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Conduction velocity of the spinothalamic tract in humans as assessed by CO(2) laser stimulation of C-fibers
Abstract
We measured the conduction velocity (CV) of C-fibers in the spinothalamic tract (STT) following stimulation with a CO(2) laser using a new method. We delivered non-painful laser pulses to tiny areas of the skin overlying the vertebral spinous processes at different levels from the 7(th) cervical (C7) to the 12(th) thoracic (T12), and recorded cerebral evoked potentials in 11 healthy men. We used the term "ultra-late laser evoked potentials" (ultra-late LEPs), since the peak latency was much longer than that for conventional LEPs related to Adelta-fibers following painful laser stimulation (late LEPs). The mean CV of C-fibers in the STT was 2.2+/-0.6 m/s, which was significantly lower than the CV of the Adelta-fibers (10.0+/-4.5 m/s). This technique is novel and simple, and should be useful as a diagnostic tool for assessing the level of spinal cord lesions.
... The normalization of the latencies to the baseline temperature of 35° C drew the latencies closer to the previously published values obtained with CO 2 laser stimulation, which ranged between 290-320 ms Iannetti et al., 2003) and 320-360 ms (Qiu et al., 2001) for stimulation on the highest and lowest location on the back, respectively. Nevertheless, the normalized latencies are still considerably longer (about 50 ms) than the previously published values. ...
... These fibers conduct more slowly than Aδ-fibers supposed to be involved in N2 and P2 generation and are already excited by lower stimulation temperature. It is hypothesized, that as long as Aδ-fiber mediated potentials occur, no C-fiber evoked potential can be recorded (Bragard et al., 1996;Opsommer et al., 1999;Qiu et al., 2001). In contrast to the simultaneous appearance of Aδ-and C-fiber mediated evoked potentials in disease (Granot et al., 2001) this has not been confirmed in healthy subjects (Mouraux and Plaghki, 2007). ...
... Furthermore, for being evoked by C-fiber excitation, this late component occurs too early when compared to the related painful laser stimulation (Baumgartner et al., 2005;Bragard et al., 1996;Magerl et al., 1999;Opsommer et al., 1999;Qiu et al., 2001;Truini et al., 2007). Due to this uncertain identity of the late positive component use of the earlier and more constant N2 as CHEP read out parameter seems generally recommendable. ...
Physical disability following spinal cord injury (SCI) is the most striking problem noted
by the general public. But for the affected subjects urogenital difficulties or
depression and pain are often more burdensome. Pain after SCI can have various
reasons but only neuropathic pain below the level of lesion (bNP) is thought to be
caused by injury of the spinal nervous tissue. This type of pain is in the focus of this
thesis. Once bNP has established it is mostly chronic and medication is generally
ineffective. Currently, more and more treatments trying to restore function after SCI
enter the clinical trial phase. Besides improving function, however, treatments
increasing nerve growth in the spinal cord risk to induce or exacerbate bNP.
Therefore, observation of bNP is a crucial factor in such interventional studies. A
method to objectively supervise bNP has, however, not yet been established.
The spinothalamic tract (STT) mainly transmits nociceptive and temperature
information in the spinal cord. This tract was dysfunctional in SCI subjects suffering
from bNP in clinical examinations. Nevertheless, STT dysfunction was not predictive
for bNP and sensory differences between subjects with and without bNP could not be
detected. In contrast to clinical examination which is always subjective and only
offers limited resolution, electrophysiological measures allow for a more detailed and
objective investigation.
The novel electrophysiological method of contact heat evoked potentials (CHEP)
measures STT function. Establishment of this method was the goal of the first study.
The painful stimulation on locations along the spine allowed the calculation of the
conduction velocity of the STT in healthy subjects. Furthermore the CHEP latency
depended linearly on the heat pain threshold with 1° C higher threshold leading to
approximately 10 ms longer latency. It was hypothesized that the rather low heating
rate combined with the time-consuming passive heat spread from skin surface to
nociceptors was responsible for this.
The second study aimed at clarifying this dependence through comparison of the
results of study 1 with those of a theoretical heat transfer model. According to this
model, 1° C higher pain threshold leads to approximately 15 ms longer CHEP
latency. The close similarity between the experimentally determined (study 1) and the
computed dependence, proved the influence of the pain threshold on CHEP latency.
Summary
Electrophysiological markers for Neuropathic Pain in SCI Subjects 2
Subjects suffering from neuropathic pain (NP) in general and not only in SCI, have
lowered EEG peak frequency. It was hypothesized in literature that the reduced EEG
peak frequency emerged from thalamic deafferentiation and from the ensuing
dysrhythmia in thalamocortical feedback loops. Therefore, the third study
investigated EEG peak frequency in addition to STT function and compared both
between SCI subjects with and without bNP and controls. The STT function
(measured with CHEP) below the level of injury was distinctly impaired in SCI
compared to control subjects. Furthermore, the EEG peak frequency was generally
lower in the SCI subjects. While the CHEP measurements did not reveal differences
between subjects with and without bNP, the EEG peak frequency was lowered in
subjects with bNP. This difference, however, was only apparent after the linear
dependence of EEG peak frequency from the level of SCI was taken into account. In
consideration of this dependence, the EEG peak frequency could in future be helpful
to supervise bNP both in studies aiming at restoring function or reducing pain after
SCI.
Currently, the clinical read-out parameter for STT function is pinprick sensation. In
the fourth study this pinprick sensation was traced over the first year after SCI.
Comparison of this STT function with the bNP state of the same subjects 2-5 years
after SCI disclosed larger functional STT recovery in subjects suffering from bNP.
Despite the different STT functional recovery, the initial and end measurements did
not discriminate between subjects with and without bNP. This was in agreement with
earlier studies. The results corroborate the above mentioned hypothesis that new
therapies intending to promote sensorimotor recovery after SCI could simultaneously
induce bNP by boosting recovery of spinothalamic function.
... afferent sensory terminals in the skin have a higher density and lower activation threshold than the Ad terminals (Schmidt et al., 1994;Treede et al., 1994). Our new method for recording ultra-late LEP Qiu et al., 2001Qiu et al., , 2002Qiu et al., , 2003Qiu et al., , 2004) was based on their method. ...
... We also measured the CV of the spinal cord, probably ascending through STT, using ultra-late LEP (Qiu et al., 2001;Tran et al., 2002a). The principle of this method was recently reported by Cruccu et al. (2000). ...
... The CV in STT related to Ad-fibers measured from the late LEPs and that related to C-fibers in this subject was 9.1 and 2.4 m/s, respectively. Adapted from Qiu et al. (2001). difference in latency ranged from 19 to 94 ms (32C/ K26 ms) (PZ0.002) (Fig. 12). ...
We reviewed the recent progress in electrophysiological studies using electroencephalography (EEG), magnetoencephalography (MEG) and repetitive transcranial magnetic stimulation (rTMS) on human pain perception.
For recording activities following A delta fiber stimulation relating to first pain, several kinds of lasers such as CO2, Tm:YAG and argon lasers are now widely used. The activity is frequently termed laser evoked potential (LEP), and we reviewed previous basic and clinical reports on LEP. We also introduced our new method, epidermal stimulation (ES), which is useful for recording brain activities by the signals ascending through A delta fibers. For recording activities following C fiber stimulation relating to second pain, several methods have been used but weak CO2 laser stimuli applied to tiny areas of the skin were recently used.
EEG and MEG findings following C fiber stimulation were similar to those following A delta fiber stimulation except for a longer latency. Finally, we reviewed the effect of rTMS on acute pain perception. rTMS alleviated acute pain induced by intracutaneous injection of capsaicin, which activated C fibers, but it enhanced acute pain induced by laser stimulation, which activated A delta fibers.
One promising approach in the near future is to analyze the change of a frequency band. This method will probably be used for evaluation of continuous tonic pain such as cancer pain, which evoked response studies cannot evaluate.
... First introduced by Bragard et al. [2], the method is based on the observation that C-and A␦fiber terminals are distributed with different density in the human skin [14], with significantly more C-fiber terminals per unit of skin area than A␦-fiber terminals. Stimulation of tiny skin areas was shown to be useful for the evaluation of conduction velocity of C-fibers [16] [21] [23], the registration of ultra-late brain electrical potentials (ULPs) [2] [11] [17] [22], the detection of dipole sources of ULPs and evoked magnetic fields [6] [18] [22]. Although many of these studies indicate that this method is easy to apply, less invasive, and in technical terms less costly than some of the other methods mentioned above, a major difficulty for the study of central responses to tiny skin areas is based on the fact that a considerable number of stimuli applied to such tiny skin areas is not perceived by the subjects. ...
... These distributions showed a bimodal distribution with an early and a late peak (Fig. 1). Since A␦fibers are known to have faster conduction velocities (about 3–30 m/s) than C-fibers (about 0.5–2 m/s), shorter latencies were interpreted to correspond to A␦-fiber activations whereas longer latencies were interpreted to correspond to Cfiber input [2] [17] [18] [21] [23]. Thus, trials of stimulation whose reaction times were within the first peak of the RT distribution around the average latency of about 750 ms post-stimulus were taken as A␦-fiber input whereas trials with longer latencies around the second peak of the RT distribution with an average latency of about 1.550 ms post-stimulus were interpreted to correspond to C-fiber input [2] [17] [21]. ...
... Since A␦fibers are known to have faster conduction velocities (about 3–30 m/s) than C-fibers (about 0.5–2 m/s), shorter latencies were interpreted to correspond to A␦-fiber activations whereas longer latencies were interpreted to correspond to Cfiber input [2] [17] [18] [21] [23]. Thus, trials of stimulation whose reaction times were within the first peak of the RT distribution around the average latency of about 750 ms post-stimulus were taken as A␦-fiber input whereas trials with longer latencies around the second peak of the RT distribution with an average latency of about 1.550 ms post-stimulus were interpreted to correspond to C-fiber input [2] [17] [21]. In the present study, the critical threshold of distinction between C-and A␦-fiber activation was set between the two latency peaks of each subject's bimodal RT distribution. ...
The stimulation of tiny skin areas has been shown to be a useful method for the investigation of the central nervous processing of C-fiber stimulation. However, recent studies have also indicated that most subjects fail to recognize a large number of such stimulation. This fact renders this method to be rather time consuming, a fact that limits its applicability. To reduce the duration of examination, we here examined the effects of double stimulation of tiny skin areas as compared to the stimulation of tiny skin areas with a single stimulus. The comparison is based on subjects' number of recognized stimuli for single and double stimulation and ratings of stimulus intensity. Double stimulation of tiny skin areas resulted in a significant increase of the number of recognized stimuli as compared to single stimulation. This increase of the number of recognized stimuli is accompanied by an increase of the averaged subjects' experience of stimulus intensity. However, there was no significant increase of intensity rating for the different types of fibers stimulated. Data indicate that the double stimulation of tiny skin areas represents an alternative option to the application of single stimuli to tiny skin areas that significantly reduces the exposure time of subjects in order to evaluate behavioral consequences of the stimulation as well as central nervous processing of C- and Adelta-fiber input.
