Department of Neuroscience, Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455
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ABSTRACT |
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Zhang, Xijing, Heather N. Wenk, Christopher N. Honda, and Glenn J. Giesler Jr.. Locations of Spinothalamic Tract Axons in Cervical and Thoracic Spinal Cord White Matter in Monkeys. J. Neurophysiol. 83: 2869-2880, 2000. The spinothalamic tract (STT) is the primary pathway carrying nociceptive information from the spinal cord to the brain in humans. The aim of this study was to understand better the organization of STT axons within the spinal cord white matter of monkeys. The location of STT axons was determined using method of antidromic activation. Twenty-six lumbar STT cells were isolated. Nineteen were classified as wide dynamic range neurons and seven as high-threshold cells. Fifteen STT neurons were recorded in the deep dorsal horn (DDH) and 11 in superficial dorsal horn (SDH). The axons of 26 STT neurons were located at 73 low-threshold points (<30 µA) within the lateral funiculus from T9 to C6. STT neurons in the SDH were activated from 33 low-threshold points, neurons in the DDH from 40 low-threshold points. In lower thoracic segments, SDH neurons were antidromically activated from low-threshold points at the dorsal-ventral level of the denticulate ligament. Neurons in the DDH were activated from points located slightly ventral, within the ventral lateral funiculus. At higher segmental levels, axons from SDH neurons continued in a position dorsal to those of neurons in the DDH. However, axons from neurons in both areas of the gray matter were activated from points located in more ventral positions within the lateral funiculus. Unlike the suggestions in several previous reports, the present findings indicate that STT axons originating in the lumbar cord shift into increasingly ventral positions as they ascend the length of the spinal cord.
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INTRODUCTION |
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Many lines of evidence extending back more than
100 yr indicate that the spinothalamic tract (STT) is the primary
pathway for the transmission of nociceptive information from the spinal cord in primates, including humans (reviewed in Willis
1985). Until relatively recently, it was widely believed that
virtually all STT axons ascend within the contralateral ventral and
ventral lateral funiculi (VLF). This belief was based primarily on a
large number of studies in which restricted lesions in the ventral
spinal cord white matter, and not in other areas of the spinal cord, caused degeneration of axons in the ipsilateral thalamus (Boivie 1971
; Bowsher 1961
; Kerr and Lippman
1974
; Mehler et al. 1960
; Mott
1895
). Such lesions also markedly reduce pain and temperature sensations on the contralateral side of the body in monkeys
(Vierck et al. 1971
) and humans (Spiller and
Martin 1912
; White and Sweet 1969
).
Several recent anatomic studies have indicated that STT axons are not
restricted to the ventral half of the cord. Apkarian and Hodge
(1989) combined retrograde tract tracing methods with lesions
in midthoracic segments to examine the location of STT axons in
monkeys. They found that lesions of the dorsal lateral funiculus (DLF)
prevented retrograde labeling of almost all STT neurons in the
contralateral marginal zone below the lesion, and that lesions of the
VLF prevented labeling of STT neurons in lamina V and other areas of
the deep dorsal horn. These results suggested that the axons of STT
neurons in the marginal zone ascend in the DLF, not in the VLF, as STT
axons had been traditionally believed to do. These and other results
led the authors to conclude that there are two separate spinothalamic
pathways in cats and monkeys: a dorsal STT within the DLF made up
primarily of the axons of lamina I cells, and a ventral STT within the
VLF made up of the axons of lamina V-VIII neurons (Jones et al.
1985
, 1987
; Stevens et al. 1989
,
1991
).
Other workers (Craig 1991; Ralston and Ralston
1992
) suggested that axons of STT neurons in the marginal zone
are located at approximately the dorsal-ventral middle of the lateral
funiculus. Using injections of the anterograde tracer phaseolus
vulgaris leucoagglutinin (PHA-L) into the superficial
dorsal horn (SDH) of cats, Craig (1991)
labeled axons in
an intermediate position in the contralateral white matter, at about
the level of the denticulate ligament. The idea that STT axons are
concentrated in this area of the lateral funiculus was supported by the
findings of Ralston and Ralston (1992)
, who found that
relatively small lesions within this area in monkeys greatly reduced
anterograde labeling of STT axons in the posterior thalamus.
