. The figure shows that trigeminal NS units were located in the peripheral part of a compartment of VPM in which the contralateral trigeminal integument is represented. The majority of trigeminal NS units had a receptive field either in the tongue or in the rest of oral mucosa. The data presented on the figurine overlays show that in the ventral VPM, there was an orderly sequence of nociceptive representation of the tongue, oral mucosa and mandibular skin from the medial to the lateral edge of the nucleus. NS units in the dorsal fringe of VPM had a receptive field in the tongue or maxillary skin. In the experiment illustrated in Fig. 4, trigeminal NS neurons were found around the dorsomedial and ventrolateral borders of VPM which presumably correspond to calbindin-positive areas described by Rausell and Jones (1991a,b) (see Section 4).
3.2. Trigeminal WDR units WDR units had a graded response to brush, pressure and noxious pinch applied to the center of the receptive
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field (black area in Fig. 5B), and responded best to noxious pinch (Fig. 5Ca). Outside this zone (crosshatched area in Fig. 5B), they were unresponsive to low-intensity mechanical stimuli, but responded differentially to pressure and noxious pinch (Fig. 5Cb). Finally the latter area was surrounded by an area (shaded area in Fig. 5B) in which only noxious pinch resulted in unit discharges (Fig. 5Cc). The receptive field was strictly confined to the contralateral integument. Trigeminal WDR units were located more rostrally than trigeminal NS units. Fig. 6 illustrates an experiment in which three trigeminal WDR units were obtained. They had a receptive field in the facial skin. Although the peri- and intraoral structures dominated in the rostral NS zone, other parts of the facial skin were significantly represented at this level.
3.3. Spinal NS units Spinal NS units were obtained at levels in which trigeminal NS units were found. Fig. 7 illustrates an experiment in which a transverse plane through the caudal VB complex was explored. Trigeminal and spinal NS units were found in the periphery of a compartment of VB complex in which the contralateral integument is represented. The hand was represented by only one LTM unit at this level. Locations and receptive fields of spinal NS units obtained in 12 experiments which explored more rostral planes than the one presented in Fig. 7, are shown in Fig. 8. In this figure, results are summarized in a transverse plane explored in one experiment. Spinal NS units were located in the dorsal and ventral fringes of a
Fig. 5. A trigeminal WDR unit. (A) Location of the unit. (B) Receptive field. (C) Responses of the unit to graded mechanical stimulation of the receptive field. Areas a, b, and c indicated by arrows in (B) were stimulated and responses to these areas are shown in a, b, and c, respectively. Upper traces show peristimulus time histograms, whereas lower traces show spike discharges. Horizontal bars indicate periods of stimulus application.
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Fig. 6. Reconstruction of three microelectrode penetrations through VPM, showing locations and receptive fields of trigeminal WDR and LTM units. Half-filled and open circles in the photomicrograph indicate locations of trigeminal WDR and LTM units, respectively.
compartment of VPLc in which the contralateral spinal integument is represented. In the medial half, most of the NS units obtained had a circumscribed receptive field in the hand. Excluding the hand, there was an orderly sequence of representation of the cervical, thoracic, lumbar, sacral and caudal segments in the mediolateral direction in the lateral two-thirds of the dorsal region. In the ventral region, there is a gap in the middle due to interposition of VPI. The lateral half is dislocated more ventrally than the medial half. In the medial half, the upper body half was represented, whereas in the lateral half, the lower body half. The foot was represented at and near the medial edge of the lateral half, and more proximal parts of the hindlimb were represented more laterally. The medial half was
dominated by the distal forelimb, especially by the hand.
3.4. Spinal WDR units As in the case of VPM, spinal WDR units were located more rostrally than spinal NS units. Fig. 9 illustrates an experiment in which the border between NS and WDR zones was explored. NS units were located medially, whereas WDR units were found laterally. The contralateral spinal body surface compartment was dominated by representation of the hand at this level. Nine units encountered in dorsal parts of two lateral penetrations responded to manipulation of the forelimb which activates receptors in the muscle. Thus,
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nociceptive units were encountered in these two lateral penetrations at or near the border between the core of VPLc in which the contralateral integument is represented and the shell of Jones and Friedman (1982) in which deep tissues are represented. In five experiments, a level comparable to the one shown in Fig. 9 was explored. In each experiment, both NS and WDR units were found, and altogether 10 NS and 16 WDR units were obtained. Fig. 10 illustrates an experiment in which four WDR units were obtained. Representation of the hand occupied a relatively small volume of VPLc and that of the
trunk occupied a significant volume. Of four WDR units obtained, two had a receptive field in the chest wall. In general, there was a somatotopic organization within the spinal WDR zone as in the case of spinal NS zone. In the dorsal region, rostral segments were represented medially, and more caudal segments more laterally. In the ventral region, the upper body half was represented medially, whereas the lower half laterally. The foot was represented near the medial edge of the lower body half zone.
3.5. Nocicepti6e units in VPI Although we did not systematically explore the structures ventral to the VB complex, three nociceptive units were obtained from these structures. One example is illustrated in Fig. 11. The unit was located in nucleus ventralis inferior (VPI), and had nociceptive peripheral receptive fields in the trunk, proximal parts of forelimbs, perioral region, bilateral pinna and bilateral cornea. Nociceptive receptive fields of two other units were also much larger than those of NS and WDR units recorded from the VB complex.
4. Discussion
Fig. 7. Reconstruction of four microelectrode penetrations through caudal part of VB complex, showing locations and receptive fields of NS and LTM units.