... In preliminary experiments, we observed that laser pulses of low intensity (4.5-7.5 mJ/mm 2 ), relatively long duration (30 -50 ms), and a large irradiated area (spot diameter: 5 mm) were optimal to elicit purely warmth sensations (C warmth input); the mean temperature was 39°C. In contrast, laser pulses of higher intensity (9 -18 mJ/mm 2 ), short duration (5-5 ms), and a small irradiated area (spot diameter: 2.5 mm) were optimal to elicit pinprick sensation (A␦ input) (Romaniello et al. 2002); the mean temperature was 48°C. Stimulation sites were marked on the skin and cutaneous temperature was regulated at 30 -32°C. ...
... In this study, A␦ fibers (type II AMH receptors) were activated with pulses of comparatively high-intensity (mean 9 -18 mJ/mm 2 ), brief duration (15 ms), and a small irradiated area (about 5 mm 2 ). Laser pulses of this kind increased the skin temperature from baseline to 48°C, i.e., above the heat threshold of the type II A␦ nociceptors (Treede et al. 1995) and were perceived as a sharp pinprick, a sensation conveyed by A␦ nociceptive fibers (Arendt-Nielsen and Bjerring 1988;Romaniello et al. 2002). The peak latency of the N-wave (195-210 ms) came between the latencies of the corresponding components after stimuli delivered to the face (170 ms) and hand (240 ms) with the same laser and recording apparatus (Cruccu et al. 1999). ...
... The large irradiated area compensated for the lowdensity and punctate receptive fields of warmth receptors (Campbell et al. 1989;Green and Cruz 1998); the skin temperature increased from baseline to 39°C, i.e., above the heat threshold of C warm receptors (1°C above skin temperature) (Hallin et al. 1981;LaMotte and Campbell 1978) and below that of C nociceptors (41-46°C) (Hallin et al. 1981;LaMotte and Campbell 1978;Treede et al. 1995). All subjects perceived these stimuli as a warmth sensation; the peak latency of the main positive component of the evoked response (470 -580 ms) matched that reported for ultralate LEPs evoked by activation of CMH nociceptors after stimulation of tiny skin areas (460 -630 ms) (Qiu et al. 2001;Tran et al. 2002) and was consistently shorter than those found after activation of CMH units of the hand (840 -1,000 ms) (Bragard et al. 1996;Magerl et al. 1999;Towell et al. 1996;Tran et al. 2001) and foot (1500 ms) (Opsommer et al. 1999). From the skin temperature induced by the stimulus, the reported sensations, and the latency of the brain signals, we conclude that our stimulation selectively activates unmyelinated afferents and that, although we cannot exclude the co-activation of some CMH units, the evoked responses arise predominantly from the excitation of warmth receptors. ...
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.
... For the back, the latency of A-delta fibers LEP remains the same regardless of the spinal level stimulated (from C5 to L5) [16,22,34]. However, the latencies of C-fibers LEP vary depending on the distance between the stimulus location and the brain [34,59]. The latencies reported for C-fibers LEP in the present study are consistent with previous findings for stimuli applied to the upper back (T2, T4, T6, T8) [34,59]. ...
... However, the latencies of C-fibers LEP vary depending on the distance between the stimulus location and the brain [34,59]. The latencies reported for C-fibers LEP in the present study are consistent with previous findings for stimuli applied to the upper back (T2, T4, T6, T8) [34,59]. Besides, peak amplitude was calculated for each component instead of peak-to-peak, since each peak originates from different brain generators and reflects distinct neural processes [24,43,46]. ...
The aim of this study was to examine the mechanisms underlying hypoalgesia induced by spinal manipulation (SM). Eighty-two healthy volunteers were assigned to one of the four intervention groups: no intervention, SM at T4 (homosegmental to pain), SM at T8 (heterosegmental to pain) or light mechanical stimulus at T4 (placebo). Eighty laser stimuli were applied on back skin at T4 to evoke pain and brain activity related to Aδ- and C-fibers activation. The intervention was performed after 40 stimuli. Laser pain was decreased by SM at T4 (p=0.028) but not T8 (p=0.13), compared with placebo. However, brain activity related to Aδ-fibers activation was not significantly modulated (all p>0.05), while C-fiber activity could not be measured reliably. This indicates that SM produces segmental hypoalgesia through inhibition of nociceptive processes that are independent of Aδ fibers. It remains to be clarified whether the effect is mediated by the inhibition of C-fiber activity.
... The two different methods used to calculate conduction velocities yielded similar results, showing velocities in the range of Aδ small myelinated fibres for cold and noxious heat stimulation and in the range of C unmyelinated fibres for warm stimulation. In our study, nociceptive and warm spinal pathway conduction velocities are consistent with previous observations in healthy humans that have found nociceptive spinal pathway conduction velocities ranging from 9.9 to 21 m/s and warm spinal pathway conduction velocities ranging from 2.0 to 3.1 m/s (Cruccu et al., 2000;Kakigi et al., 1991;Qiu, Inui, Wang, Tran, & Kakigi, 2001;Valeriani et al., 2011). Unexpectedly, we F I G U R E 4 Boxplots of the CVs computed with the two methods by type of stimulation (cold in blue, noxious in red and warm in purple). ...
... Conduction velocity of the cold spinal pathway in healthy humans. Eur J Pain. 2020;24:1923-1931. https://doi.org/10.1002/ejp.1640 ...
Objectives
We aimed to investigate the conduction velocity of the cold spinal pathway in healthy humans.
Methods
Using a cold stimulator consisting of micro‐Peltier elements that was able to produce steep cooling ramps up to ‐300°C/s we recorded cold‐evoked potentials after stimulation of the dorsal midline at C5, T2, T6, and T10 vertebral levels and calculated the conduction velocity of the cold spinal pathway. In all participants, we used laser stimulation to deliver painful heat (Aδ‐fibres mediated) and warm (C‐fibres mediated) stimuli to the same sites in order to compare the conduction velocity of the cold spinal pathway with that of the nociceptive and warm spinal pathways.
Results
Cold stimulation evoked large‐amplitude vertex potentials from all stimulation sites. The mean conduction velocity of the cold spinal pathway was 12.0 m/s, which did not differ from that of the nociceptive spinal pathway (10.5 m/s). The mean conduction velocity of the warm spinal pathway was 2.0 m/s.
Discussion
This study provides previously unreported findings regarding cold spinal pathway conduction velocity in humans, that may be useful in the assessment of spinal cord lesions, as well as in intraoperative monitoring during spinal surgery.
... For example, lamina I cold-sensitive neurons in the cat present a linear increase in their response to decreasing skin temperatures in the range of 34 • C to 15 • C, a fact which is well matched by human psychophysical results on thermosensory magnitude estimation (102). Also, conduction velocities of cat and monkey' spinothalamic cold-sensitive myelinated neurons (∼8 and ∼5.6 m/s, respectively) (67, 88) resemble estimated conduction velocities (∼10 m/s) of cold-sensitive myelinated fibers in the human spinothalamic tract (168,249). Finally, cat' spinothalamic warm-sensitive unmyelinated C-fibers (conduction velocities: 1.5-3 m/s) (5) resemble estimated conduction velocities of unmyelinated warm-sensitive C-fibers in the human spinothalamic tract (∼2.2 m/s) (159,168,249). Altogether, the primarily animal-based findings reviewed earlier provides evidence in support of the role and properties of the spinothalamic tract as both the main spinal pathway as well as the first level of central integration of thermoafferent information within the central nervous system of mammals amongst which humans. ...
... Also, conduction velocities of cat and monkey' spinothalamic cold-sensitive myelinated neurons (∼8 and ∼5.6 m/s, respectively) (67, 88) resemble estimated conduction velocities (∼10 m/s) of cold-sensitive myelinated fibers in the human spinothalamic tract (168,249). Finally, cat' spinothalamic warm-sensitive unmyelinated C-fibers (conduction velocities: 1.5-3 m/s) (5) resemble estimated conduction velocities of unmyelinated warm-sensitive C-fibers in the human spinothalamic tract (∼2.2 m/s) (159,168,249). Altogether, the primarily animal-based findings reviewed earlier provides evidence in support of the role and properties of the spinothalamic tract as both the main spinal pathway as well as the first level of central integration of thermoafferent information within the central nervous system of mammals amongst which humans. ...
Undoubtedly, adjusting our thermoregulatory behavior represents the most effective mechanism to maintain thermal homeostasis and ensure survival in the diverse thermal environments that we face on this planet. Remarkably, our thermal behavior is entirely dependent on the ability to detect variations in our internal (i.e., body) and external environment, via sensing changes in skin temperature and wetness. In the past 30 years, we have seen a significant expansion of our understanding of the molecular, neuroanatomical, and neurophysiological mechanisms that allow humans to sense temperature and humidity. The discovery of temperature-activated ion channels which gate the generation of action potentials in thermosensitive neurons, along with the characterization of the spino-thalamo-cortical thermosensory pathway, and the development of neural models for the perception of skin wetness, are only some of the recent advances which have provided incredible insights on how biophysical changes in skin temperature and wetness are transduced into those neural signals which constitute the physiological substrate of skin thermal and wetness sensations. Understanding how afferent thermal inputs are integrated and how these contribute to behavioral and autonomic thermoregulatory responses under normal brain function is critical to determine how these mechanisms are disrupted in those neurological conditions, which see the concurrent presence of afferent thermosensory abnormalities and efferent thermoregulatory dysfunctions. Furthermore, advancing the knowledge on skin thermal and wetness sensations is crucial to support the development of neuroprosthetics. In light of the aforementioned text, this review will focus on the peripheral and central neurophysiological mechanisms underpinning skin thermal and wetness sensations in humans. (C) 2016 American Physiological Society.
... Estimated mean velocity of 0.46 ± 0.15 m/s is at the lower range, but still consistent, with those previously reported for cutaneous nociceptive C-fiber afferents (Serra et al., 1999). Notably, our velocity estimate is well below the described velocity for spinothalamic tract C-fiber pain transmission of around 2.2 m/s (Qiu et al., 2001), in keeping with an extra-spinal transmission path. ...