For several reasons, we have reexamined the organization of STT within
the spinal cord. One reason is that a better understanding of the
positions of the axons of STT neurons in different areas of the gray
matter might provide insights into their physiological roles. For
example, the question has been asked (e.g., Ralston and Ralston
1992), if the axons of marginal zone neurons in fact ascend
within the DLF, why do lesions of the VLF eliminate pain? Does this
mean that STT axons from marginal zone neurons are not sufficient for
producing normal pain sensation? Does this also mean that STT axons
from deep dorsal horn (DDH) neurons are necessary for pain sensation
because cutting them within the VLF eliminates pain? A second reason is
that a more conclusive description of the organization of the STT might
be of value in better understanding the effects of damage to the human
spinal cord produced by trauma or diseases. Finally, such information
might be of value to neurosurgeons because cordotomies continue to be
performed on patients suffering from several types of severe chronic
pain (Garcia-Larrea et al. 1993
; Jackson et al.
1999
; Lahuerta et al. 1994
; Nagaro et al. 1994
; Sanders and Zurmond 1995
).
We have used the technique of antidromic activation to examine the
locations of STT axons for several reasons. 1) STT axons can
be unambiguously identified using this technique. Previously used
anterograde tracing methods, such as degeneration or PHA-L techniques,
do not allow STT axons to be distinguished with certainty from other
labeled axons in the spinal cord. 2) In contrast to methods
in which lesions of spinal cord white matter have been used to locate
STT axons, the antidromic method can determine the locations of
individual axons with considerable accuracy (Dado et al.
1994a,c
; Ranck 1975
; Zhang et al.
1995
). 3) The method of antidromic activation can be
used to locate the same STT axon unambiguously at multiple levels of
the cord, thereby revealing whether individual STT axons remain within
one region of the cord or shift positions as they ascend. This method
has revealed that individual STT and spinohypothalamic tract axons in
rats often dramatically change their positions within the cord as they
ascend the length of the spinal cord (Dado et al.
1994c
). Individual axons cannot be identified at multiple
segmental levels using other methods. 4) The use of
antidromic activation allows the response characteristics of the
examined axons to be directly determined. 5) In contrast to
degeneration techniques or large injections of anterograde tracers, the
locations of the examined STT cell bodies can be determined using
antidromic activation.
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METHODS |
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All procedures followed the guidelines of the International Association for the Study Pain and were approved by the institutional animal care and use committee.
Monkeys (Macaca fascicularis or mulatta) were
anesthetized initially with ketamine (100 mg/kg im), followed by
-chloralose (60 mg/kg iv) and maintained with a continuous infusion
of nembutal (2-4 mg · kg
1 · h
1 iv). Animals were placed in a stereotaxic
frame, paralyzed with Flaxedil (10-20 mg · kg
1 · h
1 iv),
and artificially ventilated. Body temperature, end-tidal CO2, and blood pressure were monitored and kept
within physiological limits. Pneumothoraces were performed to improve
mechanical stability. Laminectomies were made over lumbar, thoracic,
and cervical segments. Craniotomies were made over the thalamus.
Multiunit recordings of somatosensory responses were used to locate the
ventral posterior lateral nucleus (VPL). The search stimulus consisted
of cathodal pulses (200 µs, 500 µA) delivered within contralateral
VPL. Single-unit recordings were made in the lumbar enlargement using
stainless steel microelectrodes (5-10 M
). After isolating an
antidromically identified unit, the stimulating electrode was moved
dorsal-ventrally, and antidromic thresholds were determined at 400-µm
intervals. This procedure was repeated within multiple tracks in the
one or more anterior-posterior planes until a point was located at which the antidromic threshold was
30 µA (referred to as
low-threshold points). Current pulses
30 µA have been shown to
activate spinohypothalamic tract axons in rats at a distance of
400
µm from the stimulating electrode (Burstein et al.
1991
; Dado et al. 1994a
). Criteria for
antidromic activation included the following: response at a relatively
constant latency (<0.2 ms variability), ability to follow
high-frequency stimulation (
333 Hz), and collision of putative
antidromic action potentials with orthodromic action potentials
(Lipski 1981
). All units included in this study met these criteria for antidromic activation.
