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A population of cells in the human thalamic principal sensory nucleus respond to painful mechanical stimuli
ELSEVIER
Neuroscience Letters 180 (1994) 46-50
NEUROSCIENCE tETTfR$
A population of cells in the human thalamic principal sensory nucleus respond to painful mechanical stimuli Fred A. Lenz a'*, Richard H. Gracely c, Lance H. RoMan&, Patrick M. Dougherty a'b "Department of Neurosurgel 3, and I'D~7~artmentq[' Neuroscience, Johns Hopkins University. Balthm~re, MD, USA ' Neurobiology aml Anesthesioh~gy Branch, Natiomd hlstilute qf Dental Research, Natiomd Institutes q[" Health, Bethes~kl, MD, USA Received 29 April 1994: Revised version received 9 August 1994; Accepted 19 August 1994
Abstract
A population of neurons located in the cutaneous core of the principal sensory nucleus of human thalamus (ventralis caudalis, Vc) has been identified that had their maximal response to mechanical stimuli which were perceived as painful by the patients involved. None of these cells responded to painful thermal stimuli. The graded responses of these cells to mechanical stimuli extending into the painful range suggest they both mediate acute pain in response to mechanical stimuli and participate in mechanical hyperalgesia. Key words." Neurophysiology: Nociception; Pain measurement: Ventral posterior thalamic nucleus; Human
Previous studies have shown that a large population of neurons in the region of the human thalamic nucleus ventralis caudalis (Vc) respond to non-painful mechanical stimulation of the skin [10,14]. However, the spinothalamic tract (STT) terminates in this region [1,2,18] and mediates both acute pain in response to mechanical stimuli [25] and mechanical hyperalgesia following cutaneous injury [7,8,22]. At present there is no evidence that the region of Vc is involved in signalling painful mechanical stimuli in humans, although neurons in Vc encode painful thermal stimuli [17]. Therefore, the human thalamic substrate of mechanical pain and hyperalgesia is uncertain. We now report a population of cells in the region of Vc that are responsive to painful mechanical but not to painful thermal stimuli. The graded response of these cells to mechanical stimuli extending into the painful range suggests that they may signal acute pain evoked by mechanical stimuli. These studies were carried out during the physiologic exploration which precedes thalamotomy for treatment
*Corresponding author. Department of Neurosurgery, Meyer Building 7-113, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287-7713, USA. Fax: (1) 1410) 955-6407. 0304-3940/94/$7.00 © 1994 Elsevier Science Ireland Ltd. All rights reserved SSD1 0304-3940(94100650-4
of movement disorders or implantation of deep brain stimulating electrodes for the treatment of chronic pain. The protocol used in these studies conforms to the principles stated in the Declaration of Helsinki regarding the use of human subjects and was reviewed and approved yearly by the Institutional Review Board at the Johns Hopkins University. Physiologic exploration of thalamus was carried out under local anesthetic as described previously [13,16]. The stereotactic coordinates of the anterior and posterior commissure line (AC-PC), determined by computer assisted tomography, were used to predict the locations of thalamic nuclei of the ventral nuclear group. The position of the stereotactic target was then confirmed physiologically by recording the activity of single neurons using a high impedance microelectrode [13]. The first trajectory targeted Vc since the response of cells in this nucleus to somatic stimulation is the most reliable physiologic landmark guiding the exploration. Sites within thalamus were characterized both by the neuronal response to innocuous somatic stimuli [14] and by the quality [16] and location of the sensations evoked by electrical stimulation of thalamus at threshold microampere currents (threshold microstimulation, TMS; see [16]). The boundaries of both receptive fields for
EA. Lenz et al. INeuroscience Letters 180 (1994) 46-50
innocuous somatic stimuli (RF) and projected fields for microstimulation evoked responses (PF) were recorded. The patients described the sensations evoked by TMS using the same protocol and descriptor list as used in a previous study [15]. Background activity of each cell was recorded over a period of 30 seconds before application of somatic stimuli at cutaneous sites contained within the RF and PF for that site. At sites where no RF could be determined with innocuous stimuli somatic stimuli were applied within the PF for TMS. A series of thermal and mechanical stimuli were applied in the study of each cell; each stimulus was applied for a duration of 10-15 s. Thermal stimuli were applied using either cylindrical brass probes (diameter 2 cm) maintained at 43°C and 51°C or 53°C or using a peltier device with a one inch square head [24] to deliver pulses of the same temperatures. Control stimuli included room temperature plastic (black delrin) probes otherwise identical to the brass probes or application of the peltier device at 35°C. Mechanical stimuli included a camel hair brush, large arterial clip and small arterial clip identical to the series of stimuli used in studies of monkey ventral posterior nucleus (VP) by Willis and co-workers [6,11]. The small clip and the highest temperature thermal stimuli evoked pain sensations that were rated by all patients at 3 to 8 out of 10 on a visual analog scale of pain intensity [16]; the other stimuli were non-painful. Stimuli which were normally non-painful never evoked the sensation of pain when applied following a painful stimulus. This was taken as evidence that the painful stimuli, as applied in this protocol, did not produce hyperalgesia. Neuronal activity and a footswitch indicating the onset and duration of the stimuli were recorded intraoperatively on magnetic tape. Postoperatively, action potentials were discriminated by the criterion of constant shape of the action