Human sensory transmission from limbs to brain crosses and ascends through the spinal cord. Yet, descriptions exist of ipsilateral sensory transmission as well as transmission after spinal cord transection. To elucidate a novel ipsilateral cutaneous pathway, we measured facial perfusion following painfully-cold water foot immersion in 10 complete spinal cord-injured patients, 10 healthy humans before and after lower thigh capsaicin C-fiber cutaneous conduction blockade, and 10 warm-immersed healthy participants. As in healthy volunteers, ipsilateral facial perfusion in spinal cord injured patients increased significantly. Capsaicin resulted in contralateral increase in perfusion, but only following cold immersion and not in 2 spinal cord-injured patients who underwent capsaicin administration. Supported by skin biopsy results from a healthy participant, we speculate that the pathway involves peripheral C-fiber cross-talk, partially bypassing the cord. This might also explain referred itch and jogger's migraine and it is possible that it may be amenable to training spinal-injured patients to recognize lower limb sensory stimuli.
... Among the methods used to selectively activate C-fibers, stimulation of tiny areas of skin requires few adjustments of the laser stimulator. This process can be implemented by interposing a thin plate, drilled with one or more small holes, between the stimulus probe and the skin surface in order to act as a spatial filter for the laser beam 15,16,17 . The principle of this method is based on higher innervation density of C-fiber terminals on the skin (three or four times more numerous than Aδ-fibers in humans), resulting in a higher probability of stimulating the terminals of C-fibers than those of Aδ-fibers 18 . ...
Objective
The evaluation of selective activation of C-fibers to record evoked potentials using the association of low-power diode laser (810 nm), tiny-area stimulation and skin-blackening.
Method
Laser-evoked potentials (LEPs) were obtained from 20 healthy young subjects. An aluminum plate with one thin hole was attached to the laser probe to provide tiny-area stimulation of the hand dorsum and the stimulated area was covered with black ink.
Results
The mean intensity used for eliciting the ultra-late laser-evoked potential (ULEP) was 70 ± 32 mW. All subjects showed a clear biphasic potential that comprised a negative peak (806 ± 61 ms) and a positive deflection (1033 ± 60 ms), corresponding to the ULEP related to C-fiber activation.
Conclusion
C-fiber-evoked responses can be obtained using a very low-power diode laser when stimulation is applied to tiny areas of darkened skin. This strategy offers a non-invasive and easy methodology that minimizes damage to the tissue.
... Future studies should examine whether comparison of the latencies of C-fibre LEPs elicited by stimulation of proximal vs distal segments of the same limb, by stimulation of the upper and lower limbs, or by stimulation of the dorsal skin innervated by different dermatomes could be used to obtain reliable Table 1 Latency and amplitude of C-fibre laser-evoked potentials after stimulation of the hand and foot dorsum. estimates of the conduction velocity of peripheral C-fibres and/or spinothalamic tracts [7,14,27,32,36]. Both when stimulating the hand and when stimulating the foot, the scalp topographies of the N2 and P2 peaks were maximal at the scalp vertex and were symmetrically distributed over both hemispheres. ...
C‐fibre laser‐evoked potentials can be obtained reliably at single‐subject level from the hand and foot using a temperature‐controlled CO2 laser combined with an adaptive algorithm based on reaction times. ABSTRACT: Brain responses to the activation of C‐fibres are obtained only if the co‐activation of Aδ‐fibres is avoided. Methods to activate C‐fibres selectively have been proposed, but are unreliable or difficult to implement. Here, we propose an approach combining a new laser stimulator to generate constant‐temperature heat pulses with an adaptive paradigm to maintain stimulus temperature above the threshold of C‐fibres but below that of Aδ‐fibres, and examine whether this approach can be used to record reliable C‐fibre laser‐evoked brain potentials. Brief CO2 laser stimuli were delivered to the hand and foot dorsum of 10 healthy subjects. The stimuli were generated using a closed‐loop control of laser power by an online monitoring of target skin temperature. The adaptive algorithm, using reaction times to distinguish between late detections indicating selective activation of unmyelinated C‐fibres and early detections indicating co‐activation of myelinated Aδ‐fibres, allowed increasing the likelihood of selectively activating C‐fibres. Reliable individual‐level electroencephalogram (EEG) responses were identified, both in the time domain (hand: N2: 704 ± 179 ms, P2: 984 ± 149 ms; foot: N2: 1314 ± 171 ms, P2: 1716 ± 171 ms) and the time‐frequency (TF) domain. Using a control dataset in which no stimuli were delivered, a Receiver Operating Characteristics analysis showed that the magnitude of the phase‐locked EEG response corresponding to the N2‐P2, objectively quantified in the TF domain, discriminated between absence vs presence of C‐fibre responses with a high sensitivity (hand: 85%, foot: 80%) and specificity (hand: 90%, foot: 75%). This approach could thus be particularly useful for the diagnostic workup of small‐fibre neuropathies and neuropathic pain.
... The physiological background of this method is that the C afferent sensory terminals in the skin have a higher density and lower activation threshold than the A-delta terminals. We have recorded a clear ultra-late LEP by modifying the method and reported that the conduction velocity of the peripheral nerve and spinal cord following this specific stimulation was approximately 1-4 m/s, which is within the range for unmyelinated fibers [3,5,7,8]. We reported that 3-dipole model of SI and bilateral SII sources could explain the 1M component of MEG responses following stimulation of C- fibers [9], and that cingulate cortex and medial temporal area (MT) around amygdala and hippocampus in bilateral hemisphere were also activated for the subsequent component, 2M [6], and also clarified the mechanisms underlying the effects of attention/distraction on second pain perception in detail by using EEG [4] and MEG [6]. ...
Cerebral processing of first pain, associated with A-delta fibers, has been studied intensively, but the cerebral processing associated with C-fibers, relating to second pain, remains to be investigated. This is the first study to clarify the primary cortical processing of second pain by magnetoencephalography (MEG). We selectively activated C-fibers by the stimulation of a tiny area of skin with a CO2 laser. As for the primary component (1M), in the hemisphere contralateral to the stimulation, two regions in the hand area of the primary somatosensory cortex (SI) and secondary somatosensory cortex (SII)-insular were activated. The onset and peak latency of the two sources in SI and SII-insular were not significantly different. In the hemisphere ipsilateral to the stimulation, only one source was estimated in SII-insular, and its peak latency was significantly longer than that of the SII-insular source in the contralateral hemisphere, probably through corpus callosum. Our findings suggest that parallel activation of SI and SII-insular contralateral to the stimulation represents the first step in the cortical processing of C-fiber-related activities. In addition to SI and SII-insular, cingulate cortex and medial temporal area (MT) around amygdala and hippocampus in bilateral hemispheres were also activated for the subsequent component, 2M. All components of EEG and MEG responses were significantly reduced in amplitude during distraction and diminished during sleep, particularly 2M component. These findings indicate that these regions are related to the cognitive aspect of second pain perception, particularly activities in cingulate cortex.
... Ad and/or C nociceptors, spinothalamic tract neurons and pain-related thalamo-cortical networks producing cortical LEPs (Bromm and Treede, 1984; Treede et al., 1995; reviews in Plaghki and Mouraux, 2003; Garcia-Larrea et al., 2003). LEPs are being increasingly used for diagnosis and clinical research in patients with peripheral or central nervous system lesions (reviews in Treede et al., 2003; ) as well as in research on the cortical mechanisms of pain perception (Beydoun et al., 1996; Valeriani et al., 1996; Qiu et al., 2001; Kakigi et al., 2005; Legrain et al., 2005; Nahra and Plaghki, 2005; Frot et al., 2007 Frot et al., , 2008 Wang et al., 2007). As pioneered by Mor and Carmon (1975) and extensively discussed by Plaghki and Mouraux (2003), high power CO 2 lasers are very appropriate LEP-inducing heat stimulators. ...
This study compares the amplitude, latency, morphology, scalp topography and intracranial generators of laser-evoked potentials (LEPs) to CO(2) and Nd:YAP laser stimuli.
LEPs were assessed in 11 healthy subjects (6 men, mean age 39+/-10 years) using a 32-channel acquisition system. Laser stimuli were delivered on the dorsum of both hands (intensity slightly above pain threshold), and permitted to obtain lateralised (N1) and vertex components (N2-P2) with similar scalp distribution for both types of lasers.
The N1-YAP had similar latencies but significantly higher amplitudes relative to N1-CO(2). The N2-P2 complex showed earlier latencies, higher amplitudes (N2) and more synchronised responses when using Nd:YAP stimulation. The distribution of intracranial generators assessed with source localization analyses (sLORETA) was similar for Nd:YAP and CO(2) lasers. The insular, opercular, and primary sensorimotor cortices were active during the N1 time-window, whereas the anterior midcingulate, supplementary motor areas and mid-anterior insulae were active concomitant to the N2-P2 complex.
Earlier latencies and larger amplitudes recorded when using Nd:YAP pulses suggest a more synchronized nociceptive afferent volley with this type of laser.
This, together with its handy utilization due to optic fibre transmission, may favour the use of Nd:YAP lasers in clinical settings.
... C warmth receptors have a slightly lower threshold than C nociceptors and a far lower density in the skin (LaMotte and Campbell, 1978; Tillman et al., 1995; Green and Cruz, 1998). Hence, the highest probabilities of selective activation for warmth receptors are yielded by lowintensity laser pulses irradiating a large skin area (Towell et al., 1996; Agostino et al., 2000; Iannetti et al., 2003) and those for C nociceptors by stimulation of very small areas (~0.2 mm) (Bragard et al., 1996; Opsommer et al., 1999; Qiu et al., 2001; Tran et al., 2002). To assess trigeminal C-®bre function, we used laser pulses directed to the facial skin and recorded the related brain potentials in healthy humans. ...
