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Determination of nerve conduction velocity of C-fibres in humans from thermal thresholds to contact heat (thermode) and from evoked brain potentials to radiant heat (CO2 laser)
Abstract
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.
... In order to calculate conduction velocities of peripheral nociceptive fibers we measured latencies of LEP components. Furthermore, study subjects pressed a button upon the detection of a Aδ-or C-fiber mediated heat stimulus, in order to calculate reaction times and conduction velocities [9,10]. ...
... The participants were instructed to press a button with the index finger of the dominant hand when they perceived a painful sensation [9,10]. Mean reaction times (RT) were measured over each stimulation block (10 stimuli). ...
... Furthermore, it provides an alternative method to calculate conduction time and conduction velocity. It had been shown that pressing a button (a so-called motor task) upon perceiving a stimulus does not affect the latency of the P2 late of late LEP's as compared to the situation without the motor task [9,10]. Thus, in this study we did not succeed to reliably generate C-fiber cortical responses with the use of a grid. ...
... Myelinated Aδ-fibers are known to have faster conduction velocities (± 10 m/s) than unmyelinated C-fibers (± 1 m/s). Aδ-or C-fiber related activity was defined as a response time less than 650 ms or between 650 and 2,500 ms, respectively [2,13,14]. Response times longer than 2,500 ms were classified as stimulus not detected. From the number of responses in relation to the amount of stimuli, the response rate was derived. ...
... A mixture of two Gaussian distributions can be seen, with peak responses at 500 and 1,000 ms. The cut-off point lies at 650 ms, which corresponds to the cut-off between Aδ-and C-fiber response times described in literature [2,13,14]. ...
... Our results indicate that using 650 ms as a cut-off point to discriminate between Aδ-and C-responses is valid (Fig. 3). This matches the cut-off described in literature, which is also 650 ms [2,13,14]. When examining the response times per individual in general, two clusters can be seen that represent Aδand C-fiber responses. ...
Background: Pain is perceived through different pathways involving thinly myelinated Aδ-fibers and unmyelinated C-fibers. Aδ-fibers are responsible for a quick, sharp pain, whereas C-fibers relate to a late-onset, burning sensation. Several studies suggest that it is essential to investigate nociceptive fibers separately and in relation to each other. The aim of this study was to selectively stimulate Aδ-and C-fibers using a 980-nm diode laser by varying the laser settings and the stimulated surface area in healthy subjects.
... Brief noxious stimuli activate A␦-and C-nociceptors. These distinct fiber classes can be differentiated by conduction velocity [4], heat thresholds [5,6], and distribution density [7]. C-fibers exhibit a slow conduction velocity in the range of 0.5-2.5 m/s [4,6] compared to the faster conducting A␦-fibers (4-30 m/s) [8,9]. ...
... These distinct fiber classes can be differentiated by conduction velocity [4], heat thresholds [5,6], and distribution density [7]. C-fibers exhibit a slow conduction velocity in the range of 0.5-2.5 m/s [4,6] compared to the faster conducting A␦-fibers (4-30 m/s) [8,9]. Due to these differences, the A␦-input will reach the central projections earlier than the C-fiber-derived input. ...
... C-fibers or mechano-heat C-fibers (CMHs) respond to heat stimuli in a way similar to that of Type II AMHs [5] and are sensitive to capsaicin [18][19][20]. Distinct from the CMH nociceptors, there is a population of C-warm fibers with a slightly lower heat threshold and a lower distribution density in the skin [4,21,22]. ...
Background and purpose
Conventional neurophysiological techniques do not assess the function of nociceptive pathways and are inadequate to detect abnormalities in patients with small-fiber damage. This overview aims to give an update on the methods and techniques used to assess small fiber (Aδ- and C-fibers) function using evoked potentials in research and clinical settings.
Methods
Noxious radiant or contact heat allows the recording of heat-evoked brain potentials commonly referred to as laser evoked potentials (LEPs) and contact heat-evoked potentials (CHEPs). Both methods reliably assess the loss of Aδ-fiber function by means of reduced amplitude and increased latency of late responses, whereas other methods have been developed to record ultra-late C-fiber-related potentials. Methodological considerations with the use of LEPs and CHEPs include fixed versus variable stimulation site, application pressure, and attentional factors. While the amplitude of LEPs and CHEPs often correlates with the reported intensity of the stimulation, these factors may also be dissociated. It is suggested that the magnitude of the response may be related to the saliency of the noxious stimulus (the ability of the stimulus to stand out from the background) rather than the pain perception.
Results
LEPs and CHEPs are increasingly used as objective laboratory tests to assess the pathways mediating thermal pain, but new methods have recently been developed to evaluate other small-fiber pathways. Pain-related electrically evoked potentials with a low-intensity electrical simulation have been proposed as an alternative method to selectively activate Aδ-nociceptors. A new technique using a flat tip mechanical stimulator has been shown to elicit brain potentials following activation of Type I A mechano-heat (AMH) fibers. These pinprick-evoked potentials (PEP) have a morphology resembling those of heat-evoked potentials following activation of Type II AMH fibers, but with a shorter latency. Cool-evoked potentials can be used for recording the non-nociceptive pathways for cooling. At present, the use of cool-evoked potentials is still in the experimental state. Contact thermodes designed to generate steep heat ramps may be programmed differently to generate cool ramps from a baseline of 35 °C down to 32 °C or 30 °C. Small-fiber evoked potentials are valuable tools for assessment of small-fiber function in sensory neuropathy, central nervous system lesion, and for the diagnosis of neuropathic pain. Recent studies suggest that both CHEPs and pinprick-evoked potentials may also be convenient tools to assess sensitization of the nociceptive system.
Conclusions
In future studies, small-fiber evoked potentials may also be used in studies that aim to understand pain mechanisms including different neuropathic pain phenotypes, such as cold- or touch-evoked allodynia, and to identify predictors of response to pharmacological pain treatment.
Implications
Future studies are needed for some of the newly developed methods.
... Manfron et al. 2020a, b). The nociceptive system mainly consists of thinly myelinated Aδ fibers with a conduction velocity of ~ 10 m/s (Kakigi and Shibasaki 1991) and unmyelinated C fibers with a conduction velocity of ~ 1 m/s (Opsommer et al. 1999). When applying brief heat stimuli on the hand dorsum, the generated nociceptive inputs are expected to elicit their first cortical response at about 150 ms for inputs conveyed by Aδ fibers and at almost 1 s for inputs transmitted by C fibers (Plaghki and Mouraux 2005). ...
... When applying brief heat stimuli on the hand dorsum, the generated nociceptive inputs are expected to elicit their first cortical response at about 150 ms for inputs conveyed by Aδ fibers and at almost 1 s for inputs transmitted by C fibers (Plaghki and Mouraux 2005). The more distant the stimulated body part, the greater the delay between the latencies of Aδ-and C-fiber responses, i.e. smaller when the face is stimulated (Romaniello et al. 2003;Truini et al. 2007) and greater for the foot (Opsommer et al. 1999). In contrast, visual inputs reach their first cortical relay in less than 100 ms (Michel et al. 2004). ...
To protect our body against physical threats, it is important to integrate the somatic and extra-somatic inputs generated by these stimuli. Temporal synchrony is an important parameter determining multisensory interaction, and the time taken by a given sensory input to reach the brain depends on the length and conduction velocity of the specific pathways through which it is transmitted. Nociceptive inputs are transmitted through very slow conducting unmyelinated C and thinly myelinated Aδ nociceptive fibers. It was previously shown that to perceive a visual stimulus and a thermo-nociceptive stimulus applied on the hand as coinciding in time, the nociceptive stimulus must precede the visual one by 76 ms for nociceptive inputs conveyed by Aδ fibers and 577 ms for inputs conveyed by C fibers. Since spatial proximity is also hypothesized to contribute to multisensory interaction, the present study investigated the effect of spatial congruence between visual and nociceptive stimuli. Participants judged the temporal order of visual and nociceptive stimuli, with the visual stimuli flashed either next to the stimulated hand or next to the opposite unstimulated hand, and with nociceptive stimuli evoking responses mediated by either Aδ or C fibers. The amount of time by which the nociceptive stimulus had to precede the visual stimulus for them to be perceived as appearing concomitantly was smaller when the visual stimulus occurred near the hand receiving the nociceptive stimulus as compared to when it occurred near the contralateral hand. This illustrates the challenge for the brain to process the synchrony between nociceptive and non-nociceptive stimuli to enable their efficient interaction to optimize defensive reaction against physical dangers.
... IW can at times feel temperature fluctuations from moving air particles displaced 143 by gesture-movements, but he stresses that these are very minimal cues for the presence of 144 movement. Movement control via air-flow sensing is also unlikely given the relatively slow 145 nerve-conduction velocity of temperature sensitive nerve fibers [21]. 146 What additional possible sources of information are available to IW to coordinate 147 speech and gesture? ...
... Active 154 exploratory movements generated forces that affected both the insensate peripheral tissues 155 of the hands and arms, as well as sensorily intact tissues of the trunk and neck. The 156 patterns of tissue deformation generated in the trunk and neck are structured by the 157 physical act of the limb wielding the object, therefore carrying information about the 158 properties of the object being wielded [19,21]. This suggests that dynamic perturbations of 159 movements can be exploited in haptic perception, and similarly dynamic resources could be 160 available to IW in orchestrating gesture and speech. ...
We investigate the classic gesture-speech coordination experiments performed with a person (IW) with deafferentation (McNeill, 2005). Although IW has lost both his primary source of information about body position (i.e., proprioception) and touch from the neck down, his gesture-speech coordination has been reported to be largely unaffected, even if his vision is blocked. This is surprising as, without vision, his object-directed actions almost completely break down. We examine the hypothesis that IW’s gesture-speech coordination is supported by the biomechanical effects of gesturing on head posture and speech. We find that when vision is blocked there are micro-scale increases in gesture-speech timing variability, consistent with IW’s reported experience that gesturing is difficult without vision. Supporting the hypothesis that IW exploits biomechanical consequences of the act of gesturing, we find that: 1) gestures with larger physical impulses co-occur with greater head movement, 2) gesture-speech synchrony produced larger head movements (i.e. for bimanual gestures), 3) when vision was blocked gestures recruited greater physical impulse, and 4) moments of acoustic prominence became more coupled with peaks of physical impulse when vision was blocked. We conclude that IW recruits different sensorimotor solutions for gesture-speech synchrony depending on whether or not his hands are in view.
... Additional differences in timing may arise from differences in receptor transduction times as well as the time required for that sensory input to reach the cortex. Considering nociception and vision, the slow conduction velocities of thinly-myelinated Aδ fibers (∼10 m/s [7]) and unmyelinated C fibers (∼1 m/s [8]) can be expected to introduce very large timing differences, especially when nociceptive stimuli are delivered to the distal end of a limb, i.e. when peripheral conduction distance is large. Visual information is transmitted to the cortex in less than 100 ms [9]. ...
... The current study explored, using the PSS of a TOJ task, the necessary asynchrony between the onset of a visual stimulus and the onset of a thermo-nociceptive stimulus activating Aδ-and/or C-fiber afferents for the two stimuli to be perceived at the same time by the participant. Indeed, sensory inputs transmitted to the cortex by the nociceptive system have far greater conduction times than sensory inputs transmitted by the visual system, especially for stimuli delivered to the distal end of a limb (i.e. when peripheral conduction distance is large), and for nociceptive inputs conveyed by unmyelinated C fibers (i.e. when peripheral conduction velocity is very slow) [7][8][9]. ...
Multisensory interactions between pain and vision allow us to adapt our behavior to optimize detection and reaction against bodily threats. Interactions between different sensory inputs are enhanced when they are perceived closely in space and time. However, thermo-nociceptive and visual stimuli are conveyed to the cortex through specific pathways with their own conduction velocity. The present experiment aims to measure the necessary asynchrony between a nociceptive stimulus and a visual stimulus for both to be perceived as occurring simultaneously. Healthy volunteers performed a temporal order judgment task during which they discriminated the temporal order between a laser-induced nociceptive stimulus applied on one hand dorsum and a visual stimulus presented next to the stimulated hand. Laser stimulus temperature selectively activated Aδ- and/or C- fiber afferents. In order to be perceived as occurring simultaneously with a visual stimulus, a thermo-nociceptive input selectively conveyed by C-fiber afferents must precede the visual stimulus by 577 ms on average, while the stimulus-evoked input conveyed by Aδ-fiber afferents must precede it by 76 ms on average. This experiment focuses on the necessary asynchrony between thermo-nociceptive and visual inputs for them to be perceived simultaneously, to optimize the conditions under which they interact closely. Since C-fibers are unmyelinated, the asynchrony between a C-fiber stimulus and a visual stimulus is much greater than the asynchrony between a nociceptive stimulus additionally activating Aδ-fibers and that same visual stimulus. It is crucial to consider these discrepancies in further studies interested in multisensory interactions.
... 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.
... Provided that the peripheral conduction distance is sufficiently large, a brief and intense thermal stimulus applied onto the skin elicits sensations referred to as first and second pain [17]. This double sensation is related to the fact that the stimulus coactivates myelinated Ad-fibre and unmyelinated C-fibre afferents [3], each having different conduction velocities [27,37]. Using such stimuli, laser-evoked brain potentials (LEPs) reveal components whose latencies (160 to 390 ms when stimulating the hand dorsum) are only compatible with the faster conduction velocity of Ad-fibres [3]. ...
... 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.
... Taking into account the peripheral conduction distance of afferent input originating from the hand, and taking into account the distribution of reaction times to laser stimuli after blocking the conduction of myelinated fibres [10,11], a criterion of 650 ms was chosen to discriminate between C-fibre responses (reaction time $650 ms) and Ad-fibre responses (reaction time ,650 ms) [11,20]. Additional evidence that reaction-times can be used to distinguish between Ad-and Cfiber responses is provided by Opsommer et al. [21], showing that the time interval between the two peaks of the bimodal distribution of reaction-times increases with peripheral distance. As shown inFigure 2, this criterion effectively discriminated the two response categories. ...