potential (Brainwave Systems, Thornton, CO). The time of occurrence of action potentials and the footswitch signa! were digitized using standard techniques [17]. A population of 141 cells were recorded along 20 trajectories through the region of Vc in 9 patients with movement disorders and 3 with chronic pain. This report excludes neuronal activity recorded from regions of Vc that represented the parts of the body where the chronic pain patients experienced sensory abnormalities or pain. The area of Vc was divided into the region where the majority of cells responded to innocuous somatic stimuli (core region) and the region posterior and inferior to the core region (posteroinferior region). Testing with the series of somatic stimuli was carried out on 42 cells, 21 of 87 cells recorded in the core region and 21 of 54 cells in the posteroinferior region. These 42 cells were recorded both in patients with movement disorders (37 cells) and in those with chronic pain (5 cells). The activity of a single cell responding to painful me-
47
chanical but not thermal stimuli is shown in Fig. 1. During pre-operative sensory testing the patient described brush (Fig. 1D) as a natural, non-painful, surface, touch and movement sensation [16]. The large arterial clip (Fig. 1E) was described as an unnatural, non-painful, pressure sensation involving both surface and deep structures. The small arterial clip (Fig. 1F) was described as an unnatural, painful, squeezing sensation involving both surface and deep structures; it was rated at 3 out of 10 on the visual analog scale. The plastic probe at room temperature (Fig. 1G) was described as a natural, pressure and cool sensation involving both surface and deep structures. The brass probe at 43°C (Fig. 1H) was described as a natural, surface, non-painful, warm sensation. The brass probe at 51°C (Fig. 1I) was described as a natural, surface, hot, painful sensation, rated at 7 out of 10 on the visual analog scale. Therefore, both the mechanical and thermal series of stimuli span intensities extending into the painful range. There is a clear increase in firing rate of the cell in Fig. 1 to stimuli across the mechanical series (Fig. 1D-F and 1J, left). However, the response of the cell to painful heat (Fig. 1I) was similar to the response to room temperature plastic and innocuous thermal stimuli (Fig. G H, and 1J, right). Statistical analysis was carried out by comparing the responses in each series with each other and with the background firing rate. The response to any stimulus was defined as the firing rate over the interval during which the footswitch was depressed. A one-way ANOVA comparing firing rates between the responses to mechanical stimuli and the background (Fig. 1J, left) found significant differences between firing rates in this series (F--4.97, d f - - 3 , P < 0.03). In contrast, an ANOVA comparing thermal stimuli and the background (Fig. 1J, right) found that differences between these firing rates were not significant (F = 2.35, df -- 3, P > 0.05). Therefore, to a significant degree, this cell encodes painful mechanical but not thermal stimuli. Six other cells with response patterns similar to those seen in Fig. 1 have been identified in these studies. These seven cells were all located in the region where the majority of cells responded to innocuous mechanical stimuli the core of Vc. Four of the seven units were located anterior to a vertical line (midline) located midway between the anterior and posterior borders of the core of Vc. The mean anterior-posterior position of the 7 cells was not significantly different (P > 0.05, t-test) from the midline of the core (cf. Fig. 1A). Although all cells responding selectively to noxious mechanical stimuli were recorded in patients with movement disorders, it is not clear that these patients are different from those with chronic pain because of the small sample size in the latter group. Non-painful, tingling sensations were evoked by stimulation (thresholds: 5-15/IA) at 6 sites, including the site shown in Fig. 1. A hot, painful vibration (visual analog scale 2/10) was evoked by stimulation (threshold
48
EA, Lenz et al./ Neuroscience Letters 180 (1994) 46-50
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Fig. 1. Location and activity of a cell in Vc responding to painful mechanical stimuli. A shows the location of the cell (arrowhead) relative to the positions of trajectories, nuclear boundaries and other recorded cells. The AC-PC line is indicated by the horizontal line (left-anterior) while the trajectories are shown by the oblique lines (up-dorsal). Nuclear location was approximated from the position of the AC-PC line. Trajectories have been shifted along the AC-PC line so the most anterior cell with a cutaneous receptive field is aligned with the anterior border of Vc. The locations of cells are indicated by ticks to the right of each trajectory, Cells with cutaneous RFs are indicated by long ticks with attached symbols which indicate modality (see inset); those without RFs are indicated by short ticks. The core region of Vc is defined as the area where the majority of ticks are long and have attached symbols. Note that the recorded cell is located in the antero-dorsal core. The scale is as indicated. B shows the R F for this cell and PF for the natural, surface, non-painful, tingling sensation evoked by TMS at the recording site (threshold: 15 pA). C shows the shape of action potentials discriminated during the application of the small clip (see F). The response of the cell to the series of somatic stimuli is shown in D to I. The lower trace in each panel is a footswitch signal indicating the onset and duration of the stimulus. The scales for the axes for all histograms (binwidtb: 100 ms) are indicated in D and G. J shows mean and standard error of the mean for the firing rate during the background period and the application of stimuli shown in D to l, as labelled. Ret, nucleus reticularis; Vc, ventralis caudalis; Vim, ventralis intermedius; Bkgd, background.