Laser pulses excite superficial free nerve endings innervated by small-myelinated (Adelta) and unmyelinated (C) fibres. Whereas laser-evoked scalp potentials (LEPs) are now reliably used to assess function of the Adelta-fibre nociceptive pathways in patients with peripheral or central lesions, the selective activation of C-fibre receptors and recording of the related brain potentials remain difficult. To investigate trigeminal C-fibre function, we directed laser pulses to the facial skin and studied sensory perception and scalp evoked potentials related to Adelta- or C-fibre activation in healthy humans and patients--one having a bilateral facial palsy, two a trigeminal neuropathy, and two a Wallenberg syndrome. We also measured afferent conduction velocity and, with source analysis, studied the brain generators. Whereas laser pulses of low intensity and small irradiated area elicited pinprick sensations and standard Adelta-LEPs, laser pulses of very-low intensity and large irradiated area elicited warmth sensations and scalp potentials with a latency compatible with C-fibre conduction (negative wave 280 ms, positive wave 380 ms); the estimated conduction velocity was 1.2 m/s. The main waves of the scalp potentials originated from the anterior cingulate gyrus; they were preceded by activity in the opercular region and followed by activity in the insular region. The patient with bilateral facial palsy, who had absent trigeminal-facial reflexes, had normal Adelta- and C-related scalp potentials; the patients with trigeminal neuropathy, characterized by loss of myelinated and sparing of unmyelinated fibres, had absent Adelta- but normal C-related potentials; and the patients with Wallenberg syndrome had absent Adelta- and C-related potentials. We conclude that laser pulses with appropriate characteristics evoke brain potentials related to the selective activation of trigeminal nociceptive Adelta or thermal C fibres. The trigeminal territory yields rewarding LEP findings owing to the high density of thermal receptors and, because the short conduction distance, minimizes the problem of signal dispersion along slow-conducting unmyelinated afferents. The opercular-insular region and the cingulate gyrus are involved in the processing of C-fibre trigeminal inputs. The method we describe may prove useful in patients with lesions affecting the trigeminal thermal pain pathways.
... From studies in normal subjects and in patients with various types of sensory impairment, it has been established that CO 2 laser stimuli cause the excitation of nociceptive receptors in the skin and that their signals ascend through small myelinated A-d fibers of the peripheral nerves and are probably mediated through the spinothalamic tract (see reviews by Kakigi et al. [32,33]). In addition, we recently established a new method for selectively stimulating C fibers (see a review by Kakigi et al. [41]) and reported the peripheral conduction [42], spinal conduction [43,44] and responses at the cerebral cortex [36,45]. We are investigating the effects of sleep on C-fiber related SEP [45] and SEF [5], and would like to summarize the results in detail in a future review article. ...
We reported the changes of brain responses during sleep following auditory, visual, somatosensory and painful somatosensory stimulation by using magnetoencephalography (MEG). Surprisingly, very large changes were found under all conditions, although the changes in each were not the same. However, there are some common findings. Short-latency components, reflecting the primary cortical activities generated in the primary sensory cortex for each stimulus kind, show no significant change, or are slightly prolonged in latency and decreased in amplitude. These findings indicate that the neuronal activities in the primary sensory cortex are not affected or are only slightly inhibited during sleep. By contrast, middle- and long-latency components, probably reflecting secondary activities, are much affected during sleep. Since the dipole location is changed (auditory stimulation), unchanged (somatosensory stimulation) or vague (visual stimulation) between the state of being awake and asleep, different regions responsible for such changes of activity may be one explanation, although the activated regions are very close to each other. The enhancement of activities probably indicates two possibilities, an increase in the activity of excitatory systems during sleep, or a decrease in the activity of some inhibitory systems, which are active in the awake state. We have no evidence to support either, but we prefer the latter, since it is difficult to consider why neuronal activities would be increased during sleep.
... Several investigators have reported methods of studying C-fibre related ('ultralate') LEPs after stimulation of the hand (Bromm et al., 1983;Treede et al., 1988;Bragard et al., 1996), a territory which is affected only in a small proportion of PHN patients. A recently reported method of eliciting both A-delta and C-related LEPs after stimulation of the skin overlying the spine (Cruccu et al., 2000;Qiu et al., 2001;Iannetti et al., 2003), however, may be applied to patients with PHN in thoracic or cervical dermatomes. ...
We evaluated the reliability of laser-evoked potentials (LEPs) as a diagnostic tool in patients with post-herpetic neuralgia (PHN), i.e. a chronic painful condition that causes small-diameter fibre dysfunction. Furthermore, we sought information on pathophysiology of PHN pain.
We recorded 'late' LEPs after stimulation of the supraorbital, upper cervical, lower cervical, upper thoracic, mid thoracic, and lower thoracic territories in 12 control subjects and 40 patients with PHN. We also determined the correlation of LEP data with age, duration of disease, and severity and quality of pain.
At all stimulation sites, laser pulses invariably evoked high-amplitude brain potentials related to small-myelinated (A-delta) fibre activation. The laser perceptive threshold and LEP latency correlated with the distance of the dermatome from the brain (P<0.001). In patients, the perceptive threshold was higher and the LEP amplitude was lower in the affected dermatome than on the contralateral side (P<0.001). We found no significant LEP-clinical correlation except for a correlation between LEP abnormality and age.
Being sensitive and reliable in assessing sensory function also in proximal dermatomes, LEPs are a promising diagnostic tool in radiculopathies. Although PHN severely impairs small myelinated fibres, the lack of a significant correlation between LEP abnormalities and pain suggests that pain in PHN does not chiefly arise from a dysfunction of small-myelinated afferents.
... We used an aluminum plate with many holes whereas the Belgian group used a plate with 1 hole attached at the top of the laser stimulation probe. We concluded that this method selectively activates C nociceptors based on studies using microneurography (Qiu and others 2003), electroencephalography (EEG) (Qiu and others 2001, 2002; Tran and others 2001; Tran and others 2003), and magnetoencephalography (Tran and others 2002; Qiu and others 2004). ...
Event-related functional magnetic resonance imaging was used to investigate brain processing of the signals ascending from
peripheral C and Aδ fibers evoked by phasic laser stimuli on the right hand in humans. The stimulation of both C and Aδ nociceptors
activated the bilateral thalamus, bilateral secondary somatosensory cortex, right (ipsilateral) middle insula, and bilateral
Brodmann's area (BA) 24/32, with the majority of activity found in the posterior portion of the anterior cingulate cortex
(ACC). However, magnitude of activity in the right (ipsilateral) BA32/8/6, including dorsal parts in the anterior portion
of the ACC (aACC) and pre-supplementary motor area (pre-SMA), and the bilateral anterior insula was significantly stronger
following the stimulation of C nociceptors than Aδ nociceptors. It was concluded that the activation of C nociceptors, related
to second pain, evokes different brain processing from that of Aδ nociceptors, related to first pain, probably due to the
differences in the emotional and motivational aspects of either pain, which are mainly related to the aACC, pre-SMA, and anterior
insula.
... The RT and latency of the P1 when the electrical stimuli were applied to the right wrist were 1215 ± 150 ms and 963 ± 75 ms, respectively. In studies of pain, several researchers have observed that the RT and latency of the P1 for pain stimuli were around 1000 ms when C-fibers of the hand were selectively activated [2,18,20,21,26,27]. The stimulated body part mentioned in this study (i.e., wrist) was very close to that mentioned in the previous studies (i.e., hand). ...
Electrically evoked itching has the strong potential to be used to investigate the central processing associated with itching at high temporal resolution by employing magnetoencephalography, electroencephalography (EEG), and event-related functional magnetic resonance imaging. However, it has not been investigated whether time-locked brain activity can be measured using this stimulus, and whether the itching sensation induced by electrical stimulation of the skin is associated with C-fibers. Thus, we investigated these problems in this study. Itching sensations were elicited when electrical stimuli were applied to the skin of the right wrist and right forearm. EEG activity was recorded from 5 electrodes (Fz, FCz, Cz, CPz and Pz). When the right wrist was stimulated, the reaction time (RT) and latency of the positive component of somatosensory evoked potentials (P1) were 1215 ms and 963 ms, respectively. When the right forearm was stimulated, the RT and peak latency of the P1 were 1013 ms and 772 ms, respectively. The conduction velocity estimated from the RT and latency of the P1 was 1.04 m/s and 0.92 m/s, respectively. In addition, the itching sensation and P1 were inhibited when the current intensity was increased into the range eliciting pain and touch sensations, implying interaction between C- and A-fibers. These findings demonstrate that time-locked brain activity can be measured using electrically evoked itching and that the itching sensation induced by the electrically evoked itching is associated with C-fibers. Thus, this method is useful for research into the central processing of itching.
Objectives
In clinical neurophysiology practice, various methods of stimulation can be used to activate small-diameter nociceptive cutaneous afferents located in the epidermis. These methods include different types of laser and intraepidermal electrical stimulation techniques. The diffusion of the stimulation in the skin, inside or under the epidermis, depends on laser wavelength and electrode design, in particular. The aim of this study was to compare several of these techniques in their ability to selectively stimulate small nerve fibers.
Methods
In 8 healthy subjects, laser stimulation (using a CO2 or Nd:YAP laser) and intraepidermal electrical stimulation (using a micropatterned, concentric planar, or concentric needle electrode), were applied at increasing energy or intensity on the dorsal or volar aspect of the right hand or foot. The subjects were asked to define the perceived sensation (warm, pinprick, or electric shock sensation, corresponding to the activation of C fibers, Aδ fibers, or Aβ fibers, respectively) after each stimulation. Depending on the difference in the sensations perceived between dorsal (hairy skin with thin stratum corneum) and volar (glabrous skin with thick stratum corneum) stimulations, the diffusion of the stimulation inside or under the epidermis and the nature of the activated afferents were determined.
Results
Regarding laser stimulation, the perceived sensations turned from warm to pinprick with increasing energies of stimulation, in particular with the Nd:YAP laser, of which pulse could penetrate deep in the skin according to its short wavelength. In contrast, CO2 laser stimulation produced only warm sensations and no pricking sensation when applied to the glabrous skin, perhaps due to a thicker stratum corneum and the shallow penetration of the CO2 laser pulse. Regarding intraepidermal electrical stimulation using concentric electrodes, the perceived sensations turned from pinprick to a combination of pinprick and electrical shocks with increasing intensities. Using the concentric planar electrode, the sensations perceived at high stimulation intensity even consisted of electric shocks without concomitant pinprick. In contrast, using the micropatterned electrode, only pinprick sensations were produced by the stimulation of the hairy skin, while the stimulation of the glabrous skin produced no sensation at all within the limits of stimulation intensities used in this study.
Conclusions
Using the CO2 laser or the micropatterned electrode, pinprick sensations were selectively produced by the stimulation of hairy skin, while only warm sensation or no sensation at all were produced by the stimulation of glabrous skin. These two techniques appear to be more selective with a limited diffusion of the stimulation into the skin, restricting the activation of sensory afferents to the most superficial and smallest intraepidermal nerve fibers.
