- Email: [email protected]
The ability of humans to localise noxious stimuli
Neuroscience Letters, 150 (1993) 219-222
219
Elsevier Scientific Publishers Ireland Ltd.
NSL 09327
The ability of humans to localise noxious stimuli M a r t i n Koltzenburg a, H e r m a n n O. H a n d w e r k e r b and H. Erik Torebj6rk c aNeurologische Universitiits-Klinik, Warzburg (FRG), blnstitutf~r Physiologie und Biokybernetik, Erlangen ( FRG) and CDepartmentof Clinical Neurophysiology, Uppsala (Sweden) (Received 28 September 1992; Revised version received 23 November 1992; Accepted 30 November 1992)
Key words: Nociceptor; Pain; Itch; Touch; Unmyelinated primary afferent; Cortical map; Psychophysics; Differential nerve block We have investigated the ability of humans to localise noxious stimuli on the dorsum of the hand. Pin-prick (non-penetrating needle prick), noxious heat (round 1 cm 2 copper probe heated to 50°C), mustard oil (100% applied topically in a small cotton ball, diameter 5 mm) and histamine (iontophoresis of 20 mC delivered to an area of 75 mm 2) were applied to skin with intact innervation and during a differential nerve compression block of the superficial radial nerve when only C-fibres were conducting. The mean mislocalisation (_+ S.E.M.; n = 8) of all stimuli was 9.5 + 0.8 mm with normal nerve conduction and 8.9 + 1.2 during the differential nerve block. There was no significant difference between the noxious submodalities. By contrast, when nerve conduction was intact, purely tactile stimulation (7 mN von Frey hair) was significantly better localised having a mean error of 5.5 + 0.4 mm. We conclude that focal stimuli evoking itch or pain can be localised with high precision which is only marginally worse than for tactile stimuli. This suggests the existence of a somatotopical representation for noxious inputs in the brain similar to that found for tactile stimuli.
The conscious human brain has the ability to accurately localise tactile stimuli within a small error of few millimetres at the fingertips [4, 22, 23]. It is thought that this accuracy reflects the orderly representation of the body surface by cortical maps [9, 10, 21]. By contrast it is often touted in texts that the pain signalled by unmyelinated nociceptive afferents is ill-localised suggesting that the cortical representation for noxious stimuli is rather poor. Moreover, it is not known whether there are systematic differences between different submodalities which are signalled by cutaneous unmyelinated afferents. Knowledge about the spatial resolution would be important for the understanding of the cerebral organisation of nociceptive inputs. We have therefore investigated the ability of humans to localise different submodalities of focal noxious stimuli. Eight volunteers (2 females, 6 males) aged 29-52 years including the authors participated in the experiments after having given informed consent. They were comfortably seated in a reclining chair and either left or right hand was randomly chosen and stabilised in an intermediate position between pro- and supination. Differential nerve blocks of the superficial radial nerve were performed by placing a 2.5-cm-wide band onto the wrist, Correspondence: M. Koltzenburg, Neurologische Universit/its-Klinik, Josef-Schneider-Str.11, W-8700 Wiirzburg, FRG. Fax: (49) 931-2012697
with 2.1 kg weights hanging at each side. This technique results in the progressive loss of tactile and cold sensations corresponding to the differential block of large and thin myelinated fibres, respectively [14, 28]. Sensory testing commenced when the subjects could no longer feel slightly stroking the skin with a cotton bud, the application of a 7 mN von Frey hair or the coolness of a cold copper probe maintained at 20°C. The onset of this differential nerve block varied from 28 to 47 min between subjects and the subsequent duration of the tests was 7-12 min. All stimuli were presented in a balanced pseudo-randomised order to the radial side of the dorsum of the hand and to the proximal portion of the first three fingers within the usual autonomous innervation territory of the superficial radial nerve. Noxious stimuli consisted of (i) a non-penetrating needle prick, (ii) a 3-s-long application of a circular contact probe (1 cm 2) heated to 50°C [8, 20], (iii) iontophoresis of histamine [16] delivering 20 mC within 30 s to a circular area of 5 mm in diameter, (iv) topical application of a cotton ball (diameter 5 mm) soaked in pure mustard oil (allyl-isothiocyanat) [15]. Either before or after the differential nerve block the same four stimuli were applied to the contralateral hand. To test locognosia for touch a 7 mN von Frey hair was applied 10 times to the unblocked side and the average distance of the mislocalisation was recorded for each subject.