5 pA) at one site. In addition to the seven cells described above, three cells responded to both mechanical and thermal painful stimuli and one cell responded to thermal painful stimuli. These studies demonstrate the presence of a population of cells within the region of human Vc which respond to painful mechanical but not thermal stimuli. These cells may be the thalamic substrate of acute pain in response to mechanical stimuli. The stimulus response functions of these cells extend into the painful range (Fig. 1J) and so may encode painful mechanical stimuli.
A shift in the stimulus response function of these cells may mediate mechanical hyperalgesia. Cells in the region of the principal sensory nucleus of other species (ventralis posterior, VP) encode noxious mechanical stimuli. Studies in anesthetized cats [12,26], anesthetized old world primates [6,11] and awake old- [3] and new-world primates [4,5,19] have reported the presence of cells responding to noxious mechanical stimuli. Studies in monkeys suggest that cells responding to noxious mechanical stimuli are located in the core region [3-6,11, l 9,20] although the posteroinferior area was usu-
EA. Lenz et al./Neuroscience Letters 180 (1994) 46 50
ally not explored (cf. [4,20]). Noxious thermal and mechanical stimuli were applied to the same cells in only two of these studies [6,11]. In those two studies noxious thermal stimuli were applied to the receptive field of half the cells responding to noxious mechanical stimuli. Of the cells so studied, approximately 20% responded to noxious mechanical but not heat stimuli [6,11]. Therefore, a population of cells in monkey VP have properties similar to those of the cells in the present study in humans. The present results suggest that many nociceptive cells in the region of Vc respond to painful mechanical but not thermal stimuli. The relatively large proportion of these selectively responding cells (64%, 7/11; see above) is surprising in view of the degree of convergence between thermal and mechanical modalities in the cells of origin of the primate dorsal and ventral STT [9,23]. Differences in the degree of convergence may be due to thalamic synaptic circuitry specific to different tracts ascending to the thalamus [21]. Lemniscal inputs terminate in synaptic profiles including inhibitory thalamic interneurons [21] whereas STT terminals do not. Thalamic processing of this type might account for differences between the activity of STT cells and cells receiving STT inputs. The results of the study suggest that there is modality segregation of nociceptive inputs to the area of Vc. The majority of cells responding to painful mechanical stimuli were located in the anterior aspect of the core of Vc. The remainder were located in the posterior aspect of the core and none was located in the posteroinferior region. This is different from the location of cells responding to painful thermal stimuli, 40% of which were located in the posteroinferior region [17] while the remainder were located near the posterior border of the core region. Therefore the present results suggest that there may be segregation of nociceptive cells in the area of human Vc based upon modality. Supported by grants to FAL from the Eli Lilly Corporation and the NIH (NS28598, K08-NS1384, P01NS32386-01). [1] Apkarian, A.V. and Hodge, C.J., Primate spinothalamic pathways: II. The cells of origin of the dorsolateral and ventral spinothalamic pathways, J. Comp. Neurol., 288 (1989) 474-492. [2] Burton, H. and Craig, A.D., Jr., Spinothalamic projections in cat, raccoon and monkey: a study based on anterograde transport of horseradish peroxidase. In G. Macchi, A. Rustioni and R. Spreafico (Eds.), Somatosensory Integration in the Thalamus, Elsevier, Amsterdam, 1983, pp. 17~,1. [3] Bushnell, M.C. and Duncan, G.H., Mechanical response properties of ventroposterior medial thalarrfic neurons in the alert monkey, Exp. Brain Res., 67 (1987) 603-614. [4] Casey, K.L., Unit analysis of nociceptive mechanisms in the thalamus of the awake squirrel monkey, J. Neurophysiol., 29 (1966) 727-750. [5] Casey, K.L. and Morrow, T.J., Ventral posterior thalamic neurons
49