Clinical neurophysiologic investigation of pain pathways in humans is based on specific techniques and approaches, since conventional methods of nerve conduction studies and somatosensory evoked potentials do not explore these pathways. The proposed techniques use various types of painful stimuli (thermal, laser, mechanical, or electrical) and various types of assessments (measurement of sensory thresholds, study of nerve fiber excitability, or recording of electromyographic reflexes or cortical potentials). The two main tests used in clinical practice are quantitative sensory testing and pain-related evoked potentials (PREPs). In particular, PREPs offer the possibility of an objective assessment of nociceptive pathways. Three types of PREPs can be distinguished depending on the type of stimulation used to evoke pain: laser-evoked potentials, contact heat evoked potentials, and intraepidermal electrical stimulation evoked potentials (IEEPs). These three techniques investigate both small-diameter peripheral nociceptive afferents (mainly Aδ nerve fibers) and spinothalamic tracts without theoretically being able to differentiate the level of lesion in the case of abnormal results. In routine clinical practice, PREP recording is a reliable method of investigation for objectifying the existence of a peripheral or central lesion or loss of function concerning the nociceptive pathways, but not the existence of pain. Other methods, such as nerve fiber excitability studies using microneurography, more directly reflect the activities of nociceptive axons in response to provoked pain, but without detecting or quantifying the presence of spontaneous pain. These methods are more often used in research or experimental study design. Thus, it should be kept in mind that most of the results of neurophysiologic investigation performed in clinical practice assess small fiber or spinothalamic tract lesions rather than the neuronal mechanisms directly at the origin of pain and they do not provide objective quantification of pain.
Objective:
To elucidate Aδ-fiber dysfunction at the trunk in patients with hereditary transthyretin (ATTRm) amyloidosis using intra-epidermal electrical stimulation (IES).
Methods:
In 16 patients with ATTRm amyloidosis and 18 healthy subjects, sensory thresholds using IES and cooling detection thresholds using the Computer-Aided Sensory Evaluation (CASE IV) system, were assessed to investigate Aδ-fiber functions at the Th10 level of the anterior, lateral, and posterior trunk. Furthermore, evoked potentials (EPs) following electrical stimulation using IES at the anterior and posterior trunk were evaluated.
Results:
In patients with ATTRm amyloidosis, both IES and CASE IV sensory thresholds tended to be higher at the anterior trunk than at the lateral and posterior trunks. The amplitudes of EPs following electrical stimulation at the anterior trunk were lower than those at the posterior trunk. Aδ-fiber dysfunction at the anterior trunk was conspicuous in patients with more intense polyneuropathy at the limbs. In healthy subjects, there were no differences in both sensory thresholds and EP amplitudes among any examination sites. Sensory thresholds with IES and CASE IV were correlated.
Conclusions:
Evaluation using IES demonstrated length-dependent Aδ-fiber dysfunction at the trunk in patients with ATTRm amyloidosis.
Significance:
IES may be a useful clinical tool for investigating Aδ-fiber dysfunction at various parts of the body in patients with neuropathy.
In the field of behavioral neuroscience, the continuous and mutichannel recording of bioelectric activities, such as electroencephalography, electromyography, and electrocardiography, is necessary to understand the physiological correlates with brain activity. In this review, I address issues based on my research interests: (1) the recent development and future directions of multichannel recording and analysis systems in freely moving rats are discussed; (2) functional aspects of sleep in sensory processing, including sleep-dependent learning and memory consolidation and the possibility of sleep learning, are included; and (3) the network operation of absence epilepsy is elucidated, particularly the relationship between sleep and absence epilepsy. It is hoped that improved understanding of sleep and absence epilepsy will ultimately lead to more-effective treatment options.
Cortical neurons are excited by signals from the thalamus that are conducted via thalamocortical fibers. As the cortex receives these signals, electric currents are conducted through the apical dendrites of pyramidal cells in the cerebral cortex. These electric currents generate magnetic fields. These electric and magnetic currents can be recorded by electroencephalography (EEG) and magnetoencephalography (MEG), respectively. The spatial resolution of MEG is higher than that of EEG because magnetic fields, unlike electric fields, are not affected by current conductivity. MEG also has several advantages over functional magnetic resonance imaging (fMRI). It (1) is completely non-invasive; (2) measures neuronal activity rather than blood flow or metabolic changes; (3) has a higher temporal resolution than fMRI on the order of milliseconds; (4) enables the measurement of stimulus-evoked and event-related responses; (5) enables the analysis of frequency (i.e., brain rhythm) response, which means that physiological changes can be analyzed spatiotemporally; and (6) enables the detailed analysis of results from an individual subject, which eliminates the need to average results over several subjects. This latter advantage of MEG therefore enables the analysis of inter-individual differences.
We investigated C-fiber discharges and cerebral potentials evoked by weak CO2 laser beams applied to a tiny skin area in five healthy subjects. Microneurography was performed from the peroneal nerve in the right popliteal area. Cerebral potentials were recorded from the Cz electrode referred to linked earlobes. The mean conduction velocity of five stable single units was 1.1±0.3 m/s. The mean latency of the positive peak of cerebral potentials was 1327.4±46.2 ms. These findings indicated that this new stimulation method selectively activated C-fiber nociceptors of the skin.
The brain's response to external painful stimuli can be assessed through contact heat evoked cortical potentials that enable the evaluation of the integrity of pain pathways. This work aims to improve the reliability of this diagnostic procedure by decoupling the effects of heat transfer and nerve fiber conduction. It is herein shown experimentally that the latency of the N2 contact heat evoked cortical potentials component is the most stable diagnostic parameter. The contribution of heat transfer to N2 contact heat evoked cortical potentials latency was modeled as a function of the subject's pain threshold, allowing for the separation of nerve fiber pathology from thermodynamic influences.
Pain-temperature sensation and other somatosensory sensations, such as touch or vibration, ascend through different peripheral and central pathways, so both pain SEP and pain SEF are useful for elucidating the pathophysiology of various types of sensory impairments. Somatosensory evoked potential (SEP) relating to pain (pain SEP) can be recorded by different types of lasers, including CO2 argon, Nd-YAG, and thulium laser. Differences among these types depend mainly on the wavelengths, as this parameter determines skin reflectance, absorbency, scattering, and transmittance (Chen et al. 1998a,b). Recently, CO2 laser stimulation (10.6 11m wavelength) has become popular. Other important factors causing a change of pain SEP waveforms are attention or distraction effects. The chapter describes these factors in brief and mentions several important findings. The amplitude of the P2 component is significantly reduced during sleep and during distraction (mental calculation or memorizing numbers). This change positively correlates with a decrease of visual analog scale (VAS). These results indicate that vigilance and attentiveness to the painful stimuli should be monitored during the acquisition of pain SEP.
This chapter discusses the central mechanisms underlying pain sensation and perception based on the physiological findings in normal subjects and patients with sensory disturbances. The conventional noxious stimuli, such as pinprick and touching the skin with a test tube filled with ice water activate not only the nociceptive receptors but also other kinds of somatosensory receptors, such as tactile and mechanical receptors. When electrical stimulation of the peripheral nerves is employed, the stimulus intensity must be extremely high to activate small nerve fibers, such as A-delta and C fibers, which mediate nociceptive input. Mechanisms of human nociception can be studied by the use of CO2 laser stimulation, which selectively activates nociceptive receptors, and by the use of various noninvasive techniques. Apart from the contralateral thalamus, at least several cortical areas, including the contralateral primary somatosensory cortex (SI), bilateral second somatosensory cortex (SII), anterior cingulated cortex, and insular cortices are involved in the pain sensation/perception.
We recorded evoked potentials (EPs) induced by intra-epidermal electrical stimulation using a needle electrode with specific parameters. We identified the fibers activated by this specific stimulation by assessing the conduction velocity (CV) of the peripheral nerve. The EPs were recorded from the Cz electrode (vertex) of the International 10-20 system in ten healthy male subjects. The dorsum of the left hand and forearm were stimulated with an intensity of 0.01 mA above the sensory threshold. The mean P1 latency of EPs for the hand and forearm were 1007 ± 88 and 783 ± 80 ms, respectively, and the CV estimated from the latency of P1 was 1.5 ± 0.7 m/s. The CV indicated that the fibers activated by the stimulation were C fibers. Since the method of stimulation is convenient and non-invasive, it should be useful for investigating the functions of small fibers.
The choice of a system specific stimulus is difficult when investigating the human nociceptive system, in contrast with the tactile, auditory and visual systems, because it should be noxious but not actually damage the tissue. The discomfort accompanying system specific stimulation must be kept to a minimum for ethical reasons. In this review, recent progress made in the study of human pain perception using intraepidermal electrical stimulation (IES) is described. Also, whether IES is a viable alternative to laser stimulation is discussed. IES selectively activates Aδ nociceptors, elicits a sharp pricking sensation with minimal discomfort and evokes cortical responses almost identical to those produced by laser stimulation. As IES does not require expensive equipment, and is easy to control, it would seem useful for pain research as well as clinical tests.
To investigate the presence of multiple spinothalamic pathways for warmth in the human spinal cord.
Laser evoked potentials to C-fiber stimulation (C-LEPs) were recorded in 15 healthy subjects after warmth stimulation of the dorsal midline at C5, T2, T6, and T10 vertebral levels. This method allowed us to calculate the spinal conduction velocity (CV) in two different ways: (1) the reciprocal of the slope of the regression line was obtained from the latencies of the different C-LEP components, and (2) the distance between C5 and T10 was divided by the latency difference of the responses at the two sites. In particular, we considered the C-N1 potential, generated in the second somatosensory (SII) area, and the late C-P2 response, generated in the anterior cingulate cortex (ACC).
The calculated CV of the spinal fibers generating the C-N1 potential (around 2.5m/s) was significantly different (p<0.01) from the one of the pathway producing the P2 response (around 1.4m/s).
Our results suggest that the C-N1 and the C-P2 components are generated by two parallel spinal pathways.
Warmth sensation is subserved by parallel spinothalamic pathways, one probably reaching the SII area, the other the ACC.
Although nociceptive afferents innervating the body have been heavily studied form many years, much less attention has been paid to trigeminal afferent biology. In particular, very little is known concerning trigeminal nociceptor responses to heat, and almost nothing in the rat. This study uses a highly controlled and reproducible diode laser stimulator to investigate the activation of trigeminal afferents to noxious skin heating.
The results of this experiment demonstrate that trigeminal thermonociceptors are distinct from themonociceptors innervating the limbs. Trigeminal nociceptors have considerably slower action potential conduction velocities and lower temperature thresholds than somatic afferent neurons. On the other hand, nociceptors innervating both tissue areas separate into those that respond to short pulse, high rate skin heating and those that respond to long pulse, low rate skin heating.
This paper provides the first description in the literature of the in vivo properties of thermonociceptors in rats. These finding of two separate populations aligns with the separation between C and A-delta thermonociceptors innervating the paw, but have significant differences in terms of temperature threshold and average conduction velocities. An understanding of the temperature response properties of afferent neurons innervating the paw skin have been critical in many mechanistic discoveries, some leading to new pain therapies. A clear understanding of trigeminal nociceptors may be similarly useful in the investigation of trigeminal pain mechanisms and potential therapies.