Once antidromic activation from the contralateral thalamus was
demonstrated, a second stainless steel stimulating electrode was
inserted into the cervical or thoracic white matter contralateral to
the recording site. Initially, large current pulses (500 µA, 200 µs) were delivered as the electrode was lowered through the cord
until the same neuron was antidromically activated. The threshold for
antidromic activation was determined at 200- to 400-µm intervals in
each track. The electrode was lowered through a series of tracks, each
separated by 500 µm, across the medial-lateral extent of the cord. At
the lowest threshold point for antidromic activation, each neuron was
activated using current pulses 30 µA. In each case, action
potentials at the lowest threshold point in the cord collided with
antidromic action potentials produced at the lowest threshold point in
the thalamus. This procedure established that the action potentials
elicited at both stimulation sites traveled in the same axon.
Cutaneous receptive fields and response characteristics of examined
neurons were determined using innocuous and noxious mechanical stimulation. Responses to such stimuli were used to classify the examined neurons as low-threshold (LT), wide dynamic range (WDR) or
high-threshold (HT) cells (see Dado et al. 1994b for details).
In almost all experiments, the location of more than one STT axon was examined on each side of the cord in the same monkey. In an effort to avoid cutting STT axons that were yet to be examined, lesions (25 µA for 40 s) were often made either 1.0 or 1.5 mm medial to the low-threshold point (at the same anterior-posterior plane). One lesion was made at the same dorsal-ventral position as the low-threshold point. A second lesion was made either 1.0 mm ventral or dorsal to the first. The distance between these two lesions in histological material was used as an indication of shrinkage or expansion of the tissue during processing. The distance between the two lesions, divided by 1.0, provided a ratio that was used in reconstructing the location of the low-threshold point. We attempted to test the accuracy of this method in two cases by making lesions medial to the low-threshold points and also at the actual low-threshold points. The results were similar in both cases. Figure 1 illustrates the results of one of these experiments. Lesions A and B were made 1.5 mm medial to the low-threshold point. Lesion B was made at the same dorsal-ventral position as the low-threshold point. Lesion A was made 1.0 mm dorsal to B. The distance between lesions A and B in histological material was 1.12 mm. The calculated position of the low-threshold point is indicated by the plus sign in Fig. 1; it falls within the lesion (C) made at the low-threshold point. Thus these findings indicate that this method can be used to reconstruct lesion sites accurately.
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In cases in which only one axon was examined on a side of the cord, lesions were made directly at each low-threshold point. Lesions were also made at each low-threshold point for the final case examined on each side of the cord. At the end of each experiment, electrolytic lesions were made at the tip of the stimulating electrode at each of the low-threshold points in the thalamus (100 µA for 40 s). Each recording side was marked (25 µA for 15 s).
Monkeys were perfused with 0.9% saline followed by 10% Formalin containing 1% potassium ferrocyanide (Prussian blue reaction). The areas of the thalamus and spinal cord containing lesions were cut transversely at 100 and 50 µm using a freezing microtome. Sections were counterstained with neutral red and microscopically examined. The locations of lesions were reconstructed with the aid of an attached camera lucida drawing tube.
In two monkeys, thoracic and cervical segments were removed with the dura intact. The denticulate ligaments were identified under a dissecting microscope in C6, T2, and T6. A needle was inserted into the bases of the ligaments to mark their positions on the surface of the lateral funiculus. The marked areas were sectioned on a freezing microtome. A line was drawn in the reconstructions from the mark on the lateral edge of the cord to the midline. In each case, this line passed in close proximity to the central canal. Therefore a line from the center of the central canal (at 90° to the midline) extending to the lateral edge of the cord was used as the border between the DLF and VLF. This line was used for statistical comparisons of the dorsal-ventral locations of low-threshold points.
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RESULTS |
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Antidromic activation from the contralateral thalamus
Twenty-six neurons in lumbar enlargement were antidromically
activated from low-threshold points (30 µA) in the contralateral thalamus. A photomicrograph of a lesion at a low-threshold point in the
contralateral thalamus is presented in Fig.
2A. Low-threshold points were
concentrated in the ventral and lateral parts of VPL (Fig.
3). There was no apparent segregation of
the locations of the low-threshold points for antidromic activation of
axons of neurons recorded in the SDH or DDH.
