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The effects of A-fiber pressure block on perception and neurophysiological correlates of brief non-painful and painful CO2 laser stimuli in humans
Abstract
This study examined the relative capacity of Adelta- and C-fibers to encode non-painful and painful brief CO(2) laser stimuli by comparing the effects of Adelta/C-fiber activation versus C-fiber activation alone. In nine normal subjects, brief CO(2) laser pulses of four different intensities (range 5.8-10.6mJ/mm(2)) were delivered at random on the first intermetacarpal zone of the dorsum of the hand. A-fiber pressure block of the superficial radial nerve was performed to fully isolate the activity of C-fibers. Quality and intensity (VAS) of percepts, reaction time (RT) and laser-evoked potentials (LEPs) were examined in baseline and A-fiber block conditions. During A-fiber block, absolute detection threshold increased dramatically from 4.8+/-1.8 to 10.9+/-4.8mJ/mm(2), proportion of detected stimuli decreased from 87% to 47% and proportion of pain reports from 39% to 10%. The quality of sensations became mainly 'light touch' and the 'pricking' sensation almost vanished. The stimulus-VAS curve shifted to the right and the slope was reduced. Signal Detection Theory analysis revealed that discrimination performance (P(A)) was significantly depressed and that response bias (B) evolved from a neutral towards a stoical attitude. Median RT increased from 492 to 1355ms. The late LEPs, attributed to the activation of Adelta-fibers, disappeared and ultra-late LEPs were recorded at Cz with a positivity peaking around 800ms. Collectively, these observations lead to the conclusion that Adelta-fibers are the main peripheral mediators for the perception of brief CO(2) laser stimuli and that they provide more sensory information than C-fibers.
... Cowhage spiculae activate the subset of pruriceptive fibres leading to the perception of both itch and mild pricking/stinging pain (3,8,13). The co-activation of Aδ-fibres should conceivable result in better spatial resolution and localizability of the non-histaminergic itch compared with histaminergic itch (7,(19)(20)(21)(22)(23), but this has not been confirmed. This could theoretically parallel the findings in the area of pain, where Aδ-fibre-mediated pricking pain is well localized, whereas C-fibre-mediated burning pain is more diffuse (19)(20)(21)(22)(23). Pruriceptive primary afferents of both the histaminergic and non-histaminergic itch pathway are multimodal, in the sense that they are also capable of transmitting nociceptive signals in response to algogenic stimuli, such as capsaicin (24). ...
... The co-activation of Aδ-fibres should conceivable result in better spatial resolution and localizability of the non-histaminergic itch compared with histaminergic itch (7,(19)(20)(21)(22)(23), but this has not been confirmed. This could theoretically parallel the findings in the area of pain, where Aδ-fibre-mediated pricking pain is well localized, whereas C-fibre-mediated burning pain is more diffuse (19)(20)(21)(22)(23). Pruriceptive primary afferents of both the histaminergic and non-histaminergic itch pathway are multimodal, in the sense that they are also capable of transmitting nociceptive signals in response to algogenic stimuli, such as capsaicin (24). ...
... In the present study, the analysis did not reveal a significantly larger area of itch perception for histamine than for cowhage, as previously suggested. It is unclear why cowhage-induced itch, which is in part Aδfibre driven, does not result in a more spatially confined and localizable itch area than that of histamine, which is conveyed via CMi-fibres, as this has been shown for Aδpricking and C-fibre burning pain (19)(20)(21)(22)(23). A potential confounding factor could be the initial mechanical stimulation associated with the application of cowhage and histamine and, in lieu of the high variability of the reported itch areas, it could be that the present study did not have adequate statistical power to detect such a difference. ...
Numerous exploratory, proof-of-concept and interventional studies have used histaminergic and non-histaminergic human models of itch. However, no reliability studies for such surrogate models have been conducted. This study investigated the test-retest reliability for the response to histamine- and cowhage- (5, 15, 25 spiculae) induced itch in healthy volunteers. Cowhage spiculae were individually applied with tweezers and 1% histamine was applied with a skin prick test (SPT) lancet, both on the volar forearm. The intensity of itch was recorded on a visual analogue scale and self-reported area of itch was assessed 5 and 10 min after itch provocation. Reliability of the evoked itch (area under the curve and peak intensity) was assessed by the coefficient of variation (CV), intra-class correlation coefficient (ICC), and sample size estimation for parallel and cross-over designs. Cowhage (ICC = 0.57-0.77, CVbetween = 97%, CVwithin = 41%) and histamine: (ICC = 0.83-0.93, CVbetween = 97%, CVwithin = 20%) exhibited moderate-to-excellent intra-individual reliability and moderate inter-individual reliability for the itch intensity. For an observation period of one week, SPT-delivered histamine and application of cowhage-spiculae are reproducible human models of itch. The high inter-individual and low intra-individual variability suggests cross-over designed studies when applicable.
... 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). The C-fibre staircase algorithm was therefore based on a detection/no detection criterion, whereas the Adfibre staircase was based on RTs (Churyukanov et al., 2012). ...
... The inverse variance can be interpreted as a measure of the noisiness in a sensory channel (Green and Swets, 1988). This may result from the fact that Adfibre inputs are more salient than C-fibre inputs (Nahra and Plaghki, 2003;Vierck et al., 2004;Churyukanov et al., 2012), leading to a faster central accumulation of sensory information and ultimately to a faster decision making (Ratcliff and Van Dongen, 2011). This, together with the already very short response latencies to Ad-fibre stimulation, makes it unlikely that congenitally blind individuals would show faster reaction times to this type of input. ...
