1Department of Surgery and
2Department of Physiology,
Davis, Karen D.,
Andres M. Lozano,
Marosh Manduch,
Ronald R. Tasker,
Zelma H. T. Kiss, and
Jonathan O. Dostrovsky.
Thalamic relay site for cold perception in humans.
The neural pathways subserving the sensation of temperature are
virtually unknown. However, recent findings in the monkey suggest that
the sensation of cold may be mediated by an ascending pathway relaying in the posterior part of the thalamic ventromedial nucleus (VMpo). To
test this hypothesis we examined the responses of neurons to thermal
stimulation of the skin and determined the perceptual effects of
microstimulation in the VMpo region in awake patients undergoing
functional stereotactic surgery. In 16 patients, microstimulation in
the VMpo region evoked cold sensations in a circumscribed body part.
Furthermore, at some of these sites thalamic neurons were found that
responded to innocuous cooling of the skin area corresponding to the
stimulation-evoked cold sensations. These data provide the first direct
demonstration of a pathway mediating cold sensation and its location in
the human thalamus.
Previous attempts to identify the thalamic and
cortical sites involved in temperature sensation were largely
unsuccessful, and their identities remain unclear. Some
cooling-responsive neurons in thalamus and cortex were reported in
animal studies (Auen et al. 1980 Data were obtained from 16 awake patients during stereotactic
exploration of the thalamus for lesion making or implantation of
stimulating electrodes. The patients consisted of eight males and eight
females, 52 ± 16 yr old, and suffered from either a movement
disorder (n = 10) or chronic pain (n = 6). All patients consented to the procedures, which were approved by
the University of Toronto/Toronto Hospital Human Experimentation Committee.
Before surgery, a magnetic resonance imaging (MRI)-compatible
stereotactic frame was fixed to the patient's head under local anesthesia. The coordinates of MRI-determined locations of the anterior
(AC) and posterior commissures (PC) were then used to modify
computerized brain maps of the thalamus (Schaltenbrand and
Wahren 1977 Routine testing of neurons to cutaneous inputs included touch (with a
soft brush), pressure, and thermal stimuli. The thermal stimuli were
delivered by cold and thermally neutral rods and a 20 × 25 mm
Peltier-type thermode (Thermal Devices). Further details of the methods
used were previously described (Davis et al. 1996 Trajectories containing microstimulation-evoked cold sensations and/or
tactile RFs were reconstructed on computer-generated sagittal maps as
follows. The anterior-posterior and dorsoventral coordinates of each
cold site were measured with respect to PC and the AC-PC line,
respectively, and standardized to the normal 23 mm AC-PC length (i.e.,
coordinates were multiplied by a normalization factor determined by the
ratio of the standard 23 mm AC-PC length/the patient's AC-PC length).
Because there can be considerable variation between the locations of
recording sites predicted by the atlas maps and the physiologically
determined locations of tactile neurons obviously located within Vc, we
plotted the locations of recording sites with reference to the
locations of the tactile responsive neurons in a manner similar to that
employed by Lenz et al. (Lenz and Dougherty 1998 In 16 patients, pure cold sensations were evoked during thalamic
microstimulation. At sites of thalamic stimulation-evoked cold
sensations, the mean threshold for evoking cold was 11.0 ± 2.4 (SE) µA, which is comparable with intensities necessary for evoking tactile (paraesthesia) sensations by stimulation in Vc
(Davis et al. 1996
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
; Burton et al.
1970
; Bushnell et al. 1993
; Kosar and Schwartz 1990
; Landgren 1960
, Landgren 1957
;
Poulos and Benjamin 1968
). These studies identified
either cold-specific neurons in the thalamus and cortex with tongue or
perioral-receptive fields (RFs) or neurons that were sensitive to both
mechanical and cooling stimuli within the thalamic tactile relay
nucleus. In the human, a recent study reported a few nonspecific
cooling-sensitive neurons that also responded to tactile stimulation
within the thalamic tactile relay nucleus, the ventrocaudal nucleus
(Vc) (Lenz and Dougherty 1998
). It is not clear whether
these multimodal neurons are involved in mediating the sensation of
touch or cold. However, recent findings in the monkey suggest that the
sensation of cold may be mediated by a pathway ascending from lamina I
of the spinal and medullary dorsal horn to the insular cortex via a
relay in VMpo, a region medial and ventroposterior to Vc (Craig
1994
; Craig et al. 1994
; Dostrovsky and
Craig 1996
). Those studies in the monkey revealed that VMpo
contains neurons activated by innocuous cooling of various parts of the
body and that cooling-specific lamina I spinal neurons can be
antidromically activated from the VMpo region. An anatomically
homologous region to monkey VMpo appears to exist in humans
(Craig et al. 1994
). Microstimulation combined with
neuronal recordings is a powerful technique only possible in awake
human subjects that provides information on the sensations mediated by
the neurons surrounding the electrode tip. Thus we used
electrophysiological techniques to test the hypothesis that this region
in the human thalamus plays a role in the processing of cutaneous cold
stimuli. Toward this goal, we examined the effects of thalamic
microstimulation and determined the responses of thalamic neurons to
cutaneous cooling in the thalamus of 16 awake patients undergoing
functional stereotactic surgery.
METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
) in the sagittal plane. A small hole was made in
the skull under local anesthesia to permit insertion of a guide tube
through which the microelectrode was inserted. Single and multiunit
extracellular recordings were obtained as the microelectrode was driven
through the thalamus in a series of electrode penetrations. Tungsten
microelectrodes were gold and platinum plated with an exposed conical
tip of 15-40 µm and an impedance of <1 M
. The electrodes were
driven through the thalamus with a hydraulic microdrive in the
parasagittal plane and were directed ventroposteriorly ~50-60° to
the AC-PC line.
;
Lenz et al. 1988
; Tasker et al. 1997
).
Neurons were tested for responses to active and passive movements and
tactile and thermal stimuli. Microstimulation was carried out at
regular 0.5- to 1-mm intervals with 1-s trains of 300 Hz, 0.2-ms
pulses, 1-100 µA. The location (projected field, PF) and quality of
sensations evoked by threshold and in some cases suprathreshold stimuli
were determined. In each patient the first electrode trajectories were based on theoretical brain atlas maps (Schaltenbrand and Wahren 1977
) and the patient's AC and PC coordinates. This initial
target was modified during the mapping procedure based on physiological landmarks. The first electrode trajectories were used to locate the
somatosensory relay nucleus, Vc, as determined by neuronal responses to
touch of the hand or face and low-threshold (<20 µA)
microstimulation-induced tingling sensations in the hand or face.
Subsequent trajectories were tailored to each individual's thalamic
somatotopy and particular disease. The data for this study were
collected during these initial trajectories in which regions more
medial than the theoretical Vc target were encountered and therefore
passed through or close to VMpo.
;
Lenz et al. 1993
). Thus in the sagittal plane cold sites
were plotted in relation to the posterior- and ventral-most recording
sites where tactile RFs were found in that electrode track. When no
tactile-responsive neurons were encountered in a track, the cold sites
were plotted with respect to the Vc borders determined from the nearest
adjacent sagittal plane containing an electrode track traversing Vc.
The cold sites were also plotted in a coronal plane in which the
stereotactic medial-lateral coordinates were adjusted for functional
somatotopy of Vc. Each patient's trajectories were adjusted along the
medial-lateral axis to align the tactile representation of the
face/hand border (a track traversing both face and hand). For patients
lacking a track traversing face/hand Vc, other tracks passing through
Vc were used to interpolate the probable position of the tactile
face/hand region and were adjusted accordingly. The new medial-lateral
coordinates were then plotted versus the dorsal-ventral coordinates of
the cold sites. The location of the ventral Vc border was determined in
the same manner as in the sagittal plot.
RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
; Lenz et al. 1994
).
The cold sensations evoked were typically described as quite natural
and were perceived to arise from a small-to-medium size region of the
contralateral hand, face, leg, or torso (see Fig.
1). Increasing the intensity of
stimulation resulted in graded increases in the intensity of the cold
sensation (Fig. 1). Suprathreshold stimuli resulted in little or no
change in the PF size.
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Fig. 1.
Thalamic stimulation-evoked cold sensations. Verbal ratings (0-10
scale) of the innocuous cold sensations evoked by threshold and
suprathreshold intensities of thalamic microstimulation were obtained
in 8 patients. Figurines adjacent to each line depict the location of
the thalamic stimulation-evoked sensation (i.e., PF) at threshold. Note
that the stimulus intensities subthreshold for evoking cold perception
(i.e., zero cold ratings) did not evoke any sensation.
Neuronal recordings at many of the sites of thalamic stimulation-evoked
cold sensation indicated a relatively cell-sparse region compared with
Vc. However, in nine patients there was adequate neuronal activity to
warrant RF testing. Neurons responsive to innocuous cooling were
demonstrated in five of these patients at sites of stimulation-evoked
cold sensations. These neurons responded to small (5°C) cooling
steps applied to the body region corresponding to the thalamic
stimulation-evoked cold PF. The responses to a maintained cold stimulus
included both a dynamic response at the onset of cooling and a static,
somewhat lower response during the maintained cold (see Fig.
2), similar to those of cold-sensitive
neurons reported in lamina I of the spinal and medullary dorsal horn in
animal studies (Christensen and Perl 1970
; Craig
and Hunsley 1991
; Dickenson et al. 1979
;
Dostrovsky and Craig 1996
; Dostrovsky and Hellon
1978
; Hutchison et al. 1995
; Poulos et
al. 1979
). None of these cold-responsive neurons were activated
by tactile (brush or touch) stimuli, although two neurons also
responded to cutaneous heating.