... As shown inFigure 2, and as predicted by previous results (e.g.10111221,22]), the frequency distribution of reaction-times appeared bimodal, and the arbitrarily-defined cut-off to discriminate between Ad-fibre (reaction-time ,650 ms) and C-fibre (reaction-time $650 ms) responses effectively separated the two response categories. The bimodal nature of this distribution was confirmed by comparing directly the fitting of the data to a model describing a unimodal distribution vs. the fitting of the data to a model describing a bimodal distribution. ...
Brief high-power laser pulses applied onto the hairy skin of the distal end of a limb generate a double sensation related to the activation of Aδ- and C-fibres, referred to as first and second pain. However, neurophysiological and behavioural responses related to the activation of C-fibres can be studied reliably only if the concomitant activation of Aδ-fibres is avoided. Here, using a novel CO(2) laser stimulator able to deliver constant-temperature heat pulses through a feedback regulation of laser power by an online measurement of skin temperature at target site, combined with an adaptive staircase algorithm using reaction-time to distinguish between responses triggered by Aδ- and C-fibre input, we show that it is possible to estimate robustly and independently the thermal detection thresholds of Aδ-fibres (46.9±1.7°C) and C-fibres (39.8±1.7°C). Furthermore, we show that both thresholds are dependent on the skin temperature preceding and/or surrounding the test stimulus, indicating that the Aδ- and C-fibre afferents triggering the behavioural responses to brief laser pulses behave, at least partially, as detectors of a change in skin temperature rather than as pure level detectors. Most importantly, our results show that the difference in threshold between Aδ- and C-fibre afferents activated by brief laser pulses can be exploited to activate C-fibres selectively and reliably, provided that the rise in skin temperature generated by the laser stimulator is well-controlled. Our approach could constitute a tool to explore, in humans, the physiological and pathophysiological mechanisms involved in processing C- and Aδ-fibre input, respectively.
... A CO 2 laser beam is frequently used to record pain-related brain potentials (laser evoked potentials, LEP) and magnetic fields (LEF) in humans. Recently, Bragard et al., [1] and Opsommer et al., [2] reported a simple method for recording ultra-late LEP by selective activation of C afferent sensory terminals in the skin using a CO 2 laser to stimulate a tiny surface area. 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. ...
... Our new technique, based on reports from a Belgian group [1,2], enabled us to record clear ultra-late LEP and LEF. Since the subjects felt touch, pressure or a slight burning pain, we have to consider one fundamental and important question; Does this stimulus really relate to second pain? ...
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.
... Studies using laser-heat as a model to investigate the nociceptive system at the dorsal horn of the spinal cord [133][134][135] , and at the brain 91,99,110,114,115,127,[136][137][138][139][140][141][142][143] , used laser with beam diameters down to 1 mm. While Devor and coworkers observed mainly that dorsal horn neurons responding to laser-heat stimuli were located in superficial and deep zones from the dorsal horn, and were able to evoke potentials through signals mediated by C-polymodal nociceptors 133 ; Sikandar and collaborators extended those observations by recordings in dorsal horn neurons in the spinal segment L4-L5 in rodents and detected response latencies to different laser intensities mediated by both C-(in all power intensities) and Aδ-fiber afferents (only at higher power intensities) 134 . ...
Noxious heat is a natural stimulus that activates peripheral sensory neurons expressing heat-gated ion channels. Recently, the TRPM3 channel emerged as a noxious heat sensor independent of TRPV1, which is also sensitive to the neurosteroid Pregnenolone sulphate (PS). Recently, evidence of a direct mechanism that controls the agonist-induced TRPM3 channel activity by activation of the µ-opioid receptor (MOR) has been described, through direct binding of the G-beta-gamma subunit to TRPM3. The submitted thesis investigated mechanisms of heat-induced nociception using near-infrared laser stimulation as a rapid and accurate way to apply noxious heat. Responses to laser-heat were analyzed: in vitro by functional assays on heterologous expression systems and primary culture of sensory neurons, and in vivo by behavioral experiments and electrophysiological recordings at the dorsal horn of the spinal cord. Laser-heat activates TRPV1 and TRPM3 channels in heterologous expression systems with activation thresholds of about 574 µJ and 615 µJ. The response amplitudes of TRPM3 upon activation with PS exceeded those of maximum laser stimulation (1.5 ± 0.003 of the ratio 340/380 versus 0.66 ± 0.011). Chemical- and thermal- induced activity of the TRPM3 channel co-expressing the MOR was reduced with DAMGO by 63.4% and 44.5%. In DRGs, 15-25% of all neurons analyzed (n= 550) functionally co-expressed TRPV1 and TRPM3, 38% expressed TRPV1 independent of TRPM3, 7-8% expressed TRPM3 but not TRPV1. DRG neurons displayed a direct inhibition by 18 ± 4.1% and 23 ± 3% when co-applying the MOR agonist DAMGO with PS. In the dorsal horn of the spinal cord, the processing of peripheral laser stimulation was carried out by a subset of WDR and HTM neurons, which were found at all depths of the dorsal horn (range: 120-820 µm). Laser-heat stimuli induced pain-behavior in vivo. All neurons that responded to suprathreshold laser-heat were nociceptive, including one third of WDR neurons and half of HTM neurons investigated. No laser-heat responses of LTM neurons were found. The peripheral input of the laser sensitive neurons was composed of C- and A- fibers; however, responses to laser-heat were transmitted by C-fibers. The sizes of the heat receptive fields ranged 10% - 60% of the mechanical receptive field and they located always inside them. The number of AP following laser stimulation was higher in HTM neurons compared to WDR neurons (14 ± 0.7 vs 9 ± 4.3), however not significant, and the latencies after onset of the laser stimulation were 266 ± 16 ms and 308.3 ± 55. The estimated temperature threshold for laser sensitive WDR neurons and HTM neurons (40.1 °C and 43.3 °C) was comparable to the mean heat withdrawal threshold in awake rats (41 °C). Differences in the proportions of neurons expressing TRPM3 and/or TRPV1 could be responsible for those differences in receptive field sizes. Since the threshold for laser-heat activation of the TRPM3 channel was higher than the threshold for TRPV1, a greater proportion of peripheral neurons containing TRPM3 might converge in dorsal horn laser sensitive HTM neurons than for laser sensitive WDR neurons.
... Their early latency (150-300 ms) indicates that these activities are triggered by input conveyed by thinlymyelinated Aδ fibers (Gross et al. 2007). Indeed, when stimulating the hand dorsum, input conveyed by C fibers would be expected to elicit responses having a much greater latency (Opsommer et al. 1999). On average, nociception-evoked GBOs recorded from the anterior insula were greater in magnitude than nociceptionevoked GBOs recorded from the posterior insula. ...
Transient nociceptive stimuli elicit robust phase-locked local field potentials (LFPs) in the human insula. However, these responses are not preferential for nociception, as they are also elicited by transient non-nociceptive vibrotactile, auditory, and visual stimuli. Here, we investigated whether another feature of insular activity, namely gamma-band oscillations (GBOs), is preferentially observed in response to nociceptive stimuli. Although nociception-evoked GBOs have never been explored in the insula, previous scalp electroencephalography and magnetoencephalography studies suggest that nociceptive stimuli elicit GBOs in other areas such as the primary somatosensory and prefrontal cortices, and that this activity could be closely related to pain perception. Furthermore, tracing studies showed that the insula is a primary target of spinothalamic input. Using depth electrodes implanted in 9 patients investigated for epilepsy, we acquired insular responses to brief thermonociceptive stimuli and similarly arousing non-nociceptive vibrotactile, auditory, and visual stimuli (59 insular sites). As compared with non-nociceptive stimuli, nociceptive stimuli elicited a markedly stronger enhancement of GBOs (150-300 ms poststimulus) at all insular sites, suggesting that this feature of insular activity is preferential for thermonociception. Although this activity was also present in temporal and frontal regions, its magnitude was significantly greater in the insula as compared with these other regions.
... This is justified by the fact that the nerve conduction velocity of unmyelinated C-fibres is much slower than that of myelinated Ad-fibres (AE1 m/s vs. AE10 m/s) Bjerring and Arendt-Nielsen, 1988;Mouraux et al., 2003;Mouraux and Plaghki, 2007). Opsommer and colleagues (Opsommer et al., 1999) showed that the time interval between the two peaks of the bimodal distribution of reaction times increases with peripheral distance. We chose a criterion of 650 ms to discriminate between C-and Ad-fibre responses which was based on (1) the peripheral conduction distance of afferent input originating from the hand and (2) the distribution of reaction times to laser stimuli after blockade of the myelinated fibres Nahra and Plaghki, 2003). ...
Background:
We have recently shown that visual deprivation from birth exacerbates responses to painful thermal stimuli. However, the mechanisms underlying pain hypersensitivity in congenital blindness are unclear.
Methods:
To study the contribution of Aδ- and C-fibres in pain perception, we measured thresholds and response times to selective C- and Aδ-fibre activation in congenitally blind, late blind and normally sighted participants. Ultrafast constant-temperature heat pulses were delivered to the hand with a CO2 laser using an interleaved adaptive double staircase procedure. Participants were instructed to respond as quickly as possible when detecting a laser-induced sensation. We used a 650 ms cut-off criterion to distinguish fast Aδ- from slow C-fibre-mediated sensations.
Results:
Congenitally blind participants showed significantly faster reaction times to C- but not to Aδ-fibre-mediated sensations. In contrast, thresholds for Aδ- and C-fibre stimulation did not differ between groups. Late blind individuals did not differ from sighted controls in any aspect. A follow-up experiment using only suprathreshold stimuli for Aδ- and C-fibre activation confirmed these findings and further showed that congenitally blind individuals detected significantly more C-fibre-mediated stimuli than sighted controls. A decomposition analysis of the reaction times indicated that the faster response times in the congenitally blind are due to more efficient central processing of C-fibre-mediated sensations.
Conclusion:
The increased sensitivity to painful thermal stimulation in congenital blindness may be due to more efficient central processing of C-fibre-mediated input, which may help to avoid impending dangerous encounters with stimuli that threaten the bodily integrity. WHAT DOES THIS STUDY ADD?: Hypersensitivity to heat pain in congenital blindness is associated with faster responses to C-fibre activation, likely caused by more efficient central processing of C-fibre-mediated input.
... It appears that CHEPS is capable of detecting small-fiber neuropathy in the absence of other indices and that CHEPS correlates with quantitative sensory perception and objective tests of small-fiber function such as the cooling detection threshold and cold pain (Parson, Nguyen, Boyd, & Vinik, 2009). CHEPS is therefore a useful diagnostic tool for the evaluation of small nerve fiber function in neuropathic patients (Chen, Niddam, & rendt-Nielsen, 2001;Itskovich, Fei, & Harkins, 2000;Opsommer, Masquelier, & Plaghki, 1999). In the past, laser-evoked potentials were used but left undesirable thermal damage to intact nerve fibers and surrounding healthy tissue. ...
Here we review some seldom-discussed presentations of diabetic neuropathy, including large fiber dysfunction and peripheral autonomic dysfunction, emphasizing the impact of sympathetic/parasympathetic imbalance. Diabetic neuropathy is the most common complication of diabetes and contributes additional risks in the aging adult. Loss of sensory perception, loss of muscle strength, and ataxia or incoordination lead to a risk of falling that is 17-fold greater in the older diabetic compared to their young nondiabetic counterparts. A fall is accompanied by lacerations, tears, fractures, and worst of all, traumatic brain injury, from which more than 60% do not recover. Autonomic neuropathy has been hailed as the “Prophet of Doom” for good reason. It is conducive to increased risk of myocardial infarction and sudden death. An imbalance in the autonomic nervous system occurs early in the evolution of diabetes, at a stage when active intervention can abrogate the otherwise relentless progression. In addition to hypotension, many newly recognized syndromes can be attributed to cardiac autonomic neuropathy such as orthostatic tachycardia and bradycardia. Ultimately, this constellation of features of neuropathy conspire to impede activities of daily living, especially in the patient with pain, anxiety, depression, and sleep disorders. The resulting reduction in quality of life may worsen prognosis and should be routinely evaluated and addressed. Early neuropathy detection can only be achieved by assessment of both large and small- nerve fibers. New noninvasive sudomotor function technologies may play an increasing role in identifying early peripheral and autonomic neuropathy, allowing rapid intervention and potentially reversal of small-fiber loss.
... Indeed, there are two main problems in C-LEP recording: i) the preceding Aδ-LEP may hinder the following C-LEP; and ii) the extremely low range of conduction speed of the unmyelinated fibers limits the necessary synchronization of the input to produce a clear signal from the scalp (in fact, C-LEP have been mainly investigated in facial territories). There are two main methods to record C-LEP: i) Bragard et al. [24] and Opsommer et al. [30] employed a laser beam passing through a grid with micro-spots, without any substantial Aδ-LEP interference; and ii) Iannetti et al. [13] and Cruccu et al. [31] used very large and low-energy laser beams, directly focused on skin, thus stimulating warmth receptors of the skin overlying the spine. ...