... We chose a cut-off of 650 ms to discriminate between Ad-and C-fibre-mediated responses. This criterion was based on the peripheral conduction distance of afferent input originating from the hand, and on the distribution of reaction times to laser stimuli after blockade of the myelinated fibres Nahra and Plaghki, 2003). The RT analysis that was performed without any a priori on the distribution of the responses, confirmed the validity of our criterion in the adaptive staircase algorithm. ...
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.
... Despite the concomitant activation of A␦-and C-fibers from noxious stimuli and despite the fact that the subjects report the perception of both A␦-fiber-related first pain and delayed C-fiber-related second pain, only evoked potentials with latencies compatible with A␦-fibers are recorded [50,51]. Bromm et al. (1983) showed, as the first group, that ultralate responses with a latency of approximately 1260 ms could be recorded by suppressing the A␦-fiber activity using a preferential block of the superficial radial nerve [52], and this finding has been repeated more recently [53][54][55]. Other experimental techniques have been reported to activate C-fibers selectively (see [29] for review). ...
... LEP ultralate responses have been reported with a latency of approximately 700-1150 ms [5,6,52,54,58,65], although longer latencies (1000-1500 ms) have also been described [59]. This is compatible with results using CHEPs where ultralate responses with latencies >800 ms were identified [55]. ...
... Many studies using both radiant and contact heat have suggested that the amplitude of CHEP and LEP responses correlate well with the stimulus intensity and the perceived pain perception [31,37,40,64,76,[113][114][115]. However, the amplitude of the late as well as ultra-late responses and the perceived pain perception have also been shown to be dissociated under certain circumstances [30,54,58]. ...
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.
... Based on characteristics differentiating Ad-and C-fibres, several methods have been proposed to activate C-fibre afferents selectively [5]. A first method exploits the fact that unmyelinated C-fibres are more resistant to pressure than myelinated A-fibres, and consists in applying prolonged force against a peripheral nerve such as to block selectively the nerve conduction of A-fibres [10,11]. A second method takes advantage of the fact that the distribution density of C-fibres in the epidermis is greater than that of Ad-fibres, and consists in using a very small stimulation surface area to elicit isolated C-fibre responses [12,13]. ...
... Reaction time latencies were used to discriminate between detections triggered by C-fibre input and detections triggered by Ad-fibre input. This is justified by the fact that the nerve conduction velocity of unmyelinated C-fibres is much slower than the nerve conduction velocity of myelinated Adfibres (61 m/s vs. 610 m/s; [8,11,181920). 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]. ...
... This is justified by the fact that the nerve conduction velocity of unmyelinated C-fibres is much slower than the nerve conduction velocity of myelinated Adfibres (61 m/s vs. 610 m/s; [8,11,181920). 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. ...
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.
... In a first experiment, capsaicin was used to induce a selective denervation of capsaicin-sensitive nociceptors [27], and thereby test whether the responses elicited by IES are mediated by this population of afferent fibres. Second, a nerve pressure block was used to induce a temporally dissociated impairment of Ab-, Ad-and C-afferents [26,40], and thus determine the fibre populations contributing to the responses elicited by IES. ...
... Assessments were performed immediately after the end of the treatment, on both the treated (right) and the untreated (left) calves. Ab-fibre function was assessed by testing the ability of the participant to detect a 4-mN Semmes–Weinstein filament [26]. Ad-fibre function was assessed by testing the ability of the participant to detect the cold sensation elicited by touching the skin with a 7-mm diameter metal rod cooled to approximately 10 °C [26]. ...
... Ab-fibre function was assessed by testing the ability of the participant to detect a 4-mN Semmes–Weinstein filament [26]. Ad-fibre function was assessed by testing the ability of the participant to detect the cold sensation elicited by touching the skin with a 7-mm diameter metal rod cooled to approximately 10 °C [26]. Both types of stimuli were repeated five times on the treated skin and five times on the untreated skin. ...
In the past 30years, the study of nociception has relied mostly on thermal stimulation to activate nociceptors selectively. However, thermal stimulation suffers from some important limitations. For this reason, investigators have proposed intra-epidermal electrical stimulation (IES) as an alternative method to activate nociceptors selectively. This method relies on the fact that nociceptors are located mainly in the epidermis, while non-nociceptive fibres terminate more deeply in the dermis. Therefore, provided that the difference in receptor depth is sufficient, electric currents spatially restricted to the epidermal layers might activate nociceptors selectively. Here, we examined whether or not IES provides a fully selective nociceptive input. In a first experiment, we used capsaicin to induce a selective denervation of capsaicin-sensitive nociceptors, and thereby test whether the responses to IES are mediated by this population of afferent fibres. We found that capsaicin abolishes both the behavioural and the electrophysiological responses to IES applied at twice the perceptual threshold. In a second experiment, we applied a nerve pressure block to the superficial radial nerve to induce a temporally dissociated impairment of Abeta-, Adelta- and C-fibre afferents, and thereby determine the fibre populations contributing to the responses elicited by IES. We found that the time course of the blockade of the responses to IES follows closely the time course of the blockade of Adelta-fibres, but not of Abeta-fibres. Taken together, our results provide converging evidence that Adelta-nociceptors can be activated selectively using IES, provided that low intensities of stimulation are used.
... For each participant of the Aδ-fiber group, only the procedure to determine the Aδ-fiber activation threshold was used, and the experimental target temperature was set 5 °C above the Aδ-fiber activation threshold to ensure the stimulation of Aδ fibers without producing any burn lesions (for details, see Lenoir et al. 2018). Participants were asked to qualify the elicited sensation using a list of descriptor words (see Nahra and Plaghki 2003) to ensure that it was compatible with the activation of the target fiber. Accordingly, participants of the C-fiber group qualified the sensation elicited by stimuli of the target temperature as warm, while participants of the Aδ-fiber group qualified the sensation as pricking. ...