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Reconstruction of the sites of stimulation-evoked cold and neuronal responses to cutaneous cold stimuli in relation to physiological landmarks (see METHODS) suggests that the cold sensations and neuronal responses were obtained at sites in or close to Vmpo, that is, the cold sites were concentrated in a region ventroposterior and medial to the border of the tactile Vc (see Fig. 3).
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DISCUSSION |
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This is the first study to demonstrate the existence of specific
cold-sensitive neurons in human thalamus and that microstimulation at
these sites induces cold sensations. These unique data provide strong
evidence that the region where these responses were evoked is a major
component of the ascending cold pathway. Although anatomic localization
of human physiological recording sites cannot be confirmed by
histological methods, the sites where cold-responsive neurons were
recorded and cold sensations evoked are consistent with the region
identified as VMpo in the monkey and human (Craig et al.
1994). These sites were clearly not within Vc or dorsomedial VPM, where the few other thalamic studies found cold-sensitive neurons
(Auen et al. 1980
; Burton et al. 1970
;
Bushnell et al. 1993
; Landgren 1960
;
Lenz and Dougherty 1998
; Poulos and Benjamin 1968
). Furthermore, except for cooling-sensitive neurons in the dorsomedial VPM that have primarily ipsilateral RFs on the tongue, previous studies reported that the Vc cooling-sensitive neurons are
also driven by mechanical inputs, and therefore their role in
thermoreception is unclear. Stimulation within Vc almost always results
in paraesthesia (Davis et al. 1996
; Lenz et al.
1993
), and stimulation-induced cold sensations are very rare
(Lenz et al. 1993
). Stimulation at the sites in Vc where
the nonspecific cooling-sensitive neurons were previously described
(Lenz and Dougherty 1998
) did not elicit cold sensations.
In some of the cases reported here the electrode tip was likely
within fibers because no cellular action potentials could be recorded.
In these cases it is likely that the stimulation effects were due to
excitation of spinothalamic or thalamocortical axons close to VMpo. In
our experience and that of others (Tasker et al. 1982),
stimulation within the spinothalamic tract more medially usually
produces sensations of warm, pain, or paraesthesia and only very rarely
produces cold sensations, perhaps because the cold fibers are
relatively small in number and dispersed. However, in this study the
evoked sensations were typically only cold even with suprathreshold
stimuli, suggesting the electrode tip was in a segregated bundle of
axons of a cold pathway close to the thalamic site where the axons
terminated or originated. More importantly, because we were able to
record neuronal responses to cooling the skin and produce
stimulation-evoked cold sensations in the region of the neuronal RFs,
it is very likely that the neurons at these sites subserve the
sensation of cold.
These data thus provide strong evidence that a region of thalamus
ventroposterior to Vc is a major component of the temperature pathway.
There is considerable confusion and disagreement on the identities and
boundaries of the nuclei located ventroposterior to Vc in the human
thalamus. Depending on the atlas or study this region includes the
ventrocaudal parvocellular internal and external, posterior,
suprageniculate, limitans, ventroposterior intermediate, and VMpo
nuclei (Craig et al. 1994; Hirai and Jones
1989
; Morel et al. 1997
; Schaltenbrand
and Wahren 1977
). VMpo does not correspond exactly to any of
these other nuclei but does overlap some of them. Without histological
confirmation of recording sites it is not possible to definitively
localize the cold-responsive sites in our study to any one of these
nuclei. However, on the basis of the recent findings in the monkey, we
propose that this region is VMpo. It has been shown in the monkey that
VMpo is a major target of spinal and medullary lamina I neurons. Lamina
I is the only spinal and medullary region containing specific
cold-sensitive neurons, and it has been shown that they project to
VMpo. It is also known that spinal cord lesions of the lateral
spinothalamic tract, which contains the axons of ascending lamina I
neurons, result in loss of temperature sensation (Craig
1991
; Kuru 1949
; Ralston and Ralston
1992
). The projection of VMpo to insular cortex suggests that
this pathway may be involved in perception of cold stimuli, and this is
consistent with recent positron emission tomography and fMRI studies
indicating insula activation by cold stimuli (Craig
1994
; Craig et al. 1996
; Davis et al.
1998
).
In conclusion, our observations of sites at which pure cold sensations are evoked with microstimulation and where neurons respond to innocuous cooling provide the first direct electrophysiological evidence for a human thalamic relay site for the cold pathway. A cold pathway relaying in VMpo likely plays an important role in the normal discrimination of cold and possibly in the abnormal cold-evoked pain observed in many neuropathic pain states.
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ACKNOWLEDGMENTS |
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The authors thank M. Teofilo and N. Sherman for technical assistance and Dr. Bud Craig for useful comments on an earlier draft of this manuscript.
This study was supported by the Medical Research Council of Canada and by National Institute of Neurological Disorders and Stroke Grant NS-36824.
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FOOTNOTES |
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Address for reprint requests: J. O. Dostrovsky, Dept. of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
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 30 September 1998; accepted in final form 15 December 1998.
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