differentially responsive to noxious stimulation of the awake monkey, Science, 221 (1983) 675-677. [6] Chung, J.M., Lee, K.H., Surmeier, D.J., Sorkin, L.S., Kim, I. and Willis, W.D., Response characteristics of neurons in the ventral posterior lateral nucleus of the monkey thalamus, J. Neurophysiol., 56 (1986) 370-390. [7] Dougherty, P.M., Sluka, K.A., Sorkin, L.S., Westlund, K.N. and Willis, W.D., Neural changes in acute arthritis in monkeys. I. Parallel enhancement of responses of spinothalamic tract neurons to mechanical stimulation and excitatory amino acids, Brain Res. Rev., 17 (1992) 1-13. [8] Dougherty, P.M. and Willis, W.D., Enhanced responses of spinothalamic tract neurons to excitatory amino acids accompany the generation of capsaicin-induced hyperalgesia in monkeys, J. Neurosci., 12 (1992) 883 894. [9] Ferrington, D.G., Sorkin, L.S. and Willis, W.D., Responses of spinothalamic tract cells in the superficial dorsal horn of the primate lumbar spinal cord, J. Physiol., 388 (1987) 681 703. [10] Jasper, H.H. and Bertrand, G., Thalamic units involve 1 somatic sensation and voluntary and involuntary movements m man. In D.P. Purpura and M.D. Yahr (Eds.), The Thalamus, Columbia University Press, New York, 1966, pp. 365 390. [111 Kenshalo, D.R., Giesler, G.J., Leonard, R.B. and Willis, W.D., Responses of neurons in primate ventral posterior lateral nucleus to noxious stimuli, J. Neurophysiol., 43 (1980) 1594-1614. [12] Kniffki, K.D. and Vahle-Hinz, C., The periphery of the cat's ventroposteromedial nucleus (VPMp): nociceptive neurones. In J.-M. Besson, G. Guilbaud and M. Peschanski (Eds.), Thalamus and Pain, Elsevier, Amsterdam, 1987, pp. 245-257. [13] Lenz, F.A., Dostrovsky, J.O., Kwan, H.C., Tasker, R.R., Yamashiro, K. and Murphy, J.T., Methods for microstimulation and recording of single neurons and evoked potentials in the human central nervous system, J. Neurosurg., 68 (1988) 630-634. [14] Lenz, F.A., Dostrovsky, J.O., Tasker, R.R., Yamashiro, K., Kwan, H.C. and Murphy, J.T., Single-unit analysis of the human ventral thalamic nuclear group: somatosensory responses, J. Neurophysiol., 59 (1988) 299 316. [15] Lenz, F.A., Gracely, R.H., Hope, E.J., Baker, F.H., Rowland, L.H., Dougherty, P.M. and Richardson, R.T., The sensation of angina can be evoked by stimulation of the human thalamus, Pain, (1994) in press. [16] Lenz, F.A., Seike, M., Lin, Y.C., Baker, F.H., Richardson, R.T. and Gracely, R.H., Thermal and pain sensations evoked by microstimulation in the area of the human ventrocaudal nucleus (Vc), J. Neurophysiol., 70 (1993) 200-212. [17] Lenz, F.A., Seike, M., Lin, Y.C., Baker, F.H., Rowland, L.H., Gracely, R.H. and Richardson, R.T., Neurons in the area of human thalamic nucleus ventralis caudalis respond to painful heat stimuli, Brain Res., 623 (1993) 235 240. [18] Mehler, W.R., The anatomy of the so-called 'pain tract' in man: an analysis of the course and distribution of the ascending fibers of the fasciculus anterolateralis. In J.D. French and R.W. Porter (Eds.), Basic Research in Paraplegia, Thomas, Springfield, IL, 1962, pp. 26-55. [19] Morrow, T.J. and Casey, K.L., State-related modulation of thalamic somatosensory responses in the awake monkey, J. Neurophysiol., 67 (1992) 305-317. [20] Perl, E.R. and Whitlock, D.G., Somatic stimuli exciting spinothalamic projections to thalamic neurons in cat and monkey, Exp. Neurol., 3 (1961) 256 296. [21] Ralston, H.J. and Ralston, D.D., Medial lemniscal and spinal projections to the Macaque thalamus: an electron microscopic study of differing GABAergic circuitry serving thalamic somatosensory mechanisms, J. Neurosci., 14 (1994) 2485-2502. [22] Simone, D.A., Sorkin, L.S., Oh, U., Chung, J.M., Owens, C., Lamotte, R.H. and Willis, W.D., Neurogenic hyperalgesia: Cen-
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EA. Lenz et al./Neuroseience Letters 180 (1994) 46 50
tral neural correlates in responses of spinothalamic tract neurons, J. Neurophysiol., 66 (1991) 228-246. [23] Surmeier, D.J., Honda, C.N. and Willis, W.D., Response of primate spinothalamic neurons to noxious thermal stimulation of glabrous and hairy skin, J. Neurophysiol., 56 (1986) 328 350. [24] Wilcox, G.L. and Giesler, G.J., An instrument using a multiple
layer peltier device to change skin temperature rapidly, Brain Res. Bull., 12 (1984) 143-146. [25] Willis, W.D., The Pain System, Karger, Basel, 1985. [26] Yokota~ T., Asato, F., Koyama, N., Masuda, T. and Taguchi, H., Noeiceptive body representation in nucleus veutralis posterolateralis of cat thalamus, J. Neurophysiol., 60 (1988) 1714-1727.