In the present experiments, nociceptive neurons were not evenly distributed across the VB complex; two different classes of nociceptive neurons, i.e. NS and WDR neurons, were found in the periphery of a compartment of VB complex in which the contralateral body surface is represented. Thus, they formed a shell at the perimeter of the contralateral integument compartment. This compartment consisted of large parts of VPM and VPLc. Both NS and WDR neurons showed a somatotopic organization within the VB complex. Peripheral receptive field organizations of these two classes of thalamic nociceptive neurons were much the same as those of their counterparts in the spinal cord or trigeminal subnucleus caudalis. These two classes of nociceptive neurons appear to use afferent inputs to convert into output while maintaining significant features of spatial information processed at the level of spinal cord or its trigeminal homologue. In the previous studies, segregation of LTM and nociceptive neurons within the thalamus was less clear in the monkey than in the cat, but most studies show a tendency for nociceptive neurons to be unevenly distributed across the VB complex (Kenshalo et al., 1980; Casey and Morrow, 1983; Chung et al., 1986; Bushnell and Duncan, 1987; Morrow and Casey, 1992; Bushnell et al., 1993). In the present experiments, NS units were recorded caudally and WDR units were recorded rostrally. In the
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Fig. 8. Summary of locations and receptive fields of NS units in VPLc at a level rostral to the one illustrated in Fig. 7.
transitional level, both NS and WDR units were recorded. At this level, units with deep inputs were found in the dorsal and lateral parts of the VPL. Hence the number of NS or WDR units obtained depends on the level of VP nucleus explored. For example, Apkarian and Shi (1994) explored the level of VPL where neurons with deep inputs were found, and obtained more WDR units than NS units. In experiments, we explored a comparable level, and obtained 10 NS and 16 WDR units from VPL. One reason why we obtained more NS units than WDR units is that we have more extensively explored the caudal part of the VP nucleus. Another factor affecting the number of NS or WDR units obtained is the kind of search stimulus. In the awake animal, it is difficult to use noxious stimuli to search for VB complex neurons. In contrast, WDR neurons can be first detected by innocuous stimuli, and then confirmed by noxious stimuli. Thus, the number of nociceptive neurons when recordings are obtained while awake may be biased toward WDR neurons. Anatomically, there are species differences in the organization of the somatosensory thalamus. In the cat, the terminal projection zones of the dorsal column nuclei and the spinal cord are largely segregated, the dorsal column nuclei projecting to the cutaneous core of VB complex and the spinal cord projecting to a shell region (Boivie, 1979; Berkley, 1980). In contrast, there is an extensive overlap between the terminal projection
zones of these two systems in the rat (Ma et al., 1986). Some studies of primate spinothalamic tract terminations suggest that there are clusters of dense terminations near the borders of VPL (Boivie, 1979; Berkley, 1980), whereas other studies of primate spino- and trigeminothalamic tract have found diffuse terminations throughout the ventroposterior thalamus (Ganchrow, 1978; Appelbaum et al., 1979; Apkarian and Hodge, 1989). The discovery of rods and matrix in the monkey VPM (Rausell and Jones, 1991a,b) appears to reconcile these inconsistent findings. The monkey VPM has a vertical limb and a horizontal limb that points medially. Both the trigeminal lemniscus and the dorsal trigeminal tract project to VPM, carrying somatosensory inputs from the contralateral and ipsilateral trigeminal brainstem nuclei, respectively. The vertical limb contains a representation of the contralateral trigeminal integument, while the ipsilateral peri- and intraoral regions are represented in the horizontal limb (Jones et al., 1986). Both limbs are divided into smaller histochemical subcompartments. These are detectable especially by staining for cytochrome oxidase (CO) (Jones et al., 1986). Elongated clumps of CO stain extend, rod-like, through the anteroposterior extent of VPM. Neurons of each CO rod have overlapping peripheral receptive fields, and are driven by the same stimulus submodality. The organization resembles the columnar organization in the primary somatosensory
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cortex (SI) as described by Mountcastle (1957), and neurons of each CO rod project to one or a few narrow, column-like domains in the somatosensory cortex. This has been one of the bases of the rod-to-column principle of thalamocortical organization (Jones et al., 1982). The CO rods are also immunoreactive for parvalbumin (Rausell and Jones, 1991a,b). The CO rods are embedded in a matrix which shows weaker and homogenous staining for CO, but is calbindin-positive (Rausell and Jones, 1991a). The widest extent of this matrix is around the dorsomedial and ventrolateral borders of VPM. The matrix receives predominant input from the trigeminal subnucleus caudalis in which trigeminal nociceptive and thermosensitive neurons are located (Rausell and Jones, 1991b). The presence of a smallcelled matrix region, that is, at its widest extent, around the dorsomedial and ventrolateral borders of VPM, raises parallels with studies of trigeminal nociceptive neurons of the cat VPM (Rausell and Jones, 1991b). The parallels were supported by Bushnell et al. (1993) who reported that, in the awake monkey, thermosensitive neurons were concentrated in the dorsomedial aspect of VPM, with others recorded more ventrally, near the border of VPM/VPI. Most of them produced graded responses to noxious skin heating. This distribution contrasted with the more diffuse scattering of
LTM neurons recorded in the same experiments. They stated that one might expect to record nociceptive responses more easily from neurons at the periphery. These previous findings were confirmed in the present experiments. Hence, nociceptive neurons appear to be exceptions of the rod-to-column thalamocortical organization. This was supported by a physiological study in the primate SI cortex that showed that the vast majority of nociceptive neurons are located in two of the six cortical layers and not organized in columnar fashion (Kenshalo and Isensee, 1983; Kenshalo, 1996). Yasui et al. (1983) subdivided the nucleus ventralis posteromedialis parvocellularis (VPMpc) of the cat into the medial and the lateral subdivisions (VPMpcm and VPMpcl), based on the observations that VPMpcl receives mainly uncrossed afferent fibers from the dorsal subdivision of trigeminal main sensory nucleus, while VPMpcm receives afferent fibers ipsilaterally from the parabrachial nucleus. In our laboratory, it was confirmed that somatic afferent inputs from ipsilateral oral structures project to VPMpcl (Nishikawa et al., 1988; Yokota et al., 1988a). In the monkey, Jones et al. (1986) found an ipsilateral representation in the horizontal limb of VPM. This ipsilateral compartment in the monkey VPM may coincide with VPMpcl in the cat. We found trigeminal nociceptive neurons in the cat,
Fig. 9. Reconstruction of four penetrations through VB complex, showing locations of NS, WDR and LTM units and receptive fields of NS and WDR units. Filled, half-filled and open squares indicate locations of spinal NS, WDR and LTM units, respectively. Filled and open circles indicate locations of trigeminal NS and LTM units, respectively. Location of each muscle unit is indicated by × .