Noxious cutaneous contact heat stimuli (48 degrees C) are perceived as increasingly painful when the stimulus duration is extended from 5 to 10s, reflecting the temporal summation of central neuronal activity mediating heat pain. However, the sensation of increasing heat pain disappears, reaching a plateau as stimulus duration increases from 10 to 20s. We used functional magnetic resonance imaging (fMRI) in 10 healthy subjects to determine if active central mechanisms could contribute to this psychophysical plateau. During heat pain durations ranging from 5 to 20s, activation intensities in the bilateral orbitofrontal cortices and the activation volume in the left primary (S1) somatosensory cortex correlated only with perceived stimulus intensity and not with stimulus duration. Activation volumes increased with both stimulus duration and perceived intensity in the left lateral thalamus, posterior insula, inferior parietal cortex, and hippocampus. In contrast, during the psychophysical plateau, both the intensity and volume of thalamic and cortical activations in the right medial thalamus, right posterior insula, and left secondary (S2) somatosensory cortex continued to increase with stimulus duration but not with perceived stimulus intensity. Activation volumes in the left medial and right lateral thalamus, and the bilateral mid-anterior cingulate, left orbitofrontal, and right S2 cortices also increased only with stimulus duration. The increased activity of specific thalamic and cortical structures as stimulus duration, but not perceived intensity, increases is consistent with the recruitment of a thalamocortical mechanism that participates in the modulation of pain-related cortical responses and the temporal summation of heat pain.
To determine whether 5 Hz and 2000 Hz sinusoidal electric currents evoke different sensations and to indirectly evaluate which peripheral nerve fibers are stimulated by these different frequencies.
One hundred and fifty subjects chose three among eight descriptors of sensations evoked by 5 Hz and 2000 Hz currents and the results were submitted to factor analysis. In 20 subjects, reaction times to 5, 250 and 2000 Hz currents were determined at 1.1 x ST and reaction times to 5 Hz currents were also determined at 2 x ST.
Responses were grouped in four factors: Factor 1, which loaded mainly in descriptors related to tweezers stimulation, was higher than the other factors during 2000 Hz stimulation at 1.5 x ST. Factor 2, which loaded mainly in descriptors related to needle stimulation, was higher than the other factors during 5 Hz stimulation. Factor 1 increased and Factor 2 decreased with an increase in 5 Hz intensity from 1.5 to 4x ST. Reaction times measured from the fastest responses were significantly different: 0.57 s (0.16 to 1.60), 0.34 s (0.12 to 0.71) and 0.22s (0.08 to 0.35) for 5, 250 and 2000 Hz, respectively, and 0.22s (0.11 to 0.34) for 5 Hz at 2 x ST.
Sinusoidal electrical stimulation of 5 Hz and 2000 Hz evoke different sensations. At juxta-threshold intensities, RT measurements suggest that 2000 Hz stimulates Abeta-fibers, 250 Hz Abeta- or A partial differential-fibers, 5 Hz Abeta-, A partial differential- or C-fibers. The fiber type, which was initially stimulated by the lower frequencies, depended on inter-individual differences.
Cerebral processing of first pain, associated with A delta-fibers, has been studied intensively, but the cerebral processing associated with unmyelinated C-fibers, relating to second pain, remains to be investigated. This is the first study to clarify the primary cortical processing of second pain by magnetoencephalography, through the selective activation of C-fibers, by the stimulation of a tiny area of skin with a CO2 laser. In the hemisphere contralateral to the side stimulated, a one-source generator in the upper bank of the Sylvian fissure (secondary somatosensory cortex, SII) or two-source generators in SII and the hand area of the primary somatosensory cortex (SI) were the optimal configurations for the first component 1M. The onset and peak latency of the two sources in SI and SII were not significantly different. In the hemisphere ipsilateral to the stimulation, only one source was estimated in SII, and its peak latency was significantly (approximately 18 ms on average) longer than that of the SII source in the contralateral hemisphere. From our findings we suggest that parallel activation of SI and SII contralateral to the stimulation represents the first step in the cortical processing of C-fiber-related activities, probably related to second pain.
Our study aimed at investigating the scalp topography of ultra-late CO(2) laser evoked potentials (LEPs), which are related to C fiber activation, and at exploring the effect of attention deviation on ultra-late LEPs. Brain responses to non-painful CO(2) laser stimuli were recorded in ten healthy subjects in three different conditions: (i) neutral condition in which subjects did not have any task; (ii) distraction condition in which subjects were asked to perform a mathematical task; and (iii) attention condition in which subjects had to count the number of stimuli. In all subjects, also A fiber-related late LEPs were recorded after painful CO(2) laser stimulation. The ultra-late LEPs in attention condition included an earlier negative potential (ultra-late N1) in the contralateral temporal region and a simultaneous frontal positive response (ultra-late P1). Later, a vertex biphasic component (ultra-late N2a and ultra-late P2) was identifiable. The vertex ultra-late LEP amplitude was significantly decreased in both neutral and distraction condition. Ultra-late LEPs showed a longer latency than late LEPs, but the scalp distributions of both ultra-late and late LEPs were very similar, thus suggesting that the same cerebral areas may be involved in their generation. Since attention deviations have a strong effect on ultra-late LEP amplitude, the subject's attention should be addressed to CO(2) laser stimuli when ultra-late LEPs are used for clinical purposes.
The objective of this study is to evaluate the effects of attention, distraction and sleep on CO(2) laser-evoked potentials (LEP) relating to C-fibers (ultra-late LEP).
Non-painful CO(2) laser pulses were delivered to a tiny skin area of the dorsum of the right hand. Ultra-late LEP were recorded from 10 normal subjects in 5 different conditions: control (wakefulness), attention, distraction, drowsiness and sleep (stage 2).
The amplitude of ultra-late LEP was slightly increased during attention and significantly decreased during distraction, relative to the control. The ultra-late LEP decreased much in amplitude or almost disappeared during sleep. However, significant differences in latency among the conditions were not found.
We confirmed that the brain responses relating to signals ascending through C-fibers were much affected by the level of consciousness, being consistent with the findings of late LEP relating to Adelta-fibers. This is the first study to indicate the important characteristics of ultra-late LEP relating to consciousness, suggesting that they include cognitive function and also that one has to be careful of the change in alertness when recording.
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.
We investigated C-fiber discharges and cerebral potentials evoked by weak CO(2) laser beams applied to a tiny skin area in five healthy subjects. Microneurography was performed from the peroneal nerve in the right popliteal area. Cerebral potentials were recorded from the Cz electrode referred to linked earlobes. The mean conduction velocity of five stable single units was 1.1+/-0.3 m/s. The mean latency of the positive peak of cerebral potentials was 1327.4+/-46.2 ms. These findings indicated that this new stimulation method selectively activated C-fiber nociceptors of the skin.
Using magnetoencephalography (MEG), we evaluated the cerebral regions relating to second pain perception ascending through C-fibers and investigated the effect of distraction on each region.
Thirteen normal subjects participated in this study. CO2 laser pulses were delivered to the dorsum of the left hand to selectively activate C-fibers. The MEG responses were analyzed using a multi-dipole model.
(1) primary somatosensory cortex (SI), and (2) secondary somatosensory cortex (SII)--insula were the main generators for the primary component, 1M, whose mean peak latency was 744 ms. In addition to (1) and (2), (3) cingulate cortex and (4) medial temporal area (MT) were also activated for the subsequent component, 2M, whose mean peak latency was 947 ms. During a mental calculation task (Distraction), all 6 sources were significantly reduced in amplitude, but the SII-insula (P < 0.01) and cingulate cortex (P < 0.001) were more sensitive than the SI (P < 0.05) and MT (P < 0.05).
We confirmed that SI in the contralateral hemisphere and SII-insula, cingulate cortex and MT in bilateral hemispheres play a major role in second pain perception, and all sites were much affected by a change of attention, indicating that these regions are related to the cognitive aspect of second pain perception.
The SI, SII, cingulate and MT were activated during the C-fiber-related MEG response, and responses in these regions were significantly diminished during mental distraction.
We review the recent progress of electroencephalography (EEG) and magnetoencephalography (MEG) to elucidate pain perception mechanisms in humans, since EEG and MEG have an excellent temporal resolution in order of msec. MEG is more useful to detect activated areas following painful stimulation, because the spatial resolution of EEG is not very high. For recording activities following Adelta fiber stimulation relating to the first pain, painful CO2 laser stimulation is now widely used, but our new method, epidermal stimulation (ES), is also very useful. The primary small activity was recorded from the primary somatosensory cortex (SI), probably in area 1, in the hemisphere contralateral to the stimulation. Then, secondary somatosensory cortex (SII) and insula were activated with the second activity in SI. These 3 regions were activated in parallel with almost the same time period. This is a very characteristic finding in pain perception. Then, the cingulate cortex and medial temporal area (MT) around the amygdala and hippocampus were activated. In the hemisphere ipsilateral to the stimulation as well, the above regions were activated, except for SI. Therefore, we speculated that SI plays a main role in localization of the stimulus point, the SII and insula are important sites for pain perception, and the cingulate and MT are mainly responsible for cognitive or emotional aspects of pain perception. For recording activities following C fiber stimulation relating to the second pain, we recently developed a new method, that is, applying weaker CO2 laser stimuli to tiny areas of the skin. MEG findings following C fiber stimulation were also similar to those following Adelta fiber stimulation. However, the effects of sleep and attention on MEG following C fiber stimulation was much larger than that following Adelta fiber stimulation. This finding may suggest greater effects of cognitive or emotional functions on second pain than the first pain.
It has been found difficult to stimulate the primary C-fibre afferents separately from those of Adelta fibres. A necessary and sufficient condition for the investigation of the C-fibre system is the selective stimulation of C fibres without activation of Adelta fibres. The stimulation of tiny skin areas allows such a selective activation of C fibres.
The main aspects of the method for stimulation of tiny skin areas as well as some results obtained by this method are reported here. The application of this method is compared with applications of other methods that allow an investigation of central processing of human C-fibre input.
The stimulation of tiny skin areas represents a simple method for selective stimulation of C fibres.