Neuroscience Letters 180 (1994) 46-50
NEUROSCIENCE tETTfR$
A population of cells in the human thalamic principal sensory nucleus respond to painful mechanical stimuli Fred A. Lenz a'*, Richard H. Gracely c, Lance H. RoMan&, Patrick M. Dougherty a'b "Department of Neurosurgel 3, and I'D~7~artmentq[' Neuroscience, Johns Hopkins University. Balthm~re, MD, USA ' Neurobiology aml Anesthesioh~gy Branch, Natiomd hlstilute qf Dental Research, Natiomd Institutes q[" Health, Bethes~kl, MD, USA Received 29 April 1994: Revised version received 9 August 1994; Accepted 19 August 1994
Abstract
A population of neurons located in the cutaneous core of the principal sensory nucleus of human thalamus (ventralis caudalis, Vc) has been identified that had their maximal response to mechanical stimuli which were perceived as painful by the patients involved. None of these cells responded to painful thermal stimuli. The graded responses of these cells to mechanical stimuli extending into the painful range suggest they both mediate acute pain in response to mechanical stimuli and participate in mechanical hyperalgesia. Key words." Neurophysiology: Nociception; Pain measurement: Ventral posterior thalamic nucleus; Human
Previous studies have shown that a large population of neurons in the region of the human thalamic nucleus ventralis caudalis (Vc) respond to non-painful mechanical stimulation of the skin [10,14]. However, the spinothalamic tract (STT) terminates in this region [1,2,18] and mediates both acute pain in response to mechanical stimuli [25] and mechanical hyperalgesia following cutaneous injury [7,8,22]. At present there is no evidence that the region of Vc is involved in signalling painful mechanical stimuli in humans, although neurons in Vc encode painful thermal stimuli [17]. Therefore, the human thalamic substrate of mechanical pain and hyperalgesia is uncertain. We now report a population of cells in the region of Vc that are responsive to painful mechanical but not to painful thermal stimuli. The graded response of these cells to mechanical stimuli extending into the painful range suggests that they may signal acute pain evoked by mechanical stimuli. These studies were carried out during the physiologic exploration which precedes thalamotomy for treatment
*Corresponding author. Department of Neurosurgery, Meyer Building 7-113, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287-7713, USA. Fax: (1) 1410) 955-6407. 0304-3940/94/$7.00 © 1994 Elsevier Science Ireland Ltd. All rights reserved SSD1 0304-3940(94100650-4
of movement disorders or implantation of deep brain stimulating electrodes for the treatment of chronic pain. The protocol used in these studies conforms to the principles stated in the Declaration of Helsinki regarding the use of human subjects and was reviewed and approved yearly by the Institutional Review Board at the Johns Hopkins University. Physiologic exploration of thalamus was carried out under local anesthetic as described previously [13,16]. The stereotactic coordinates of the anterior and posterior commissure line (AC-PC), determined by computer assisted tomography, were used to predict the locations of thalamic nuclei of the ventral nuclear group. The position of the stereotactic target was then confirmed physiologically by recording the activity of single neurons using a high impedance microelectrode [13]. The first trajectory targeted Vc since the response of cells in this nucleus to somatic stimulation is the most reliable physiologic landmark guiding the exploration. Sites within thalamus were characterized both by the neuronal response to innocuous somatic stimuli [14] and by the quality [16] and location of the sensations evoked by electrical stimulation of thalamus at threshold microampere currents (threshold microstimulation, TMS; see [16]). The boundaries of both receptive fields for
EA. Lenz et al. INeuroscience Letters 180 (1994) 46-50
innocuous somatic stimuli (RF) and projected fields for microstimulation evoked responses (PF) were recorded. The patients described the sensations evoked by TMS using the same protocol and descriptor list as used in a previous study [15]. Background activity of each cell was recorded over a period of 30 seconds before application of somatic stimuli at cutaneous sites contained within the RF and PF for that site. At sites where no RF could be determined with innocuous stimuli somatic stimuli were applied within the PF for TMS. A series of thermal and mechanical stimuli were applied in the study of each cell; each stimulus was applied for a duration of 10-15 s. Thermal stimuli were applied using either cylindrical brass probes (diameter 2 cm) maintained at 43°C and 51°C or 53°C or using a peltier device with a one inch square head [24] to deliver pulses of the same temperatures. Control stimuli included room temperature plastic (black delrin) probes otherwise identical to the brass probes or application of the peltier device at 35°C. Mechanical stimuli included a camel hair brush, large arterial clip and small arterial clip identical to the series of stimuli used in studies of monkey ventral