Cerebral responses following stimulation of unmyelinated C-fibers in humans: electro- and magneto-encephalographic study

There are two kinds of pain, a sharp pain ascending through Adelta fibers (first pain) and a second burning pain ascending though C fibers (second pain). By using a novel method, the application of a low intensity CO(2) laser beam to a tiny area of skin using a very thin aluminum plate with numerous tiny holes as a spatial filter, we succeeded in selectively stimulating unmyelinated C fibers of the skin in humans, and could record consistent and clear brain responses using electroencephalography (EEG) and magnetoencephalography (MEG). The conduction velocity (CV) of the C fibers of the peripheral nerve and spinal cord, probably spinothalamic tract (STT), is approximately 1-4 m/s, which is significantly slower than that of Adelta (approximately 10-15 m/s) and Abeta fibers (approximately 50-70 m/s). This method should be very useful for clinical application. Following C fiber stimulation, primary and secondary somatosensory cortices (SI and SII) are simultaneously activated in the cerebral hemisphere contralateral to the stimulation, and then, SII in the hemisphere ipsilateral to the stimulation is activated. These early responses are easily detected by MEG. Then, probably limbic systems such as insula and cingulate cortex are activated, and those activities reflected in EEG components. Investigations of the cortical processing in pain perception including both first and second pain should provide a better understanding of pain perception and, therefore, contribute to pain relief in clinical medicine.

[1]  R Kakigi,et al.  Pain-Related somatosensory evoked potentials. , 2000, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[2]  Lars Arendt-Nielsen,et al.  Understanding of human pain in the brain through topographic mapping and quantification of laser-evoked potentials - An integration , 1998 .

[3]  J. Ochoa,et al.  Sensations evoked by intraneural microstimulation of C nociceptor fibres in human skin nerves. , 1989, The Journal of physiology.

[4]  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.

[5]  R. Helme,et al.  Cerebral event-related responses induced by CO2 laser stimulation in subjects suffering from cervico-brachial syndrome , 1991, Pain.

[6]  A. Carmon,et al.  Peripheral fiber correlates to noxious thermal stimulation in humans , 1980, Neuroscience Letters.

[7]  Hiroshi Shibasaki,et al.  Primary somatosensory cortex is actively involved in pain processing in human , 2000, Brain Research.

[8]  H. Burton,et al.  Somatic submodality distribution within the second somatosensory (SII), 7b, retroinsular, postauditory, and granular insular cortical areas of M. fascicularis , 1980, The Journal of comparative neurology.

[9]  Andrew C. N. Chen,et al.  Laser-evoked potentials in human pain: I. Use and possible misuse , 1998 .

[10]  J. Lorenz,et al.  Recovery from brain-stem lesions involving the nociceptive pathways: comparison of clinical findings with laser-evoked potentials. , 1996, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[11]  R. Kakigi,et al.  Magnetoencephalographic responses to painful impact stimulation , 1999, Brain Research.

[12]  R. Coggeshall,et al.  Numbers of myelinated and unmyelinated axons in the dorsal, lateral, and ventral funiculi of the white matter of the S2 segment of cat spinal cord , 1985, The Journal of comparative neurology.

[13]  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.

[14]  A. Carmon,et al.  Evoked cerebral responses to noxious thermal stimuli in humans , 1976, Experimental Brain Research.

[15]  Erik Stålberg,et al.  Recommendations for the practice of Clinical Neurophysiology: Guidelines of the International Federation of clinical physiology (EEG suppl 52) , 1999 .

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

[17]  B L Whitsel,et al.  Response of anterior parietal cortex to different modes of same-site skin stimulation. , 1998, Journal of neurophysiology.

[18]  H Shibasaki,et al.  Pain-related and cognitive components of somatosensory evoked potentials following CO2 laser stimulation in man. , 1995, Electroencephalography and clinical neurophysiology.

[19]  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.

[20]  R. Helme,et al.  Altered heat pain thresholds and cerebral event-related potentials following painful CO2 laser stimulation in subjects with fibromyalgia syndrome , 1994, Pain.

[21]  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.

[22]  E. Perl,et al.  Sensory experiences in man evoked by intraneural electrical stimulation of intact cutaneous afferent fibers , 2004, Experimental Brain Research.

[23]  O. Keren,et al.  [Somatosensory evoked potentials]. , 1989, Harefuah.

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

[25]  H. E. Torebjörk,et al.  Functional Attributes Discriminating Mechano-Insensitive and Mechano-Responsive C Nociceptors in Human Skin , 1999, The Journal of Neuroscience.

[26]  R Kakigi,et al.  Effects of distraction on pain perception: magneto- and electro-encephalographic studies. , 1999, Brain research. Cognitive brain research.

[27]  J. Sarvas Basic mathematical and electromagnetic concepts of the biomagnetic inverse problem. , 1987, Physics in medicine and biology.

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

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

[30]  Ryusuke Kakigi,et al.  The somatosensory evoked magnetic fields , 2000, Progress in Neurobiology.

[31]  K. Reinikainen,et al.  Neuromagnetic localization of cortical activity evoked by painful dental stimulation in man , 1983, Neuroscience Letters.