... Laser stimuli were applied on either the left or the right hand depending on the stimulation blocks. Across blocks, the visual stimulus was presented either next to the stimulated hand (ipsilateral condition), or next to the opposite non-stimulated hand (contralateral condition) a list of descriptor words (Nahra and Plaghki 2003). A trial was discarded and repeated if the laser stimulus was not perceived, if the C-fiber laser stimulus was qualified as pricking, or if the Aδ-fiber laser stimulus was qualified as warm. ...
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.
... Nerve block placement. We initiated a nerve compression block over the left superficial radial nerve following validated procedures (Ziegler et al., 1999;Nahra and Plaghki, 2003;Forstenpointner et al., 2019): while the left hand rested in semi-prone position, a ;1-inch cloth tourniquet was placed over the left forearm ;7 cm from the wrist. A five-pound weight was dangled from the tourniquet, similar to the weights used in some nerve compression studies (Wahren et al., 1989;Fig. ...
... 2). This technique often takes an hour to achieve loss of touch and cold perception (Nahra and Plaghki, 2003), but does not affect major blood vessels or induce significant pain (Wasner et al., 2004). The block was released within a common safety time window of 90 min for healthy research participants (Forstenpointner et al., 2019). ...
Gentle stroking of the skin is a common social touch behavior with positive affective consequences. A preference for slow versus fast stroking of hairy skin has been closely linked to the firing of unmyelinated C-tactile (CT) somatosensory afferents. Because the firing of CT afferents strongly correlates with touch pleasantness, the CT pathway has been considered a social-affective sensory pathway. Recently, ablation of the spinothalamic pathway- thought to convey all C-fiber sensations- in patients with cancer pain impaired pain, temperature, and itch, but not ratings of pleasant touch. This suggested integration of afferent A and CT fiber input in the spinal cord, or mechanoreceptive A-fiber contributions to computations of touch pleasantness in the brain. However, contribution of mechanoreceptive A-fibers to touch pleasantness, in humans without pain, remains unknown. In the current, single-blinded study, we performed two types of peripheral nerve blocks in healthy adults to temporarily eliminate the contribution of A-fibers to touch perception. Our findings show that when mechanoreceptive A-fiber function is greatly diminished, the perceived intensity and pleasantness of both gentle stroking and deep pressure are nearly abolished. These findings demonstrate that explicit perception of the pleasantness of CT-targeted brushing and pressure both critically depend on afferent A-fibers.
... Several studies already aimed at preferentially activating specific types of thermosensitive afferents, mainly using electroencephalography (EEG) and the recording of event-related brain potentials (ERPs) [9]. For example, brief laser heat stimuli applied onto the skin generate laser-evoked brain potentials (LEPs) that are thought to mainly result from the activation of one class of polymodal nociceptors: so-called 'Type 2' (quickly-adapting) mechano-and heatsensitive Aδ fiber nociceptors (AMH-2) [10,11]. Although such stimuli are also expected to activate quickly-adapting C fiber thermonociceptors, co-activation of these unmyelinated afferents does not elicit any evident brain activity compatible with their slow conduction velocities [12,13]. ...
... The continuous ratings were digitized at 1000 Hz with an analog/ digital converter (USB-6343, National Instruments, Texas) and the two epochs of each condition were then averaged. Furthermore, at the end of each 75-s stimulus, subjects were asked to describe the quality of the sensation by selecting one or more descriptors from the following list: 'not perceived', 'light touch', 'touch', 'tingling', 'pricking', 'warm', 'hot', 'burning', 'cool', 'cold' and 'humid' [10]. These reports lead to an average inter-stimulus interval of 50 seconds and the experiment lasted approximately 20 minutes. ...
Thermosensation is crucial for humans to probe the environment and detect threats arising from noxious heat or cold. Over the last years, EEG frequency-tagging using long-lasting periodic radiant heat stimulation has been proposed as a means to study the cortical processes underlying tonic heat perception. This approach is based on the notion that periodic modulation of a sustained stimulus can elicit synchronized periodic activity in the neuronal populations responding to the stimulus, known as a steady-state response (SSR). In this paper, we extend this approach using a contact thermode to generate both heat- and cold-evoked SSRs. Furthermore, we characterize the temporal dynamics of the elicited responses, relate these dynamics to perception, and assess the effects of displacing the stimulated skin surface to gain insight on the heat- and cold-sensitive afferents conveying these responses. Two experiments were conducted in healthy volunteers. In both experiments, noxious heat and innocuous cool stimuli were applied during 75 seconds to the forearm using a Peltier-based contact thermode, with intensities varying sinusoidally at 0.2 Hz. Displacement of the thermal stimulation on the skin surface was achieved by independently controlling the Peltier elements of the thermal probe. Continuous intensity ratings to sustained heat and cold stimulation were obtained in the first experiment with 14 subjects, and the EEG was recorded in the second experiment on 15 subjects. Both contact heat and cool stimulation elicited periodic EEG responses and percepts. Compared to heat stimulation, the responses to cool stimulation had a lower magnitude and shorter latency. All responses tended to habituate along time, and this response attenuation was most pronounced for cool compared to warm stimulation, and for stimulation delivered using a fixed surface compared to a variable surface.
... Previously, we tested SSP with stimuli of fast rate of rise (Raz et al. 2015), increasing the likelihood of selective activation of A-delta fibers (Yomans and Proudfit 1996;Zachariou et al. 1997;Nahra and Plaghki 2003). However, SSP was tested by measuring heat pain threshold and perceived pain intensity. ...