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at the ventromedial fringe of VPM proper confronting the lateral perimeter of VPMpcl (Yokota et al., 1985, 1986). In the present experiments, trigeminal nociceptive neurons were found in the ventromedial periphery of the contralateral integument compartment of VPM. This trigeminal nociceptive zone is within the core of VPM according to Jones et al. (1986), but appears to be the ventromedial fringe of the contralateral integument compartment of VPM confronting the dorsolateral perimeter of the ipsilateral compartment of VPM. Friedman and Jones (1981) and Jones and Friedman (1982) have shown segregation of inputs from deep and
Fig. 10. Reconstruction of three microelectrode penetrations through VPLc, showing locations and receptive fields of WDR and LTM units. Half-filled and open squares indicate locations of spinal WDR and LTM units, respectively.
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cutaneous structures within VPLc of monkeys. Their experiments provide evidence that the rostral and dorsal portion of VPLc is activated by receptors located in deep tissues and that it projects to both area 3a and area 2 in monkeys. Their illustrations attest to the abruptness of the change from cutaneous to deep. This border forms a curving line across the rostral and dorsal VP thalamus causing the input from deep tissues to sit as a cap on the central core of VP. They named this cap region the anterodorsal shell. Dykes (1983) proposed that this region is a submodality specific relay nucleus for muscle spindle information and it should be renamed nucleus ventroposterior oralis (VPO). In the present experiments, nociceptive units were found at or near the border between the contralateral integument compartment of VPLc and this anterodorsal shell. Rose and Mountcastle (1952) studied tactile representation within the VP nucleus in rabbits and cats and argued that several of the ventroposterior thalamic nuclei together formed a single and complete representation of the contralateral body surface, and could be subsumed under a more inclusive term, the ventrobasal (VB) complex. This term was generally accepted in the ensuing four decades. Jones and Burton (1974) pointed out that the primate VB complex is only the posterior division of the VP nucleus. Jones (1985) defined the VB complex of the monkey as a complex consisting of VPM and VPLc. He included in VPM the compartment for ipsilateral trigeminal representation and in VPLc the anterodorsal shell. Dykes (1983) excluded this shell from VPL. The present experiments provide evidence that NS and WDR units are located in the periphery of a compartment in which the contralateral body surface is represented. The contralateral integument compartment is smaller than the VB complex of Jones (1985). Dykes et al. (1981) found in the squirrel monkey that neurons are grouped according to submodality in the VP nucleus. Dykes (1983) further extended these findings and proposed a general theory about the organization of the somatosensory pathways. It states that distinct classes of afferent input are relayed from the periphery to the cerebral cortex on separate and parallel paths. Thus, the cutaneous SA and RA units of the dorsal column nuclei project to the central region of VP, interdigitating within the VB complex. The muscle spindle input from the external cuneate nucleus project to VPO (the anterodorsal shell). The present data indicate that a path for nociceptive input must be included in this parallel processing scheme. Clinical, physiological and anatomical evidence implicates various regions of the thalamus in pain perception (Albe-Fessard et al., 1985; Willis, 1985; Besson and Chaouch, 1987; Apkarian and Hodge, 1989). Obviously the VB complex is not the only thalamic structure involved in pain perception. Various groups have demonstrated that neurons in VPL, VPI and the poste-
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Fig. 11. A nociceptive unit recorded in VPI. The recording site of the unit is shown on the left (indicated by an arrow), and the peripheral receptive field on the right.
rior ventral medial nucleus (VMpo) of monkeys respond to noxious stimuli (Kenshalo et al., 1980; Morrow and Casey, 1992; Apkarian and Shi, 1994; Craig et al., 1994). We partially confirmed these previous findings. Pain has both sensory – discriminative and affective –motivational components, and these may be mediated by distinct anatomical pathways (Willis, 1994).
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N. Koyama et al. / Neuroscience Research 31 (1998) 39–51 Honda, C.N., Mense, S., Perl, E.R., 1983. Neurons in ventrobasal region of cat thalamus selectively responsive to noxious mechanical stimulation. J. Neurophysiol. 49, 662–673. Hutchison, W.D., Luhn, M.A.B., Schmidt, R.F., 1992. Knee joint input into the peripheral region of the ventral posterior lateral nucleus of cat thalamus. J. Neurophysiol. 67, 1092–1104. Jones, E.G., 1985. The Thalamus. Plenum, New York. Jones, E.G., Burton, H., 1974. Cytoarchitecture and somatic sensory connectivity of the thalamic nuclei other than the ventrobasal complex in the cat. J. Comp. Neurol. 154, 395–432. Jones, E.G., Friedman, D.P., 1982. Projection pattern of functional components of thalamic ventrobasal complex on monkey somatosensory cortex. J. Neurophysiol. 48, 521–544. Jones, E.G., Friedman, D.P., Hendry, S.H.C., 1982. Thalamic basis of place and modality-specific columns in monkey somatosensory cortex: a correlative anatomical and physiological study. J. Neurophysiol. 48, 545 – 568. Jones, E.G., Schwank, H.D., Callahan, P.A., 1986. Extent of the ipsilateral representation in the ventral posterior medial nucleus of the monkey thalamus. Exp. Brain Res. 62, 310–320. Kenshalo, D.R., 1996. Pain and the primary sensory cortex. Is its role overrated? Pain Forum 5, 181–183. Kenshalo, D.R., Isensee, O., 1983. Responses of primate SI cortical neurons to noxious stimuli. J. Neurophysiol. 50, 1479–1496. Kenshalo, D.R., Giesler, G.J. Jr., Leonard, R.B., Willis, W.D., 1980. Responses of neurons in primate ventral posterior lateral to noxious stimuli. J. Neurophysiol. 43, 1370–1389. Kniffki, K.-D., Mizumura, K., 1983. Responses of neurons in VPL and VPL-VL region of the cat to algesic stimulation of muscle tendon. J. Neurophysiol. 49, 649–661. Ma, W., Peschanski, M., Besson, J.M., 1986. The overlap of spinothalamic and dorsal column nuclei projections in the ventrobasal complex of the rat thalamus: A double blind anterograde labeling study using light microscopic analysis. J. Comp. Neurol. 245, 531 – 540. Morrow, T.J., Casey, K.L., 1992. State-related modulation of thalamic somatosensory responses in the awake monkey. J. Neurophysiol. 67, 305 – 317. Mountcastle, V.B., 1957. Modality and topographic properties of single neurons of cat’s somatic sensory cortex. J, Neurophysiol. 20, 408 – 434.