220
Subjects were blindfolded during the stimulus and were asked to mark the site where they localised the stimulus with a felt pen. Dimming the lights in the room and wearing of dark goggles permitted the subjects to see only the general contours of the hand. The distance from the marking of the subject to the centre of the actual stimulus site was then measured to the nearest millimetre. In experiments with intact nerve conduction subjects could readily differentiate the distinct qualities of the four noxious stimuli. Needle prick was described as a sharp pricking pain, noxious heat or mustard oil application were described as burning pain while iontophoresis of histamine evoked itch. Pin prick and noxious heat were felt almost instantaneously, but there was a latency between application and the first sensation for mustard oil ( 3 2 + 6 s) and histamine ( 1 6 + 2 s) application (mean + S.E.M; P > 0.05, Wilcoxon matched pairs test). At the stage of a differential nerve block when only unmyelinated fibres conducted, both the quality of sensation and the latency remained virtually unchanged after topical mustard oil treatment (29 + 7 s; P > 0.5; Wilcoxon matched pairs test) and histamine iontophoresis (15 + 2 s; P > 0.4; Wilcoxon matched pairs test). We infer that the modalities of itch and burning pain are mainly signalled by C-fibres [5]. By contrast the latency and quality of pin-prick and heat pain sensations changed in a characteristic way during the differential nerve block. The sensations typically occurred with a delay of 1-2s after both stimuli. Furthermore, the quality of pin prick evoked-pain became burning and some subjects confused pin prick and heat stimuli. The change of quality and latency confirm that myelinated fibres are important for signalling pin prick and heat pain in normal hairy skin [2]. The average mislocalisation between all noxious stimuli was 9.5 + 0.8 (range 5.8-13.0) under normal conditions and 8.9 + 1.2 (range 6-12.8) mm during a differential nerve block (P > 0.5; Wilcoxon matched pairs test). There was no significant difference (P always > 0.1; Wilcoxon matched pairs test) of the localisation between the different noxious submodalities and there was no significant impairment of localisation for any single submodality in the blocked or unblocked condition (Fig. 1). With normal nerve conduction the localisation of tactile stimuli was significantly better than for noxious stimuli (P < 0.05; Wilcoxon matched pairs test). The average mislocalisation of a stimulus with a 7 mN von Frey hair was 5.5 + 0.4 (range 3.7-7.9) mm. The application of the copper probe which was maintained at warm, but nonpainful temperatures, was localised with similar precision. There was no significant correlation between subjects' performance to localise noxious or tactile stimuli
/5mm .
.
to m
10-
-]-]
D
t~ ¢D ¢,0
5_
0_ ~
X(\~\~
Fig. 1. Mean (+S.E.M.; n : 8 ) mislocalisation of different submodalities of noxious stimulation with normal nerve conduction (open bars) and during a differential nerve block when only unmyelinated fibres were conducting (filled bars). There was no significant difference between the values obtained for the different submodalities.
(r = -0.24; P > 0.5, linear correlation), nor was there any obvious preference for the direction in which stimuli were mislocalised. The principle finding of the present investigation is that humans have a good ability to localise noxious stimuli even when these are exclusively transmitted by unmyelinated afferents. This is in contrast to the reasoning formulated by eminent neurologists working at the turn of the century [6] and is at variance with the statements still found in virtually all textbooks, which imply that C-fibre mediated pain is only poorly localised. However, here we have determined that the precision of locognosia of various forms of cutaneous pain is only marginally worse than that of pure tactile stimuli. This suggests that there is an orderly representation of cutaneous nociceptors in the brain, perhaps similar to the distribution of cortical elements responding to tactile stimuli. The results of the present investigations support previous reports showing that noxious pin-prick [13], noxious heat [20] or innocuous warm stimuli [19] applied to the hand are localised with an accuracy almost as good as that for tactile stimuli. Microneurographic experiments have also demonstrated a remarkable matching between localisation of painful sensations evoked by intraneural microstimulation and the receptive fields of the stimulated unmyelinated nociceptive units [8~ 20, 29]. Here we have extended those observations to show that the accuracy of localisation is little influenced by the noxious submodality or the temporal profile of the stimulus. This is an interesting observation since chemical stimuli often yield less vigorous discharge frequencies from nociceptive afferents compared to heat or pin-prick stimuli [5, 12]. This