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Recording sites and physiological characteristics
The locations of lesions marking 26 recording sites are shown in Fig. 4. Two units were recorded in L5, 11 in L6, and 13 in L7. Eleven recording sites were located in the SDH. Fifteen were in the DDH. Within the DDH, eight recording sites were located in nucleus proprius and seven in the lateral reticulated area. These recording sites were concentrated laterally in nucleus proprius and the dorsal half of the lateral reticulated area (Fig. 4). Photomicrographs of lesions at recording sites in the SDH and DDH are shown in Fig. 2, D and E, respectively.
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Seven STT neurons were classified as HT neurons, and 19 as WDR neurons. One HT neuron was recorded in the SDH, six in DDH, including five in nucleus proprius. Ten WDR neurons were recorded in the SDH, nine in DDH (3 in nucleus proprius, 6 in lateral reticular area).
All 26 STT neurons had excitatory receptive fields on the ipsilateral hindpaw or hindlimb. Most STT neurons (9/11) recorded in the SDH had receptive fields that covered an area of less than half of the hindpaw. Neurons recorded in the nucleus proprius tended to have slightly larger receptive fields. All neurons recorded in the lateral reticular area had large receptive fields that covered more than half of the hindlimb.
The estimated mean conduction velocity from the recording site to the lowest threshold point for antidromic activation in the contralateral thalamus for the examined neurons was 49.6 ± 3.0 (SE) m/s (Fig. 5). The mean conduction velocity from the recording site to the contralateral thalamus for 11 neurons recorded in the SDH was 45.5 ± 3.2 m/s (Table 1), and that for 15 neurons recorded in the DDH was 52.7 ± 4.5 m/s (no significant difference).
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Antidromic activation of STT axons in the contralateral spinal cord white matter
The positions of the axons of 26 STT neurons were determined at a
total of 74 low-threshold points (30 µA) in the contralateral lateral funiculus from T9 to
C6. The mean threshold in the low-threshold point
for antidromically activating STT neurons was 11.9 ± 0.7. Lesions
were made directly at the low-threshold points in 48 cases. One of
these lesions was not recovered and not included in the results.
Lesions were made medial to 26 low-threshold points. The locations of
axons of 2 neurons were determined at one segmental level, 5 axons at 2 levels, 14 axons at 3 levels, and 5 axons at 4 levels. At each
segmental level, only one low-threshold point was determined for each axon.
Figure 6 illustrates an example of an STT neuron recorded in the SDH (Fig. 6C) that was antidromically activated from low-threshold points within the contralateral DLF. The neuron was initially antidromically activated from a low-threshold point in contralateral VPL (Fig. 6A, a1-a3) at a latency of 5.2 ms (a1). Within the spinal cord, the position of its axon was determined at three levels (Fig. 6B). In T4, a series of 10 electrode penetrations was made across the medial-lateral extent of the cord. The neuron could not be activated (using 500-µA pulses) from any of the sites within six tracks made throughout the ipsilateral side of the cord. The neuron was activated from a single lowest threshold point (15 µA) in the contralateral DLF (circled in Fig. 6B) at a latency of 2.6 ms (Fig. 6B, b1). Antidromic action potentials elicited in the thoracic cord and the thalamus collided (Fig. 6B, b2 and b3), indicating that the action potentials evoked from the two locations traveled in the same axon. The lowest threshold point was surrounded medially, laterally, dorsally, and ventrally by points in which higher currents were required for antidromic activation. In T6, five electrode penetrations were made; the lowest threshold point for antidromic activation (20 µA) was also located in the contralateral DLF (latency = 2.4 ms, Fig. 6B, b4). In T7, six electrode penetrations were made, and a single lowest threshold point (8 µA) was again located in the contralateral DLF (latency = 2.1 ms, Fig. 6B, b7). The neuron had a small receptive field on the ipsilateral foot (Fig. 6D). It responded to innocuous mechanical stimuli but responded at higher frequencies to noxious mechanical stimuli and was classified as a WDR neuron (Fig. 6E).
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Figure 7 shows an example of an STT neuron that was recorded in the DDH (Fig. 7C). In contrast to the example illustrated in Fig. 6, this neuron was antidromically activated from a low-threshold point within the contralateral VLF of each of the three examined thoracic segments (Fig. 7B). The neuron had a cutaneous receptive field on the ipsilateral hindpaw (Fig. 7D). It was classified as an HT neuron (Fig. 7E).