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Nishikawa, Y., Koyama, N., Yokota, T., 1988. Ipsilateral somatsensory tongue representation within the lateral subdivision of the nucleus ventralis posteromedialis parvocellularis of the cat thalamus. Brain Res. 458, 394 – 396. Olszewski, J., 1952. The Thalamus of the Macaca Mulata. An Atlas for Use in the Stereotaxic Instruments. Karger, Basel. Rausell, E., Jones, E.G., 1991a. Histochemical and immunohistochemical compartments of the thalamic VPM nucleus in monkeys and their relationship to the representation map. J. Neurosci. 11, 210 – 225. Rausell, E., Jones, E.G., 1991b. Chemically distinct compartments of the thalamic VPM nucleus in monkeys relay principal and spinal trigeminal pathways to different layers of the somatosensory cortex. J. Neurosci. 11, 226 – 237. Rose, J.E., Mountcastle, V.B., 1952. The thalamic tactile region in rabbit and cat. J. Comp. Neurol. 97, 441 – 489. Simone, D.A., Hanson, M.E., Bernau, N.A., Pubols, B.H., 1993. Nociceptive neurons of the raccoon lateral thalamus. J. Neurophysiol. 69, 318 – 328. Willis, W.D., 1985, The Pain System. Karger, Basel. Willis, W.D., 1994. Cold, pain and brain. Nature 373, 19 – 20. Yasui, Y., Itoh, K., Mizuno, N., Nomura, S., Tanaka, M., Konishi, A., Kudo, M., 1983. The posteromedial ventral nucleus of the thalamus (VPM) of the cat: direct ascending projections to the cytoarchitectonic subdivisions. J. Comp. Neurol. 220, 219–228. Yokota, T., Koyama, N., Matsumoto, N., 1985. Somatotopic distribution of trigeminal nociceptive neurons in ventrobasal complex of cat thalamus. J. Neurophysiol. 53, 1387 – 1400. Yokota, T., Nishikawa, Y., Koyama, N., 1986. Tooth pulp input to the shell region of nucleus ventralis posteromedialis of the cat thalamus. J. Neurophysiol. 56, 80 – 98. Yokota, T., Koyama, N., Nishikawa, Y., Hasegawa, A., 1988a. Dual somatosensory representation of the periodontium in nucleus ventralis posteromedialis of the cat thalamus. Brain Res. 475, 187 – 191. Yokota, T., Asato, F., Koyama, N., Masuda, T., Taguchi, H., 1988b. Nociceptive body representation in nucleus ventralis posterolateralis of cat thalamus. J. Neurophysiol. 60, 1714 – 1727. Zagami, A.S., Lambert, G.A., 1990. Stimulation of cranial vessels excites nociceptive neurones in several thalamic nuclei of the cat. Exp. Brain Res. 81, 552 – 566.
Distribution of nociceptive neurons in the ventrobasal complex of macaque thalamus Natsu Koyama a,*, Yasuo Nishikawa b, Toshikatsu Yokota a b
a Department of Physiology, Shiga Uni6ersity of Medical Science, Seta, Otsu 520 -2192, Japan Department of Physiology, Osaka Dental Uni6ersity, 8 -1, Kuzuhahanazono-cho, Hirakata-shi, Osaka 573 -1121, Japan
Received 2 September 1997; accepted 28 February 1998
Abstract In urethane–chloralose anesthetized Japanese macaques, the distribution of nociceptive neurons within the thalamic ventrobasal (VB) complex was studied. Nociceptive specific (NS) and wide dynamic range (WDR) neurons were found in the periphery of the contralateral integument compartment of the VB complex. Thus, they formed a shell at the perimeter of this compartment with a somatotopic organization. The compartment consisted of large parts of nucleus ventralis posteromedialis (VPM) and nucleus ventralis posterolateralis, pars caudalis (VPLc). NS neurons were located more caudally than WDR neurons. In the NS zone of VPM, the forehead was represented caudally, and oral structures rostrally. In the ventral NS zone of VPM, there was a sequential representation of the tongue, gum and mandibular skin from the medial to the lateral edge. The hand was represented medially in the NS zone of VPLc, and its representation dominated in the rostral NS zone. There was a sequential representation of the cervical, thoracic, lumbar, sacral and caudal segments mediolaterally along the dorsal VPLc. In the medial half of ventral NS zone of VPLc, the upper body half was represented, and in the lateral half, the lower body half. The foot was represented at or near the medial edge of lateral half. In the rostral WDR zone, the trunk and peripheral face were represented. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Thalamus; Nociception; Ventrobasal complex; Monkey
1. Introduction The nucleus ventralis posterior (VP) of the monkey’s thalamus consists of four parts: nucleus ventralis posteromedialis (VPM), nucleus ventralis posteromedialis parvocellularis (VPMpc), nucleus ventralis posterolateralis (VPL) and nucleus ventralis posterior inferior (VPI). The VPL is further subdivided into pars oralis (VPLo) and pars caudalis (VPLc) (Olszewski, 1952; Jones, 1985). The ventrobasal (VB) complex of the thalamus comprises somatosensory parts of the nucleus ventralis posterior. In the monkey, it is coextensive with VPM and VPLc, exclusive of the VPMpc and VPLo (Olszewski, 1952; Jones, 1985). * Corresponding author. Tel.: + 81 775 2147; fax.: + 81 775 2146; e-mail: [email protected]
It is widely accepted that there are nociceptive specific (NS) and wide dynamic range (WDR) neurons in the VB complex of mammalian thalamus (Kenshalo et al., 1980; Guilbaud et al., 1980; Casey and Morrow, 1983; Honda et al., 1983; Kniffki and Mizumura, 1983; Albe-Fessard et al., 1985; Yokota et al., 1985, 1986, 1988a,b; Chung et al., 1986; Bushnell and Duncan, 1987; Zagami and Lambert, 1990; Chandler et al., 1992; Hutchison et al., 1992; Morrow and Casey, 1992; Berkley et al., 1993; Bushnell et al., 1993; Simone et al., 1993; Apkarian and Shi, 1994). Previously we reported that both NS and WDR neurons in the cat are somatotopically distributed in the periphery of VB complex, thus forming a shell at the perimeter of this complex (Yokota et al., 1985, 1988b). The detailed pattern of nociceptive representation within the primate VB complex is still unknown. The present study was undertaken to clarify this problem.