... Considering the aforementioned, our previous psychophysical finding showing greater SSP in hairy than in glabrous skin led us to conclude that low threshold AMH-II are the dominant subserving system of SSP (Raz et al. 2015). This interpretation was reinforced by the use of stimuli of fast rate of rise that were found to selectively activate A-delta fibers (Yarnitsky et al. 1992;Yomans and Proudfit 1996;Zachariou et al. 1997;Nahra and Plaghki 2003). ...
Although spatial summation of pain (SSP) is central to the processing of pain intensity and quality, its mechanism is not fully understood. We previously found greater heat SSP in hairy than in glabrous skin, suggesting that perhaps A-mechano-heat II (AMH-II) nociceptors are the dominant subserving system. In order to further explore the role of A-delta fibers in heat-induced SSP, we analyzed the electrophysiological correlates of SSP under conditions that minimize the influence of skin thicknesses. Among 17 subjects, fast rate of rise (70 °C/sec) heat stimuli that induced a pre-fixed, similar, SSP magnitude for hairy and glabrous skin were repeatedly administered using large and small probes, during which time the contact heat-evoked potentials (CHEPs) and pain ratings were recorded. Both N2 and P2 amplitudes were larger in hairy than in glabrous skin, but a differential effect of SSP was found on the CHEPs. Despite similar psychophysical SSP in hairy and glabrous skin, the electrophysiological SSP reflected in N2 but not P2 amplitude was larger in hairy skin. Nevertheless, regardless of skin type, SSP was manifested by an increase in P2 amplitudes. Considering the uniform psychophysical SSP for the two skin types, the fast stimulation rate and lower activity of AMH-II in glabrous skin, a greater electrophysiological SSP in hairy than in glabrous skin may suggest that SSP is mainly subserved by AMH nociceptors. The overall SSP effect, manifested in greater P2 amplitude, may reflect specific brain responses aimed to prepare the individual to an increased potential tissue damage.
... 32 Laser-evoked potentials show clear components at latencies compatible with the conduction velocity of Ad fibers. 6 The components reflecting the later arrival of the C-fiber input to the cortex 33,45 are much more difficult to detect because of the lower saliency content of the C-fiber sensation after the Ad-fiber sensation. For this reason, C-LEPs have been initially suggested to be only detectable when the concomitant activation of Ad fibers was avoided or reduced. ...
... For this reason, C-LEPs have been initially suggested to be only detectable when the concomitant activation of Ad fibers was avoided or reduced. 41,45 However, it has been recently shown that when (1) laser pulses are delivered within a small skin territory and (2) LEP peaks are aligned in the time domain, C-LEPs can be clearly detected even when preceded by an Ad-LEP. 15 Indeed, given the slow and variable conduction velocity of C fibers, 55 changes of just 1 cm in their length result in latency shifts of ;10 milliseconds. ...
The neural mechanisms of the powerful analgesia induced by touching a painful body part are controversial. A long tradition of neurophysiological studies in anaesthetized, spinal animals indicate that touch can gate nociceptive input at spinal level. In contrast, recent studies in awake humans have suggested that supra-spinal mechanisms can be sufficient to drive touch-induced analgesia. To investigate this issue, we evaluated the modulation exerted by touch on established electrophysiological markers of nociceptive function at both subcortical and cortical levels in humans. Aδ and C skin nociceptors were selectively activated by high-power laser pulses. As markers of subcortical and cortical function, we recorded the Laser-Blink Reflex (LBR), which is generated by brainstem circuits prior to the arrival of nociceptive signals at the cortex, and Laser-Evoked Potentials (LEPs), which reflect neural activity of a wide array of cortical areas. If subcortical nociceptive responses are inhibited by concomitant touch, supraspinal mechanisms alone are unlikely to be sufficient to drive touch-induced analgesia. Touch induced a clear analgesic effect, suppressed the LBR, and inhibited both Aδ-fibre and C-fibre LEPs. Thus, we conclude that touch induced-analgesia is likely to be mediated by a subcortical gating of the ascending nociceptive input, which in turn results in a modulation of cortical responses. Hence, supra-spinal mechanisms alone are not sufficient to mediate touch-induced analgesia.
... Although heat-sensitive C afferents must be excited also by this stimulus, the only suggestion of a C fiber response was the attenuated positive wave shown around 660 ms in Figure 2B. This has been observed in some laser evoked potential studies [15,29], but the fiber type, if any, associated with this response is unknown and, in our study, there was no psychophysical characteristic associated with it. That is, the subjects did not report on a second, delayed, heat sensation after the 51 °C stimuli. ...
... 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. ...
... A stainless steel reference electrode that serves as anode is concentrically located and has an inner diameter of 22 mm and an outer diameter of 40 mm. To avoid interference of handedness, handedness was determined using the Flinders Handedness survey (Nicholls et al. 2013), and the arm onto which HFS was applied was balanced across participants. ...
... Note the increase of the N1 wave elicited by vibrotactile stimuli delivered to the treated arm at T1 and T2. Ziegler et al. (1999) applied prolonged pressure to the superficial branch of the radial nerve to block the conduction of myelinated afferents without affecting the conduction of unmyelinated afferents (unmyelinated afferents are more resistant to pressure than myelinated afferents; Nahra and Plaghki 2003;Torebjörk and Hallin 1973;Yarnitsky and Ochoa 1991). During nerve compression, they observed substantially reduced pricking pain to punctate stimuli (75%). ...