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The locations of 73 low-threshold points in the lower cervical and upper thoracic cord white matter (T9-C6) are illustrated in Fig. 8. Eleven STT neurons in the SDH were activated from 33 low-threshold points; 15 neurons in the DDH were activated from 40 low-threshold points. All low-threshold points were located in the lateral funiculus. Within segments T4-T9, low-threshold points for axons of neurons in SDH were located largely in the ventral part of the DLF, near the dorsal-ventral level of the denticulate ligament (Figs. 2B, 6B, and 8). Low-threshold points for axons of neurons in DDH were located farther ventrally, primarily within the VLF (Figs. 2C, 7B, and 8). Within upper thoracic segments and the cervical enlargement, low-threshold points for axons of neurons in SDH continued to be generally located dorsal to those of neurons in the DDH. However, low-threshold points for activation of both types of neurons were located farther ventrally. Indeed, within segments C6-C8, all low-threshold points, including those for activation of SDH neurons, were located in the VLF (Fig. 8). Axons of SDH neurons were significantly dorsal to the axons of DDH neurons in C6-C8, T1-T3, T4-T6, and T7-T9 (unpaired t-test, P < 0.002). The dorsal-ventral locations of low-threshold points for all neurons within each segmental grouping were analyzed using an ANOVA. Low-threshold points were found to be located farther ventrally in rostral segments (P < 0.05). Post hoc analysis revealed that low-threshold points within C6-C8 were significantly ventral to those in T7-C9 and T4-T6 (Duncan's multiple range test, P < 0.05).
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In addition to shifting ventrally, STT axons also appeared to shift laterally as they ascended through the cord. In segment T4-T8, low-threshold points were concentrated in the approximate medial-lateral center of the lateral funiculus, and only one was found within 300 µm of the lateral edge of the cord. Within segments C6-C8, low-threshold points were concentrated farther laterally, and eight were located within 300 µm of the lateral edge of the cord (Fig. 8). The mean distance to the lateral edge of the cord was 740 ± 83 µm in T7-T9, 751 ± 69 µm in T4-T6, 566 ± 61 µm in T1-T3, and 474 ± 90 µm in C6-C8. Within segments T7-T9, none of the examined STT axons were located within 300 µm of the lateral edge of the cord. In contrast, in C6-C8, 8 of 15 (53%) STT axons were located within 300 µm of the edge of the cord. Low-threshold points were found to be located significantly farther laterally within rostral segments (ANOVA, P < 0.05). Post hoc analysis revealed that low-threshold points within C6-C8 were significantly lateral to those in T7-T9 and T4-T6 (Duncan's multiple range test, P < 0.05). There were no significant differences in the mean distance to the edge of the cord between axons of SDH and DDH neurons at any segmental level.
Sixteen low-threshold points for activation of axons of 7 HT neurons (1 SDH neuron, 6 DDH neurons) and 57 low-threshold points for activation of axons of 19 WDR neurons (10 SDH neurons, 9 DDH neurons) are plotted in Fig. 9. Low-threshold points for activation of axons of HT neurons were primarily found in the VLF; low-threshold points for activation of axons of WDR neurons were located within the DLF and VLF.
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Estimated current spread in the spinal cord white matter
The distance at which current pulses activate STT and
spinohypothalamic tract axons was examined previously in rats
(Burstein et al. 1991; Dado et al.
1994a
). Because primate STT neurons have average conduction
velocities that are more than twice that of rat STT axons, it was
necessary to determine the distance at which current pulses were
effective for the presently examined axons. The effective spread of the
stimulating current pulses in the cervical and thoracic cord white
matter was estimated from plots of antidromic thresholds versus
distances from lowest threshold points. Threshold readings from 73 electrode penetrations containing the lowest threshold are plotted in
Fig. 10. The mean threshold for
antidromic activation at the lowest threshold points in the spinal cord
was 11.9 ± 0.7 µA. Four hundred micrometers dorsal or ventral
to the lowest threshold point in each track, the mean current required
for antidromic activation increased to 35.6 ± 2.6 µA (Fig.
10C). This difference of 23.7 µA over a distance of 400 µm indicates that between the lowest threshold point and points located 400 µm from the lowest threshold point, the effective spread
of current was ~17 µm/µA. Thus the mean stimulus currents of 12 µA at the lowest threshold points probably spread effectively ~200
µm from the tip of the stimulating electrodes.
