Thalamic Relay Site for Cold Perception in Humans

Karen D. Davis,1,3 Andres M. Lozano,1,3 Marosh Manduch,2 Ronald R. Tasker,1,3 Zelma H. T. Kiss,1 and Jonathan O. Dostrovsky2,3

 1Department of Surgery and  2Department of Physiology, University of Toronto; and  3Playfair Neuroscience Unit/The Toronto Hospital Research Institute, The Toronto Hospital, Toronto, Ontario M5S 1A8, Canada


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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.


    INTRODUCTION
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ABSTRACT
INTRODUCTION
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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; 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.


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METHODS
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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) 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 MOmega . 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.

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; 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.

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; 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.


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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; 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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Fig. 2. Single neuron responses to cooling stimuli in 2 patients. In each example, the temperature profile of the stimulus delivered by a peltier-type thermal probe is shown above the peristimulus time histogram of a single neuronal response. An excerpt of the raw multiunit oscilloscope recording during a cooling step is shown below each histogram. A: responses are shown to repeated cooling stimuli applied to the receptive field on the dorsum of the hand. B: responses are shown for application of increasing intensities of cooling stimuli applied within the neuronal receptive field on the fifth digit.

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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Fig. 3. Location of stimulation-evoked cold sites and the posterior part of the thalamic ventromedial nucleus (VMpo). In each patient the stimulation site that evoked cold at the lowest threshold is shown in the coronal (A) and sagittal (B) planes. Reconstruction of these sites was based on the physiological findings as described in METHODS. The horizonal line depicts the inferior border of Vc and is perpendicular to the sagittal plane in A and parallel to the anterior commissure (AC)-posterior commissure (PC) line in B. The vertical line depicts the medial (A) or posterior (B) border of the face/hand representation and is parallel to the sagittal plane in A and is perpendicular to the AC-PC line in B. The dotted outline represents the approximate location of the boundaries of tactile Vc typically encountered. C: modified excerpt taken from Craig et al. (1994) of the proposed anatomic location of VMpo in the sagittal and horizontal planes.


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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.


    ACKNOWLEDGMENTS

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.


    FOOTNOTES

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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