221
could mean that the localisation capacity is largely independent of the temporal discharge phttern. An unexpected finding of the present investigation was that the localisation capacity using painful pin prick or contact heat stimuli was no significantly increased in the unblocked condition even though the tactile component of the stimulus would be expected to provide greater accuracy on its own. This means that the presence of simultaneous tactile clues do not increase the precision of localisation of painful stimuli and suggests that there are central interactions between mechanosensitive and nociceptive afferents which impair locognosia of tactile stimuli. Other investigations have also shown that tactile senitivity is compromised in the presence of painful stimuli [1, 18], and gating of tactile sensations can also occur by excitation of afferent inputs through innocuous movements [24]. Little is known about the cerebral representation of noxious inputs which is presumably important for the localising function. In humans, focal painful heat stimuli can activate thalamus, the anterior cingulate and the primary and secondary somatosensory cortex [3, 7, 27] and it has been suggested that the parietal cortical areas participate in the spatial and temporal analysis of a noxious stimulus [27]. Moreover, neurones in the primary sensory cortex of awake monkeys respond to noxious heat and can encode the stimulus intensity [11]. For the cortical representation of large myelinated afferent input it has been shown that there are discrete maps for different populations of rapidly or slowly adapting mechanoreceptors [10, 21]. It would be of some interest to know whether a differentiation into submodalities can be also found for noxious stimuli. It is possible that the accuracy of localisation of noxious stimuli is only high for cutaneous nociceptors. In skeletal muscle, the accuracy of localising a painful stimulus appears to be less detailed than in skin [25]. Moreover, electrical stimuli of muscle nociceptors innervating the forearm or hand often evoke pain sensations referred to the upper arm, axilla, pectoral region or shoulder blade [17, 30]. The accuracy of localisation is probably much worse in visceral organs as visceral pains are notoriously ill-localised. A host of experimental evidence obtained in animal experiments has shown that the cortical representation of primary afferent inputs possesses a life-long capacity for dynamic change [26, 31]. One particularly striking example of the plasticity of cortical maps is their malleability following experimental peripheral nerve lesions, when deprived cortical regions become activated by afferent inputs from adjacent nerve territories. It would therefore be of some interest to know how locognosia changes following damage of peripheral and central
pathways or in chronic pain states in humans. Since the performance in localising noxious stimuli is not significantly different during normal nerve conduction or in the presence of a differential A-fibre block, it would be possible in the future to investigate locognosia for noxious stimuli in these conditions without nerve block procedures. In conclusion, the present investigation has determined that there is fair precision of the ability to localise noxious stimuli regardless of the submodality. This suggests that the brain contains maps for the spatial representation of noxious stimuli. We wish to thank Max Pause for critically reading' the manuscript. This work was supported by the WilhelmSander Stiftung (M.K.), the Deutsche Forschungsgemeinschaft (SFB 353; H.O.H.) and the Swedish Medical Research Council (14X-05206-16B; H.E.T.).