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DISCUSSION |
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In the present study, we have determined the location within the
spinal cord of the axons of 26 antidromically identified STT neurons in
monkeys. Eleven STT neurons were recorded in the SDH, and the remaining
15 were recorded throughout the DDH. In this sample, the distribution
of the recording points and virtually all of the other physiological
characteristics resembles those found in many previous studies of
lumbar STT neurons in monkeys (e.g., Giesler et al.
1981; Willis et al. 1974
). One feature of the
neurons in this study does appear to differ from the results of several
previous studies. In this study, 10 of the 11 of examined STT neurons
in the SDH were classified as WDR. In many previous studies, the
percentage of WDR neurons recorded in the SDH was considerably lower
(e.g., see Giesler et al. 1981
; Willis et al. 1974
; however, cf. Ferrington et al. 1987
and
Owens et al. 1992
, who found high percentages of WDR-STT
neurons in the SDH).
In an attempt to gather more accurate information on the position of
primate STT axons within the thalamus, the stimulating electrode was
lowered through several tracks until the examined neurons could be
antidromically activated using current pulses of 30 µA (see also
Applebaum et al. 1979
). Because current pulses of these
amplitudes do not spread effectively more than 400 µm (Fig. 10)
(Dado et al. 1994a
; Ranck 1975
), it is
highly unlikely that current spread effectively beyond the borders of
VPL. We found that the areas in VPL from which SDH and DDH neurons
could be antidromically activated overlapped almost completely.
Although considerable attention has been paid in recent years to
projections of STT neurons in the SDH to areas other than VPL, our
findings are consistent with the idea that VPL is a prominent target
for such projections (Applebaum et al. 1979
;
Willis et al. 1979
).
The principle findings of this study are illustrated schematically in Fig. 11. At all examined levels of the cord, almost all of the axons of STT neurons in the SDH were located dorsal to those of neurons in the DDH. In mid- and lower thoracic segments, SDH axons were most often located at the level of, or even slightly dorsal to, the denticulate ligament; several were clearly located within the DLF. Within segments T1-T6, the axons of SDH neurons continued to be located dorsal to those of neurons in the DDH. However, at these levels SDH axons were found with increasing frequency ventral to the denticulate ligament, within the VLF, and less frequently within the DLF. This shifting ventrally of SDH axons continued within the cervical enlargement. At this level, all of the examined SDH axons were found within the VLF.
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The bulk of axons of examined neurons in the DDH were located within the VLF within all examined segments. However, as was the case with axons of SDH neurons, the axons of DDH neurons also migrated ventrally as they ascended. In mid- and lower thoracic segments, several axons of DDH neurons were located at the level of the denticulate ligament. Within the cervical enlargement, however, the axons of DDH neurons were all located within the VLF at some distance ventral to the denticulate ligament.
In addition to shifting ventrally, ascending STT axons migrated
laterally. In mid- and lower thoracic segments, STT axons were
distributed fairly widely across the medial-lateral extent of the cord.
None were found in proximity to the lateral edge of the cord within
T7-T9. However, at the
level of the cervical enlargement, more than half of the STT axons were
located within 300 µm of the lateral edge of the cord. These findings
confirm early degeneration studies in monkeys and humans (Walker
1940; Weaver and Walker 1941
; White
1954
) in which it was noted that degenerating sacral and lumbar
STT axons were located on the "extreme periphery" of the cervical
spinal cord. Additional support for this idea was provided in a study
in which antidromically identified STT axons were recorded in the upper
lumbar VLF in monkeys (Applebaum et al. 1975
). These
workers found that STT axons within the lateral funiculus with sacral
receptive fields were often located ventral and lateral to those having
lumbar receptive fields.