To investigate the pathways of noxious information in the spinal cord in humans, we recorded cortical potentials following the stimulation of A-delta fibers using a YAG laser applied to two cutaneous points on the back at the C7 and Th10 level, 4cm to the right of the vertebral spinous process. A multiple source analysis showed that four sources were activated; the primary somatosensory cortex (SI), bilateral parasylvian region (Parasylvian), and cingulate cortex. The activity of the cingulate cortex had two components (N2/P2). The mean peak latencies of the activities obtained by C7 and Th10 stimulation were 166.9 and 186.0 ms (SI), 144.3 and 176.8 ms (contralateral Parasylvian), 152.7 and 185.5 ms (ipsilateral Parasylvian), 186.2 and 215.8 ms (N2), and 303.0 and 332.3 ms (P2). Estimated spinal conduction velocities (CVs) of the respective activities were 16.8, 9.3, 8.7, 10.1 and 10.7 m/s. CV of SI was significantly faster than the others (P<0.05). Therefore, our results suggested that noxious signals were conveyed through at least two distinct pathways of the spinal cord probably reaching distinct groups of thalamic nuclei. Further studies are required to clarify the functional significance of these two pathways.
Laser-evoked potentials have been shown to be clinically useful for the electrophysiological assessment of nociceptive pathways. Contact heat evoked potentials (CHEP) are less established but might be advantageous for clinical purposes. This study aimed at determining the conduction velocity (CV) of central pain (spinothalamic tract, STT) pathways using contact heat stimulation in order to replicate previous findings using laser stimulation.
Contact heat stimulation 3 degrees C higher than the pain threshold was applied at different body locations in 20 subjects.
The CHEP latencies correlated significantly with the respective pain thresholds. Without normalization for this effect no significant linear regression between distance to the brain and the latencies was found. Conversely, if thresholds were considered, the regression was significant and the CV of the STT (ranging between 11.2 and 13.4m/s) was comparable to CVs estimated after laser stimulation.
Pain thresholds seem crucial in interpreting CHEP latencies. It is suggested that the rather low heating rate is responsible for the dependence of latencies on the pain thresholds.
This study shows the importance of pain thresholds and their control to attain valid CV of the STT after contact heat stimulation in healthy subjects.
The shape (amplitude and latency) of single cortical responses to argon laser stimulation was found to match six perceptual classes: three pre-pain and three pain. The amplitude of the pain related single cortical responses correlated with the perceived feeling of pain. Easy detectable responses were obtained because habituation to the stimuli was reduced and a high degree of attention was given to each stimulus. Single cortical responses to argon laser stimuli are suggested as a new quantitative technique with application in the assessment of function in the thermal and nociceptive pathways.
Feedback-controlled laser heat was used to stimulate the hairy skin of the hand dorsum and forearm, and heat-evoked cerebral potentials were recorded at midline (Fz, Cz, Pz) and temporal (T3, T4) scalp positions. Based on data from primary afferent electrophysiology a stimulus level (40 degrees C) was chosen, which is above C-fiber heat threshold, but clearly below A delta-nociceptor heat threshold in order to excite selectively C-fibers without concomitant excitation of A delta-fibers. Feedback-controlled stepped heat stimuli to 40 degrees C elicited ultralate laser evoked potentials (LEPs) at the vertex in a high proportion of experiments (90%). Estimates of conduction velocity calculated from latency shifts between the hand and forearm sites of ultralate LEPs (2.4 m/s) and of reaction times (2.8 m/s) confirmed mediation of ultralate potentials by unmyelinated nerve fibers (nociceptors and/or warm fibers). The ultralate LEP could be differentiated from resolution of contingent negative variation (CNV), an endogenous potential related to expectation and response preparation, by its scalp topography. Strong heat stimuli of 48 degrees C, which is suprathreshold for most A delta- and C-fiber nociceptors, elicited the well-known late LEPs mediated by nociceptive Adelta-fibers confirming previous studies. The LEP waveform to strong heat stimuli also contained an ultralate component reminiscent of an ultralate LEP following the late LEP. Ultralate and late LEP had identical scalp topography. In conclusion, the method of temperature-controlled laser heat stimuli allows the selective and reliable examination of A delta- and C-fiber-mediated afferent pathways and the related cortical processing without the complication of dissociating A-fiber nerve blocks.
The aim of this study was to evaluate the conduction of the thermal-pain pathway along the human spinal cord. Laser radiant heat pulses, exciting mechanothermal nociceptors in the superficial skin layers, selectively activate A-δ or C fibers and evoke brain potentials (LEPs, laser evoked potentials). CO 2 laser pulses (wavelength 10.6 μm, intensity 1.5-15 W, diameter 2.5-5 mm, duration 15-50 ms) were delivered to the dorsal skin at different spinal levels from C5 to T10; brain LEPs were recorded in 15 healthy subjects. A-δ fiber stimulation easily evoked reproducible brain potentials, consisting of a negative wave with a latency of about 200 ms (N200) followed by a positive wave with a latency of about 320 ms (P320). C fiber stimulation evoked brain potentials in 10 subjects only; these potentials consist of a single positive wave with a mean latency of 450 ms (P450). Brain potentials induced by both A-δ and C fiber inputs reached their highest amplitude at the vertex. The mean conduction velocity of the A-δ pathway along the spinal cord was approximately 20 m/s, while that of the C fiber pathway was about 3 m/s. For both pathways the mean conduction velocity along the spinal cord was higher than the reported velocity of the corresponding primary sensory neurons.
Conduction velocity of A delta fibers of the human peripheral nerves was measured by using pain-related somatosensory evoked potentials following CO2 laser stimulation. It was found to be approximately 9 m/s in the forearm as well as in the lower leg. Because conventional conduction study using electric stimulation reflects only functions of large myelinated fibers related to deep proprioceptive and tactile sensations, the present noninvasive and simple, novel method is the only laboratory examination currently available to investigate physiological functions of the small diameter fibers mediating pain-temperature sensations.
In a combined light and electron microscope study of sural nerves of seven normal individuals, aged between 15 and 59 years, the increase with age in the number of degenerating myelinated fibres is confirmed.
Destruction of unmyelinated fibres starting early in life is reported for the first time. The sequence of events in the involution of unmyelinated fibres was found to be the budding of their Schwann cells followed by increasing evidence of their denervation and axonal sprouting.
Comments are made on the value of several direct and indirect indices of destruction of nerve fibres. The relevance of denervation and regeneration of fibres in assessing pathological change in slowly progressive disorders of peripheral nerves is emphasised.
This is the first report of estimating conduction velocity (CV) of the slowly conducting somatosensory spinal tracts or the spino-thalamic tract (STT) in man. The CV of the STT was measured by recording somatosensory evoked potentials (SEPs) following CO2 laser stimulation of the hand and foot, which was previously shown to cause pain or heat sensation by activating cutaneous nociceptors and by its ascending signals through Aδ fibers and probably STT. When the CV of Aδ fibers was assumed to be 10–15 m/sec, the CV of STT was found to be approximately 8–10 m/sec in normal young subjects. It was slightly slower in subjects over 60 years of age. In contrast, the CV of the posterior column, which was calculated based on SEPs following electrical stimulation of the median and posterior tibial nerves, was approximately 50–60 m/sec.
Psychophysical experiments were carried out on 6 huma subjects to determine how first and second pain are influenced by peripheral receptor mechanisms and by central nervous system inhibitory and facilitatory mechanisms. For these experiments, brief natural painful stimuli delivered to the hand were a train of 4-8 constant waveform heat pulses generated by a contact thermode (peak temp. = 51-5% C). The magnitude of first and second pain sensations was estimated using cross-modality matching procedures and reaction times were determined. The latter confirmed the relationship between first and second pain and impulse conduction in Adelta and C noxious heat afferents, respectively. The intensity of first pain decreased with each successive heat pulse when the interpulse interval was 80 sec or less. This decrease was most likely the result of heat induced suppression of Adelta heat nociceptors since it did not occur if the probe location changed between successive heat pulses. In contrast, second pain increased in intensity with each successive heat pulse if the interval was 3 sec or less. This summation was most likely due to central nervous system summation mechanisms since it also occurred after blockage of first pain by ulnar nerve compression and when the location of the thermode changed between heat pulses. These observations and their interpretations are supported by our recording of responses of singlt Adelta heat nociceptive afferents, C polymodal nociceptive afferents, and "warm" afferents of rhsus monkeys to similar trains of noxious heat pulses. Their responses to these heat pulses show a progressive suppression. Furthermore, previous studies have shown that wide dynamic range dorsal horn neurons show summated responses to repeated volleys in C fibers (greater than 1/3 sec). These spinal cord summation mechanisms could account for the summation of second pain.
The present work determines the numbers of myelinated and unmyelinated axons in the dorsal, lateral, and ventral funiculi of the S2 segment of the cat spinal cord. The major finding is that unmyelinated axons are almost as numerous as myelinated axons in these pathways. The myelinated axons tend to be distributed uniformly, although there is a slight concentration of these fibers in the dorsal part of the lateral funiculus. By contrast, the unmyelinated fibers, although found in significant numbers in all parts of these funiculi, concentrate in the dorsal part of the lateral funiculus and in the dorsal funiculus. Of particular note are the unmyelinated fibers in the dorsal funiculus, because it is highly likely that some of these are sensory. The findings in this study will serve as a basis for experimental studies to determine the numbers, locations, and types of unmyelinated fibers in the white matter of the mammalian cord.
A combined light and electron microscope study of the normal sural nerve in 7 people aged 15-59 years is reported. Qualitative and quantitative studies of the Schwann cells and fibroblasts, myelinated and unmyelinated fibres are made in isolated fascicles. Schwann cells predominate over fibroblasts in the ratio of about 9-1. Most Schwann cells, almost 80%, are attached to unmyelinated fibres. Factors influencing the densities of these cells per cross sectional area are discussed. Some ultrastructural features of the myelinated fibres are described and their numbers per sq.mm and frequency distribution of their sizes are produced. An indirect method is proposed for assessing the mean internodal length for earch of the myelinated fibre size populations in cross sections of fascicles of normal nerves by estimating the proportion of myelinated segments cut through their nucleus. The ultrastructure of unmyelinated fibres is described and the identification of axons of extreme diameter is discussed. Their densities and size frequency histograms are the first to be reported in man by systematic electron microscope studies. The average ratio of unmyelinated to myelinated fibre density is about 3.7:1 though it varies in the fascicles of the different individuals. The implications of axonal diameter in the presence of myelin are commented on.