posterior nucleus (VP) by Willis and co-workers [6,11]. The small clip and the highest temperature thermal stimuli evoked pain sensations that were rated by all patients at 3 to 8 out of 10 on a visual analog scale of pain intensity [16]; the other stimuli were non-painful. Stimuli which were normally non-painful never evoked the sensation of pain when applied following a painful stimulus. This was taken as evidence that the painful stimuli, as applied in this protocol, did not produce hyperalgesia. Neuronal activity and a footswitch indicating the onset and duration of the stimuli were recorded intraoperatively on magnetic tape. Postoperatively, action potentials were discriminated by the criterion of constant shape of the action potential (Brainwave Systems, Thornton, CO). The time of occurrence of action potentials and the footswitch signa! were digitized using standard techniques [17]. A population of 141 cells were recorded along 20 trajectories through the region of Vc in 9 patients with movement disorders and 3 with chronic pain. This report excludes neuronal activity recorded from regions of Vc that represented the parts of the body where the chronic pain patients experienced sensory abnormalities or pain. The area of Vc was divided into the region where the majority of cells responded to innocuous somatic stimuli (core region) and the region posterior and inferior to the core region (posteroinferior region). Testing with the series of somatic stimuli was carried out on 42 cells, 21 of 87 cells recorded in the core region and 21 of 54 cells in the posteroinferior region. These 42 cells were recorded both in patients with movement disorders (37 cells) and in those with chronic pain (5 cells). The activity of a single cell responding to painful me-
47
chanical but not thermal stimuli is shown in Fig. 1. During pre-operative sensory testing the patient described brush (Fig. 1D) as a natural, non-painful, surface, touch and movement sensation [16]. The large arterial clip (Fig. 1E) was described as an unnatural, non-painful, pressure sensation involving both surface and deep structures. The small arterial clip (Fig. 1F) was described as an unnatural, painful, squeezing sensation involving both surface and deep structures; it was rated at 3 out of 10 on the visual analog scale. The plastic probe at room temperature (Fig. 1G) was described as a natural, pressure and cool sensation involving both surface and deep structures. The brass probe at 43°C (Fig. 1H) was described as a natural, surface, non-painful, warm sensation. The brass probe at 51°C (Fig. 1I) was described as a natural, surface, hot, painful sensation, rated at 7 out of 10 on the visual analog scale. Therefore, both the mechanical and thermal series of stimuli span intensities extending into the painful range. There is a clear increase in firing rate of the cell in Fig. 1 to stimuli across the mechanical series (Fig. 1D-F and 1J, left). However, the response of the cell to painful heat (Fig. 1I) was similar to the response to room temperature plastic and innocuous thermal stimuli (Fig. G H, and 1J, right). Statistical analysis was carried out by comparing the responses in each series with each other and with the background firing rate. The response to any stimulus was defined as the firing rate over the interval during which the footswitch was depressed. A one-way ANOVA comparing firing rates between the responses to mechanical stimuli and the background (Fig. 1J, left) found significant differences between firing rates in this series (F--4.97, d f - - 3 , P < 0.03). In contrast, an ANOVA comparing thermal stimuli and the background (Fig. 1J, right) found that differences between these firing rates were not significant (F = 2.35, df -- 3, P > 0.05). Therefore, to a significant degree, this cell encodes painful mechanical but not thermal stimuli. Six other cells with response patterns similar to those seen in Fig. 1 have been identified in these studies. These seven cells were all located in the region where the majority of cells responded to innocuous mechanical stimuli the core of Vc. Four of the seven units were located anterior to a vertical line (midline) located midway between the anterior and posterior borders of the core of Vc. The mean anterior-posterior position of the 7 cells was not significantly different (P > 0.05, t-test) from the midline of the core (cf. Fig. 1A). Although all cells responding selectively to noxious mechanical stimuli were recorded in patients with movement disorders, it is not clear that these patients are different from those with chronic pain because of the small sample size in the latter group. Non-painful, tingling sensations were evoked by stimulation (thresholds: 5-15/IA) at 6 sites, including the site shown in Fig. 1. A hot, painful vibration (visual analog scale 2/10) was evoked by stimulation (threshold
48
EA, Lenz et al./ Neuroscience Letters 180 (1994) 46-50
B°
Am
C.
Antero-Dorsal
RF
PF
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ANoxious+Innocuous v MechanicalStimuli
15 uA.
E.
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I.