It has been shown that the presence of Aδ-fiber laser evoked potentials (Aδ-LEP) in patients suffering from chronic disorders of consciousness (DOC), such as vegetative state (VS) and minimally conscious state (MCS), may be the expression of a residual cortical pain arousal. Interestingly, the study of C-fiber LEP (C-LEP) could be useful in the assessment of cortical pain arousal in the DOC individuals who lack of Aδ-LEP. To this end, we enrolled 38 DOC patients following post-anoxic or post-traumatic brain injury, who met the international criteria for VS and MCS diagnosis. Each subject was clinically evaluated, through the coma recovery scale-revised (CRS-R) and the nociceptive coma scale-revised (NCS-R), and electrophysiologically tested by means of a solid-state laser for Aδ-LEP and C-LEP. VS individuals showed increased latencies and reduced amplitudes of both the Aδ-LEP and C-LEP components in comparison to MCS patients. Although nearly all of the patients had both the LEP components, some VS individuals showed only the C-LEP ones. Notably, such patients had a similar NCS-R score to those having both the LEP components. Hence, we could hypothesize that C-LEP generators may be rearranged or partially spared in order to still guarantee cortical pain arousal when Aδ-LEP generators are damaged. Therefore, the residual presence of C-LEP should be assessed when Aδ-LEP are missing, since a potential pain experience should be still present in some patients, so to properly initiate, or adapt, the most appropriate pain treatment.
... We did not elicit a clearly painful sensation with contact heat stimuli that evoked a cerebral potential mediated by C fibers without evidence for Aδ fiber excitation. The inability to evoke pain reliably, if at all, with single, brief C fiber selective stimuli is in accord with previous studies [9,14,17,27,29,31,[33][34][35][36][37]. Indeed, when psychophysical measures have been obtained, these brief C fiber stimuli have been rated below pain threshold. ...
... QST can be applied to investigate the integrity of the sensory function in order to define and classify pathologies, to analyze pathogenesis or to evaluate changes in diseases [2]. Over the past decades, there has been an increasing interest in QST in clinical and research settings, for example to determine the conduction velocity of peripheral nerve fibres [3] or to assess a treatment's effectiveness [4]. QST is a psychophysical measurement, relying on the subjective perception of a physical stimulus [5]. ...
Introduction:
Quantitative sensory testing (QST) is widely used in human research to investigate the integrity of the sensory function in patients with pain of neuropathic origin, or other causes such as low back pain. Reliability of QST has been evaluated on both sides of the face, hands and feet as well as on the trunk (Th3-L3). In order to apply these tests on other body-parts such as the lower lumbar spine, it is important first to establish reliability on healthy individuals. The aim of this study was to investigate intra-rater reliability of thermal QST in healthy adults, on two sites within the L5 dermatome of the lumbar spine and lower extremity.
Methods:
Test-retest reliability of thermal QST was determined at the L5-level of the lumbar spine and in the same dermatome on the lower extremity in 30 healthy persons under 40 years of age. Results were analyzed using descriptive statistics and intraclass correlation coefficient (ICC). Values were compared to normative data, using Z-transformation.
Results:
Mean intraindividual differences were small for cold and warm detection thresholds but larger for pain thresholds. ICC values showed excellent reliability for warm detection and heat pain threshold, good-to-excellent reliability for cold pain threshold and fair-to-excellent reliability for cold detection threshold. ICC had large ranges of confidence interval (95%).
Conclusion:
In healthy adults, thermal QST on the lumbar spine and lower extremity demonstrated fair-to-excellent test-retest reliability.
... In the present study, S1 activation was observed following stimulation of nine of the 14 feet, and the evoked sensation was usually sharp pricking and well-localized, which supports the notion that S1 is involved in the processing of the sensory aspect of C-fiber signals, as it is in processing the sensory aspect of A-␦ signals [37]. CV calculated by both the cortical responses and the reaction time was approximately 1.0 m/s, which is within the range of CV of C-fibers measured in a microneurographic study [38] and is consistent with previous EEG studies reporting CVs of 0.5-2.5 m/s [6,39]. The reaction time of longer than 1 s also indicates that C-fibers were responsible for the evoked sensations. ...
Intra-epidermal electric stimulation (IES) is an alternative to laser stimulation for selective activation of cutaneous Aδ-fibers. IES is based on the fact that nociceptive fiber terminals are located in the epidermis, whereas receptors of other fibers end deep in the dermis. IES can selectively stimulate C-fibers if the electrode structure and stimulation parameters are carefully selected. However, stable selective stimulation of C-fibers using IES has proven difficult and cannot currently be used in clinical settings. The purpose of the present study was to determine if IES performed using a modified electrode reliably stimulates C-fibers. Magnetoencephalographic responses to IES to the foot were measured in seven healthy subjects. IES elicited somatosensory evoked fields in all subjects. The mean peak latency was 1327±116ms in the opercular region contralateral to the stimulated side, 1318±90ms in the opercular region ipsilateral to the stimulated side, and 1350±139ms in the primary somatosensory cortex. These results indicate that IES performed using the modified electrode can selectively stimulate C-fibers and may be a useful tool for pain research as well as clinical evaluation of peripheral small fiber function.
... Brain responses to pain Accordingly, spatial summation has been shown to modify the cognitive, affective, but also the sensorydiscriminative dimension of pain appraisal [72,113,150]. From a pragmatic point of view, increasing the total stimulated surface (and possibly also the total stimulation time) may be the simplest way of increasing the likelihood of SI activation in further imaging studies. ...
... However, previous studies frequently activated nociceptors simultaneously rather than selectively. Selective activation of Ad-or C-nociceptors can be achieved by making use of differences in resistance to ischemic pressure be-tween fibers91011, differences in heat thresholds between fibers [37], differences in distribution density of the fibers [8,41,42], and differential responses of fibers to the heating rate of the skin and to pharmacological treatment [40,626364656668]. The present study was designed to separate C-and Ad-fiber activation by exploiting differences in thermal thresholds, rate of thermal activation sensitivity, and spatial properties of the nociceptor types. ...
... Secondly, a smaller part of this delay is due to the time needed for heat transmission from the skin surface to the epidermal nerve fiber endings of the nociceptors. Thirdly, some authors speculated that contact heat and radiant heat might stimulate different C-fiber subpopulations with different conduction velocities [92]. However, it is unclear whether this assumption may be extrapolated to A␦-responses. ...
Laser-evoked potentials are the most extensively validated method to objectively assess nociceptive pathway function in humans. Here, we review merits and shortcomings of alternative techniques using different principles of stimulus generation to stimulate Aδ- or C-fibers. Fast ramp contact heat stimuli yield reproducible responses; however, stimulus location needs to be changed to reduce peripheral habituation, and the limited steepness of temperature ramps may result in response jitter and absence of averaged responses even in some healthy subjects. Inverse temperature ramps can serve to evoke cool evoked potentials to specifically test the cold pathway; the clinical impact of such findings is promising but uncertain to date, and availability of devices optimized for this purpose is currently limited. Mechanical stimuli excite low- or high-threshold mechanoreceptors depending on both the probe surface and the applied force. Electrical stimuli can be used to excite nerve fibers directly in the epidermis, the mucosa of the gut, or the tooth pulp. Principle limitation of the applicability of mechanical and electrical stimuli is the inevitable co-excitation of tactile (Aβ-) fibers. The nasal mucosa can be stimulated using pulsed-CO(2) air streams, which excite chemo-nociceptors; although these stimuli are specific to excite thin trigeminal afferents, their use is limited as it is restricted to a relatively small region. Current data do not allow a comparative analysis on their respective diagnostic values. Quantification of analgesic efficacy in healthy subjects has been established and may be useful in phase I and IIa clinical trials.
... Reaction times show a bimodal distribution in response to stimulation of tiny skin areas [11,44,63]. This is due to the faster conduction velocities of Ad fibres (5-20 m/s) in comparison to that of C fibres (0.5-2 m/s) [38,43,44,51]. Hence, for each participant, the individual distribution was examined and the critical distinction was set between the two latency peaks of the bimodal distribution according to the visual inspection ( Fig. 1). ...
Clinical studies have revealed that up to 92% of major depressed patients report pain complaints such as back or abdominal pain. Furthermore, patients suffering from depression exhibit increased superficial pain thresholds and decreased ischemic (deep) pain thresholds during experimental pain testing in comparison to healthy controls. Here, we aimed to investigate a putative role of Aδ- and C-fibre activation in altered pain perception in the disease. Laser-evoked potentials (LEPs) of 27 unmedicated depressed patients and 27 matched controls were recorded. Aδ and C fibres were activated separately. Amplitudes and latencies of N2 and P2 peaks of Aδ- (Aδ-LEP) and C-fibre- (C-LEP) related LEPs were evaluated. Depressed patients showed significantly decreased Aδ-LEP amplitudes (N2 peak: P=0.019; P2 peak: P=0.024) and delayed C-LEP latencies (P2 peak: P=0.0495; N2 peak: P=0.0556). In contrast, C-LEP amplitudes and Aδ-LEP latencies were unaffected. Our results might be suggestive of the differential impact of physiological changes on pain processing in depression. Thus, Aδ-LEP might reflect the physiological correlate of the augmented superficial pain thresholds during depression. On the contrary, the C-fibre component mediates the facets of pain processing, outlasting the stimulation period, and has been shown to be exaggerated in chronic pain states. Therefore, the functional over-representation of the C-fibre component found in our study might be a possible link between depression and associated pain complaints.
... The main drawbacks of the technique are the fact that it is invasive, time-consuming and painful. In contrast, the use of the surface recording technique is less painful, non-invasive, and less time consuming (Opsommer et al. 1999). However, high skin impedance may hinder the recording of sensory potential, and absence of an action potential that may occasionally happen in severely diseased nerves (Dahan and Boitte 1986). ...
xiii, 148 leaves : col. ill. ; 30 cm. PolyU Library Call No.: [THS] LG51 .H577P RS 2010 Cheng Diabetic peripheral neuropathy (DPN) is a major risk factor in developing diabetic foot ulcers. Sensory deficits and hardening of plantar soft tissues are commonly found in people with DPN, which should be monitored carefully since these are risk factors in developing foot ulcers. Semmes-Weinstein monofilament (SWM) is a reliable, widely used measurement tool that examines sensory deficits in the foot in clinical settings. However, there is no consensus on either the size choice of monofilament or the assessment site for DPN screening. The Tissue Ultrasound Palpation System (TUPS) is an instrument that measures the biomechanical properties of plantar soft tissues, which may be a potential tool for detecting DPN. Currently, there is a lack of non-pharmacological intervention for DPN. Pulsed electromagnetic field (PEMF) therapy is known to increase blood circulation that may promote regeneration of peripheral nerves. However, few studies have examined the effects of PEMF stimulation in people with DPN and this area has not been fully explored. Therefore, this thesis consists of three inter-related studies. The first study examines the thickness and stiffness of plantar soft tissues in subjects who suffer from DPN, compared to healthy control subjects. In addition, the relationship between the stiffness and thickness of plantar soft tissues with subject demographic characteristics, foot sensation, sensory nerve functions, and blood glucose level were explored. Secondly, the sensitivity and specificity of the stiffness measurement of plantar soft tissues and SWM for detecting DPN in a group of people with diabetes was studied. Thirdly, a randomized placebo controlled trial was conducted to compare the effects of 10 daily sessions of active PEMF stimulation (Duration: 30 minutes; frequency: 10 Hz; and intensity: 40 Gauss) to placebo PEMF stimulation. The outcome measures used in this study were the plantar sensation, Sural nerve conduction test and biomechanical properties (i.e. thickness and stiffness) of plantar soft tissues in people with DPN. In the first study, the plantar soft tissues thickness and stiffness were measured by TUPS in 69 subjects with DPN and 41 healthy control subjects. Our results showed that there was no significant difference in thickness of plantar soft tissues between the DPN group and the control group over the four sites. However, the plantar soft tissues of DPN group were stiffer than those of the control group over the big toe (p = 0.002), the first metatarsal head (p = 0.033), and the second metatarsal head (p = 0.003). Multiple linear regression analysis was then used to determine which clinical variables were most strongly associated with thickness and stiffness of plantar soft tissues. A relatively small variance (6%) of thickness of plantar soft tissues under the first metatarsal head was explained by the length of DM history in the DPN subjects (p < 0.01). About 35% of the variability of thickness of plantar soft tissues at the second metatarsal head of the DPN group could be explained by age, body weight, and foot sensation (p < 0.001). The HbA1c level and body weight explained 29% of the heel thickness of the DPN group (p < 0.001). Nineteen per cent of the variability in heel stiffness of the DPN group was explained by the heel thickness and the Sural nerve conduction velocity (p < 0.01), while 15% of the variability in the second metatarsal head was explained by Sural nerve conduction velocity and the fasting blood glucose level (p < 0.01). For the control group, the independent variables were able to predict the variability of the stiffness measurement, but not the thickness measurement. Fasting blood glucose explained 13% of the variability in plantar soft tissue stiffness at the big toe. The amplitude of Sural nerve action potential explained 10% of the variability of stiffness in plantar soft tissue at the second metatarsal. Thickness of plantar soft tissue at the heel region and the amplitude of Sural nerve action potential explained 29% of the variability of stiffness in plantar soft tissue at the heel. Sixty-one subjects with diabetes participated in the second study, of whom 18 have confirmed the diagnosis of DPN by reduced Sural nerve conduction velocity and action potential amplitude. All subjects were assessed with TUPS over four plantar regions and three SWM over 10 foot regions. The sensitivity and specificity for DPN screening with stiffness measurement of plantar soft tissues by TUPS and SWM tests were calculated. The mean values of plantar soft tissues stiffness of healthy control subjects obtained in the first study were used as the cut-off points for having abnormally high plantar soft tissues stiffness for the DPN subjects in this exploratory study. The stiffness of plantar soft tissues at the second metatarsal head obtained the best balance between the sensitivity (56%) and the specificity (70%), which was comparable to that of the monofilaments. When using more than 40% of foot regions (4 out of 10 sites) that were insensate to the monofilament was used as the cut-off point, the SWM 4.31 (sensitivity: 78%, specificity: 63%) had a better balance in sensitivity and specificity than the SWM 4.17 (sensitivity: 94%, specificity: 21%) or SWM 5.01 (sensitivity: 39%, specificity: 91%). In the third study, a randomized controlled trial was performed. Forty-seven subjects with DPN were randomly allocated to receive 10 daily sessions of active PEMF treatment or placebo treatment. The assessor and the subjects were not aware of the type of treatment they received. The number of sites in the foot that was insensate to SWM 4.31 was documented. Sural nerve conduction test and the measurement of thickness and stiffness of plantar soft tissues were also conducted. The subjects were assessed in the initial session, in a final session, and in a one-month follow-up. Repeated measures ANCOVA found no significant difference between groups for all outcomes. Age, body weight, body mass index and HbA1c level were used as co-variates in the repeated measures ANCOVA analysis since significantly between-group differences (p < 0.05) were observed in those data. In conclusion, our findings demonstrated that people with DPN have stiffer plantar soft tissues as compared to non-diabetic control subjects. The use of TUPS for measuring stiffness of plantar soft tissues at the second metatarsal head seems to be a good tool for detecting people with DPN. Moreover, the use of SWM 4.31 is probably a better choice for detecting DPN than SWM 4.17 and SWM 5.07, due to a better balance in sensitivity and specificity. Ten daily sessions of active PEMF stimulation (Duration: 30 minutes; frequency: 10 Hz; and intensity: 40 Gauss) produced no significant effects in improving plantar sensation, Sural nerve conduction test, thickness and stiffness of plantar soft tissues for people with DPN when compared with placebo PEMF stimulation. A future study, with a larger sample size, investigating the long term treatment effects of PEMF on the signs and symptoms of DPN patients, is warranted. Ph.D., Dept. of Rehabilitation Sciences, The Hong Kong Polytechnic University, 2010
... We did not elicit a clearly painful sensation with contact heat stimuli that evoked a cerebral potential mediated by C fibers without evidence for Aδ fiber excitation. The inability to evoke pain reliably, if at all, with single, brief C fiber selective stimuli is in accord with previous studies [9,14,17,27,29,31,3334353637. Indeed, when psychophysical measures have been obtained, these brief C fiber stimuli have been rated below pain threshold. ...