0168-0102/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0168-0102(98)00021-2
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2. Materials and methods A total of 53 Japanese macaques (Macaca fuscata) weighing 4.3–9.4 kg, were used. They were supplied by the Laboratory Animal Institute of our university and the protocol was approved by our Animal Care and Use Committee. The animals were pretreated with intramuscular ketamine (20 mg/kg) and were then anesthetized with intravenous administration of 3.5 ml/kg of urethane–chloralose solution (urethane 125 mg/ml and chloralose 10 mg/ml). Supplementary doses of urethane–chloralose solution were administered as required. Anesthesia was considered sufficiently deep when the pupils were small, and when no pupillary dilatation or blood pressure changes occurred on noxious heating or mechanical stimulation of the integument. In addition, animals were routinely allowed to recover from paralysis during the course of experiment, and the flexion–withdrawal reflexes were checked. In rare cases in which any motor or autonomic reflexes occurred, urethane– chloralose solution was infused. Body temperature was monitored with an esophageal probe and was maintained at 3791°C. Acraniotomy was performed on the right side to allow introduction of a recording microelectrode into the thalamus. During exploration, muscle paralysis was maintained with pancuronium bromide (2 – 4 mg kg − 1
h − 1). The animal was artificially ventilated with room air, and end-tidal CO was maintained between 3.5 and 4.5%. Glass capillary microelectrodes filled with 4% pontamine sky blue in 0.5 M sodium acetate were used to record single unit activity in the thalamus. The thalamus was explored by making rows of microelectrode penetrations in Horsley-Clarke frontal planes. In most experiments, these penetrations were made 0.5 mm apart in the mediolateral direction, but in others at 0.25-mm intervals. Single unit potentials were amplified and fed into a window discriminator. The output pulses of the window discriminator were used by a spike counter to compile peristimulus time histograms. Once well-isolated unitary activity had been recorded from the thalamus, the somatic receptive field of the unit was examined and mapped using mechanical stimuli. The mechanical stimuli included displacement of hairs, stroking and probing the skin, firm but innocuous pressure exerted by picking up a fold of skin with flattened forceps or an arterial clip, and noxious pinch with small serrated forceps or an alligator clip. For thalamic units that responded to mechanical stimuli in the noxious range, a graded radiant heat stimulus was, if accessible, applied to the skin near the center of the receptive field as determined by mechanical stimulation.
Fig. 1. Responses of a trigeminal NS unit exclusively driven by noxious stimulation. (A) Receptive field in the forehead (black area). (B) Responses to graded mechanical stimuli. Upper trace illustrates peristimulus time histogram. Bin width is 1 s. Histogram calibration shows number of spike discharges/s. Lower trace illustrates spike discharges. (C) Responses to heat stimuli graded in temperature. Upper trace shows peristimulus time histogram, whereas lower trace shows skin temperature. Both mechanical and heat stimuli were applied to the black area in (A).
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Fig. 2. Recording sites of NS and LTM units and their receptive fields. Observations were made during three microelectrode penetrations through caudal VB complex. Filled circles, open circles, filled squares and open squares along vertical lines indicate positions at which trigeminal NS, trigeminal LTM, spinal NS and spinal LTM units were identified, respectively. Corresponding receptive fields are shown in figurines.
Precisely controlled local skin temperatures were obtained using a servo-controlled thermostimulator, coupled with a quartz halogen lamp. The lamp was focused onto the skin through a condenser lens. The current to the lamp was controlled by feedback from a thermister in contact with the skin. The duration of heat stimuli was preset at 20 s. The skin temperature was adapted to 35°C for 3 min before each heat stimulus. After concluding an observation of interest, the recording site was marked with pontamine sky blue, extruded from the tip of the microelectrode by passing a current of 5 mA (electrode negative) through it for 10 min. At the termination of each experiment, the brain
was cleared of blood and fixed in situ by perfusing 1000 ml of normal saline through the beating heart, followed by 3000 ml of 10% formalin–saline. After postfixation for at least 1 week, the brain was frozen, cut into 50-mm coronal sections, and stained with cresyl violet. Dye marks were identified in the stained sections, and these were photographed. Abbreviations used in photomicrographs are as follows: CL, nucleus centralis lateralis; CM, nucleus centrum medianum; GL, corpus geniculatum laterale; GM, corpus geniculatum mediale; LP, nucleus lateralis posterior; MD, nucleus medialis dorsalis; PuO, nucleus pulvinaris oralis; R, nucleus reticularis thalami; Ret,
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formatio reticularis; VPI, nucleus ventralis posterior inferior; VPLc, nucleus ventralis posterolateralis, pars caudalis; VPM, nucleus ventralis posteromedialis.
3. Results Altogether 4483 units were studied. All units included in this report were located in the VB complex and had a receptive field on the contralateral integument. We did not systematically explore the ipsilateral compartment of VPM described by Jones et al. (1986). Of the neurons examined, 2416 were located in VPM, and the rest in VPLc. VPM units had a receptive field in the contralateral trigeminal nerve territory, whereas VPL units in the contralateral spinal nerve territory. Of VPM units, 2229 were trigeminal low-threshold mechanoreceptive (LTM) units, 174 were trigeminal NS units and 13 were trigeminal WDR units. Of VPL units, 1858 were spinal LTM units, 170 were spinal NS units and 39 were spinal WDR units.