At each examined segmental level, a stimulating electrode was lowered
in a series of tracks spanning the entire side of the cord
contralateral to the recording site. In every case, a single low-threshold point for antidromic activation was located within the
lateral funiculus; none were found in the ventral funiculus. In early
anatomic studies (Hyndman and Van Epps 1939; Kerr
1975
; Morin et al. 1951
; Walker
1940
), it was noted that a small component of the STT was
located within the ventral funiculus. This component of the STT was
assigned the role of carrying information regarding "crude touch"
or "pressure" (Foerster and Gagel 1932
). Kerr
(1975)
reported that lesions restricted to the ventral
funiculus of cervical segments in monkeys caused degeneration of STT
fibers in a number of areas including VPL. We found no evidence to
confirm an STT projection ascending through the ventral funiculus to
VPL. There are several possible reasons for the conflicting findings
that lesions of the ventral funiculus in upper cervical segments
produced degeneration in VPL, and we did not find any STT axons within the ventral funiculus. One is that cell bodies in segments above the
lumbar enlargement, the level sampled in the present study, might give
rise to STT axons that ascend in the ventral funiculus. Another is that
lesions in the ventral funiculus might cut the fibers of the large
number of STT neurons in upper cervical segments as they cross through
the ventral funiculus en route to the VLF and eventually to VPL.
Clinically effective cordotomies often do not cut the ventral funiculus
(White and Sweet 1969
). Thus if an STT projection exists
in the ventral funiculus, it is likely that the projection is not
sufficient for production of normal pain sensation in humans.
In several early studies, it was concluded that STT axons shift
dorsally, not ventrally, as they ascend the length of the spinal cord
(Foerster and Gagel 1932; Hyndman and Van Epps
1939
; Kahn and Rand 1952
; Walker
1940
; White 1954
). This conclusion was based on
two principle findings. 1) The authors concluded that it was
necessary to cut farther dorsally in the lateral funiculus in the
rostral spinal cord than it was in lower thoracic segments to produce
analgesia in lower dermatomes. 2) Degenerating fibers were
found farther dorsally within the lateral funiculus in rostral segments
following surgically effective cordotomies. The conclusion that
ascending STT axons migrate dorsally was also supported in studies in
monkeys; degenerating axons were stained farther dorsally in the
lateral funiculus in rostral segments following spinal cord lesions
(Morin et al. 1951
; Weaver and Walker
1941
). It is difficult to explain fully how this conclusion,
the opposite of that made here, was reached in these studies. Regarding
the surgical result, it is possible that important nociceptive
projections to thalamic areas other than VPL or to the brain stem
ascend farther dorsally within the DLF. Regarding the anatomic results,
it is possible that changes in the organization of STT axons were
masked in these studies by labeling of several other types of
degenerating ascending axons within the lateral funiculus. Our results
indicate that STT axons consistently migrate ventrally as they ascend
through upper thoracic segments and the cervical enlargement. In
addition, in recent preliminary studies using the same antidromic
stimulation techniques in monkeys, we (Zhang, Honda, and Giesler,
unpublished observations) have found that STT axons are located
ventrally within upper cervical segments.
Apkarian and Hodge (1989) reported that lesions of the
DLF in squirrel monkeys disrupt the retrograde labeling of the majority of STT neurons in the contralateral marginal zone after injections of
retrograde tracers into the thalamus. In addition, they found that
lesions of the VLF block the retrograde labeling of STT neurons in
lamina V and other areas of the deep dorsal horn. These findings led to
the proposal of the existence of two spinothalamic tracts: one in the
DLF, the DSTT, composed of the axons of marginal zone neurons and
another in the VLF, the VSTT, composed of the axons of neurons in the
DDH and ventral horn. It is important to note that all of the lesions
in this study were made in midthoracic segments. The results of our
studies using antidromic activation techniques in these segments
confirm those of Apkarian and Hodge (1989)
. At these
levels, we found that the majority of the axons of SDH neurons were
located within the DLF and almost all axons of DDH neurons ascended
within the VLF. However, our results suggest that lesions of the DLF
and VLF at rostral levels would produce very different effects on
retrograde labeling of STT neurons. Our data indicate that lesions at
the level of the denticulate ligament and dorsal to it in the cervical
enlargement would have little, if any, effect on retrograde labeling of
STT neurons in either the SDH or DDH. Our data also indicate that
lesions of the VLF in the cervical enlargement would have similar
effects on the retrograde labeling of STT neurons in both areas of the gray matter; the labeling of both types of cells would likely be prevented.
Ralston and Ralston (1992) found that relatively small
lesions of the lateral funiculus at the level of the denticulate
ligament in lower thoracic and upper lumbar segments disrupted the
anterograde labeling of many lumbar STT axons. They suggested that the
labeled STT axons in this area of the cord emanated in large part from neurons in SDH. Our data support the idea that their lesions at the
level of the denticulate ligament likely cut many STT axons of neurons
in the SDH. Our data also suggest that had such lesions been made in
the cervical enlargement, they would have cut far fewer lumbar STT axons.