Brief heat stimuli that excite nociceptors innervated by finely myelinated (Aδ) fibers evoke an initial, sharp, well-localized pain ("first pain") that is distinguishable from the delayed, less intense, more prolonged dull pain attributed to nociceptors innervated by unmyelinated (C) fibers ("second pain"). In the present study, we address the question of whether a brief, noxious heat stimulus that excites cutaneous Aδ fibers activates a distinct set of forebrain structures preferentially in addition to those with similar responses to converging input from C fibers. Heat stimuli at two temperatures were applied to the dorsum of the left hand of healthy volunteers in a functional brain imaging (fMRI) paradigm and responses analyzed in a set of volumes of interest (VOI).
Brief 41°C stimuli were painless and evoked only C fiber responses, but 51°C stimuli were at pain threshold and preferentially evoked Aδ fiber responses. Most VOI responded to both intensities of stimulation. However, within volumes of interest, a contrast analysis and comparison of BOLD response latencies showed that the bilateral anterior insulae, the contralateral hippocampus, and the ipsilateral posterior insula were preferentially activated by painful heat stimulation that excited Aδ fibers.
These findings show that two sets of forebrain structures mediate the initial sharp pain evoked by brief cutaneous heat stimulation: those responding preferentially to the brief stimulation of Aδ heat nociceptors and those with similar responses to converging inputs from the painless stimulation of C fibers. Our results suggest a unique and specific physiological basis, at the forebrain level, for the "first pain" sensation that has long been attributed to Aδ fiber stimulation and support the concept that both specific and convergent mechanisms act concurrently to mediate pain.
... However, previous studies frequently activated nociceptors simultaneously rather than selectively. Selective activation of Aδ-or C-nociceptors can be achieved by making use of differences in resistance to ischemic pressure between fibers [9][10][11], differences in heat thresholds between fibers [37], differences in distribution density of the fibers [8,41,42], and differential responses of fibers to the heating rate of the skin and to pharmacological treatment [40,[62][63][64][65][66]68]. The present study was designed to separate C-and Aδ-fiber activation by exploiting differences in thermal thresholds, rate of thermal activation sensitivity, and spatial properties of the nociceptor types. ...
An important question remains as to how the brain differentially processes first (pricking) pain mediated by Adelta-nociceptors versus second (burning) pain mediated by C-nociceptors. In the present cross-over randomized, within-subjects controlled study, brain activity patterns were examined with event-related fMRI while pricking and burning pain were selectively evoked using a diode laser. Stimuli evoking equivalent pain intensities were delivered to the dorsum of the left foot. Different laser parameters were used to elicit pricking (60ms pulse duration) and burning (2.0s pulse duration) pain. Whole brain group analysis showed that several brain areas were commonly activated by pricking and burning pain, including bilateral thalamus, bilateral anterior insula, bilateral posterior parietal lobule, contralateral dorsolateral prefrontal cortex, ipsilateral cerebellum, and mid anterior cingulate cortex. These findings show that pricking and burning pain were associated with activity in many of the same nociceptive processing brain regions. This may be expected given that Adelta-and C-nociceptive signals converge to a great extent at the level of the dorsal horn. Other brain regions showed differential processing. Stronger activation in the pricking pain condition was found in the ipsilateral hippocampus, bilateral parahippocampal gyrus, bilateral fusiform gyrus, contralateral cerebellum and contralateral cuneus/parieto-occipital sulcus. Stronger activation in the burning pain condition was found in the ipsilateral dorsolateral prefrontal cortex. These differential activation patterns suggest preferential importance of Adelta-fiber signals versus C-fiber signals for these specific brain regions.
40 Do communicative actions such as gestures fundamentally differ in their control mechanisms 41 from other actions? Evidence for such fundamental differences comes from a classic gesture-42 speech coordination experiment performed with a person (IW) with deafferentation (McNeill, 43 2005). Although IW has lost both his primary source of information about body position (i.e., 44 proprioception) and discriminative touch from the neck down, his gesture-speech coordination 45 has been reported to be largely unaffected, even if his vision is blocked. This is surprising 46 because, without vision, his object-directed actions almost completely break down. We examine 47 the hypothesis that IW's gesture-speech coordination is supported by the biomechanical effects 48 of gesturing on head posture and speech. We find that when vision is blocked there are micro-49 scale increases in gesture-speech timing variability, consistent with IW's reported experience that 50 gesturing is difficult without vision. Supporting the hypothesis that IW exploits biomechanical 51 consequences of the act of gesturing, we find that: 1) gestures with larger physical impulses co-52 occur with greater head movement, 2) gesture-speech synchrony was related to larger gesture-53 concurrent head movements (i.e. for bimanual gestures), 3) when vision was blocked gestures 54 generated more physical impulse, and 4) moments of acoustic prominence became more coupled 55 with peaks of physical impulse when vision was blocked. We conclude that IW's gesturing 56 ability is not based on a specialized language-based feedforward control as originally concluded 57 from previous research, but is still dependent on a varied means of recurrent feedback from the 58 body. 59 60
Small fiber neuropathy (SFN) is a peripheral nervous system disease due to affection of A‐delta or C‐fibers in a proximal, distal, or diffuse distribution. Selective SFN (without large fiber affection) manifests with pain, sensory disturbances, or autonomic dysfunction. Though uniform diagnostic criteria are unavailable, most of them request typical clinical features and reduced intra‐epidermal nerve fiber density on proximal or distal skin biopsy. Little consensus has been reached about the treatment of SFN, why this narrative review aims at summarizing and discussing treatment options for SFN. Treatment of SFN can be classified as symptomatic, pathophysiologic, or causal. Prerequisites for treating SFN are an established diagnosis, knowledge about the symptoms and signs, and the etiology. Pain usually responds to oral/intravenous pain killers, antidepressants, anti‐seizure drugs, or topical, transdermal specifications. Some of the autonomic disturbances respond favorably to symptomatic treatment. SFN related to Fabry disease or hATTR are accessible to pathogenesis‐related therapy. Immune‐mediated SFN responds to immunosuppression or immune‐modulation. Several of the secondary SFNs respond to causal treatment of the underlying disorder. In conclusion, treatment of SFN relies on a multimodal concept and includes causative, pathophysiologic, and symptomatic measures. It strongly depends on the clinical presentation, diagnosis, and etiology, why it is crucial before initiation of treatment to fix the diagnosis and etiology. Due to the heterogeneous clinical presentation and multi‐causality, treatment of SFN should be individualized with the goal of controlling the underlying cause, alleviating pain, and optimizing functionality.
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.
It remains unclear which nerve fibers are responsible for mediating hyperalgesia following skin injury. Here, we examined the role of A∂- and C-fibers in inflammatory hyperalgesia following a first-degree burn injury. A CO2-laser delivered ultrafast short constant-temperature heat pulses to the upper part of the lower leg, to stimulate selectively the relatively fast conducting thinly myelinated A∂ and the slowly conducting unmyelinated C-fibers. Participants were asked to respond as fast as possible whenever they detected a thermal stimulus. Thresholds and reaction times to selective Aδ- and C-fiber activations were measured in the conditioned and the surrounding intact skin, at pre-injury, and 1- and 24-hours post-injury. First-degree burn injury caused a significant decrease in Aδ-fiber detection thresholds and a significant increase in the proportion of Aδ-fiber mediated responses in the inflamed area 24 hours, but not 1 hour, following burn injury. No changes in heat perception were observed in the intact skin surrounding the injury. No group differences in C-fiber mediated sensations were observed. Our findings indicate that quickly-adapting Aδ-fibers but not quickly-adapting C-fibers are sensitized when activated by short and ultra-fast heat stimuli following skin burn injury. Our results further show that this change occurs between 1- and 24-hours post-injury and that it does not extend to the skin surrounding the injury.
Background:
Cold-evoked potentials (CEPs) are known to assess the integrity of A-delta fibres and the spinothalamic tract. Nevertheless, the clinical value was not investigated previously. The aim of this study was to measure CEPs in 16 healthy subjects from the face, hand and foot sole and to investigate whether CEPs reliably detect A-delta fibre abnormalities.
Methods:
Swift cold stimuli were applied to the skin with a commercially available thermode, which cooled down from 30 to 25 °C in approximately 0.5 s. CEP latencies (N1, N2 and P2) and amplitudes (N1, N2/P2) were recorded with EEG. Reversible A-fibre function loss was induced by applying a selective A-fibre block at the superficial radial nerve.
Results:
In all 16 subjects CEPs could be recorded from all locations; N2, P2 mean latencies were 276.4 ± 38.9 and 389.8 ± 52.5 (face), 318.6 ± 31.6 ms and 477.7 ± 43.6 (hand), and 627.6 ± 84.4 and 774.2 ± 94.0 (foot sole). N2/P2 amplitudes were 10.7 ± 4.1, 11.3 ± 4.1 and 7.5 ± 4.1 μV. During A-fibre block no CEPs were detectable in the grand average, which restored 10 min after block removal.
Conclusions:
CEPs were reliably recorded in healthy subjects at the hand, face and foot. Experimentally induced reversible A-delta fibre function loss was detected by CEPs. Functional recovery was assessed as well. This study is basis for further CEP evaluation studies and might be the first step for implementing CEPs in clinical routine for the early diagnosis of small-fibre disease. WHAT DOES THIS STUDY ADD?: Cold-evoked potentials are capable of reliably measuring A-delta fibre integrity, loss of function and functional recovery in healthy subjects, which is an essential prerequisite for diagnostic use in patients with small-fibre disease.
Recent studies applied laser-evoked potentials (LEP) for the analysis of small nerve fibre function and focused on the detection of stable C-fibre-mediated potentials (C-LEPs); high technical requirements were needed. The diagnostic significance is still controversially discussed. So far, only few studies focused on the susceptibility of C-LEPs to distraction and other influences. We hypothesized that C-LEPs are altered by habituation processes and distraction.
Twelve subjects were tested with a C-fibre laser set-up (neodymium:yttrium-aluminium-perovskite laser with a 10-mm beam diameter and 10-ms stimulus time) at the left perioral area. In condition I, the subjects received repetitive painful laser stimuli at the right hand to induce habituation. In condition II, the subjects had to fulfil an auditory discrimination task (where the subjects had to estimate the pitch of different tones on a scale for 20 min). C-LEPs were retrieved before and after the habituation or distraction paradigm. C-LEPs were also measured in a control group who was not influenced by laser stimuli or other disturbances during a 23-min break between the two test sessions.
In both test conditions, there was significant C-LEP amplitude reduction. The LEP amplitudes of the control group remained unchanged.
In the approach of detecting C-fibre-mediated potentials with LEP, future studies should take the high susceptibility to distraction and habituation into account.
© 2015 European Pain Federation - EFIC®
Die evozierten Potentiale nach schmerzhaften Reizen sind eine Sonderform somatosensorisch evozierter Potentiale (SEP). Gegenüber den Standard-SEP zeichnen sie sich durch andere periphere und zentrale Leitungsbahnen aus (zur Übersicht s. Willis 1985): Schmerzhafte Reize aktivieren A3- und C-Fasern in peripheren Nerven. Diese primären Afferenzen werden bereits im Hinterhorn des Rückenmarks auf sekundäre Neurone umgeschaltet, deren Axone im kontralateralen Tractus spinothalamicus nach rostral projizieren. Diese Bahn verläuft weit lateral bis in den unteren Hirnstamm hinein und trifft erst kurz unterhalb des Thalamus auf den Lemniscus medialis. Deshalb können durch schmerzhafte Reize evozierte Potentiale in der neurologischen Topodiagnostik eine wichtige Ergänzung zu den SEP liefern.
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.