3.1. Trigeminal NS units Trigeminal NS units had a circumscribed receptive field on the facial skin, oral mucosa or pinna. The great
majority of them responded exclusively to noxious mechanical stimuli with a maintained discharge (Fig. 1B). Some of them responded to innocuous pressure applied with flattened forceps or an arterial clip. They discharged, however, more vigorously, when a noxious pinch was applied. Some NS units responded to noxious heat stimulation of the same receptive field as previously defined by noxious mechanical stimulation. Fig. 1C illustrates responses evoked by graded radiant heat stimulation. All NS units studied showed a resting activity. The activity was suppressed when a supplementary dose of urethane–chloralose solution was administered. The administration also suppressed responses evoked by noxious mechanical stimulation, but the size of receptive field remained unchanged. Fig. 2 illustrates locations and receptive fields of trigeminal and spinal units recorded from a transverse plane of the caudal part of VB complex in one animal. The circles and squares placed along the tracks mark positions at which unit responses were obtained. The receptive fields of units obtained at these positions are presented in the form of figurine drawings. At this level, VPM is ventrally and laterally surrounded by VPLc. Two trigeminal NS units were isolated from the dorsal fringe of the VPM. The medial unit had a cutaneous
Fig. 3. Reconstruction of 10 microelectrode penetrations through VB complex. Observations were made in a transverse plane at a level rostral to the one illustrated in Fig. 2. Each figurine represents receptive field of corresponding trigeminal NS unit.
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Fig. 4. Reconstruction of three microelectrode penetrations through VPM, showing locations of NS and LTM units and receptive fields of NS units.
receptive field in the maxillary nerve territory, and the lateral unit in the ophthalmic nerve division. In the present experiments, altogether 10 trigeminal NS units were obtained at or near this transverse plane. All of them were located in the dorsal fringe of VPM. Of these, four were maxillary NS units, five were ophthalmic NS units and one NS unit had a receptive field in the pinna. Maxillary NS units were located more medially, and the pinna NS unit most laterally. None of them had a cutaneous receptive field in the mandibular nerve territory of facial skin or in the oral cavity. Fig. 3 illustrates an experiment which explored VPM at a level more rostral to the one illustrated in Fig. 2. The figure shows data obtained from 10 microelectrode penetrations 250 mm apart which passed through VPM and the adjacent VPLc. Of 168 units within the VB complex, 85 were trigeminal NS and LTM units activated by stimulation of the maxillary skin (12 units), mandibular skin (37 units), tongue (eight units) or the rest of oral mucosa (28 units). Receptive fields of facial units were mainly located in the perioral or paranasal area. The forehead was no longer represented at this
level. The figure shows that trigeminal NS units were located in the peripheral part of a compartment of VPM in which the contralateral trigeminal integument is represented. The majority of trigeminal NS units had a receptive field either in the tongue or in the rest of oral mucosa. The data presented on the figurine overlays show that in the ventral VPM, there was an orderly sequence of nociceptive representation of the tongue, oral mucosa and mandibular skin from the medial to the lateral edge of the nucleus. NS units in the dorsal fringe of VPM had a receptive field in the tongue or maxillary skin. In the experiment illustrated in Fig. 4, trigeminal NS neurons were found around the dorsomedial and ventrolateral borders of VPM which presumably correspond to calbindin-positive areas described by Rausell and Jones (1991a,b) (see Section 4).
3.2. Trigeminal WDR units WDR units had a graded response to brush, pressure and noxious pinch applied to the center of the receptive
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field (black area in Fig. 5B), and responded best to noxious pinch (Fig. 5Ca). Outside this zone (crosshatched area in Fig. 5B), they were unresponsive to low-intensity mechanical stimuli, but responded differentially to pressure and noxious pinch (Fig. 5Cb). Finally the latter area was surrounded by an area (shaded area in Fig. 5B) in which only noxious pinch resulted in unit discharges (Fig. 5Cc). The receptive field was strictly confined to the contralateral integument. Trigeminal WDR units were located more rostrally than trigeminal NS units. Fig. 6 illustrates an experiment in which three trigeminal WDR units were obtained. They had a receptive field in the facial skin. Although the peri- and intraoral structures dominated in the rostral NS zone, other parts of the facial skin were significantly represented at this level.
3.3. Spinal NS units Spinal NS units were obtained at levels in which trigeminal NS units were found. Fig. 7 illustrates an experiment in which a transverse plane through the caudal VB complex was explored. Trigeminal and spinal NS units were found in the periphery of a compartment of VB complex in which the contralateral integument is represented. The hand was represented by only one LTM unit at this level. Locations and receptive fields of spinal NS units obtained in 12 experiments which explored more rostral planes than the one presented in Fig. 7, are shown in Fig. 8. In this figure, results are summarized in a transverse plane explored in one experiment. Spinal NS units were located in the dorsal and ventral fringes of a
Fig. 5. A trigeminal WDR unit. (A) Location of the unit. (B) Receptive field. (C) Responses of the unit to graded mechanical stimulation of the receptive field. Areas a, b, and c indicated by arrows in (B) were stimulated and responses to these areas are shown in a, b, and c, respectively. Upper traces show peristimulus time histograms, whereas lower traces show spike discharges. Horizontal bars indicate periods of stimulus application.
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Fig. 6. Reconstruction of three microelectrode penetrations through VPM, showing locations and receptive fields of trigeminal WDR and LTM units. Half-filled and open circles in the photomicrograph indicate locations of trigeminal WDR and LTM units, respectively.
compartment of VPLc in which the contralateral spinal integument is represented. In the medial half, most of the NS units obtained had a circumscribed receptive field in the hand. Excluding the hand, there was an orderly sequence of representation of the cervical, thoracic, lumbar, sacral and caudal segments in the mediolateral direction in the lateral two-thirds of the dorsal region. In the ventral region, there is a gap in the middle due to interposition of VPI. The lateral half is dislocated more ventrally than the medial half. In the medial half, the upper body half was represented, whereas in the lateral half, the lower body half. The foot was represented at and near the medial edge of the lateral half, and more proximal parts of the hindlimb were represented more laterally. The medial half was
dominated by the distal forelimb, especially by the hand.