Since the publication of the first papers (Apkarian et al.
1985) suggesting that the axons of marginal zone STT neurons
ascend within the DLF and not the VLF, there has been considerable
discussion of the implications of these findings. One implication is
that, if cutting the VLF alone during a cordotomy produces analgesia and yet spares the axons of marginal zone neurons, then in these patients the unimpaired outflow of STT axons from SDH neurons is not
sufficient to maintain normal nociception. The present findings bear on
this controversy. Many cordotomies have been performed within rostral
thoracic or cervical levels (Sweet et al. 1994
). Our
data suggest that at these segmental levels, the STT axons of both SDH
and DDH neurons ascend within the VLF. Therefore our data would predict
that a cordotomy restricted to the VLF at rostral levels of the cord
would cut STT axons from both regions of the gray matter. Thus the
results from cordotomies at these levels do not appear to provide any
insight into the roles of the SDH versus DDH in nociceptive processing.
On the other hand, our findings confirm the suggestion by others that
within mid- and lower thoracic segments the axons of SDH neurons are
located farther dorsally within, or near, the DLF (Apkarian and
Hodge 1989), at the level of the denticulate ligament
(Craig 1991
; Ralston and Ralston 1992
).
It is clear that many histologically confirmed cordotomies extended
dorsally to at least the level of the denticulate ligament
(Foerster and Gagel 1932
; Gardner and Cuneo
1945
; Kahn and Rand 1952
; Nathan and
Smith 1979
; Sweet 1976
; White and Sweet
1969
). Thus in such cases, these cordotomies would have also
probably cut STT axons from both DDH and SDH neurons.
There are examples in the literature of clinically effective,
histologically confirmed small cordotomies that were restricted to the
lateral funiculus at roughly the level of the denticulate ligament
(Fig. 99, A and B, in White and Sweet
1969). These lesions would likely have cut SDH axons, while
sparing most DDH fibers. Thus these results suggest that, in these
cases, the STT projection originating in the DDH was not sufficient to
maintain normal pain sensation. Surprisingly, we are unable to find in
the literature examples of histologically confirmed cordotomies in
thoracic and lower cervical segments that were sufficiently restricted
to the VLF such that they would have been unlikely to cut the axons of SDH neurons. Therefore there appears to be little, if any, evidence to
suggest that the axons of SDH neurons are not sufficient for production
of the sensation of pain.
The results of this study indicate that the optimum strategy for cutting the lumbar component of the STT is dependent on the segmental level of the cord in which the cordotomy is performed. In midthoracic segments, lumbar STT axons are located in a relatively widespread distribution, extending dorsally into the DLF and medially to an area near the gray matter. Thus our results suggest that lesions intended to cut the entire lumbar STT at this level would have to extend a considerable distance medially and well into the DLF, into an area very near the corticospinal and rubrospinal tracts. Therefore in midthoracic segments, lesions large enough to cut the entire STT would be likely to produce ipsilateral motor impairments. However, our results also indicate that smaller, more circumscribed lesions would be sufficient to cut the lumbar STT if performed within the cervical enlargement. At this level, lumbar STT axons appear to be confined to an area closer to the lateral edge of the cord and, perhaps more importantly, restricted entirely to the VLF. Thus the present findings suggest that surgical lesions of the entire lumbar STT at the level of the cervical enlargement could be smaller and that they need not extend into the proximity of the corticospinal and rubrospinal tracts. Therefore the altered organization of ascending STT axons suggests that lesions of the lumbar STT in the cervical enlargement offer important advantages over lesions at lower levels of the cord.
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ACKNOWLEDGMENTS |
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We thank H. Truong for valuable technical assistance and Dr. Donald Simone for critically reading an early version of this manuscript.
This work was supported by National Institutes of Health Grants NS-25932 to G. J. Giesler, DA-09641 to C. N. Honda, and Training Grant DE-07288 to H. N. Wenk.
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FOOTNOTES |
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Address for reprint requests: G. Giesler, Dept. of Neuroscience, 6-145 Jackson Hall, University of Minnesota, Minneapolis, MN 55455.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 21 December 1999; accepted in final form 7 February 2000.
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REFERENCES |
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