Les potentiels évoqués laser (PEL) constituent une technique électrophysiologique fiable, non invasive permettant d’étudier spécifiquement et de façon objective les nocicepteurs. Les PEL sont indiqués lorsqu’il y a forte suspicion de neuropathie à petites fibres, en particulier lorsque les examens en stimulo-détection sont normaux, en cas de topographie douloureuse atypique et/ou sans contexte étiologique évident. En cas de douleur neuropathique d’allure périphérique, l’analyse des seuils nociceptifs et des potentiels tardifs permet de confirmer l’existence d’un dysfonctionnement des fibres Aδ. L’exploration des fibres C en PEL reste délicate en routine mise à part lorsque l’on explore la face. Les PEL sont également indiqués pour mettre en évidence une dysfonction des voies spino-thalamiques en cas de lésion médullaire ou supra-médullaire. Ils sont particulièrement utiles lorsque l’imagerie est normale ou discordante avec la clinique, et lorsque les potentiels évoqués somesthésiques (PES) sont normaux. Les PEL ont également un intérêt médicolégal pour authentifier un dysfonctionnement neuronal lié à un contexte post-traumatique ou post-chirurgical qu’il s’agisse d’une douleur neuropathique centrale ou périphérique. Enfin, ils peuvent être utilisés pour faire la part entre des douleurs neuropathiques et des douleurs purement psychogènes.
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.
El dolor fisiológico o nocicepción es una experiencia multidimensional o compuesta, en la que intervienen diferentes sistemas (perceptivos, emocionales, de la atención, motores, anticipatorios, etc.). La participación de estos distintos componentes permite a continuación que se elabore una respuesta integradora. En este artículo se describirá una primera parte anatómica, en la que se detallarán las vías de la nocicepción, tras lo que se expondrá una segunda parte anatomofuncional, en la que se mostrarán los conocimientos sobre el modo de funcionamiento en el ser humano de las estructuras implicadas ante una estimulación dolorosa. En esta segunda parte se describirán en especial las principales modulaciones del dolor conocidas en la actualidad, incluidos los dispositivos terapéuticos que permiten tratar a los pacientes en la práctica médica. Una parte destacada de los datos presentados en el último apartado se basa en los estudios que utilizan la tomografía por emisión de positrones (PET), la resonancia magnética funcional (RMF) o la magnetoencefalografía (MEG).
Il dolore fisiologico, o nocicezione, è un’esperienza multidimensionale o composita, che fa intervenire diversi sistemi, percettivi, emozionali attenzionali, motori, anticipatori… La messa in gioco di queste diverse componenti consente poi la costruzione di una risposta integrativa. In questo articolo prendiamo in considerazione una prima parte anatomica, che descrive le vie della nocicezione, poi una seconda parte anatomofunzionale, che descrive quello che si sa del modo di funzionare nell’uomo delle strutture implicate di fronte a una stimolazione dolorosa. In questa seconda parte vengono affrontate in particolare le principali modulazioni del dolore note ad oggi, inclusi i dispositivi terapeutici che consentono di alleviare il dolore dei pazienti nella pratica medica. Una parte importante dei dati presentati nell’ultimo capitolo si richiama agli studi che utilizzano la tomografia per emissione di positroni (PET), la risonanza magnetica funzionale (RMF) e la magnetoencefalografia (MEG).
This chapter describes the various methods of somatosensory evoked potential (SSEP) recordings using electrical as well as various natural stimuli, and discusses the usefulness and limitations of various modes of stimulation used to evaluate the central sensory pathways and function of peripheral nerves. Because SSEPs track the functional integrity of the peripheral and central nervous system, a lesion affecting any part of somatosensory pathway may alter the recorded SSEP. SSEP components, especially far-field potentials of short latency, prove useful in localizing lesions that affect the spinal cord, brainstem, subcortical, and cortical regions. SSEPs are conventionally elicited by electrical stimulation of either mixed or cutaneous nerves. Although more natural stimulations, such as pain, temperature, and pressure, can elicit SSEPs, the early responses are much smaller than those of electrically elicited SSEPs, because the onset and offset of natural stimuli are more gradual and the natural stimulus devices are more complicated. Thus, the use of SSEP studies to evaluate pain and temperature function has not been popularized as clinical diagnostic tests.
Het onderzoek naar pijn, haar ontstaansmechanismen en mogelijke farmacologische en andere behandelingen vergt adequate meetinstrumenten
om de activiteit van verschillende typen zenuwcellen van elkaar te kunnen onderscheiden. Pijn in de huid ontstaat door prikkeling
van de nociceptoren of vrije zenuweinden. Al naargelang het type en de lokalisatie van de nociceptor zal de prikkel snel worden
doorgegeven via de Aδ-vezels (gemyeliniseerde vezels) of langzamer via de C-vezels (dunne ongemyeliniseerde vezels). Deze twee typen zenuwvezels zijn de belangrijkste voor de pijntransmissie.
Laser somatosensory evoked potentials (LSEP) evaluate the functional integrity of thermoalgic pathways by the specific stimulation of A delta and C nociceptive afferences. As compared to a CO2 laser, the thulium Yttrium Aluminium Garnet (YAG) laser may be conducted by an optic fiber, which allows easier access to the stimulated body sites. We present normative data on thulium YAG LSEPs recorded after stimulation of upper and lower limbs (N = 15). LSEPs were obtained with a stimulation intensity that was twice the nociceptive threshold at the upper limbs (UL) and one and a half at the lower limbs (LL). To ensure a stable attentional level, subjects were asked to estimate stimulus intensity after each stimulation. The nociceptive thresholds at upper and lower limbs were respectively 319 ± 65 mJ and 359 ± 95, and with the above methodology the LSEPs could be obtained in every subject. The latencies of N2 and P2 were respectively 199 ± 18 ms and 325 ± 37 ms at the UL, 239 ± 36 ms and 378 ± 38 ms at the LL. This method produced robust and reproducible results, and proved to be reliable for routine clinical use. To optimise response stability we propose that right/left stimulation be conducted following an ‘A-B-B-A’ procedure.
Background/aims
Brief noxious heat stimuli activate Aδ and C fibers, and contact heat evoked potentials (CHEPs) can be recorded from the scalp. Under standard conditions, late responses related to AS fibers can be recorded. This study examines C-fiber responses to contact heat stimuli.
Methods
A preferential A-fiber blockade by compression to the superficial radial nerve was applied in 22 healthy subjects. Quality and intensity of heat evoked pain (NRS, 0–10), and CHEPs were examined at baseline, during nerve compression, and during further nerve compression with topical capsaicin (5%).
Results
During the A-fiber blockade, 3 subjects had CHEPs with latencies below 400 ms, 8 subjects within 400–800 ms and 6 subjects later than 800 ms. Pain intensity to contact heat stimuli was reduced and fewer subjects reported the heat stimuli as stinging. Following acute capsaicin application, ultralate CHEPs with latencies >800 ms could be recorded in 13 subjects, pain intensity to the contact heat stimuli was increased ( p <0.01) and more subjects reported the heat stimuli as being more warm/hot-burning.
Conclusion
The results indicate that following a compression to the superficial radial nerve, CHEPs compatible within complete A fibers or C fibers were recorded. Following sensitization with capsaicin, C-fiber responses were recorded in 62% of subjects.
The majority of the studies on laser evoked potentials (LEPs) have been focused on hand and foot stimulations and only lately on the trigeminal system. Because of a high receptor density in the facial skin and the very short conduction distance, LEP recordings after trigeminal stimulation are easier and quicker than those after stimulation of the limb extremities. Laser pulses with a stimulus intensity close to perception threshold can evoke well-defined LEPs. Few trials are sufficient to yield stable and reproducible averages. Even ultralate LEPs related to the C-fibre input are comparatively easily obtained from the trigeminal territory. The brain generators of the main LEP waves are probably very close for the trigeminal and limb stimulations. Trigeminal LEPs have been found absent or delayed in patients with trigeminal neuralgia, trigeminal neuropathies, posterior fossa tumors, and brainstem infarctions or demyelinating plaques. Conversely, trigeminal LEPs appear to be enhanced in patients with migraine. High-intensity pulses directed to any trigeminal division also elicit reflex responses: a blink-like reflex in the orbicularis oculi and a single silent period in the contracting masseter muscle. The availability of a neurophysiological method of assessing function of the trigeminal nociceptive pathways reaching both the cerebral cortex and the brainstem reflex circuits, has provided new opportunities for investigating the pathophysiology of orofacial pain syndromes. Résumé La majorité des études portant sur les potentiels évoqués laser (PEL) se sont focalisées sur la stimulation de la main ou du pied, et seulement récemment sur la stimulation du système trigéminal. Du fait de la haute densité des récepteurs sur la peau du visage et de la très faible vitesse de conduction, les enregistrements des PEL obtenus en réponse à une stimulation trigéminale sont plus faciles à réaliser et plus rapides que ceux obtenus après une stimulation des membres supérieurs ou inférieurs. Les pulses laser délivrés avec une intensité de stimulation proche du seuil de perception donnent en général des PEL déjà bien définis. Un petit nombre d'essais est suffisant pour obtenir des réponses reproductibles et stables. Même les PEL ultra-tardifs, correspondant à une stimulation des fibres C sont obtenus plus facilement en stimulant le territoire trigéminal. Les générateurs cérébraux des principaux PEL sont probablement les mêmes pour des stimulations des membres inférieurs/supérieurs et pour des stimulations trigéminales. Les PEL obtenus en réponse à des stimulations trigéminales sont absents ou retardés chez des patients présentant une névralgie trigéminale, des neuropathies trigéminales, des tumeurs de la fosse postérieure, des infarctus du tronc cérébral ou des plaques de démyélinisation. Inversement, l'amplitude des PEL obtenus en réponse à des stimulations trigéminales est augmentée chez les patients migraineux. La délivrance de stimulations à haute intensité sur chaque division trigéminale entraîne aussi des réponses réflexes : un réflexe de clignement dans la zone orbitaire de l'oeil et une période de silence au sein du muscle masséter en contraction. La possibilité d'utiliser une méthode neurophysiologique pour explorer les fonctions du système nociceptif trigéminal, et celle du cortex aux circuits réflexes du tronc cérébral, a ouvert de nouvelles perspectives dans l'étude de la pathophysiologie des syndromes de douleur orofaciale.
To compare the pain-related evoked potentials (PREPs) obtained by superficial electrical stimulation using a concentric planar electrode to those obtained by CO2 laser stimulation.
In 12 healthy subjects, PREPs, sympathetic skin reflexes (SSRs), motor reaction times (mRTs), and the conduction velocity (CV) of the recruited nerve fibres were assessed in response to electrical and laser stimulation.
In response to superficial electrical stimulation, PREP latencies and mRTs were shorter, while PREP amplitude tended to be increased. By contrast, SSR amplitudes and latencies and estimated CVs of the stimulated nerve fibres did not differ between electrical and laser stimulation. Fifteen minutes after PREP recordings, the residual pain intensity and the degree of unpleasantness were higher for laser stimulation than for electrical stimulation. In addition, CO2 laser stimuli induced dyschromic spots on the skin. For these reasons, all subjects declared that they would prefer superficial electrical stimulation rather than CO2 laser stimulation if they had to perform PREPs again.
The estimated CVs of the recruited nerve fibres and the localized pinprick sensation felt by the subjects suggest that small-diameter fibres in the A-delta range, conveying "first-pain" information, were stimulated in response to superficial electrical stimulation as for laser stimulation. Superficial electrical stimulation using a concentric planar electrode could be a valuable alternative to laser stimulation for assessing PREPs in the practice of clinical neurophysiology.
The conduction velocity of C-fibers of a peripheral nerve in the upper limb was measured following CO2 laser stimulation of a tiny area of the surface of the skin in a number of normal subjects. A thin aluminum plate with many tiny holes was used as a filter and placed on the skin at the stimulation site. The array of holes allowed the 2-mm laser beam to pass through one to four holes to reach the skin. 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 Aδ-terminals. The value obtained was 1.2 m/s. The finding demonstrated that this noninvasive method is useful for experimental and clinical exploration of the physiological function and pathophysiological role of C-fibers.
The necessary and sufficient condition to record brain responses to signals ascending through C-fibers seems to be avoidance of concomitant activation of Adelta-fibers. Several explanations are offered in the literature. One more is added, based on the phenomenon of post-event desynchronisation. Four methods, having in common the ability to selectively activate C-fiber afferents, are currently used to obtain ultralate-laser evoked potentials (LEPs) in a reliable way and with the appropriate latency. Exception made for the difference in latency, mainly due to the difference in peripheral conduction time, morphology and dynamic topography of the ultralate-LEPs (C-fibers), are similar to the late-LEPs (Adelta-fibers). These results suggest that both pathways have common cortical generators.
Compared volleys induced by artifical stimuli can be recorded from peripheral nerves of human subjects with extraneural electrodes. In contrast, the study of the normal traffic of impulses requires other methods. A powerful technique for recording this type of activity with percutaneously inserted intraneural electrodes was introduced in 1966. The development of the technique was promoted by interest in studying somatosensory and proprioceptive mechanisms in organisms with an intact sensorium and intact volition, particularly human subjects. This method opened up the possibility of investigating a number of neural mechanisms and is has been used mainly for studies of proprioceptive mechanism, tactile and nociceptive cutaneous activity, and efferent sympathetic discharges. In addition, cutaneous thermosensitive activity and oral mechanosensitive activity have been analyzed. Single-unit activity has been recorded from large myelinated nerve fibers and from unmyelinated nerve fibers, whereas rather few recordings from small myelinate fibers have been reported. In addition, multiunit activity from myelinated and unmyelinated fibers has been studied. Pathological mechanisms as well as normal conditions have been analyzed. Our aim here is to review findings extracted by recording impulses in human nerves with emphasis on the implications these findings may have on current theories within a number of fields. As far as it is feasible, the findings from human subjects are related to knowledge based on studies in other species. This review is based on reports published or known to be in the process of publication when the article was being written.
With the current practice of measuring thresholds for warming and cooling separately, the question of the exact nature of afferents subserving these sensations assumes new importance. Experiments to measure reaction times to warming and cooling stimuli at two sites on the lower limb are described. The conduction velocity for each sensation was estimated from the conduction distance and conduction time in the limb. The estimated mean conduction velocity for warming was 0.5, SD 0.2 m/s and cooling 2.1, SD 0.8 m/s. These figures confirm that the sensation of warming is conveyed in unmyelinated and cooling in small myelinated peripheral nerve fibres.