3.4. Spinal WDR units As in the case of VPM, spinal WDR units were located more rostrally than spinal NS units. Fig. 9 illustrates an experiment in which the border between NS and WDR zones was explored. NS units were located medially, whereas WDR units were found laterally. The contralateral spinal body surface compartment was dominated by representation of the hand at this level. Nine units encountered in dorsal parts of two lateral penetrations responded to manipulation of the forelimb which activates receptors in the muscle. Thus,
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nociceptive units were encountered in these two lateral penetrations at or near the border between the core of VPLc in which the contralateral integument is represented and the shell of Jones and Friedman (1982) in which deep tissues are represented. In five experiments, a level comparable to the one shown in Fig. 9 was explored. In each experiment, both NS and WDR units were found, and altogether 10 NS and 16 WDR units were obtained. Fig. 10 illustrates an experiment in which four WDR units were obtained. Representation of the hand occupied a relatively small volume of VPLc and that of the
trunk occupied a significant volume. Of four WDR units obtained, two had a receptive field in the chest wall. In general, there was a somatotopic organization within the spinal WDR zone as in the case of spinal NS zone. In the dorsal region, rostral segments were represented medially, and more caudal segments more laterally. In the ventral region, the upper body half was represented medially, whereas the lower half laterally. The foot was represented near the medial edge of the lower body half zone.
3.5. Nocicepti6e units in VPI Although we did not systematically explore the structures ventral to the VB complex, three nociceptive units were obtained from these structures. One example is illustrated in Fig. 11. The unit was located in nucleus ventralis inferior (VPI), and had nociceptive peripheral receptive fields in the trunk, proximal parts of forelimbs, perioral region, bilateral pinna and bilateral cornea. Nociceptive receptive fields of two other units were also much larger than those of NS and WDR units recorded from the VB complex.
4. Discussion
Fig. 7. Reconstruction of four microelectrode penetrations through caudal part of VB complex, showing locations and receptive fields of NS and LTM units.
In the present experiments, nociceptive neurons were not evenly distributed across the VB complex; two different classes of nociceptive neurons, i.e. NS and WDR neurons, were found in the periphery of a compartment of VB complex in which the contralateral body surface is represented. Thus, they formed a shell at the perimeter of the contralateral integument compartment. This compartment consisted of large parts of VPM and VPLc. Both NS and WDR neurons showed a somatotopic organization within the VB complex. Peripheral receptive field organizations of these two classes of thalamic nociceptive neurons were much the same as those of their counterparts in the spinal cord or trigeminal subnucleus caudalis. These two classes of nociceptive neurons appear to use afferent inputs to convert into output while maintaining significant features of spatial information processed at the level of spinal cord or its trigeminal homologue. In the previous studies, segregation of LTM and nociceptive neurons within the thalamus was less clear in the monkey than in the cat, but most studies show a tendency for nociceptive neurons to be unevenly distributed across the VB complex (Kenshalo et al., 1980; Casey and Morrow, 1983; Chung et al., 1986; Bushnell and Duncan, 1987; Morrow and Casey, 1992; Bushnell et al., 1993). In the present experiments, NS units were recorded caudally and WDR units were recorded rostrally. In the
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Fig. 8. Summary of locations and receptive fields of NS units in VPLc at a level rostral to the one illustrated in Fig. 7.
transitional level, both NS and WDR units were recorded. At this level, units with deep inputs were found in the dorsal and lateral parts of the VPL. Hence the number of NS or WDR units obtained depends on the level of VP nucleus explored. For example, Apkarian and Shi (1994) explored the level of VPL where neurons with deep inputs were found, and obtained more WDR units than NS units. In experiments, we explored a comparable level, and obtained 10 NS and 16 WDR units from VPL. One reason why we obtained more NS units than WDR units is that we have more extensively explored the caudal part of the VP nucleus. Another factor affecting the number of NS or WDR units obtained is the kind of search stimulus. In the awake animal, it is difficult to use noxious stimuli to search for VB complex neurons. In contrast, WDR neurons can be first detected by innocuous stimuli, and then confirmed by noxious stimuli. Thus, the number of nociceptive neurons when recordings are obtained while awake may be biased toward WDR neurons. Anatomically, there are species differences in the organization of the somatosensory thalamus. In the cat, the terminal projection zones of the dorsal column nuclei and the spinal cord are largely segregated, the dorsal column nuclei projecting to the cutaneous core of VB complex and the spinal cord projecting to a shell region (Boivie, 1979; Berkley, 1980). In contrast, there is an extensive overlap between the terminal projection
zones of these two systems in the rat (Ma et al., 1986). Some studies of primate spinothalamic tract terminations suggest that there are clusters of dense terminations near the borders of VPL (Boivie, 1979; Berkley, 1980), whereas other studies of primate spino- and trigeminothalamic tract have found diffuse terminations throughout the ventroposterior thalamus (Ganchrow, 1978; Appelbaum et al., 1979; Apkarian and Hodge, 1989). The discovery of rods and matrix in the monkey VPM (Rausell and Jones, 1991a,b) appears to reconcile these inconsistent findings. The monkey VPM has a vertical limb and a horizontal limb that points medially. Both the trigeminal lemniscus and the dorsal trigeminal tract project to VPM, carrying somatosensory inputs from the contralateral and ipsilateral trigeminal brainstem nuclei, respectively. The vertical limb contains a representation of the contralateral trigeminal integument, while the ipsilateral peri- and intraoral regions are represented in the horizontal limb (Jones et al., 1986). Both limbs are divided into smaller histochemical subcompartments. These are detectable especially by staining for cytochrome oxidase (CO) (Jones et al., 1986). Elongated clumps of CO stain extend, rod-like, through the anteroposterior extent of VPM. Neurons of each CO rod have overlapping peripheral receptive fields, and are driven by the same stimulus submodality. The organization resembles the columnar organization in the primary somatosensory