High frequency electrical stimulation (HFS) of the human skin induces increased pain sensitivity in the surrounding unconditioned skin. The aim of the present study was to characterize the relative contribution of the different types of nociceptive and non-nociceptive afferents to the heterotopical hyperalgesia induced by HFS. In seventeen healthy volunteers (9 men and 8 women) we applied HFS to the ventral forearm. The intensity of perception and event-related brain potentials (ERPs) elicited by vibrotactile stimuli exclusively activating non-nociceptive low-threshold mechanoreceptors and thermonociceptive stimuli exclusively activating heat-sensitive nociceptive afferents were recorded before and after HFS. The previously-described mechanical hyperalgesia following HFS was confirmed by measuring the changes in the intensity of perception elicited by mechanical punctate stimuli. HFS increased the perceived intensity of both mechanical punctate and thermonociceptive stimuli applied to the surrounding unconditioned skin. The time course of the effect of HFS on the perception of mechanical and thermal nociceptive stimuli was similar. This indicates that HFS does not only induce mechanical hyperalgesia but also induces heat hyperalgesia in the heterotopical area. Vibrotactile ERPs were also enhanced after HFS, indicating that non-nociceptive somatosensory input could contribute to the enhanced responses to mechanical pinprick stimuli. Finally, the magnitude of thermonociceptive ERPs was unaffected by HFS, indicating that type II A-fibre mechanoheat nociceptors, thought to be the primary contributor to these brain responses, do not significantly contribute to the observed heat hyperalgesia.
... Painful stimulation was generated with an infrared CO 2 laser stimulator, a system able to generate predictable levels of punctuate pain, after the amount of energy delivered. 12 We worked under the hypothesis that the reported pain intensity would display a linear relation to the intensity of stimulation in the conditions of the study because (i) such linearity is suggested for VAS in the range of moderate pain (30Y50/100) 6 and (ii) the cross-modality matching of force of handgrip to warmth on the arm following a Stevens power function exponent is close to 1 (0.96). 13 ...
... We chose this paradigm to compare the parameters from tPM with VAS, with the best possibility to collect data encoding the intensity of a transient punctuate stimulation, 12,16 with the aim to validate these parameters for assessment of transient pain not to dispute the well-established indication for the use of VAS in clinical conditions of ongoing pain. We must remind that a handgrip dynamometer had already been used to assess the intensity of warmth in the Stevens historical cross-modality matching studies, in which the only painful stimulus studied was electrical stimulation through fingers. ...
Transient pain in humans is usually quantified using visual analog or numeric rating scales, but no assessment method has yet been validated in real time during such stimulation.
To validate a transient pain monitor, healthy volunteers submitted to stimulations generated by a CO(2) laser at graded levels of stimulation were trained to close the dominant hand around a handgrip dynamometer as strongly as they felt the pain, and the signal was computerized.The parameters recorded for each response were the peak intensity, the area under the curve, and pain expressed on a visual analog scale as a control. The volunteers underwent a second session 1 week later to assess reproducibility.
The 3 parameters studied had a similar capacity to report the intensity of stimulation. The peak intensity showed many similarities with the visual analog scale, although a downward drift of the values throughout the session was observed. The area under the curve displayed a greater interindividual variability than other parameters, but it was better to assess low-intensity stimulation; a better fit for crossover designs was also suggested with the area under the curve.
This study validates in human volunteers under a laser stimulation of skin the metrological properties of an electronic handgrip device to assess the intensity of transient punctuate pain (compared with visual analog scale). The transient pain monitor validated here should now be tested in the clinical context.
... Although heat-sensitive C afferents must be excited also by this stimulus, the only suggestion of a C fiber response was the attenuated positive wave shown around 660 ms inFigure 2B. This has been observed in some laser evoked potential studies [15,29], but the fiber type, if any, associated with this response is unknown and, in our study, there was no psychophysical characteristic associated with it. That is, the subjects did not report on a second, delayed, heat sensation after the 51 °C stimuli. ...
... 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.
... Thus, the first goal of this study was to combine the QST, in the form of electrical stimuli provided by a commercial PainVision system, with simultaneous EEG recording. Aδ-fibers is mainly responsible for heat pain detection (Nahra and Plaghki, 2003), intraepidermal electrical nociception activates both C-and Aδfibers (Inui et al., 2002;Tanaka et al., 2021). The supraspinal mechanism underlying pain signal processing in distinct phenotypes of nociception remains elusive. ...
Introduction: The complex and multidimensional nature of pain poses a major challenge in clinical pain assessments. In this study, we aimed to evaluate a novel approach combining quantitative sensory testing (QST) with event-related potential measurements for assessment of experimental pain in healthy individuals.
Methods: QST was performed with a commercial device (PainVision, PS-2100), and numeric rating scale (NRS) scores after exposure to different sensory stimuli were reported by the participants. Resting-state electroencephalography (EEG) was simultaneously performed to capture the cortical responses to peripheral stimulation.
Results: Pain scores increased with the intensity of stimuli, with mean NRS scores of 2.7 ± 1.0 after mild stimuli and 5.6 ± 1.0 after moderate stimuli. A reproducible, significant P2-N2 complex was evoked by both mild and moderately painful stimuli, but not by non-painful stimuli. The latency of pain-related potentials was not significantly different between stimuli. The amplitudes of both P2 and N2 components significantly increased when intense nociception was applied, and the increments mainly originated from theta oscillations.
Conclusion: The combination of QST with EEG was feasible for subjective and objective pain assessment. Distinct patterns of brain potentials were associated with the phenotype of the peripheral stimuli (e.g., noxious versus. innoxious, high versus. low pain intensity).
... 38,39 Furthermore, it was not supported by fiber-specific pain qualities (2) 5 and rapidly increasing laser stimulation does not exclusively activate A fibers (3). 22 With different rates of heat stimulation, it was shown that the periaqueductal grey (PAG) shows marked differences in the descending control of spinal nociception mediated by C and Ad fibers 19,32 with the activation of functionally distinct neuron populations (4). 13 The latter, in particular, seems interesting because it has also been shown that OA underlies an endogenous inhibitory mechanism originating in the PAG, 8,36 a key structure for descending pain inhibition. ...