Fig. 1. Location and activity of a cell in Vc responding to painful mechanical stimuli. A shows the location of the cell (arrowhead) relative to the positions of trajectories, nuclear boundaries and other recorded cells. The AC-PC line is indicated by the horizontal line (left-anterior) while the trajectories are shown by the oblique lines (up-dorsal). Nuclear location was approximated from the position of the AC-PC line. Trajectories have been shifted along the AC-PC line so the most anterior cell with a cutaneous receptive field is aligned with the anterior border of Vc. The locations of cells are indicated by ticks to the right of each trajectory, Cells with cutaneous RFs are indicated by long ticks with attached symbols which indicate modality (see inset); those without RFs are indicated by short ticks. The core region of Vc is defined as the area where the majority of ticks are long and have attached symbols. Note that the recorded cell is located in the antero-dorsal core. The scale is as indicated. B shows the R F for this cell and PF for the natural, surface, non-painful, tingling sensation evoked by TMS at the recording site (threshold: 15 pA). C shows the shape of action potentials discriminated during the application of the small clip (see F). The response of the cell to the series of somatic stimuli is shown in D to I. The lower trace in each panel is a footswitch signal indicating the onset and duration of the stimulus. The scales for the axes for all histograms (binwidtb: 100 ms) are indicated in D and G. J shows mean and standard error of the mean for the firing rate during the background period and the application of stimuli shown in D to l, as labelled. Ret, nucleus reticularis; Vc, ventralis caudalis; Vim, ventralis intermedius; Bkgd, background.
5 pA) at one site. In addition to the seven cells described above, three cells responded to both mechanical and thermal painful stimuli and one cell responded to thermal painful stimuli. These studies demonstrate the presence of a population of cells within the region of human Vc which respond to painful mechanical but not thermal stimuli. These cells may be the thalamic substrate of acute pain in response to mechanical stimuli. The stimulus response functions of these cells extend into the painful range (Fig. 1J) and so may encode painful mechanical stimuli.
A shift in the stimulus response function of these cells may mediate mechanical hyperalgesia. Cells in the region of the principal sensory nucleus of other species (ventralis posterior, VP) encode noxious mechanical stimuli. Studies in anesthetized cats [12,26], anesthetized old world primates [6,11] and awake old- [3] and new-world primates [4,5,19] have reported the presence of cells responding to noxious mechanical stimuli. Studies in monkeys suggest that cells responding to noxious mechanical stimuli are located in the core region [3-6,11, l 9,20] although the posteroinferior area was usu-
EA. Lenz et al./Neuroscience Letters 180 (1994) 46 50
ally not explored (cf. [4,20]). Noxious thermal and mechanical stimuli were applied to the same cells in only two of these studies [6,11]. In those two studies noxious thermal stimuli were applied to the receptive field of half the cells responding to noxious mechanical stimuli. Of the cells so studied, approximately 20% responded to noxious mechanical but not heat stimuli [6,11]. Therefore, a population of cells in monkey VP have properties similar to those of the cells in the present study in humans. The present results suggest that many nociceptive cells in the region of Vc respond to painful mechanical but not thermal stimuli. The relatively large proportion of these selectively responding cells (64%, 7/11; see above) is surprising in view of the degree of convergence between thermal and mechanical modalities in the cells of origin of the primate dorsal and ventral STT [9,23]. Differences in the degree of convergence may be due to thalamic synaptic circuitry specific to different tracts ascending to the thalamus [21]. Lemniscal inputs terminate in synaptic profiles including inhibitory thalamic interneurons [21] whereas STT terminals do not. Thalamic processing of this type might account for differences between the activity of STT cells and cells receiving STT inputs. The results of the study suggest that there is modality segregation of nociceptive inputs to the area of Vc. The majority of cells responding to painful mechanical stimuli were located in the anterior aspect of the core of Vc. The remainder were located in the posterior aspect of the core and none was located in the posteroinferior region. This is different from the location of cells responding to painful thermal stimuli, 40% of which were located in the posteroinferior region [17] while the remainder were located near the posterior border of the core region. Therefore the present results suggest that there may be