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cortex (SI) as described by Mountcastle (1957), and neurons of each CO rod project to one or a few narrow, column-like domains in the somatosensory cortex. This has been one of the bases of the rod-to-column principle of thalamocortical organization (Jones et al., 1982). The CO rods are also immunoreactive for parvalbumin (Rausell and Jones, 1991a,b). The CO rods are embedded in a matrix which shows weaker and homogenous staining for CO, but is calbindin-positive (Rausell and Jones, 1991a). The widest extent of this matrix is around the dorsomedial and ventrolateral borders of VPM. The matrix receives predominant input from the trigeminal subnucleus caudalis in which trigeminal nociceptive and thermosensitive neurons are located (Rausell and Jones, 1991b). The presence of a smallcelled matrix region, that is, at its widest extent, around the dorsomedial and ventrolateral borders of VPM, raises parallels with studies of trigeminal nociceptive neurons of the cat VPM (Rausell and Jones, 1991b). The parallels were supported by Bushnell et al. (1993) who reported that, in the awake monkey, thermosensitive neurons were concentrated in the dorsomedial aspect of VPM, with others recorded more ventrally, near the border of VPM/VPI. Most of them produced graded responses to noxious skin heating. This distribution contrasted with the more diffuse scattering of
LTM neurons recorded in the same experiments. They stated that one might expect to record nociceptive responses more easily from neurons at the periphery. These previous findings were confirmed in the present experiments. Hence, nociceptive neurons appear to be exceptions of the rod-to-column thalamocortical organization. This was supported by a physiological study in the primate SI cortex that showed that the vast majority of nociceptive neurons are located in two of the six cortical layers and not organized in columnar fashion (Kenshalo and Isensee, 1983; Kenshalo, 1996). Yasui et al. (1983) subdivided the nucleus ventralis posteromedialis parvocellularis (VPMpc) of the cat into the medial and the lateral subdivisions (VPMpcm and VPMpcl), based on the observations that VPMpcl receives mainly uncrossed afferent fibers from the dorsal subdivision of trigeminal main sensory nucleus, while VPMpcm receives afferent fibers ipsilaterally from the parabrachial nucleus. In our laboratory, it was confirmed that somatic afferent inputs from ipsilateral oral structures project to VPMpcl (Nishikawa et al., 1988; Yokota et al., 1988a). In the monkey, Jones et al. (1986) found an ipsilateral representation in the horizontal limb of VPM. This ipsilateral compartment in the monkey VPM may coincide with VPMpcl in the cat. We found trigeminal nociceptive neurons in the cat,
Fig. 9. Reconstruction of four penetrations through VB complex, showing locations of NS, WDR and LTM units and receptive fields of NS and WDR units. Filled, half-filled and open squares indicate locations of spinal NS, WDR and LTM units, respectively. Filled and open circles indicate locations of trigeminal NS and LTM units, respectively. Location of each muscle unit is indicated by × .
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at the ventromedial fringe of VPM proper confronting the lateral perimeter of VPMpcl (Yokota et al., 1985, 1986). In the present experiments, trigeminal nociceptive neurons were found in the ventromedial periphery of the contralateral integument compartment of VPM. This trigeminal nociceptive zone is within the core of VPM according to Jones et al. (1986), but appears to be the ventromedial fringe of the contralateral integument compartment of VPM confronting the dorsolateral perimeter of the ipsilateral compartment of VPM. Friedman and Jones (1981) and Jones and Friedman (1982) have shown segregation of inputs from deep and
Fig. 10. Reconstruction of three microelectrode penetrations through VPLc, showing locations and receptive fields of WDR and LTM units. Half-filled and open squares indicate locations of spinal WDR and LTM units, respectively.
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cutaneous structures within VPLc of monkeys. Their experiments provide evidence that the rostral and dorsal portion of VPLc is activated by receptors located in deep tissues and that it projects to both area 3a and area 2 in monkeys. Their illustrations attest to the abruptness of the change from cutaneous to deep. This border forms a curving line across the rostral and dorsal VP thalamus causing the input from deep tissues to sit as a cap on the central core of VP. They named this cap region the anterodorsal shell. Dykes (1983) proposed that this region is a submodality specific relay nucleus for muscle spindle information and it should be renamed nucleus ventroposterior oralis (VPO). In the present experiments, nociceptive units were found at or near the border between the contralateral integument compartment of VPLc and this anterodorsal shell. Rose and Mountcastle (1952) studied tactile representation within the VP nucleus in rabbits and cats and argued that several of the ventroposterior thalamic nuclei together formed a single and complete representation of the contralateral body surface, and could be subsumed under a more inclusive term, the ventrobasal (VB) complex. This term was generally accepted in the ensuing four decades. Jones and Burton (1974) pointed out that the primate VB complex is only the posterior division of the VP nucleus. Jones (1985) defined the VB complex of the monkey as a complex consisting of VPM and VPLc. He included in VPM the compartment for ipsilateral trigeminal representation and in VPLc the anterodorsal shell. Dykes (1983) excluded this shell from VPL. The present experiments provide evidence that NS and WDR units are located in the periphery of a compartment in which the contralateral body surface is represented. The contralateral integument compartment is smaller than the VB complex of Jones (1985). Dykes et al. (1981) found in the squirrel monkey that neurons are grouped according to submodality in the VP nucleus. Dykes (1983) further extended these findings and proposed a general theory about the organization of the somatosensory pathways. It states that distinct classes of afferent input are relayed from the periphery to the cerebral cortex on separate and parallel paths. Thus, the cutaneous SA and RA units of the dorsal column nuclei project to the central region of VP, interdigitating within the VB complex. The muscle spindle input from the external cuneate nucleus project to VPO (the anterodorsal shell). The present data indicate that a path for nociceptive input must be included in this parallel processing scheme. Clinical, physiological and anatomical evidence implicates various regions of the thalamus in pain perception (Albe-Fessard et al., 1985; Willis, 1985; Besson and Chaouch, 1987; Apkarian and Hodge, 1989). Obviously the VB complex is not the only thalamic structure involved in pain perception. Various groups have demonstrated that neurons in VPL, VPI and the poste-
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Fig. 11. A nociceptive unit recorded in VPI. The recording site of the unit is shown on the left (indicated by an arrow), and the peripheral receptive field on the right.
rior ventral medial nucleus (VMpo) of monkeys respond to noxious stimuli (Kenshalo et al., 1980; Morrow and Casey, 1992; Apkarian and Shi, 1994; Craig et al., 1994). We partially confirmed these previous findings. Pain has both sensory – discriminative and affective –motivational components, and these may be mediated by distinct anatomical pathways (Willis, 1994).
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