Recordings were made from convergent neurons in the lumbar dorsal horn of the spinal cord of the rat. These neurons were activated by both innocuous and noxious mechanical stimuli applied to their excitatory receptive fields located on the extremity of the hindpaw. Transcutaneous application of suprathreshold 2-ms square-wave electrical stimuli to the center of the excitatory field, resulted in responses to C-fiber activation being observed. This type of response was inhibited by applying a noxious thermal conditioning stimulus on the muzzle. The immersion of the muzzle in a 52 degrees C waterbath resulted in a strong reduction of the response during the application of the noxious conditioning stimulus and this was followed by long lasting poststimulus effects. Such inhibitory processes have been termed diffuse noxious inhibitory controls (DNIC). The effects on these inhibitions of lesions including the dorsolateral funiculus (DLF) were investigated in acute experiments: tests were performed before and at least 30 min after the DLF lesion. A lesion including the DLF ipsilateral to the neuron under study completely abolished the inhibitory processes triggered from the muzzle. Concomitantly, a facilitation of C-fiber responses was observed. Nevertheless, DNIC was still impaired even using a juxtathreshold current to elicit a weak C-fiber response. To ascertain further the main, if not entire, participation of the ipsilateral DLF in the descending projections responsible for the heterotopic inhibitory processes, the effects of a lesion of the contralateral DLF were investigated. Neither the inhibitory processes nor the unconditioned C-fiber responses were altered by this procedure. Again, a second lesion including the ipsilateral DLF induced a blockade of DNIC. It is concluded that the descending projections involved in the triggering of DNIC are mainly, if not entirely, confined to the DLF ipsilateral to the neuron under study. The contralateral DLF did not appear to play a role in these processes.
1. Electromyographic recordings were made from the biceps femoris muscle through a pair of noninsulated platinum/iridium needle electrodes in male Sprague-Dawley rats artificially ventilated and anesthetized with 0.8% halothane in a N2O-O2 mixture (2/3:1/3). The animals' ventilation, heart rates, and body temperatures were continuously monitored. Electrical stimuli (2-ms duration, 0.16 Hz) were delivered to the sural nerve territory through a pair of noninsulated platinum/iridium needle electrode inserted subcutaneously in the medial aspect of the 4th and the lateral part of the 5th toe. Such stimulation elicited a two-component reflex response in the ipsilateral biceps femoris muscle: The first had a short latency (17.5 +/- 2.3 ms), short duration (20.7 +/- 2.6 ms), and low threshold (1.5 +/- 0.6 mA), whereas the second had a longer latency (162.4 +/- 5.1 ms), longer duration (202.3 +/- 6.2 ms), and higher threshold (5.7 +/- 0.5 mA). 2. Lidocaine (0.02-0.1%; 0.1 ml), but not saline, injected subcutaneously over the proximal part of the sural nerve, produced a selective depression of the late component of the reflex response, whereas the first component remained unchanged. The conduction velocity of the afferent fibers was estimated from the stimulation needles in the sural nerve territory to the nerve's projection in the lumbar spinal cord: it was concluded that the second, late component of the reflex response was due to afferent signals transmitted via unmyelinated C-fibers, whereas the first component was related to activation of fine myelinated fibers (A delta group). 3. Electrical stimulation of the sural nerve was still able to elicit the two-component reflex responses in the ipsilateral biceps femoris muscle of chronic spinal rats, indicating that these responses were genuine reflex responses, transmitted completely through a spinal circuit. 4. The C-fiber reflex was recorded when the duration and frequency of the stimuli applied to the sural nerve varied within the 0.5- to 4-ms and 0.02- to 1-Hz ranges, respectively. It was concluded that a single 2-ms duration shock at an intensity of 1.2 times the C-fiber reflex threshold, delivered every 6 s (0.16 Hz), constituted an acceptable and optimal protocol for experiments in which the C-fiber reflex was studied as a function of time. These parameters were used throughout the subsequent experiments.(ABSTRACT TRUNCATED AT 400 WORDS)
1. The response of C polymodal nociceptors to thermal and mechanical stimuli applied to the monkey's face was recorded extracellulary in the trigeminal ganglion in rhesus monkeys anesthetized with sodium pentobarbital. Conduction velocities, determined from electrical stimulation of receptive fields (RFs), were in the range for unmyelinated C fibers (mean=0.82 m/s, n=20; SD=+/-0.17). With two exceptions cutaneous RFs were single spots (median=2 mm2; n=37) and usually were identical for thermal and mechanical stimuli. The median force threshold for the sample of units was 1.2 g (von Frey technique; n = 39; range = 0.07-8.5 g). 2. Discharges to thermal stimuli were investigated with a feedback-controlled contact thermode which permitted temperature changes less than or equal 12.0 degrees C/s. Thermal thresholds ranged from 38 degree to 49 degree C (median=46 degrees C; n=37), and maximum discharge frequencies were obtained in the noxious heat range (45-55 degrees C). For a graded series of 5 s duration stimuli from an adapting temperature of 35 degrees C, the number of impulses increased as a monotonic function of stimulus intensity over the range from threshold temperature to 50-53 degrees C. Many stimulus-response functions were positively accelerated, and linear regression analyses showed that most units examined were best fit by nonlinear functions. 3. The typical pattern of activity to 5 s duration temperature shifts into the noxious heat range was a short accelerating burst of impulses followed by deceleration to a lower rate of discharge prior to termination of the stimulus. The temporal profile of the discharge of impulses was virtually identical at different adapting temperatures. In units tested with 30 s duration stimuli at 2-6 degrees C above threshold, the mean frequency of discharge during the final 25 s was 1.46 impulses/s (n=6; SD=+/-0.89). 4. Application of noxious heat stimuli a few degrees above threshold temperature typically sensitized or enhanced the response of the unit to subsequent application of heat stimuli. The signs of sensitization consisted of a decrease in threshold temperature, increased frequency of discharge, decreased latency to the first impulse, and afterdischarges. Units failed to respond throughout the duration of 30 s stimuli if the final temperature exceeded 50 degrees C. Depressed responses were sometimes produced by application of intense (greater than or equal 55 degrees C) stimuli, presumably as a result of partial inactivation of the receptor. 5. In a correlative analysis, the latency and pattern of discharge in a sample of units were compared with escape responses in two monkeys to temperature shifts into the noxious heat range (49 and 51 degrees C). The analysis revealed that the discharge of C polymodal nociceptors alone cannot account for fast escape responses, but the discharge may contribute to escape responses which occur more than 3.5 s after the onset of stimulation.
C unit activity was recorded with microelectrodes from intact sensory fascicles in the human peroneal nerve. The analysis includes 46 afferent units with receptive fields predominantly on the dorsum of the foot and ankle. 16 units were tested quantitatively. Another 30 units were tested qualitatively by a combination of electrical and natural stimuli in the skin. This method was valuable for a reliable identification of activity in individual afferent C elements, when several C units with similar potential amplitudes responded to testing in the skin. The units were not spontaneously active at normal skin temperatures but one unit showed a low frequency discharge at a skin temperature of 22o C. Cooling by ether evaporation was an inefficient stimulus except for 2 units. Gentle mechanical stimuli did not activate any of the units, whereas afferent C unit impulses were induced by moderately intense mechanical stimuli, noxious heat and various chemical irritants. The sensations produced by stimuli inducing intense afferent C unit activity were reported as “burning or delayed pain”, whereas stimuli eliciting low frequency activity often were reported as “itch”. It is concluded that polymodal C receptors, similar with “polymodal nociceptors” in the cat and monkey, are numerous in skin areas sparsely covered with hairs on the dorsum of the foot and ankle in man, whereas no low threshold C mechanoreceptors were identified. The experiments do not exclude the possibility that both delayed pain and burning itch sensations may be mediated by different impulse patterns from polymodal C receptors.
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.
The latency to detection of heat stimuli applied to the distal forearm and thenar eminence was measured in 3 subjects in order to determine whether short latency responses correlated with perception of first pain. Only one temperature was used in a given run and stimuli ranged from 39 to 51 °C. In addition, subjects were interviewed at the end of each run regarding the quality of sensations experienced. In one series of experiments the quality of the first sensation evoked by each stimulus rather than latency was recorded. The median response latency decreased exponentially from 1100 ms to 400 ms for the distal arm and 1100 ms to 700 ms for the hand. The higher temperatures elicited a double pain sensation on the arm, but not on the glabrous hand. Warmth was always the first sensation felt on the hand. It is concluded that short latencies (less than 450 ms) reliably denote the presence of first pain, and that at least some portion of the primary afferents that signal first pain must have conduction velocities greater than 6m/s.
Unmyelinated nociceptive afferents, responsive to intense mechanical and heat stimuli, exhibited either a quickly adapting or slowly adapting response to step increases in skin temperature. These two classes of C fibers were found to differ also in other properties. The quickly adapting C fibers had significantly lower thresholds to mechanical and heat stimuli, and smaller receptive field areas than the slowly adapting C fibers.
The capacity of humans to detect and scale the magnitude of pain elicited by small increments in temperature, delivered by a contact thermal stimulator to localized areas of the arm or leg, was measured on non-painful and painful adaption temperatures. Subjects continuously rated the magnitude of any pain sensation elicited by heat increments superimposed on base temperatures of 38, 44, 47 or 48 °C. Detection threshold was also measured using a two-alternative forced choice method. The increment detection thresholds were lower for a continuously painful base of 47 °C than for a non-painful base of 38 °C in normal skin, and likewise were lower for a base of 38 °C following hyperalgesia induced by a mild burn. Incremental pain thresholds were nearly equal to detection thresholds on the base of 47 °C. The sensitivity with which subjects could scale the magnitude of pain was 2–7 times better for increments delivered on a 48 °C as opposed to a 38 °C base.
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.
CO2 laser emitted radiant heat pulses of 20 ms duration were used to activate predominantly slowly conducting nociceptive cutaneous afferents in man. Stimuli of two-fold individual pain threshold caused stinging and burning pain and elicited cerebral potentials with latencies consistent with Aδ-fibre activity. After preferential block of the myelinated nerve fibres by pressure only the burning pain remained with significantly increased reaction time (about 1433 ms). The Aδ-fibre-induced evoked potential components disappeared, and a marked ultralate positive component became visible with mean peak latency of 1260 ms, consistent with C-fibre activity.
1. Experiments were designed to answer the question: how well does a single warm fiber innervating the glabrous skin of the monkey's hand resolve incremental changes in the intensity of near-rectangular warming pulses applied to the fiber's receptive field? 2. In these experiments the measure of the warm fiber's capacity to resolve incremental changes in the intensity of successive warming pulses was termed the discriminable stimulus increment (DSI). The DSI is defined as that incremental difference in the intensity of a pair of warming pulses that could be resolved correctly, with a probability of 0.75, by comparing the fiber's responses to these two stimuli. In the specified conditions of the experiment, DSI = 0.67 sigma delta tau/(dR/dI) where sigma delta tau is the standard deviation of the difference in responses of the fiber to pairs of stimuli, and dr/dI is the fiber's sensitivity to incremental stimulus change. (dr/dI) was experimentally determined as the mean rate of change of the fiber's responses to incremental changes in the intensity of the warming pulse. 3. The DSI, as defined above, assumes that the basis for differentiating the stimuli in each pair was that the larger response in the fiber was in each instance generated by the more intense stimulus. A more general form of the DSI was also developed and used to examine the effects on intensity resolution of different discrimination rules that the brain might use. 4. In the experimental analysis the response measure of each warm fiber was the cumulative impulse count over successively longer segments of the stimulus period. With short integration intervals the DSI was high (i.e., intensity resolution was poor), but typically the DSI fell to a plateau level within 2.0--2.5 s of the onset of the warming stimulus. 5. The DSI was measured on 23 warm fibers in Macaca nemestrina for warming pulses with intensities of 0, 2, 4, 6, and 8 degrees C, at T-base levels of 29, 34 (near normal temperature of palmar skin), and 39 degrees C. For most observations the intensity resolution possible from the responses of single warm fibers, measured over this wide variety of stimulus conditions, was less than is achieved by the human observer trained to differentiate comparable warming pulses applied to the skin of the thenar eminence.
Clinical and electrophysiological observations are described in 7 patients with clinically well-identified vascular lesions of the brain-stem or diencephalon. In the patients of Group A with a thalamic syndrome, the somatosensory cerebral evoked potentials had a reduced voltage and increased latency on the affected side. No significant anomalies were recorded in the patients of Group B with a Wallenberg or Weber syndrome. In patients of group C with a locked-in syndrome, the cerebral evoked potentials presented marked bilateral anomalies which provided interesting data about the extension of the pontine vascular lesions into the tegmentum. The pathophysiological mechanisms involved in the changes of average cerebral evoked potentials and in the slowing of corticipetal conduction are discussed.
A quantitative method for the examination of thermal sensibility was applied in 26 normal subjects and in patients with various neurological disorders. The stimulation technique resembled Békésy audiometry: the patient reversed the direction of the temperature change of a thermode whenever warm, cold, or thermal pain thresholds were reached. The resulting temperature curve enables a quantitative description of the subject's thermal sensibility and of the degree of impairment displayed by neurological patients.