1 Apkarian, A.V., Stea, R.A. and Bolanowski, S., A gate that swings in the opposite direction: inhibition of touch by pain, Soc. Neurosci. Abstr., 18 (1992) 831. 2 Campbell, J.N., Raja, S.N., Cohen, R.H., Manning, A.A.K. and Meyer, R.A., Peripheral neural mechanisms of nociception. In P.D. Wall and R. Melzack (Eds.), Textbook of Pain, Vol. 2, Churchill Livingstone, Edinburgh, 1989, pp. 2245. 3 Casey, K.L., Minoshima, S., Berger, K.L., Koeppe, R.A., Morrow, T.J. and Frey, K.A., PET analysis of brain structures differentially activated by noxious thermal stimuli, Soc. Neurosci. Abstr., 18 (1992) 833. 4 Hamburger, H.L., Locognosia, University of Amsterdam, Amsterdam, 1980. 5 Handwerker, H.O., Forster, C. and Kirchoff, C., Discharge properties of human C-fibres induced by itching and burning stimuli, J. Neurophysiol., 66 (1991) 307-315. 6 Head, H., Rivers, W.H. and Sherren, J., The afferent nervous system from a new aspect, Brain, 28 (1905) 99 115. 7 Jones, A.K., Brown, W.D., Friston, K.J., Qi, L.Y. and Frackowiak, R.S., Cortical and subcortical localization of response to pain in man using positron emission tomography, Proc. R. Soc. Lond., 244 (1991) 39-44. 8 Jorum, E., Lundberg, L.E.R. and Torebj6rk, H.E., Peripheral projections of nociceptive unmyelinated axons in the human peroneal nerve, J. Physiol., 416 (1989) 291-301. 9 Kaas, J.H., What, if anything, is SI? Organization of first somatosensory area of cortex, Physiol. Rev., 63 (1983) 206-231. 10 Kaas, J.H., Nelson, R.J., Sur, M., Lin, C.S. and Merzenich, M.M., Multiple representations of the body within the primary somatosensory cortex of primates, Science, 204 (1979) 521-523. 11 Kenshalo, D.R., Anton, F. and Dubner, R., The detection and perceived intensity of noxious thermal stimuli in monkey and in human, J. Neurophysiol., 62 (1989) 429436. 12 LaMotte, R.H., Lundberg, L.E.R. and Torebjrrk, H.E., Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin, J. Physiol., 448 (1992) 749-764. 13 Lewis, T., Experiments relating to cutaneous hyperalgesia and its spread through somatic nerves, Clin. Sci., 2 (1935) 373416. 14 Mackenzie, R.A., Burke, D., Skuse, N.F. and Lethlean, A.K., Fibre
222
15
16
17
18
19 20
21
22
function and perception during cutaneous nerve block, J. Neurol. Neurosurg. Psychiat., 38 (1975)865-873. Magerl, W., Grfimer, G. and Handwerker, H.O., Sensations and local inflammatory responses induced by appliction of carbachol, dopamine, 5-HT, histamine and mustard oil to the skin in humans, Pfliigers Arch., 415 (1990) R107. Magerl, W., Westerman, R.A., Mohner, B. and Handwerker, H.O., Properties of transdermal histamine iontophoresis: differential effects of season, gender, and body region, J. Invest. Dermatol., 94 (1990) 347-352. Marchettini, P., Cline, M. and Ochoa, J.L., Innervation territories for touch and pain afferents of single fascicles of the human ulnar nerve. Mapping through intraneural microrecording and microstimulation, Brain, 113 (1990) 1491-1500. Nathan, P.W., Improvement of cutaneous sensibility associated with relief of pain, J. Neurol. Neurosurg. Psychiat., 23 (1960) 202206. Nathan, P.W. and Rice, R.C., The localization of warm stimuli, Neurology, 16 (1966) 533-540. Ochoa, J. and Torebjrrk, E., Sensations evoked by intraneural microstimulation ofC nociceptor fibres in human skin nerves, J. Physiol., 415 (1989) 583-599. Penfield, W. and Boldrey, E., Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation, Brain, 60 (1937) 389-433. Schady, W.J. and Torebjrrk, H.E., Projected and receptive fields: a comparison of projected areas of sensations evoked by intraneural stimulation of mechanoreceptive units, and their innervation territories, Acta Physiol. Scand., 119 (1983) 267-275.
23 Schady, W.J., Torebjrrk, H.E. and Ochoa, J.L., Cerebral localisation function from the input of single mechanoreceptive units in man, Acta Physiol. Scand., 119 (1983) 277-285. 24 Schmidt, R.F., Schady, W.J. and Torebjrrk, H.E., Gating of tactile input from the hand. I. Effects of finger movement, Exp. Brain Res., 79 (1990) 97-102. 25 Simone, D.A., Caputi, G., Marchettini, P. and Ochoa, J., Muscle nociceptors identified in humans: intraneural recordings, microstimulation and pain, Soc. Neurosci. Abstr., 17 (1991) 1368. 26 Snow, P.J. and Wilson, P., Plasticity in the somatosensory system Of developing and mature mammals: the effects of injury to the central and peripheral nervous system, Progr. Sensory Physiol., 11 (1991) 1-482. 27 Talbot, J.D., Marrett, S., Evans, A.C., Meyer, E., Bushnell, M.C. and Duncan, G.H., Multiple representations of pain in human cerbral cortex, Science, 251 (1991) 1355-1358. 28 Torebjrrk, H.E. and Hallin, R.G., Perceptual changes accompanying controlled preferential blocking of A and C fibre responses in intact human skin nerves, Exp. Brain Res., 16 (1973) 321-332. 28 Torebj6rk, H.E. and Ochoa, J.L., New method to identify nociceptor units innervating glabrous skin of the human hand, Exp. Brain Res., 81 (1990) 509-514. 30 Torebjrrk, H.E., Ochoa, J.L. and Schady, W., Referred pain from intraneural stimulation of muscle fascicles in the median nerve, Pain, 18 (1984) 145-156. 31 Wall, J.T., Variable organization in cortical maps of the skin as an indication of the lifelong adaptive capacities of circuits in the mammalian brain, Trends Neurosci., 11 (1988) 549-557.