Introduction:
Offset analgesia describes the effect of a slightly reduced nociceptive stimulus, resulting in a disproportionate large reduction in the pain perception. This effect may be associated with descending pain inhibition, but parameters influencing this phenomenon are poorly understood.
Objectives:
In this study, 2 separate experiments were conducted to investigate both, the spatial aspects of offset analgesia and the influence of different rates of temperature rise.
Methods:
In both experiments, 29 healthy participants received individualized and heat-based offset analgesia paradigms applied to the forearm, with continuous assessment of pain intensity. In experiment 1, offset analgesia paradigms with 3 different rates of temperature rise were applied, whereas in experiment 2, offset analgesia paradigms with 2 different heat application areas were used.
Results:
The results of experiment 1 showed that different temperature rates had no effect on the offset analgesia response (P > 0.05). Experiment 2, however, showed the influence of the size of a stimulated area on offset analgesia (P = 0.009), which can be explained mainly by the influence of spatial summation of pain and habituation processes.
Conclusions:
The study showed a lack of influence of different temperature rates on offset analgesia; however, spatial aspects of offset analgesia could be identified. These are most likely based on spatial summation of pain and altered adaptation to pain.
... El efecto analgésico del contacto manual ha sido cuantificado (385), demostrando cómo la estimulación táctil de una duración de solo 1,5 segundos resultó en una reducción de la percepción dolorosa, siendo este fenómeno comprobado por más autores (386)(387)(388). ...
Effects of diaphragm muscle treatment in shoulder pain and mobility in subjects with rotator cuff injuries.
Introduction: The rotator cuff inflammatory or degenerative pathology is the main cause of shoulder pain. The shoulder and diaphragm muscle have a clear relation through innervation and the connection through myofascial tissue. In the case of nervous system, according to several studies the phrenic nerve has communicating branches to the brachial plexus with connections to shoulder key nerves including the suprascapular, lateral pectoral, musculocutaneous, and axillary nerves, besides, the vagal innervation that receives the diaphragm and their connections with the sympathetic system could make this muscle treatment a remarkable way of pain modulation in patients with rotator cuff pathology. To these should be added a possible common embryological origin in some type of vertebrates. Considering the connection through myofascial system, the improving of chest wall mobility via diaphragm manual therapy could achieve a better function of shoulder girdle muscles with insertion or origin at ribs and those that are influenced by the fascia such as the pectoralis major muscle, latissimus dorsi and subscapularis.
Objectives:
• Main objective:
To compare the immediate effect of diaphragm physical therapy in the symptoms of patients with rotator cuff pathology regarding a manual treatment over shoulder muscles.
• Specific objectives:
1. To evaluate the immediate effectiveness of each of the three groups in shoulder pain using a numerical pain rating scale (NPRS) and compare between them.
27
2. To evaluate the immediate effectiveness of each of the three groups in shoulder range of motion (ROM) using an inclinometer and compare between them. 3. To evaluate the immediate effectiveness of each of the three groups in pressure pain threshold (PPT) using an algometer and compare between them.
Material and method: A prospective, randomized, controlled, single-blind (assessor) trial with a previous pilot study in which a final sample size of 45 subjects was determined to people diagnosed with rotator cuff injuries and with clinical diagnosis of myofascial pain syndrome at shoulder. The sample were divided into 3 groups of treatment (15 subjects per group):
1. A direct treatment over the shoulder by ischemic compression of myofascial trigger points (MTP) (control / rotator cuff group).
2. Diaphragm manual therapy techniques (diaphragm group).
3. Active diaphragm mobilization by hipopressive gymnastic (hipopressive group).
The pain and range of shoulder motion were assessed before and after treatment in all the participants by inclinometry, NPRS of pain in shoulder movements and algometry. The data obtained were analyzed by an independent (blinded) statistician, who compared the effects of each one of the treatments using the Student’s t-test for paired samples or the Wilcoxon signed rank test, and calculated the post -intervention percentage of change in every variable. An analysis of variance (ANOVA) followed by the post-hoc test or a non-parametric Kruskal-Wallis test for non-parametric multiple-groups comparisons were performed to compare pre- to post-intervention outcomes between groups. Effect-size estimates of each intervention and between groups were calculated to allow interpretation of results in a more functional and meaningful way.
Results:
Both the control group and diaphragm group showed a statistically (p< 0.005) and clinically significant improvement, as well as a significant effect size (moderate to strong), on the NPRS in shoulder flexion and abduction movements. Regarding NPRS in shoulder external rotation, only the control group obtained a significant effect size. There was a significant increase in shoulder abduction and external rotation ROM (p<
Efectos del tratamiento del músculo diafragma en el dolor y la movilidad del hombro en sujetos con patología del manguito rotador.
28
0.001) with a significant effect size in the control group. The PPT at the xiphoid process of the sternum showed a statistically (p< 0.001) and clinically significant improvement in the diaphragm group. The hipopressive gymnastic treatment was found to be no clinically effective in the shoulder pain and mobility, and showed a less efficacy than the other two groups.
Conclusion:
Both the shoulder non-direct treatment by a protocol of diaphragm manual therapy techniques and the rotator cuff MTP intervention showed been clinically effective in reducing pain (NPRS) immediately in shoulder flexion and abduction movements. The ROM assessment improvements obtained post- intervention by the diaphragm group have not been enough to consider them as clinically significant. The control group has obtained a significant effect size in shoulder abduction and external rotation ROM improvement. Both the control group and the diaphragm group treatments have been more effective in improving shoulder pain and mobility than the hipopressive group. The control group intervention has been the most effective in improving shoulder external rotation pain and mobility. The diaphragm group intervention was more effective in improving PPT at the xiphoid process than the other groups. Neither the effect size nor clinical significance proves the short-term benefit of the hipopressive gymnastic treatment in shoulder pain and mobility. Future studies are necessary to show the effectiveness of the diaphragm manual therapy applied in several sessions to determine its long-term effects in shoulder pain and mobility.
