Evidence of a specific spinal pathway for the sense of warmth in humans.

While research on human sensory processing shows that warm input is conveyed from the periphery by specific, unmyelinated primary sensory neurons, its pathways in the central nervous system (CNS) remain unclear. To gain physiological information on the spinal pathways that convey warmth or nociceptive sensations, in 15 healthy subjects, we studied the cerebral evoked responses and reaction times in response to laser stimuli selectively exciting Adelta nociceptors or C warmth receptors at different levels along the spine. To minimize the conduction distance along the primary sensory neuron, we directed CO(2)-laser pulses to the skin overlying the vertebral spinous processes. Using brain source analysis of the evoked responses with high-resolution electroencephalography and a realistic model of the head based on individual magnetic resonance imaging scans, we also studied the cortical areas involved in the cerebral processing of warm and nociceptive inputs. The activation of C warmth receptors evoked cerebral potentials with a main positive component peaking at 470-540 ms, i.e., a latency clearly longer than that of the corresponding wave yielded by Adelta nociceptive input (290-320 ms). Spinal neurons activated by the warm input had a slower conduction velocity (2.5 m/s) than the nociceptive spinal neurons (11.9 m/s). Brain source analysis of the cerebral responses evoked by the Adelta input yielded a very strong fit for one single generator in the mid portion of the cingulate gyrus; the warmth-related responses were best explained by three generators, one within the cingulate and two in the right and left opercular-insular cortices. Our results support the existence of slow-conducting second-order neurons specific for the sense of warmth.

[1]  M Manfredi,et al.  Assessment of trigeminal small‐fiber function: brain and reflex responses evoked by CO2‐laser stimulation , 1999, Muscle & nerve.

[2]  J. Dostrovsky,et al.  Thermoreceptive lamina I trigeminothalamic neurons project to the nucleus submedius in the cat , 2004, Experimental Brain Research.

[3]  H. Breiter,et al.  Human brain activation under controlled thermal stimulation and habituation to noxious heat: An fMRI study , 1999, Magnetic resonance in medicine.

[4]  X. Zhang,et al.  Locations of spinothalamic tract axons in cervical and thoracic spinal cord white matter in monkeys. , 2000, Journal of neurophysiology.

[5]  Krish D. Singh,et al.  fMRI of Thermal Pain: Effects of Stimulus Laterality and Attention , 2002, NeuroImage.

[6]  L. Plaghki,et al.  Direct isolation of ultra-late (C-fibre) evoked brain potentials by CO2 laser stimulation of tiny cutaneous surface areas in man , 1996, Neuroscience Letters.

[7]  L. Arendt-Nielsen Second pain event related potentials to argon laser stimuli: recording and quantification. , 1990, Journal of neurology, neurosurgery, and psychiatry.

[8]  H. E. Torebjörk,et al.  Nociceptors and warm receptors innervated by C fibres in human skin. , 1982, Journal of neurology, neurosurgery, and psychiatry.

[9]  M. Manfredi,et al.  The problem of conduction velocity of the human spinothalamic tract , 2001, Clinical Neurophysiology.

[10]  W. Miltner,et al.  Dipole analysis of ultralate (C-fibres) evoked potentials after laser stimulation of tiny cutaneous surface areas in humans , 2001, Neuroscience Letters.

[11]  A. Craig,et al.  Spinothalamic lamina I neurones selectively responsive to cutaneous warming in cats , 2001, The Journal of physiology.

[12]  R. Treede,et al.  Evoked cerebral potential correlates of C-fibre activity in man , 1983, Neuroscience Letters.

[13]  R. LaMotte,et al.  Comparison of responses of warm and nociceptive C-fiber afferents in monkey with human judgments of thermal pain. , 1978, Journal of neurophysiology.

[14]  R. Treede,et al.  Laser-evoked cerebral potentials in the assessment of cutaneous pain sensitivity in normal subjects and patients. , 1991, Revue neurologique.

[15]  C. Büchel,et al.  Dissociable Neural Responses Related to Pain Intensity, Stimulus Intensity, and Stimulus Awareness within the Anterior Cingulate Cortex: A Parametric Single-Trial Laser Functional Magnetic Resonance Imaging Study , 2002, The Journal of Neuroscience.

[16]  F. Mauguière,et al.  Scalp topography and dipolar source modelling of potentials evoked by CO2 laser stimulation of the hand. , 1996, Electroencephalography and clinical neurophysiology.

[17]  C. L. Kwan,et al.  An fMRI study of the anterior cingulate cortex and surrounding medial wall activations evoked by noxious cutaneous heat and cold stimuli , 2000, Pain.

[18]  J. R. Augustine Circuitry and functional aspects of the insular lobe in primates including humans , 1996, Brain Research Reviews.

[19]  R. Dubner,et al.  Spatial and temporal transformations of input to spinothalamic tract neurons and their relation to somatic sensations. , 1978, Journal of neurophysiology.

[20]  W. Macrae The Pain System , 2005 .