219
Elsevier Scientific Publishers Ireland Ltd.
NSL 09327
The ability of humans to localise noxious stimuli M a r t i n Koltzenburg a, H e r m a n n O. H a n d w e r k e r b and H. Erik Torebj6rk c aNeurologische Universitiits-Klinik, Warzburg (FRG), blnstitutf~r Physiologie und Biokybernetik, Erlangen ( FRG) and CDepartmentof Clinical Neurophysiology, Uppsala (Sweden) (Received 28 September 1992; Revised version received 23 November 1992; Accepted 30 November 1992)
Key words: Nociceptor; Pain; Itch; Touch; Unmyelinated primary afferent; Cortical map; Psychophysics; Differential nerve block We have investigated the ability of humans to localise noxious stimuli on the dorsum of the hand. Pin-prick (non-penetrating needle prick), noxious heat (round 1 cm 2 copper probe heated to 50°C), mustard oil (100% applied topically in a small cotton ball, diameter 5 mm) and histamine (iontophoresis of 20 mC delivered to an area of 75 mm 2) were applied to skin with intact innervation and during a differential nerve compression block of the superficial radial nerve when only C-fibres were conducting. The mean mislocalisation (_+ S.E.M.; n = 8) of all stimuli was 9.5 + 0.8 mm with normal nerve conduction and 8.9 + 1.2 during the differential nerve block. There was no significant difference between the noxious submodalities. By contrast, when nerve conduction was intact, purely tactile stimulation (7 mN von Frey hair) was significantly better localised having a mean error of 5.5 + 0.4 mm. We conclude that focal stimuli evoking itch or pain can be localised with high precision which is only marginally worse than for tactile stimuli. This suggests the existence of a somatotopical representation for noxious inputs in the brain similar to that found for tactile stimuli.
The conscious human brain has the ability to accurately localise tactile stimuli within a small error of few millimetres at the fingertips [4, 22, 23]. It is thought that this accuracy reflects the orderly representation of the body surface by cortical maps [9, 10, 21]. By contrast it is often touted in texts that the pain signalled by unmyelinated nociceptive afferents is ill-localised suggesting that the cortical representation for noxious stimuli is rather poor. Moreover, it is not known whether there are systematic differences between different submodalities which are signalled by cutaneous unmyelinated afferents. Knowledge about the spatial resolution would be important for the understanding of the cerebral organisation of nociceptive inputs. We have therefore investigated the ability of humans to localise different submodalities of focal noxious stimuli. Eight volunteers (2 females, 6 males) aged 29-52 years including the authors participated in the experiments after having given informed consent. They were comfortably seated in a reclining chair and either left or right hand was randomly chosen and stabilised in an intermediate position between pro- and supination. Differential nerve blocks of the superficial radial nerve were performed by placing a 2.5-cm-wide band onto the wrist, Correspondence: M. Koltzenburg, Neurologische Universit/its-Klinik, Josef-Schneider-Str.11, W-8700 Wiirzburg, FRG. Fax: (49) 931-2012697
with 2.1 kg weights hanging at each side. This technique results in the progressive loss of tactile and cold sensations corresponding to the differential block of large and thin myelinated fibres, respectively [14, 28]. Sensory testing commenced when the subjects could no longer feel slightly stroking the skin with a cotton bud, the application of a 7 mN von Frey hair or the coolness of a cold copper probe maintained at 20°C. The onset of this differential nerve block varied from 28 to 47 min between subjects and the subsequent duration of the tests was 7-12 min. All stimuli were presented in a balanced pseudo-randomised order to the radial side of the dorsum of the hand and to the proximal portion of the first three fingers within the usual autonomous innervation territory of the superficial radial nerve. Noxious stimuli consisted of (i) a non-penetrating needle prick, (ii) a 3-s-long application of a circular contact probe (1 cm 2) heated to 50°C [8, 20], (iii) iontophoresis of histamine [16] delivering 20 mC within 30 s to a circular area of 5 mm in diameter, (iv) topical application of a cotton ball (diameter 5 mm) soaked in pure mustard oil (allyl-isothiocyanat) [15]. Either before or after the differential nerve block the same four stimuli were applied to the contralateral hand. To test locognosia for touch a 7 mN von Frey hair was applied 10 times to the unblocked side and the average distance of the mislocalisation was recorded for each subject.