[32]  R. Kakigi,et al.  Pain-related somatosensory evoked potentials in cortical reflex myoclonus. , 1990, Journal of neurology, neurosurgery, and psychiatry.

[33]  Koji Inui,et al.  Pain-related magnetic fields evoked by intra-epidermal electrical stimulation in humans , 2002, Clinical Neurophysiology.

[34]  R. Kakigi,et al.  CO2 laser‐induced pain‐related somatosensory evoked potentials in peripheral neuropathies: Correlation between electrophysiological and histopathological findings , 1991, Muscle & nerve.

[35]  H. Freund,et al.  Parallel activation of primary and secondary somatosensory cortices in human pain processing. , 1999, Journal of neurophysiology.

[36]  R. Kakigi,et al.  Simple and novel method for measuring conduction velocity of A delta fibers in humans. , 1998, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[37]  R. Kakigi,et al.  Scalp topography of mechanically and electrically evoked somatosensory potentials in man. , 1984, Electroencephalography and clinical neurophysiology.

[38]  Massimiliano Valeriani,et al.  Attention-related modifications of ultra-late CO2 laser evoked potentials to human trigeminal nerve stimulation , 2002, Neuroscience Letters.

[39]  R. Kakigi,et al.  Physiological study of the spinothalamic tract conduction in multiple sclerosis , 1992, Journal of the Neurological Sciences.

[40]  R. Kakigi,et al.  Estimation of conduction velocity of Aδ fibers in humans , 1991 .

[41]  Pain-related somatosensory evoked potentials in dementia , 1996, Journal of the Neurological Sciences.

[42]  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.

[43]  G Kobal,et al.  Cortical responses to painful CO2 stimulation of nasal mucosa; a magnetoencephalographic study in man. , 1986, Electroencephalography and clinical neurophysiology.

[44]  Walter Magerl,et al.  Laser-evoked potentials for assessment of nociceptive pathways in humans , 1998 .

[45]  R. Kakigi,et al.  Pain‐related somatosensory evoked potentials following CO2 laser stimulation in peripheral neuropathies , 1992, Acta neurologica Scandinavica.

[46]  D. Yarnitsky,et al.  Pain-evoked potentials: what do they really measure? , 1996, Electroencephalography and clinical neurophysiology.

[47]  Sic L. Chan,et al.  Ubiquitin and Alzheimer's amyloid ß precursor protein colocalize to endosomes‐lysosomes in cultured human cells , 1996, Neuroreport.

[48]  R Kakigi,et al.  Cerebral activation by the signals ascending through unmyelinated C-fibers in humans: a magnetoencephalographic study , 2002, Neuroscience.

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

[50]  H. Freund,et al.  Differential organization of touch and pain in human primary somatosensory cortex. , 2000, Journal of neurophysiology.

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

[52]  C C Wood,et al.  Human cortical potentials evoked by stimulation of the median nerve. II. Cytoarchitectonic areas generating long-latency activity. , 1989, Journal of neurophysiology.

[53]  B. Bromm,et al.  Human cerebral potentials evoked by CO2 laser stimuli causing pain , 2004, Experimental Brain Research.

[54]  W. Miltner,et al.  Scalp topography of ultralate (C-fibres) evoked potentials following thulium YAG laser stimuli to tiny skin surface areas in humans , 2001, Clinical Neurophysiology.

[55]  R. Hari On Brain's Magnetic Responses to Sensory Stimuli , 1991, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[56]  R. Kakigi,et al.  Pain-related magnetic fields following painful CO2 laser stimulation in man , 1995, Neuroscience Letters.

[57]  Sachiko Koyama,et al.  Pain Processing Traced by Magnetoencephalography in the Human Brain , 2004, Brain Topography.

[58]  Bengt Långström,et al.  Somatotopic organization along the central sulcus, for pain localization in humans, as revealed by positron emission tomography , 1997, Experimental Brain Research.

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

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

[61]  S. Boyd,et al.  Sensory and cognitive components of the CO2 laser evoked cerebral potential. , 1993, Electroencephalography and clinical neurophysiology.

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

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

[64]  R P Lesser,et al.  Painful stimuli evoke potentials recorded over the human anterior cingulate gyrus. , 1998, Journal of neurophysiology.

[65]  R. Kakigi Somatosensory evoked magnetic fields following median nerve stimulation , 1994, Neuroscience Research.

[66]  Koji Inui,et al.  Effects of attention, distraction and sleep on CO2 laser evoked potentials related to C-fibers in humans , 2002, Clinical Neurophysiology.

[67]  R. Kakigi,et al.  Pain-related somatosensory evoked magnetic fields following lower limb stimulation , 1997, Journal of the Neurological Sciences.

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

[69]  R. Kakigi,et al.  Preferential stimulation of Aδ fibers by intra-epidermal needle electrode in humans , 2002, Pain.

[70]  G. Deuschl,et al.  Recommendations for the practice of clinical neurophysiology: guidelines of the International Federation of Clinical Neurophysiology. , 1999, Electroencephalography and clinical neurophysiology. Supplement.