1. Radiant-heat stimuli of different intensities were delivered every 28 s to the thenar eminence of the hand of human subjects and to the receptive fields (RFs) of 58 "mechanothermal nociceptive" and 16 "warm" C-fibers, most of which innervated the glabrous skin of the monkey hand. A CO2 infrared laser under control via a radiometer provided a step increase in skin temperature to a level maintained within +/- 0.1 degrees C over a 7.5-mm-diameter spot. 2. Human subjects categorized the magnitude of warmth and pain sensations evoked by stimuli that ranged in temperature from 40 to 50 degrees C. The scale of subjective thermal intensity constructed from these category estimates showed a monotonically increasing relation between stimulus temperature and the magnitude of warmth and pain sensations. 3. The mechanothermal fibers had a mean RF size of 18.9 +/- 3.2 mm2 (SE), a mean conduction velocity of 0.8 +/- 0.1 m/s, mean thresholds of 43.6 +/- 0.6 degrees C for radiant heat and 5.95 +/- 0.59 bars for mechanical stimulation, and no spontaneous activity. In contrast, warm fibers had punctate RFs, a mean conduction velocity of 1.1 +/- 0.1 m/s, heat thresholds of less than 1 degrees C above skin temperature, no response to mechanical stimulation, and a resting level of activity in warm skin that was suppressed by cooling. 4. The cumulative number of impulses evoked during each stimulation in the nociceptive afferents increased monotonically as a function of stimulus temperature over the range described by humans as increasingly painful (45-50 degrees C). Nociceptive fibers showed little or no response to stimulus temperatures less than 45 degrees C that elicited in humans sensations primarily of warmth but not pain. In contrast, the cumulative impulse count during stimulation of each warm fiber increased monotonically with stimulus temperature over the range of 39-43 degrees C. However, for stimuli of 41-49 degrees C the cumulative impulse count in warm fibers was nonmonotonic with stimulus temperature. Warm-fiber response to stimuli of 45 degrees C or greater usually consisted of a short burst of impulses followed by cessation of activity. 5. The subjective magnitude of warmth and pain sensations in humans and the cumulative impulse count evoked by each stimulus in warm and nociceptive afferents varied inversely with the number, delivery rate, and intensity of preceding stimulations. 6. The results of these experiments suggest the following: a) that activity in the mechanothermal nociceptive C-fibers signals the occurrence of pain evoked by radiant heat, and that the frequency of discharge in these fibers may encode the intensity of painful stimulation; b) that activity in warm fibers may encode the intensity of warmth at lower stimulus temperatures, but is unlikely to provide a peripheral mechanism for encoding the intensity of painful stimulation at higher stimulus temperatures.
1. Impulses in cutaneous nerve fibres were recorded percutaneously with tungsten micro-electrodes from the superficial radial nerve of adult human subjects. 2. Eight units studied had conduction velocities below 1.5 m/sec, and thus belong to the class of C fibres. On the basis of their responsiveness to mechanical and to thermal stimuli the units were classified as 'polymodal nociceptors'. 3. Units were tested with 12 sec heat pulses starting from a base line temperature of 43.0-43.5 degrees C. Heat stimuli reaching three different maximal levels were applied in randomized order, the subjects being blind with respect to stimulus size. Each of the eight units studied was tested with more tha 20 stimuli and with four of them were 80-125 stimulus repetitions. 4. After each stimulus the subjects had to rate his sensations on a six-point rating scale extending from 'just noticeable' to 'very hot, painful'. 5. Discrimination between the three stimulus levels by the integtated spike discharges and by the ratings of the subject was compared using the P(A) measure of the Signal Detection Theory. It was found that both the neurophysiological and the psychophysical measurements provided about equal discrimination. 6. In addition it has been found that spike discharges and ratings share a common variance beyond their common dependence on the stimulus level. Among the factors contributing to this interdependence a 'temporal position effect' was the most significant. 7. In spite of this interdependence between discharge rates and subjective ratings, the latter gave a better estimation of the stimulus size than of the discharge rates of the individual C fibre under study. 8. It was concluded that the polymodal C-nociceptors might be instrumental for the quantitative aspects of heat pain sensation. The hypothesis was derived from the present results that, under the conditions of cour experiments, the loss of information in the course of central processing might be about equal to the gain by the parallel processing in a population of nociceptors excited by a stimulus.
1. The response of C polymodal nociceptors to thermal and mechanical stimuli applied to the monkey's face was recorded extracellulary in the trigeminal ganglion in rhesus monkeys anesthetized with sodium pentobarbital. Conduction velocities, determined from electrical stimulation of receptive fields (RFs), were in the range for unmyelinated C fibers (mean=0.82 m/s, n=20; SD=+/-0.17). With two exceptions cutaneous RFs were single spots (median=2 mm2; n=37) and usually were identical for thermal and mechanical stimuli. The median force threshold for the sample of units was 1.2 g (von Frey technique; n = 39; range = 0.07-8.5 g). 2. Discharges to thermal stimuli were investigated with a feedback-controlled contact thermode which permitted temperature changes less than or equal 12.0 degrees C/s. Thermal thresholds ranged from 38 degree to 49 degree C (median=46 degrees C; n=37), and maximum discharge frequencies were obtained in the noxious heat range (45-55 degrees C). For a graded series of 5 s duration stimuli from an adapting temperature of 35 degrees C, the number of impulses increased as a monotonic function of stimulus intensity over the range from threshold temperature to 50-53 degrees C. Many stimulus-response functions were positively accelerated, and linear regression analyses showed that most units examined were best fit by nonlinear functions. 3. The typical pattern of activity to 5 s duration temperature shifts into the noxious heat range was a short accelerating burst of impulses followed by deceleration to a lower rate of discharge prior to termination of the stimulus. The temporal profile of the discharge of impulses was virtually identical at different adapting temperatures. In units tested with 30 s duration stimuli at 2-6 degrees C above threshold, the mean frequency of discharge during the final 25 s was 1.46 impulses/s (n=6; SD=+/-0.89). 4. Application of noxious heat stimuli a few degrees above threshold temperature typically sensitized or enhanced the response of the unit to subsequent application of heat stimuli. The signs of sensitization consisted of a decrease in threshold temperature, increased frequency of discharge, decreased latency to the first impulse, and afterdischarges. Units failed to respond throughout the duration of 30 s stimuli if the final temperature exceeded 50 degrees C. Depressed responses were sometimes produced by application of intense (greater than or equal 55 degrees C) stimuli, presumably as a result of partial inactivation of the receptor. 5. In a correlative analysis, the latency and pattern of discharge in a sample of units were compared with escape responses in two monkeys to temperature shifts into the noxious heat range (49 and 51 degrees C). The analysis revealed that the discharge of C polymodal nociceptors alone cannot account for fast escape responses, but the discharge may contribute to escape responses which occur more than 3.5 s after the onset of stimulation.
Reponses evoked by warming the glabrous palmar skin were recorded maximally from a contralateral parietal scalp site that approximated the hand projection area of sensorimotor cortex. A smaller and later occurring response was also seen at the corresponding ipsilateral site. The temperature to which the skin was adapted was critical and was maintained at 35 degrees C rather at 30 degrees C as it was in an earlier study where no responses were seen. Peak latencies ranged from 280 msec to 356 msec for stimulus intensities of 8 degree C presented at a rate of 19 degrees C/sec. This warm evoked response appeared to have its origin in the specifically sensitive primary warm afferents. The presence of an evoked response when warming occurred from the 35 degrees C adapting temperature (AT) and its absence at the 30 degrees C AT coincide with the greater sensitivity of warm receptors at the higher AT. Comparison of these results with those for evoked responses to skin cooling and tactile tap suggest that the cortical organization of temperature (both warm and cool stimuli) in human is similar to that of touch.
Controlled radiant heat stimulation for a combined psychophysical and electrophysiological research in pain was achieved by the use of an infrared Laser beam. The computer controlled stimuli, being of very brief duration (down to 5 msec) and sharply localized, are suitable for recording of averaged evoked responses as well as for determination of pain and thermal thresholds. These stimuli can be applied to any locus on the skin. The threshold energy delivered by this technique is similar to that obtained by the Hardy-Wolff-Goodell method. Special precautions were taken to avoid injury to the skin and the eyes.
Brief pulses of Laser emitted radiant heat were used to induce cutaneous painful sensations in human volunteers. Accurate timing of the stimuli permitted recording of scalp averaged evoked potentials. A late negative-positive component of the EP which correlated in amplitude with the subjective sensation was observed in four subjects. The latency of this component (130-160 msec) correlated with stimulus intensity.
Heat stimuli, applied to the skin by non-contact radiation pulses emitted by a CO2-laser, activate simultaneously both A-delta (mean conduction velocity 14 m/s) and C-fibres (0.8 m/s), which terminate in the most superficial skin layers. Correspondingly, brief heat stimuli elicit two pain sensations with mean reaction times of about 500 ms and 1400 ms. Similarly, two evoked potential waveforms were observed in the electroencephalogram: the late components N240/P370 and the ultralate components N1050/P1250. The shape of the two components was reproducible in independent samples of healthy volunteers. In patients with dissociated sensory loss, the laser evoked cerebral potentials are affected, depending on the kind of disturbed nerve and tracts. This is shown in patients with syringomyelia, encephalomyelitis disseminata, myelitis, Brown-Sequard syndrome, Wallenberg syndrome. In cases with hereditary motor and sensory neuropathy type I or with neurosyphilis, ultralate potentials are observed as correlates of delayed pain perception in the affected body areas. The laser evoked cerebral potentials reflected the clinical disorder of pain sensitivity in most cases, whereas somatosensory evoked potentials in response to conventional nerve stimuli failed in objectifying the diagnosis. As such, evoked cerebral potentials in response to laser heat stimuli applied to the hairy skin can be used for an overall examination of the functional integrity of peripheral small fibres, anterolateral tracts and thalamocortical projections.
Perception thresholds for warm and cold sensation were measured by two methods, the method of levels and the method of limits, at various rates of temperature change. The following findings were obtained. (1) The threshold value is critically dependent upon the method through which it is obtained, being higher for the method that includes reaction time in the measurement. (2) When using a method that includes participation of reaction time, threshold increases with increasing rate of temperature change. (3) The artefactual threshold elevation recorded through the method of limits corresponds precisely to the reaction time. (4) Conduction velocities for the primary afferents mediating the sensations of warm and cold, calculated on the basis of reaction time and conduction distance are in keeping with the mediation of warm sensation by unmyelinated primary afferents and of cold sensation by small myelinated afferents. (5) Measurement of threshold by the method of levels and direct measurement of reaction time enables calculation of conduction velocity for the specific sensory submodality tested from a single stimulation site.
We have applied our technique for the measurement of thermal thresholds to 25 patients referred with symptoms and signs of small fiber peripheral neuropathy in whom conventional electrophysiological indices were individually within the range of normal values for our laboratory. Vibration threshold determinations were also within normal range. Significant abnormalities of thermal thresholds were noted in all patients.
The results indicate that the technique provides an accurate, easily performed and reproducible index of function in small Aδ and C groups of nerve fibers.
Clinical observations are presented on the sensory effects of lesions of different afferent pathways of the spinal cord, correlated whenever possible with histological evidence of the location and extent of the lesions. They are based on personal cases and on significant cases in the literature, including posterior column section, other causes of damage to the posterior columns, and cases of commissural myelotomy. It is concluded that the traditional view of the effects of lesions of the posterior columns is correct, but that evidence from cases proved by postmortem examination is still needed.
When the information normally supplied by the posterior columns is cut off, primary sensibility for light touch and pressure is not lost, but any kind of discrimination is disturbed There is also a disturbance in knowledge of movement and position, ataxia, and clumsiness in the use of the hands. These defects greatly affect the palpatory examination of objects and, although they may appear slight on routine neurological examination, they can cause severe disturbances in the activities of daily living.
For tactile modalities, a lesion of the spinothalamic complex causes minimal or no defects and a lesion of the posterior columns causes only slight defects, whereas a lesion of both pathways gives rise to total loss of tactile and pressure sensibility in the part of the body served by both pathways. This conclusion is based on 2 cases with combined commissural myelotomy and anterolateral cordotomy.
The following disturbances of mechanoreception attributed to lesions of the posterior columns are discussed: lability of threshold, persistence of sensation, tactile and postural hallucinations and temporal and spatial disturbances. In man, lesions of the posterior columns cause an increase in pain, tickle, warmth and cold.
Cases are presented with and without lesions of the posterolateral columns in conjunction with lesions of one or both anterolateral columns. As these lesions did not affect sensation and as there was no difference in the sensory state following anterolateral cordotomies with or without involvement of the posterolateral column, it is concluded that lesions of this column have no effect on sensation. Cases with lesions of the anterior two-thirds of the cord are also presented to illustrate the sensory state with only the posterior third of the cord intact. In these cases, tactile and pressure sensibility and knowledge of movement and position are normal.
Brief CO2 laser radiant heat pulses activate both A delta- and C-fibres. In the evoked potential (EP) late and ultralate components can be seen as correlates of first and second pain. Usually the ultralate EP appears to be suppressed. It could be uncovered by a preferential A-fibre block, and in two neurological patients with tabes dorsalis and with a polyneuropathy involving myelinated fibre loss. Due to a strong latency jittering the shape of the ultralate component is distorted in the conventional average. Latency corrected averaging, adaptive filters or parametric spectral estimators are needed to analyze these EP components. As a result the filtered ultralate waveforms look very similar to the late EP components. Clinical application of CO2 laser EPs promises to nonivasively assess A delta- and C-fibre function.
The clinical and EMG findings in 44 patients with syringomyelia who were seen at the Mayo Clinic between 1976 and 1985 are presented. In 10 of the patients, somatosensory evoked potentials (SEPs) of the upper and lower extremities were obtained. All 44 patients had radiographic or surgical evidence of a cervical syrinx. The most common abnormality on nerve conduction studies was a reduced hypothenar compound muscle action potential amplitude (23 patients). Abnormal findings on needle electromyography were present in 33 patients and included sparse fibrillation potentials, reduced motor unit potential (MUP) recruitment, and chronic neurogenic MUP changes in muscles innervated by the C-5, T-1 roots, with the most pronounced changes in small hand muscles. Ulnar and median nerve SEPs were usually normal in the presence of a dissociated sensory loss and were usually abnormal when all sensory modalities were impaired. Abnormalities of tibial nerve SEPs were frequent and were related to impaired proprioceptive sensation in the lower extremities.