220
Subjects were blindfolded during the stimulus and were asked to mark the site where they localised the stimulus with a felt pen. Dimming the lights in the room and wearing of dark goggles permitted the subjects to see only the general contours of the hand. The distance from the marking of the subject to the centre of the actual stimulus site was then measured to the nearest millimetre. In experiments with intact nerve conduction subjects could readily differentiate the distinct qualities of the four noxious stimuli. Needle prick was described as a sharp pricking pain, noxious heat or mustard oil application were described as burning pain while iontophoresis of histamine evoked itch. Pin prick and noxious heat were felt almost instantaneously, but there was a latency between application and the first sensation for mustard oil ( 3 2 + 6 s) and histamine ( 1 6 + 2 s) application (mean + S.E.M; P > 0.05, Wilcoxon matched pairs test). At the stage of a differential nerve block when only unmyelinated fibres conducted, both the quality of sensation and the latency remained virtually unchanged after topical mustard oil treatment (29 + 7 s; P > 0.5; Wilcoxon matched pairs test) and histamine iontophoresis (15 + 2 s; P > 0.4; Wilcoxon matched pairs test). We infer that the modalities of itch and burning pain are mainly signalled by C-fibres [5]. By contrast the latency and quality of pin-prick and heat pain sensations changed in a characteristic way during the differential nerve block. The sensations typically occurred with a delay of 1-2s after both stimuli. Furthermore, the quality of pin prick evoked-pain became burning and some subjects confused pin prick and heat stimuli. The change of quality and latency confirm that myelinated fibres are important for signalling pin prick and heat pain in normal hairy skin [2]. The average mislocalisation between all noxious stimuli was 9.5 + 0.8 (range 5.8-13.0) under normal conditions and 8.9 + 1.2 (range 6-12.8) mm during a differential nerve block (P > 0.5; Wilcoxon matched pairs test). There was no significant difference (P always > 0.1; Wilcoxon matched pairs test) of the localisation between the different noxious submodalities and there was no significant impairment of localisation for any single submodality in the blocked or unblocked condition (Fig. 1). With normal nerve conduction the localisation of tactile stimuli was significantly better than for noxious stimuli (P < 0.05; Wilcoxon matched pairs test). The average mislocalisation of a stimulus with a 7 mN von Frey hair was 5.5 + 0.4 (range 3.7-7.9) mm. The application of the copper probe which was maintained at warm, but nonpainful temperatures, was localised with similar precision. There was no significant correlation between subjects' performance to localise noxious or tactile stimuli
/5mm .
.
to m
10-
-]-]
D
t~ ¢D ¢,0
5_
0_ ~
X(\~\~
Fig. 1. Mean (+S.E.M.; n : 8 ) mislocalisation of different submodalities of noxious stimulation with normal nerve conduction (open bars) and during a differential nerve block when only unmyelinated fibres were conducting (filled bars). There was no significant difference between the values obtained for the different submodalities.
(r = -0.24; P > 0.5, linear correlation), nor was there any obvious preference for the direction in which stimuli were mislocalised. The principle finding of the present investigation is that humans have a good ability to localise noxious stimuli even when these are exclusively transmitted by unmyelinated afferents. This is in contrast to the reasoning formulated by eminent neurologists working at the turn of the century [6] and is at variance with the statements still found in virtually all textbooks, which imply that C-fibre mediated pain is only poorly localised. However, here we have determined that the precision of locognosia of various forms of cutaneous pain is only marginally worse than that of pure tactile stimuli. This suggests that there is an orderly representation of cutaneous nociceptors in the brain, perhaps similar to the distribution of cortical elements responding to tactile stimuli. The results of the present investigations support previous reports showing that noxious pin-prick [13], noxious heat [20] or innocuous warm stimuli [19] applied to the hand are localised with an accuracy almost as good as that for tactile stimuli. Microneurographic experiments have also demonstrated a remarkable matching between localisation of painful sensations evoked by intraneural microstimulation and the receptive fields of the stimulated unmyelinated nociceptive units [8~ 20, 29]. Here we have extended those observations to show that the accuracy of localisation is little influenced by the noxious submodality or the temporal profile of the stimulus. This is an interesting observation since chemical stimuli often yield less vigorous discharge frequencies from nociceptive afferents compared to heat or pin-prick stimuli [5, 12]. This