... This phenomenon has been demonstrated by more authors. [82][83][84] Even the effect of a heat stimulus applied to a part of the body, such as the hand, has been shown to activate a part of the brain, the anterior cingulate cortex, which is related to a wide range of autonomous functions, with touch pleasant and with emotions. 85,86 These investigations help to explain how prolonged contact on the skin, as was done in the 5 studies 20,27,29,35,48 that used sham groups without reaching therapeutic barriers, could alter pain perception and create a significant hypoalgesic effect. ...
Objectives
To analyze the effects at the musculoskeletal level of manual treatment of the diaphragm muscle in adults.
Data Sources
Systematic review using four databases: PubMed, Science Direct, Web of Science and Scopus.
Study selection and data extraction
Two independent reviewers applied the selection criteria and assessed the quality of the studies using the Physiotherapy Evidence Database (PEDro) scale for experimental studies. A third reviewer intervened in cases where a consensus had not been reached. A total of 9 studies were included in the review.
Results
Manual therapy directed to the diaphragm has been shown to be effective in terms of the immediate increase in diaphragmatic mobility and thoracoabdominal expansion. The immediate improvement in the posterior muscle chain flexibility test is another of the most frequently found findings in the evaluated studies. Limited studies show improvements at the lumbar and cervical level in the range of motion and in pain.
Conclusion
Manual diaphragm therapy has shown an immediate significant effect on parameters related to costal, spinal and posterior muscle chain mobility. Further studies are needed, not only to demonstrate the effectiveness of manual diaphragm therapy in the long term and in symptomatic populations, but also to investigate the specific neurophysiological mechanisms involved in this type of therapy.
... After each trial, participants qualified the sensation elicited by the laser stimulus using a list of descriptor words [20]. If the laser stimulus was not perceived, if a C-stimulus was qualified as pricking or if an Aδstimulus was qualified as warm, the trial was discarded and repeated. ...
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 studies showed that, during mechanical block, the sensations of cold and touch disappear almost simultaneously, while the pinprick sensation evoked by laser stimuli disappears over a longer period. 24 These experimental observations indicate that the myelinated Ad fibres mediating cold sensation are larger than the myelinated Ad fibres mediating mechano-heat sensations. 25 In this patient, we found that C-fibre-mediated laserevoked potentials were spared. ...
In this clinical and neurophysiological study using a novel cold stimulator, we aim at investigating whether cold-evoked potentials (CEPs) may prove to be a reliable diagnostic tool to assess trigeminal small-fibre function. Using a novel device consisting of micro-Peltier elements, we recorded CEPs after stimulating the supraorbital and perioral regions and the hand dorsum in 15 healthy participants and in 2 patients with exemplary facial neuropathic pain conditions. We measured peripheral conduction velocity at the upper arm and studied the brain generators using source analysis. In healthy participants and patients, we also compared CEPs with laser-evoked potentials. In the healthy participants, cold stimulation evoked reproducible scalp potentials, similar to those elicited by laser pulses, although with a latency of about 30 ms longer. The mean peripheral conduction velocity, estimated at the upper arm, was 12.7 m/seconds. The main waves of the scalp potentials originated from the anterior cingulate gyrus and were preceded by activity in the bilateral opercular regions and bilateral dorsolateral frontal regions. Unlike laser stimulation, cold stimulation evoked scalp potential of similar amplitude across perioral, supraorbital, and hand dorsum stimulation. In patients with facial neuropathic pain, CEP recording showed the selective damage of cold pathways providing complementary information to laser-evoked potential recording. Our clinical and neurophysiological study shows that this new device provides reliable information on trigeminal small fibres mediating cold sensation and might be useful for investigating patients with facial neuropathic pain associated with a distinct damage of cold-mediating fibres.
... In both experiments, the order of the blocks was counterbalanced across participants. Furthermore, in Experiment 2, reaction-times to the suprathreshold stimuli were recorded, and participants were asked to describe the quality of the percept elicited by suprathreshold stimuli by selecting one item from a list of seven descriptors for Aδ-heat stimuli ("not perceived", "light touch", "touch", "tingling", "warm", "pricking" and "burning") and a list of five descriptors for Aβ-vibrotactile ("not perceived", "light touch", "touch", "flutter" and "vibration") (Ochoa & Torebjork, 1983;Nahra & Plaghki, 2003;Mouraux et al., 2010). Suprathreshold Aδ-heat stimuli consisted of 60°C CO2 laser pulses. ...
Key points:
Deep continuous theta burst stimulation (cTBS) of the right operculo-insular cortex delivered with a double cone coil selectively impairs the ability to perceive thermonociceptive input conveyed by Aδ-fiber thermonociceptors without concomitantly affecting the ability to perceive innocuous warm, cold or vibrotactile sensations. Unlike deep cTBS, superficial cTBS of the right operculum delivered with a figure-of-eight coil does not affect the ability to perceive thermonociceptive input conveyed by Aδ-fiber thermonociceptors. The effect of deep operculo-insular cTBS on the perception of Aδ-fiber input was present at both the contralateral and the ipsilateral hand. The magnitude of the increase in Aδ-heat detection threshold induced by the deep cTBS was significantly correlated with the intensity of the cTBS pulses. Deep cTBS delivered over the operculo-insular cortex is associated with a risk of TMS-induced seizure.