[71]  M. Honda,et al.  Pain-related somatosensory evoked potentials following CO2 laser stimulation of foot in man. , 1989, Electroencephalography and clinical neurophysiology.

[72]  K. Berman,et al.  Neural activation during acute capsaicin-evoked pain and allodynia assessed with PET. , 1998, Brain : a journal of neurology.

[73]  D Burke,et al.  Cutaneous and muscle afferent components of the cerebral potential evoked by electrical stimulation of human peripheral nerves. , 1981, Electroencephalography and clinical neurophysiology.

[74]  F. Mauguière,et al.  Association and dissociation between laser‐evoked potentials and pain perception , 1997, Neuroreport.

[75]  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.

[76]  L. Dorfman Indirect estimation of spinal cord conduction velocity in man. , 1977, Electroencephalography and clinical neurophysiology.

[77]  R. Hari,et al.  Functional Organization of the Human First and Second Somatosensory Cortices: a Neuromagnetic Study , 1993, The European journal of neuroscience.

[78]  R. Treede,et al.  Laser-evoked potentials: exogenous and endogenous components. , 1996, Electroencephalography and clinical neurophysiology.

[79]  M. Hämäläinen Magnetoencephalography: A tool for functional brain imaging , 2005, Brain Topography.

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

[81]  R. Treede,et al.  Equivalent electrical source analysis of pain-related somatosensory evoked potentials elicited by a CO2 laser. , 1993, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[82]  H. Schaible,et al.  Silent and active nociceptors: structure, functions and clinical implications. , 1994 .

[83]  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.

[84]  R. Lesser,et al.  Painful stimuli evoke potentials recorded from the parasylvian cortex in humans. , 1998, Journal of neurophysiology.

[85]  T. Kachi,et al.  Pain-related and electrically stimulated somatosensory evoked potentials in patients with stroke. , 1995, Stroke.

[86]  R. Treede,et al.  Ultralate cerebral potentials as correlates of delayed pain perception: observation in a case of neurosyphilis. , 1988, Journal of neurology, neurosurgery, and psychiatry.

[87]  K L Casey,et al.  Variability of laser-evoked potentials: attention, arousal and lateralized differences. , 1993, Electroencephalography and clinical neurophysiology.

[88]  Lars Arendt-Nielsen,et al.  Laser-evoked potentials in human pain - II. Cerebral generators , 1998 .

[89]  F. Mauguière,et al.  Intracortical recordings of early pain-related CO2-laser evoked potentials in the human second somatosensory (SII) area , 1999, Clinical Neurophysiology.

[90]  R. Kakigi,et al.  After-effect of transcutaneous electrical nerve stimulation (TENS) on pain-related evoked potentials and magnetic fields in normal subjects , 2000, Clinical Neurophysiology.

[91]  P. Bjerring,et al.  Reaction times to painless and painful CO2 and argon laser stimulation , 2004, European Journal of Applied Physiology and Occupational Physiology.

[92]  C Büchel,et al.  Experimental cranial pain elicited by capsaicin: a PET study , 1998, Pain.

[93]  Anthony K. P. Jones,et al.  The cortical representation of pain , 1999, PAIN.

[94]  Y. Sarne,et al.  Correlation of subjective pain experience with cerebral evoked responses to noxious thermal stimulations , 1978, Experimental Brain Research.

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

[96]  A Schnitzler,et al.  Different cortical organization of visceral and somatic sensation in humans , 1999, The European journal of neuroscience.

[97]  R. Kakigi,et al.  Pain-related somatosensory evoked magnetic fields. , 1995, Electroencephalography and Clinical Neurophysiology.

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

[99]  A. Vania Apkarian,et al.  Spinothalamocortical projections to the secondary somatosensory cortex (SII) in squirrel monkey , 1993, Brain Research.

[100]  R. Kakigi,et al.  Effects of distraction on pain-related somatosensory evoked magnetic fields and potentials following painful electrical stimulation. , 2000, Brain research. Cognitive brain research.

[101]  Ryusuke Kakigi,et al.  Pain-related somatosensory-evoked potentials following CO2 laser stimulation , 1998 .

[102]  R. Kakigi,et al.  Physiological functions of the ascending spinal tracts in HTLV-I-associated myelopathy (HAM). , 1992, Electroencephalography and clinical neurophysiology.

[103]  G. Werner,et al.  Symmetry and connectivity in the map of the body surface in somatosensory area II of primates. , 1969, Journal of neurophysiology.

[104]  V. Jousmäki,et al.  Right-hemisphere preponderance of responses to painful CO2 stimulation of the human nasal mucosa , 1997, PAIN.

[105]  J D Greenspan,et al.  Anatomic evidence of nociceptive inputs to primary somatosensory cortex: Relationship between spinothalamic terminals and thalamocortical cells in squirrel monkeys , 1991, The Journal of comparative neurology.

[106]  R. Hari,et al.  Modified activation of somatosensory cortical network in patients with right-hemisphere stroke. , 1999, Brain : a journal of neurology.