221
could mean that the localisation capacity is largely independent of the temporal discharge phttern. An unexpected finding of the present investigation was that the localisation capacity using painful pin prick or contact heat stimuli was no significantly increased in the unblocked condition even though the tactile component of the stimulus would be expected to provide greater accuracy on its own. This means that the presence of simultaneous tactile clues do not increase the precision of localisation of painful stimuli and suggests that there are central interactions between mechanosensitive and nociceptive afferents which impair locognosia of tactile stimuli. Other investigations have also shown that tactile senitivity is compromised in the presence of painful stimuli [1, 18], and gating of tactile sensations can also occur by excitation of afferent inputs through innocuous movements [24]. Little is known about the cerebral representation of noxious inputs which is presumably important for the localising function. In humans, focal painful heat stimuli can activate thalamus, the anterior cingulate and the primary and secondary somatosensory cortex [3, 7, 27] and it has been suggested that the parietal cortical areas participate in the spatial and temporal analysis of a noxious stimulus [27]. Moreover, neurones in the primary sensory cortex of awake monkeys respond to noxious heat and can encode the stimulus intensity [11]. For the cortical representation of large myelinated afferent input it has been shown that there are discrete maps for different populations of rapidly or slowly adapting mechanoreceptors [10, 21]. It would be of some interest to know whether a differentiation into submodalities can be also found for noxious stimuli. It is possible that the accuracy of localisation of noxious stimuli is only high for cutaneous nociceptors. In skeletal muscle, the accuracy of localising a painful stimulus appears to be less detailed than in skin [25]. Moreover, electrical stimuli of muscle nociceptors innervating the forearm or hand often evoke pain sensations referred to the upper arm, axilla, pectoral region or shoulder blade [17, 30]. The accuracy of localisation is probably much worse in visceral organs as visceral pains are notoriously ill-localised. A host of experimental evidence obtained in animal experiments has shown that the cortical representation of primary afferent inputs possesses a life-long capacity for dynamic change [26, 31]. One particularly striking example of the plasticity of cortical maps is their malleability following experimental peripheral nerve lesions, when deprived cortical regions become activated by afferent inputs from adjacent nerve territories. It would therefore be of some interest to know how locognosia changes following damage of peripheral and central
pathways or in chronic pain states in humans. Since the performance in localising noxious stimuli is not significantly different during normal nerve conduction or in the presence of a differential A-fibre block, it would be possible in the future to investigate locognosia for noxious stimuli in these conditions without nerve block procedures. In conclusion, the present investigation has determined that there is fair precision of the ability to localise noxious stimuli regardless of the submodality. This suggests that the brain contains maps for the spatial representation of noxious stimuli. We wish to thank Max Pause for critically reading' the manuscript. This work was supported by the WilhelmSander Stiftung (M.K.), the Deutsche Forschungsgemeinschaft (SFB 353; H.O.H.) and the Swedish Medical Research Council (14X-05206-16B; H.E.T.).