Short radiant heat pulses, emitted by a high power CO2 laser, were used to investigate single nociceptor activity, cerebral potentials and concomitant sensations. Stimuli of 20 and 50 ms duration with different intensities were randomly applied to the hairy skin of the hand. Microelectroneurography was performed from the radial nerve at the wrist; 26 stable recordings were evaluated. Pre- and post-stimulus EEG segments were recorded from vertex versus linked ear lobes. Sensation was assessed on an eight-step category scale, an adjective scale, and by reaction times. In some experiments an A-fibre block was applied in order to isolate C-fibre responses. The main results were: Short heat stimuli activate C-units. In addition one of two identified A delta-units responded. None of the 15 A beta-units investigated was activated by the heat pulses. Short heat stimuli evoked cerebral potentials having a main vertex positive component at about 400 ms. These potentials were ascribed to A delta-fibre input. Laser induced pain consisted of an immediate stinging component, followed by a burning pain which often lasted several seconds. Reaction time to first pain ranged from 400-500 ms. Weak laser stimuli induced non-painful sensations mostly of tactile character. High correlations were found between the number of spikes elicited by a given stimulus and the intensity of the evoked sensation. Intensity discrimination, as evaluated by measures of Signal Detection Theory, was better in the peripheral C-units than in the subjective ratings. If conduction of A-fibres was blocked by pressure, A delta-related cerebral potential components vanished.(ABSTRACT TRUNCATED AT 250 WORDS)
In this study, it is reported that CO2 laser heat stimulation of tiny skin surface area (0.15 mm2) provides a unique method to directly and selectively activate C-fibre as assessed by the ultra-late brain potentials (peak latencies: N810, P996) evoked consistently across a set of stimulus energy levels. On a larger surface area (15.5 mm2), low energy stimulation also resulted in minute ultra-late potential, while higher intensities induced only late potentials related to A-delta fibre activity (peak latencies: N247, P394). The selective activation of C afferent sensory terminals in the skin by stimulation of tiny surface area is explained by their relative high density and lower activation threshold.
In 8 healthy subjects we have recorded cerebral evoked potentials and reaction time (RT) to CO2 laser stimulation of the hairy and glabrous skin at low and high stimulus intensities, corresponding to subjective reporting of detection and pain, respectively. At each intensity we were able to identify an evoked potential; the latencies of the major vertex positive (VP) components fell into 2 distinct populations 320 +/- 30 (VP300) and 778 +/- 80 (VP800) which did not differ between stimulation sites. The frequency of the VP300 responses was greatest in the high stimulus conditions and lower in the low stimulus conditions whilst the opposite was true for the VP800 responses. BImodal distributions of RT were seen at both stimulus intensities. In a further group of of 10 subjects we recorded the latency shift of the vertex negativity following proximal and distal stimulation of hairy skin of the left upper limb and derived conduction velocities for the VP300 (13.21 +/- 2.8 m/sec) and VP800 (1.26 +/- 0.29 m/sec) responses. These results suggest that, following CO2 laser stimulation of both hairy and glabrous skin, two different fibre populations are activated. The VP300 responses appear to be related to A delta activation, while the characteristics of the VP800 responses are consistent with activation of thermoreceptors mediated by C fibres.
This study was designed to estimate and compare nerve conduction velocity (NCV) of cutaneous heat-sensitive C-fibres obtained using two methods. The first is a method based on reaction times to different rates of temperature change produced by a large contact thermode (Thermotest). The second is a novel method based on ultra-late-evoked brain potentials to CO2 laser stimuli with tiny beam sections (< 0.25 mm2), allowing selective and direct activation of very slow conducting afferents. Both methods were applied on three sites of the right leg (foot, knee and thigh) of ten healthy subjects. When based on the reaction times to contact heat, NCV estimations were 0.4 +/- 0.22 m/s for the proximal segment (knee-thigh) and 0.6 +/- 0.23 m/s for the distal segment (foot-knee). When based on the difference in latency of the ultra-late positivity of laser-evoked brain potentials, NCV estimations were respectively 1.4 +/- 0.77 m/s and 1.2 +/- 0.55 m/s. For both methods, the difference in NCV between proximal and distal limb segments was not significant. Although both methods give NCV estimations within the range of C-fibres, the systematic difference between NCV obtained from each method may result from the activation of subpopulations of C-fibres with different NCV depending on the method of stimulation (low-threshold thermal receptors by the thermode and thermal nociceptors by the CO2 laser). Considering the difficulty of investigating peripheral fibres with slow conduction velocities (C-fibres) in humans, the methods used in the present study may be useful tools in both experimental and clinical situations.
The authors reviewed basic and clinical reports of pain-related somatosensory evoked potentials (SSEP) after high-intensity electrical stimulation [pain SSEP(E)] and painful laser stimulation [pain SSEP(L)]. The conduction velocity of peripheral nerves for both pain SSEP(E) and pain SSEP(L) is approximately 10 to 15 m/second, in a range of Adelta fibers. The generator sources are considered to be the secondary somatosensory cortex and insula, and the limbic system, including the cingulate cortex, amygdala, or hippocampus of the bilateral hemispheres. The latencies and amplitudes are clearly affected by vigilance, attention-distraction, and various kinds of stimulation applied simultaneously with pain. Abnormalities of pain SSEP(L) reflect an impairment of pain-temperature sensation, probably relating to dysfunction of A5 fibers of the peripheral nerve and spinothalamic tract. In contrast, conventional SSEP after nonpainful electrical stimulation reflects an impairment of tactile, vibratory, and deep sensation, probably relating to dysfunction of Aalpha or Abeta fibers of the peripheral nerve and dorsal column. Therefore, combining the study of pain SSEP(L) and conventional SSEP is useful to detect physiologic abnormalities, and sometimes subclinical abnormalities, of patients with peripheral and central nervous system lesions.
To study the conduction velocity of the spinothalamic tract (STT) we delivered CO2 laser pulses, evoking pinprick sensations, to the skin overlying the vertebral spinous processes at different spinal levels from C5 to T10 and recorded evoked potentials (LEPs) in 15 healthy human subjects. These stimuli yielded large-amplitude vertex potentials consisting of a negative wave at a peak latency of about 200 ms followed by a positive wave at a peak latency of about 300 ms. The mean conduction velocity of the STT was 21 m/s, i.e. higher than the reported velocity of the corresponding primary sensory neurons (type II AMH). Because dorsal stimulation readily yields reproducible brain LEPs, we expect this technique to be useful as a diagnostic tool for assessing the level of spinal cord lesions.
The object of this study was to establish a method for estimating the conduction velocity (CV) of the spinothalamic tract (STT) in relation to clinical application.
The CV of the STT was estimated by an indirect method based on that reported by Kakigi and Shibasaki in 1991 (Kakigi R, Shibasaki H. Electroenceph clin Neurophysiol 80 (1991) 39). Laser-evoked potentials (LEP) were measured in 8 subjects following hand (LEPH) and foot (LEPF) laser stimulation. The conduction times recorded at the scalp (P340, P400 and N150 potentials) were considered as the summation of peripheral and central components. The peripheral conduction times were calculated by measuring the latency of the electrical cutaneous silent period (from the same stimulus site of LEPs), corrected for F- and M-wave latency values.
The CV of the STT ranged between 8.3 and 11.01 m/s and its mean value was found to be approximately 9.87+/-1.24 m/s. The CV of the STT obtained by the N150 latencies overlapped that obtained by the P340/P400 latencies.
Our data suggest that our method appears appropriate and useful for practical clinical purposes, furnishing an additional tool for investigating the physiological function of small-fiber pathways.
Ultralate (C-fibres) laser evoked potentials (LEP) can be obtained by stimulation of a tiny skin surface area (0.23 mm(2)). Since their generators are unknown up to now, we performed brain source analyses of ultralate LEPs using high resolution electroencephalography (64 channels) and a realistic head model that was based on individual magnetic resonance images. Ultralate LEPs were characterized by a negative-positive complex with a large positive component maximal at the vertex. Source analysis revealed that ultralate LEPs could be explained by two dipole sources in the upper bank of the contralateral and ipsilateral Sylvian fissure (SII) and one dipole in the median region corresponding to the anterior cingulate gyrus.
The conduction velocities of Abeta-, Adelta- and C-fibers of a peripheral nerve of the upper limb in normal subjects were measured by a combination of conventional electric stimulation, painful CO(2) laser stimulation and non-painful CO(2) laser stimulation of a tiny skin surface area, respectively. The values obtained were 69.1+/-7.4 m/s, 10.6+/-2.1 and 1.2+/-0.2 m/s, respectively. These findings demonstrated that the combined methods are useful for experimental and clinical exploration of the physiological function and pathophysiological role of Abeta-, Adelta- and C-fibers of a given peripheral nerve.
Pain-related somatosensory-evoked potential following CO(2) laser stimulation (laser-evoked potential (LEP)) is now used not only for research objectives, but also for clinical applications. Estimating the conduction velocity (CV) of the spinothalamic tract (STT) by analyzing LEP following activation of Adelta-fibers (Adelta-CVSTT) by CO(2) laser stimulation has been performed previously, but estimating the CV of STT following activation of C-fibers (C-CVSTT) has not. This is the first report to estimate the C-CVSTT in humans; by using the novel method of CO(2) laser stimulation applied to tiny skin areas. The calculation method was based on that of Kakigi and Shibasaki (Electroenceph clin Neurophysiol 80 (1991) 39) who measured Adelta-CVSTT by conventional CO(2) laser stimulation. The C-CVSTT ranged between 1.4 and 4.0 m/s, and its mean+/-SD was 2.9+/-0.8 m/s. This C-CVSTT was significantly slower than the Adelta-CVSTT, which ranged approximately from 10 to 21 m/s. The nociceptive signal of the C-fibers in STT is probably conveyed by unmyelinated axons of projection neurons to reach the thalamus. Our findings provide the first physiological evidence of the signals ascending through unmyelinated axons in the spinal cord in humans. In addition, estimating C-CVSTT and Adelta-CVSTT combined with conventional methods to measure the CV of the posterior column using electrical stimulation should be useful and have important clinical applications, particularly in patients with spinal cord lesions showing various kinds of sensory disturbances.
Conduction velocity of the thermal-pain path-way in the human spinal cord
- G D Iannetti
- A Truini
- A Romaniello
- R Isabella
- G Cruccu
Iannetti, G.D., Truini, A., Romaniello, A., Isabella, R. and Cruccu, G., Conduction velocity of the thermal-pain path-way in the human spinal cord, Clin. Neurophysiol., 112 (2001) S35.
Similarity of threshold temperatures for first pain sensation, laser-evoked potentials, and nociceptor activation
- R D Treede
- R A Meyer
- R P Lesser
Treede, R.D., Meyer, R.A. and Lesser, R.P., Similarity of threshold temperatures for first pain sensation, laser-evoked potentials, and nociceptor activation, In G.F. Gebhart, D.L. Hammond and T.S. Jensen (Eds.), Proceed-ings of the 7 th Word Congress on Pain, IASP Press, Seattle, WA, 1994, pp. 857–865.
Similarity of threshold temperatures for first pain sensation, laser-evoked potentials, and nociceptor activation
- Treede