[21]  B. Vogt,et al.  The medial pain system, cingulate cortex, and parallel processing of nociceptive information. , 2000, Progress in brain research.

[22]  L. Arendt-Nielsen Characteristics, detection, and modulation of laser‐evoked vertex potentials , 1994, Acta anaesthesiologica Scandinavica. Supplementum.

[23]  R. Hallin,et al.  Identification of afferent C units in intact human skin nerves. , 1974 .

[24]  M. Manfredi,et al.  Conduction velocity of the human spinothalamic tract as assessed by laser evoked potentials , 2000, Neuroreport.

[25]  R. Meyer,et al.  Evidence for two different heat transduction mechanisms in nociceptive primary afferents innervating monkey skin. , 1995, The Journal of physiology.

[26]  F. Mauguière,et al.  Sources of cortical responses to painful CO2 laser skin stimulation of the hand and foot in the human brain , 2000, Clinical Neurophysiology.

[27]  K. H. Lee,et al.  Factors influencing peripheral nerve stimulation produced inhibition of primate spinothalamic tract cells , 1984, Pain.

[28]  A. Chen,et al.  Brain electrical source analysis of laser evoked potentials in response to painful trigeminal nerve stimulation. , 1995, Electroencephalography and clinical neurophysiology.

[29]  A. Dickenson,et al.  Facial thermal input to the trigeminal spinal nucleus of rabbits and rats , 1979, The Journal of comparative neurology.

[30]  M. Fuchs,et al.  An improved boundary element method for realistic volume-conductor modeling , 1998, IEEE Transactions on Biomedical Engineering.

[31]  E. Reiman,et al.  Thermosensory activation of insular cortex , 2000, Nature Neuroscience.

[32]  R. Treede,et al.  Nerve fibre discharges, cerebral potentials and sensations induced by CO2 laser stimulation. , 1984, Human neurobiology.

[33]  R. Treede,et al.  Cerebral potentials evoked by painful, laser stimuli in patients with syringomyelia. , 1991, Brain : a journal of neurology.

[34]  L. Arendt-Nielsen,et al.  Sensory and pain threshold characteristics to laser stimuli. , 1988, Journal of neurology, neurosurgery, and psychiatry.

[35]  Fred A Lenz,et al.  Pain sensitivity alterations as a function of lesion location in the parasylvian cortex , 1999, Pain.

[36]  Topographical distribution of pinprick and warmth thresholds to CO2 laser stimulation on the human skin , 2000, Neuroscience Letters.

[37]  R. Kakigi,et al.  Pain-related somatosensory evoked potentials in syringomyelia. , 1991, Brain : a journal of neurology.

[38]  R. Kakigi,et al.  Conduction velocity of the spinothalamic tract following CO2 laser stimulation of C-fibers in humans , 2002, Pain.

[39]  A. Craig,et al.  Nociceptive and thermoreceptive lamina I neurons are anatomically distinct , 1998, Nature Neuroscience.

[40]  F. Plum Handbook of Physiology. , 1960 .

[41]  G. Pozzessere,et al.  A simple method for estimating conduction velocity of the spinothalamic tract in healthy humans , 2000, Clinical Neurophysiology.

[42]  Walter Magerl,et al.  C- and Aδ-fiber components of heat-evoked cerebral potentials in healthy human subjects , 1999, Pain.

[43]  M. Mesulam,et al.  Insula of the old world monkey. III: Efferent cortical output and comments on function , 1982, The Journal of comparative neurology.

[44]  R. Treede,et al.  Pain related cerebral potentials: late and ultralate components. , 1987, The International journal of neuroscience.

[45]  A. Craig,et al.  Quantitative response characteristics of thermoreceptive and nociceptive lamina I spinothalamic neurons in the cat. , 2001, Journal of neurophysiology.

[46]  J. Dostrovsky,et al.  Differential projections of thermoreceptive and nociceptive lamina I trigeminothalamic and spinothalamic neurons in the cat. , 2001, Journal of neurophysiology.

[47]  R. Dubner,et al.  Trigeminothalamic neurons in nucleus caudalis responsive to tactile, thermal, and nociceptive stimulation of monkey's face , 1976 .

[48]  R. Kakigi,et al.  Conduction velocity of the spinothalamic tract in humans as assessed by CO2 laser stimulation of C-fibers , 2001, Neuroscience Letters.

[49]  E. Perl,et al.  Spinal neurons specifically excited by noxious or thermal stimuli: marginal zone of the dorsal horn. , 1970, Journal of neurophysiology.

[50]  M. Bushnell,et al.  Cortical representation of the sensory dimension of pain. , 2001, Journal of neurophysiology.

[51]  U. Norrsell Thermosensory defects after cervical spinal cord lesions in the cat , 1979, Experimental Brain Research.

[52]  M Nordin,et al.  Low‐threshold mechanoreceptive and nociceptive units with unmyelinated (C) fibres in the human supraorbital nerve. , 1990, The Journal of physiology.