1 Apkarian, A.V., Stea, R.A. and Bolanowski, S., A gate that swings in the opposite direction: inhibition of touch by pain, Soc. Neurosci. Abstr., 18 (1992) 831. 2 Campbell, J.N., Raja, S.N., Cohen, R.H., Manning, A.A.K. and Meyer, R.A., Peripheral neural mechanisms of nociception. In P.D. Wall and R. Melzack (Eds.), Textbook of Pain, Vol. 2, Churchill Livingstone, Edinburgh, 1989, pp. 2245. 3 Casey, K.L., Minoshima, S., Berger, K.L., Koeppe, R.A., Morrow, T.J. and Frey, K.A., PET analysis of brain structures differentially activated by noxious thermal stimuli, Soc. Neurosci. Abstr., 18 (1992) 833. 4 Hamburger, H.L., Locognosia, University of Amsterdam, Amsterdam, 1980. 5 Handwerker, H.O., Forster, C. and Kirchoff, C., Discharge properties of human C-fibres induced by itching and burning stimuli, J. Neurophysiol., 66 (1991) 307-315. 6 Head, H., Rivers, W.H. and Sherren, J., The afferent nervous system from a new aspect, Brain, 28 (1905) 99 115. 7 Jones, A.K., Brown, W.D., Friston, K.J., Qi, L.Y. and Frackowiak, R.S., Cortical and subcortical localization of response to pain in man using positron emission tomography, Proc. R. Soc. Lond., 244 (1991) 39-44. 8 Jorum, E., Lundberg, L.E.R. and Torebj6rk, H.E., Peripheral projections of nociceptive unmyelinated axons in the human peroneal nerve, J. Physiol., 416 (1989) 291-301. 9 Kaas, J.H., What, if anything, is SI? Organization of first somatosensory area of cortex, Physiol. Rev., 63 (1983) 206-231. 10 Kaas, J.H., Nelson, R.J., Sur, M., Lin, C.S. and Merzenich, M.M., Multiple representations of the body within the primary somatosensory cortex of primates, Science, 204 (1979) 521-523. 11 Kenshalo, D.R., Anton, F. and Dubner, R., The detection and perceived intensity of noxious thermal stimuli in monkey and in human, J. Neurophysiol., 62 (1989) 429436. 12 LaMotte, R.H., Lundberg, L.E.R. and Torebjrrk, H.E., Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin, J. Physiol., 448 (1992) 749-764. 13 Lewis, T., Experiments relating to cutaneous hyperalgesia and its spread through somatic nerves, Clin. Sci., 2 (1935) 373416. 14 Mackenzie, R.A., Burke, D., Skuse, N.F. and Lethlean, A.K., Fibre
222
15
16
17
18
19 20
21
22
function and perception during cutaneous nerve block, J. Neurol. Neurosurg. Psychiat., 38 (1975)865-873. Magerl, W., Grfimer, G. and Handwerker, H.O., Sensations and local inflammatory responses induced by appliction of carbachol, dopamine, 5-HT, histamine and mustard oil to the skin in humans, Pfliigers Arch., 415 (1990) R107. Magerl, W., Westerman, R.A., Mohner, B. and Handwerker, H.O., Properties of transdermal histamine iontophoresis: differential effects of season, gender, and body region, J. Invest. Dermatol., 94 (1990) 347-352. Marchettini, P., Cline, M. and Ochoa, J.L., Innervation territories for touch and pain afferents of single fascicles of the human ulnar nerve. Mapping through intraneural microrecording and microstimulation, Brain, 113 (1990) 1491-1500. Nathan, P.W., Improvement of cutaneous sensibility associated with relief of pain, J. Neurol. Neurosurg. Psychiat., 23 (1960) 202206. Nathan, P.W. and Rice, R.C., The localization of warm stimuli, Neurology, 16 (1966) 533-540. Ochoa, J. and Torebjrrk, E., Sensations evoked by intraneural microstimulation ofC nociceptor fibres in human skin nerves, J. Physiol., 415 (1989) 583-599. Penfield, W. and Boldrey, E., Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation, Brain, 60 (1937) 389-433. Schady, W.J. and Torebjrrk, H.E., Projected and receptive fields: a comparison of projected areas of sensations evoked by intraneural stimulation of mechanoreceptive units, and their innervation territories, Acta Physiol. Scand., 119 (1983) 267-275.
23 Schady, W.J., Torebjrrk, H.E. and Ochoa, J.L., Cerebral localisation function from the input of single mechanoreceptive units in man, Acta Physiol. Scand., 119 (1983) 277-285. 24 Schmidt, R.F., Schady, W.J. and Torebjrrk, H.E., Gating of tactile input from the hand. I. Effects of finger movement, Exp. Brain Res., 79 (1990) 97-102. 25 Simone, D.A., Caputi, G., Marchettini, P. and Ochoa, J., Muscle nociceptors identified in humans: intraneural recordings, microstimulation and pain, Soc. Neurosci. Abstr., 17 (1991) 1368. 26 Snow, P.J. and Wilson, P., Plasticity in the somatosensory system Of developing and mature mammals: the effects of injury to the central and peripheral nervous system, Progr. Sensory Physiol., 11 (1991) 1-482. 27 Talbot, J.D., Marrett, S., Evans, A.C., Meyer, E., Bushnell, M.C. and Duncan, G.H., Multiple representations of pain in human cerbral cortex, Science, 251 (1991) 1355-1358. 28 Torebjrrk, H.E. and Hallin, R.G., Perceptual changes accompanying controlled preferential blocking of A and C fibre responses in intact human skin nerves, Exp. Brain Res., 16 (1973) 321-332. 28 Torebj6rk, H.E. and Ochoa, J.L., New method to identify nociceptor units innervating glabrous skin of the human hand, Exp. Brain Res., 81 (1990) 509-514. 30 Torebjrrk, H.E., Ochoa, J.L. and Schady, W., Referred pain from intraneural stimulation of muscle fascicles in the median nerve, Pain, 18 (1984) 145-156. 31 Wall, J.T., Variable organization in cortical maps of the skin as an indication of the lifelong adaptive capacities of circuits in the mammalian brain, Trends Neurosci., 11 (1988) 549-557.