segregation of nociceptive cells in the area of human Vc based upon modality. Supported by grants to FAL from the Eli Lilly Corporation and the NIH (NS28598, K08-NS1384, P01NS32386-01). [1] Apkarian, A.V. and Hodge, C.J., Primate spinothalamic pathways: II. The cells of origin of the dorsolateral and ventral spinothalamic pathways, J. Comp. Neurol., 288 (1989) 474-492. [2] Burton, H. and Craig, A.D., Jr., Spinothalamic projections in cat, raccoon and monkey: a study based on anterograde transport of horseradish peroxidase. In G. Macchi, A. Rustioni and R. Spreafico (Eds.), Somatosensory Integration in the Thalamus, Elsevier, Amsterdam, 1983, pp. 17~,1. [3] Bushnell, M.C. and Duncan, G.H., Mechanical response properties of ventroposterior medial thalarrfic neurons in the alert monkey, Exp. Brain Res., 67 (1987) 603-614. [4] Casey, K.L., Unit analysis of nociceptive mechanisms in the thalamus of the awake squirrel monkey, J. Neurophysiol., 29 (1966) 727-750. [5] Casey, K.L. and Morrow, T.J., Ventral posterior thalamic neurons
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differentially responsive to noxious stimulation of the awake monkey, Science, 221 (1983) 675-677. [6] Chung, J.M., Lee, K.H., Surmeier, D.J., Sorkin, L.S., Kim, I. and Willis, W.D., Response characteristics of neurons in the ventral posterior lateral nucleus of the monkey thalamus, J. Neurophysiol., 56 (1986) 370-390. [7] Dougherty, P.M., Sluka, K.A., Sorkin, L.S., Westlund, K.N. and Willis, W.D., Neural changes in acute arthritis in monkeys. I. Parallel enhancement of responses of spinothalamic tract neurons to mechanical stimulation and excitatory amino acids, Brain Res. Rev., 17 (1992) 1-13. [8] Dougherty, P.M. and Willis, W.D., Enhanced responses of spinothalamic tract neurons to excitatory amino acids accompany the generation of capsaicin-induced hyperalgesia in monkeys, J. Neurosci., 12 (1992) 883 894. [9] Ferrington, D.G., Sorkin, L.S. and Willis, W.D., Responses of spinothalamic tract cells in the superficial dorsal horn of the primate lumbar spinal cord, J. Physiol., 388 (1987) 681 703. [10] Jasper, H.H. and Bertrand, G., Thalamic units involve 1 somatic sensation and voluntary and involuntary movements m man. In D.P. Purpura and M.D. Yahr (Eds.), The Thalamus, Columbia University Press, New York, 1966, pp. 365 390. [111 Kenshalo, D.R., Giesler, G.J., Leonard, R.B. and Willis, W.D., Responses of neurons in primate ventral posterior lateral nucleus to noxious stimuli, J. Neurophysiol., 43 (1980) 1594-1614. [12] Kniffki, K.D. and Vahle-Hinz, C., The periphery of the cat's ventroposteromedial nucleus (VPMp): nociceptive neurones. In J.-M. Besson, G. Guilbaud and M. Peschanski (Eds.), Thalamus and Pain, Elsevier, Amsterdam, 1987, pp. 245-257. [13] Lenz, F.A., Dostrovsky, J.O., Kwan, H.C., Tasker, R.R., Yamashiro, K. and Murphy, J.T., Methods for microstimulation and recording of single neurons and evoked potentials in the human central nervous system, J. Neurosurg., 68 (1988) 630-634. [14] Lenz, F.A., Dostrovsky, J.O., Tasker, R.R., Yamashiro, K., Kwan, H.C. and Murphy, J.T., Single-unit analysis of the human ventral thalamic nuclear group: somatosensory responses, J. Neurophysiol., 59 (1988) 299 316. [15] Lenz, F.A., Gracely, R.H., Hope, E.J., Baker, F.H., Rowland, L.H., Dougherty, P.M. and Richardson, R.T., The sensation of angina can be evoked by stimulation of the human thalamus, Pain, (1994) in press. [16] Lenz, F.A., Seike, M., Lin, Y.C., Baker, F.H., Richardson, R.T. and Gracely, R.H., Thermal and pain sensations evoked by microstimulation in the area of the human ventrocaudal nucleus (Vc), J. Neurophysiol., 70 (1993) 200-212. [17] Lenz, F.A., Seike, M., Lin, Y.C., Baker, F.H., Rowland, L.H., Gracely, R.H. and Richardson, R.T., Neurons in the area of human thalamic nucleus ventralis caudalis respond to painful heat stimuli, Brain Res., 623 (1993) 235 240. [18] Mehler, W.R., The anatomy of the so-called 'pain tract' in man: an analysis of the course and distribution of the ascending fibers of the fasciculus anterolateralis. In J.D. French and R.W. Porter (Eds.), Basic Research in Paraplegia, Thomas, Springfield, IL, 1962, pp. 26-55. [19] Morrow, T.J. and Casey, K.L., State-related modulation of thalamic somatosensory responses in the awake monkey, J. Neurophysiol., 67 (1992) 305-317. [20] Perl, E.R. and Whitlock, D.G., Somatic stimuli exciting spinothalamic projections to thalamic neurons in cat and monkey, Exp. Neurol., 3 (1961) 256 296. [21] Ralston, H.J. and Ralston, D.D., Medial lemniscal and spinal projections to the Macaque thalamus: an electron microscopic study of differing GABAergic circuitry serving thalamic somatosensory mechanisms, J. Neurosci., 14 (1994) 2485-2502. [22] Simone, D.A., Sorkin, L.S., Oh, U., Chung, J.M., Owens, C., Lamotte, R.H. and Willis, W.D., Neurogenic hyperalgesia: Cen-
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