[53]  R. Dykes,et al.  "Cold" fiber population innervating palmar and digital skin of the monkey: responses to cooling pulses. , 1973, Journal of neurophysiology.

[54]  A. Craig,et al.  Behavioral thermosensitivity after lesions of thalamic target areas of a thermosensory spinothalamic pathway in the cat. , 1999, Journal of neurophysiology.

[55]  M Manfredi,et al.  Usefulness of dorsal laser evoked potentials in patients with spinal cord damage: report of two cases , 2001, Journal of neurology, neurosurgery, and psychiatry.

[56]  M. Manfredi,et al.  Nociceptive quality of the laser-evoked blink reflex in humans. , 2002, Journal of neurophysiology.

[57]  J. Dostrovsky,et al.  Cooling-specific spinothalamic neurons in the monkey. , 1996, Journal of neurophysiology.

[58]  B. Vogt,et al.  Contributions of anterior cingulate cortex to behaviour. , 1995, Brain : a journal of neurology.

[59]  K. O. Johnson,et al.  Warm fibers innervating palmar and digital skin of the monkey: responses to thermal stimuli. , 1979, Journal of neurophysiology.

[60]  M. Honda,et al.  Expectation of Pain Enhances Responses to Nonpainful Somatosensory Stimulation in the Anterior Cingulate Cortex and Parietal Operculum/Posterior Insula: an Event-Related Functional Magnetic Resonance Imaging Study , 2000, The Journal of Neuroscience.

[61]  G Cheron,et al.  Spinal and far-field components of human somatosensory evoked potentials to posterior tibial nerve stimulation analysed with oesophageal derivations and non-cephalic reference recording. , 1983, Electroencephalography and clinical neurophysiology.

[62]  B. Bromm,et al.  Ultralate cerebral potentials in a patient with hereditary motor and sensory neuropathy type I indicate preserved C-fibre function. , 1991, Journal of neurology, neurosurgery, and psychiatry.

[63]  H Shibasaki,et al.  Estimation of conduction velocity of the spino-thalamic tract in man. , 1991, Electroencephalography and clinical neurophysiology.

[64]  B. Bromm,et al.  Responses of human cutaneous afferents to CO2 laser stimuli causing pain , 2004, Experimental Brain Research.

[65]  William D. Willis,et al.  Responses of primate spinothalamic tract neurons to natural stimulation of hindlimb. , 1974 .

[66]  Alan C. Evans,et al.  Multiple representations of pain in human cerebral cortex. , 1991, Science.

[67]  B. Green,et al.  "Warmth-insensitive fields": evidence of sparse and irregular innervation of human skin by the warmth sense. , 1998, Somatosensory & motor research.

[68]  A. Craig,et al.  Cytoarchitectonic and immunohistochemical characterization of a specific pain and temperature relay, the posterior portion of the ventral medial nucleus, in the human thalamus. , 2000, Brain : a journal of neurology.

[69]  A. Craig,et al.  Association of spinothalamic lamina I neurons and their ascending axons with calbindin-immunoreactivity in monkey and human , 2002, Pain.

[70]  X. Zhang,et al.  Position of spinothalamic tract axons in upper cervical spinal cord of monkeys. , 2000, Journal of neurophysiology.

[71]  H. E. Torebjörk,et al.  Afferent C units responding to mechanical, thermal and chemical stimuli in human non-glabrous skin. , 1974, Acta physiologica Scandinavica.

[72]  L. Arendt-Nielsen First pain event related potentials to argon laser stimuli: recording and quantification. , 1990, Journal of neurology, neurosurgery, and psychiatry.

[73]  P. R. Burgess,et al.  Ascending projections from marginal zone (Lamina I) neurons of the spinal dorsal horn , 1975 .

[74]  L. Plaghki,et al.  Determination of nerve conduction velocity of C-fibres in humans from thermal thresholds to contact heat (thermode) and from evoked brain potentials to radiant heat (CO2 laser) , 1999, Neurophysiologie Clinique/Clinical Neurophysiology.

[75]  J. Ochoa,et al.  The normal sural nerve in man. I. Ultrastructure and numbers of fibres and cells. , 1969, Acta neuropathologica.

[76]  A. D. Towell,et al.  CO2 laser activation of nociceptive and non-nociceptive thermal afferents from hairy and glabrous skin , 1996, Pain.

[77]  W. Willis,et al.  Responses of spinothalamic tract cells in the superficial dorsal horn of the primate lumbar spinal cord. , 1987, The Journal of physiology.

[78]  M. Taussig The Nervous System , 1991 .

[79]  R. Kakigi,et al.  A new method for measuring the conduction velocities of Aβ-, Aδ- and C-fibers following electric and CO2 laser stimulation in humans , 2001, Neuroscience Letters.

[80]  D. Bowsher The termination of secondary somatosensory neurons within the thalamus of Macaca mulatta: An Experimental Degeneration Study , 1961, The Journal of comparative neurology.