In 29Ss ulnar nerve block was performed by injection of mepivacaine in order to study the latency of warm and cold sensibility loss. Thermal stimuli of great amplitude and without perceptible tactile components were used. The conductivity of afferent fibres was tested by simple reaction time.
Warm sensibility was blocked significantly earlier than cold sensibility. The loss of warm sensibility was preceded by the block of vasomotor efferents; simultaneously with the warm sensibility block, the sensation of a pin prick changed from sharp to blunt. When both warm and cold sensibility were completely blocked, touch was still perceived and the force of the hypothenar muscle group was reduced to 60% of its normal value.
The present findings support the hypothesis that, in man, warm and cold sensations are mediated by two different groups of receptor neurones, and that at least part of the axons mediating cold sensations is myelinated whereas those mediating warm sensations are not. Thermal stimulation of cold sensitive slowly adapting mechanoreceptors did not lead to conscious sensations.
When the glabrous palmar skin of the human hand was rapidly cooled, a change in the recorded electrical potential was localized at the contralateral scalp site that approximated the primary projection of the hand on the postcentral gyrus. Typical features of the evoked potential were an initial positive peak of large amplitude (25–36 μV), long peak latency (325 msec), long duration (200–325 msec) and it was graded to the intensity of the cooling. Little, if any, potential change was simultaneously recorded from the corresponding ipsilateral scalp site. While the evoked response is specific to skin cooling neither its receptor origin nor its relationship to thermal sensation has been established. We were not able to record an evoked potential of any form to rapid warming of the hand.
Cutaneous warm and cold receptors were examined electrophysiologically in rhesus monkeys (Macaca mulatta) by recording from single units dissected from the saphenous nerve and the superficial branch of the radial nerve. Single warm and cold fibres had spot-like receptive fields in the hairy skin which were highly specific to thermal stimuli and did not respond to mechanical deformation of the skin. One group of cutaneous warm receptors had a range of static activity between 30 and 44°C and an average static maximum of 12 imp/sec at 41°C, whereas the static maximum of the other group was at temperatures higher than 44°C. About one third of the cold fibres was myelinated, with a conduction velocity from 2.2 to 9.5 m/sec (mean 6.3 m/sec), while the remaining part was unmyelinated, having a conduction velocity of 0.3 to 1.3 m/sec (mean 0.7 m/sec). All warm fibres were non-myelinated, with a conduction velocity of 0.4 to 0.9 m/sec (mean 0.7 m/sec).
For comparison with findings in neuropathy, sensory conduction was studied along distal and proximal segments of the superficial peroneal, sural, and posterior tibial nerves in 71 healthy subjects 15 to 72 years of age and normal values were established (Table 2). In the distal segments of the nerves of the leg the amplitudes of the sensory potentials were one tenth those in the nerves of the upper extremity; the potentials were split up into several components, and electronic averaging was used routinely to analyse the shape of the potentials. The maximum sensory conduction velocity was 56·5 m/sec, SD 3·4 m/sec, in proximal; and 46·1 m/sec, SD 3·7 m/sec, in distal segments of the nerves (subjects 15 to 30 years, 34 to 36°C). Slowing of conduction with increasing age was the same proximally and distally (subjects 40 to 65 years: proximally 53·1 m/sec, SD 4·6 m/sec; distally 42·5 m/sec, SD 5·5 m/sec, 34 to 36°C). The velocity in the slowest components of the sensory potentials averaged 20 m/sec. The sensory velocity was 3 to 6 m/sec faster than the motor. The error arising from measuring the conduction distance on the surface across the capitulum fibulae was evaluated.
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.
Microelectroneurographic studies in man allow the comparison of stimulus induced activity in the single peripheral nerve unit with the subject's ratings of sensation. Relationships between stimulus intensity, single unit discharges, and pain ratings were investigated using a CO2 laser stimulator which delivers radiant heat pulses of 50 ms duration. Recordings were performed percutaneously from the radial nerve at the wrist. Receptor types were identified by their response to different stimulus modalities and by their reaction delay to electrical test stimuli within the receptive field. Receptive fields of identified units were stimulated with randomised series of different radiant heat intensities between half and double the individual pain threshold (5 to 20 W; stimulation area 64 mm2).
The largest receptor class observed to be activated by CO2 laser stimuli were polymodal C-nociceptors. None of them was spontaneously active. High discharge rates up to 75/s were not necessarily associated with pain but, if pain was felt, the impulse trains usually lasted for more than 60 ms. Inter-spike intervals were distributed over a wide range between 8 and 145 ms with a peak at about 25 ms. This peak was only slightly shifted by increasing the stimulus intensity. Higher correlations were found between the number of spikes and stimulus intensity. Measures of Signal Detection Theory indicated that the single unit discharges discriminated stimulus intensities better than the subjects' ratings. These findings underline the importance of temporal summation in the processing of C-fibre input with a considerable loss of information in the nociceptive system.
The receptive properties of A-δ-fibers were studied in young healthy volunteers by single-fiber recording from the cutaneous branch of the radial nerve. Mechanical stimulation was performed with a set of von Frey hairs. Response to cooling was tested with ether or ice. A feedback-controlled radiant-heat stimulator delivered heat pulses at different temperatures, ranging from 37 to 46.5°C. A paint-removing substance, containing methylene chloride in methanol, was used as a chemical irritant. The evoked sensation was registered by asking the subjects to report about their sensations and by cross-modality matching. The conduction velocity was computed in 140 A-δ-fibers (mean ± SD, 19.2 ± 7.2 m/s). The observed values corresponded well with the diameter distribution of thin myelinated fibers in the radial nerve of man. Mechanical threshold measurements in 66 A-δ-fibers revealed a low-threshold group (≤8.8 mN), which has some characteristics in common with the 'down hair receptors' found in animal experiments. The other fibers had high mechanical thresholds (≥22.5 mN) in the C polymodal nociceptor range. Twenty-one percent of those mechanoreceptive receptors were activated also by radiant heat. Responsiveness to heat usually seemed not to be a consequence of sensitization. The discharge frequency to radiant heat was higher in some A-δ-fibers than in C-fibers. A-δ-Fibers behaved differently from C polymodal nociceptors, since not all A-δ-fibers activated by chemical stimulation were responsive to radiant heat. Comparison of reported sensation and neural activity indicated that activation of an A-δ-fiber did not always coincide with a pain sensation. From these experiments the following conclusions were drawn. 1) There exist A-δ-fibers in the human similar to those described in other mammalian species. 2) A-δ-fibers with high mechanical threshold show a higher receptor specificity than C polymodal nociceptors. 3) The firing frequency on noxious stimulation is often higher in A-δ-fibers than in C-fibers.
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)
Of 22 specifically sensitive warm units identified and the receptive fields mapped in the monkey, 8 were single spots of 1 to 2 mm diameter and were located in the glabrous skin of the hand or foot. Of the remainder, located in hairy skin, six had single spots, four had two spots, and four had three-spot receptive fields. Conduction velocities of the axons of 14 warm units were measured. With one exception, all had conduction velocities of less than 1.7 m/s, hence were clearly unmyelinated (mean, 0.8 + 0.09 (SE) m/s). The exception had a conduction velocity of 3.75 m/s and was considered to be myelineated. All warm units showed some steady-state activity at adapting temperatures (AT) above 30 and below 50°C. There appeared to be two distributions of warm units, at least with regard to their steady-state activity. In one distribution (two units) steady-state activity rose to a relatively high level at a 46-47°C AT. A further increase in the AT of 1°C suddenly silenced the steady-state activity. In the second distribution (13 units) the steady-state response increased to an average maximum of about 5 impulses/s at the 43°C AT and then declined. All were silent at the 50°C AT. Three units were seen to burst in doublets at ATs between 35 and 43°C. The discharge frequencies of all 15 units became irregular at 40-43°C and higher ATs. Three indexes of response magnitude, peak frequency, average frequency during the dynamic stimulus plus 3 s, and cumulative impulses during 4 s following stimulus onset yielded substantially the same results, i.e., the response magnitude was greatest from the 40°C AT and the rate of the temperature change did not produce much of a change in response magnitude except for the +2.5 and 5.0°C stimuli from the 30 and 35°C AT. These differences were somewhat greater when the 4 s cumulative count was used. The fourth index of response magnitude, total impulses during the temperature increase, again showed the warm units to be most sensitive to stimuli from the 40°C AT but, because of the longer stimulus durations, far more impulses were produced at the slow than at the fast rate of temperature change. The first 30 s of adaptation to a new temperature level following a +5.0°C stimulus was described by a single exponential curve, the time constant of which increased from about 5 s at the 35°C temperature level to about 12 s at the 50°C temperature level. The dynamic response of warm units to cool stimuli was a suppression of the steady-state activity. When the average frequency during stimulation was used as an index of response magnitude, it was found that -2.5°C stimuli were as effective as -5.0°C stimuli in suppressing the activity in warm units and that the rate of cooling was without effect.
The properties of 125 C fibre units recorded from the peripheral nerves of conscious man were studied. On the basis of receptive field properties and responses to natural stimulation, 120 of the units were classified as polymodal C nociceptors. Five of the units were identified as specific C warm receptors. In contrast to the polymodal nociceptors, which often had comparatively large and complex receptive fields with several receptive maxima, receptive fields of the thermo-receptors consisted of one single spot. Polymodal nociceptors responded readily to moderately intense and noxious mechanical stimuli whereas the warm receptors produced inconsistent responses to even intense mechanical skin stimulation. Thermal stimulation in the innocuous range, perceived as warmth, optimally excited the thermoreceptors whereas the polymodal C nociceptors fired most intensely to noxious painful heat.
Thermal stimulation with intense pulses of CO2 laser radiation has recently come into use as a method for generating robust cerebral evoked responses in man. Because the heat transient involved (at least 200°C/s) is at least an order of magnitude greater than that of most conventional thermal stimulators, we checked whether or not there might be anomalous activation of fiber types other than the well known cutaneous thermoreceptors. Recordings were made from primary afferent fibers in the rat sciatic nerve and second order somatosensory cells in the dorsal horn. Most of the laser-sensitive afferent fibers sampled were C polymodal nociceptors with lesser representation of other thermoreceptor types. There were no instances in which low threshold mechanoreceptors or other nonthermal afferent fibers were engaged. We conclude that the advantages of infrared laser stimulation are not compromised by a loss of receptor specificity.
1. Ramped heat stimuli were used to compare the effects of rate of temperature change on the responses of monkey nociceptors and on heat pain threshold in human subjects. Recordings were made from twenty-five cutaneous C fibre mechano-heat nociceptors (CMHs) innervating the hairy skin in the anaesthetized monkey. Heat pain thresholds were determined on the volar forearm of eight human subjects using a converging staircase technique. 2. The heat pain threshold decreased as stimulus ramp rate increased. In contrast, the CMH heat threshold, defined as the surface temperature at which the first action potential occurred, increased as stimulus ramp rate increased. Thus, the properties of the heat stimulus that dictate heat pain threshold are different from the properties of the heat stimulus that govern the initiation of a response in nociceptors. 3. Peak discharge frequency of CMHs during the heat ramp increased with stimulus ramp rate. Heat pain threshold was correlated with achievement of a minimum discharge rate in nociceptors (0.5 Hz), rather than with the threshold for action potential initiation.
The present study was aimed at examining the specificity of the action of heterotopic nociceptive conditioning stimulation (HNCS) by comparing its effects of those induced by a mental task (MT). Five test stimuli made from short CO2 laser pulses (duration: 40 msec; diameter: 10 mm; intensity: 0.25-0.8 Joules) were delivered every 30 to 45 sec at random to 4 different spots on the skin of the upper lip in 3 groups of 10 healthy subjects. The two most intense stimuli were perceived as painful, the two least intense stimuli as warm, and the intermediate stimulus as hot or near painful. Perception (VAS), reaction time (T) and cerebral evoked potentials (CEPs) were monitored before, during and after conditioning stimulation consisting either of HNCS (hand submerged in cold water) or of MT (arithmetic subtraction). Pain perception (first pain) threshold was increased in both conditioning stimulations; however, the stimulus-response curve and the neurophysiological correlates were differently affected. During HNCS, the stimulus-response curve was depressed and T was increased mainly for the intermediate stimulus, whilst CEP power density was reduced for all stimulus intensities; discrimination performance near pain threshold was dramatically depressed. During MT, the stimulus-response curve was shifted down toward higher stimulus intensities, T was equally increased for all stimulus intensities, whereas CEP power density was not changed; discrimination performance remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
The aim of this study was to distinguish the exogenous component (related to the physical properties of the stimulus) and the endogenous component (reflecting event-related cognitive processing) of the laser-evoked potential (LEP). Short painful radiant heat pulses generated by a CO2-laser were applied to the dorsum of the right and left foot. LEPs were recorded with 5 scalp electrodes in the midline versus linked earlobes in 26 healthy subjects. In order to identify the exogenous component, the LEP was recorded during a standardised distraction task (reading a short story). To identify the endogenous component P3 for the LEP, a 2-stimulus oddball paradigm was used (20% probability of targets). When the task of the oddball paradigm consisted of pressing a button, a movement-related long-latency negativity (N 1200) was recorded in frontal leads that was absent in a counting task. The LEP of targets, frequent non-targets and during distraction was dominated by a single large positivity. The amplitude of this positivity was task-dependent and increased the more attention the subject payed to the laser stimuli (distraction < neutral < non-target < target). The laser-evoked positivity during distraction had a peak latency of about 400 msec (P400) and a maximum amplitude at the vertex, which was independent of inter-stimulus interval. The P3 following laser stimulation had a significantly later peak at about 570 msec (P570) and a different scalp topography with a parietal maximum. Its amplitude decreased when the interstimulus interval was reduced from 10 to 6 sec. Under neutral instructions, the LEP positivity consisted of a superposition of both the exogenous P 400 and the endogenous P570.
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.