Abstract:
Previous studies have suggested a pivotal role of the insular cortex in nociception and pain perception. Using a double-cone coil designed for deep transcranial magnetic stimulation, our objective was to assess (1) whether continuous theta burst stimulation (cTBS) of the operculo-insular cortex affects differentially the perception of different types of thermal and mechanical somatosensory inputs, (2) whether the induced after-effects are lateralized relative to the stimulated hemisphere and (3) whether the after-effects are due to neuromodulation of the insula or neuromodulation of the more superficial opercular cortex. Seventeen participants took part in two experiments. In experiment 1, thresholds and perceived intensity of Aδ- and C-fiber heat pain elicited by laser stimulation, non-painful cool sensations elicited by contact cold stimulation and mechanical vibrotactile sensations were assessed at the left hand before, immediately after and 20 minutes after deep cTBS delivered over the right operculo-insular cortex. In experiment 2, Aδ-fiber heat pain and vibrotactile sensations elicited by stimulating the contralateral and ipsilateral hands were evaluated before and after deep cTBS or superficial cTBS delivered using a flat figure-of-eight coil. Only the threshold to detect Aδ-fiber heat pain was significantly increased 20 minutes after deep cTBS. This effect was present at both hands. No effect was observed after superficial cTBS. Neuromodulation of the operculo-insular cortex using deep cTBS induces a bilateral reduction of the ability to perceive Aδ-fiber heat pain, without concomitantly affecting the ability to perceive innocuous warm, cold or vibrotactile sensations. This article is protected by copyright. All rights reserved.
... Several prospective LEP studies in patients with peripheral and central nervous system disease or healthy controls have shown the usefulness of LEPs as a technique for investigation of the nociceptive pathway, such as familial amyloid neuropathy (Ng Wing Tin et al., 2015), Charcot-Marie-Tooth 1A (Pazzaglia et al., 2010), Fabry's disease (Valeriani et al., 2004), and multiple sclerosis (Truini et al., 2012), as well as to assess healthy subjects (Hu et al., 2014). However, the available evidence regarding LEPs for assessing the Cfiber pathways is insufficient to make recommendations because C-fiber LEPs are not detectable unless specific techniques are used (Magerl et al., 1999;Nahra and Plaghki, 2003;Jankovski et al., 2013;Hu et al., 2014) to avoid or reduce the concomitant activation of A␦ fiber. Additionally, disadvantages of LEPs as a clinical diagnostic tool are the need for expensive equipment and that the procedure is complex (Treede et al., 2003;Hansen et al., 2015). ...
Neuropathic pain can result from neuronal hyperexcitability and complex interactions of the nociceptive pathways. Intraepidermal electrical stimulation (IES) is a novel technique that can selectively activate Aδ and C fibers. To investigate patterns of changes in Aδ- and C-mediated brain responses in patients with neuropathic pain using IES, we recorded pain-related evoked potential (PREP) after IES of Aδ and C fibers in 20 patients with neuropathic pain and 15 age-matched healthy volunteers. We evaluated PREP latencies, amplitudes, and amplitude ratios of PREPs after C/Aδ-fiber stimulation. PREP amplitudes after Aδ-fiber stimulation tended to be smaller in the patient group, whereas there were no significant differences in amplitudes after C-fiber stimulation between the patient and normal control groups. PREP amplitude ratios after C/Aδ-fiber stimulation were significantly greater in the patient group than in the control group, and the higher ratio tended to be associated with a greater visual analog scale score. Patients with neuropathic pain had a tendency towards decreased Aδ amplitudes and significantly increased C/Aδ PREP amplitude ratios and this ratio appeared to be associated with the intensity of pain. Our findings suggest that decreased inhibition of the Aδ to C nociceptive systems is associated with generation of neuropathic pain.
... To block selectively the conduction of myelinated Ybers, pressure was applied to the left superYcial branch of the radial nerve, at the level of the wrist (Magerl et al., 1999;Nahra and Plaghki, 2003;Mouraux et al., 2010). Participants were comfortably seated in a chair with the left forearm immobilized on an armrest with a handle bar in their left hand preventing any pronation or supination of the hand and forearm. ...
The recording of event-related brain potentials triggered by a transient heat stimulus is used extensively to study nociception and diagnose lesions or dysfunctions of the nociceptive system in humans. However, these responses are related exclusively to the activation of a specific subclass of nociceptive afferents: quickly-adapting thermonociceptors. In fact, except if the activation of Aδ fibers is avoided or if A fibers are blocked, these responses specifically reflect activity triggered by the activation of Type 2 quickly-adapting A fiber mechano-heat nociceptors (AMH-2). Here, we propose a novel method to isolate, in the human electroencephalogram (EEG), cortical activity related to the sustained periodic activation of heat-sensitive thermonociceptors, using very slow (0.2 Hz) and long-lasting (75 s) sinusoidal heat stimulation of the skin between baseline and 50 °C. In a first experiment, we show that when such long-lasting thermal stimuli are applied to the hand dorsum of healthy volunteers, the slow rises and decreases of skin temperature elicit a consistent periodic EEG response at 0.2 Hz and its harmonics, as well as a periodic modulation of the magnitude of theta, alpha and beta band EEG oscillations. In a second experiment, we demonstrate using an A fiber block that these EEG responses are predominantly conveyed by unmyelinated C fiber nociceptors. The proposed approach constitutes a novel mean to study C fiber function in humans, and to explore the cortical processing of tonic heat pain in physiological and pathological conditions.
... The analgesic effects of touch has been quantified by Mancini et al. (2014); their experiments demonstrated how tactile stimulation lasting only 1.5 s resulted in reduced pain perception. This phenomenon is supported both recently ( Inui et al., 2006;Nahra and Plaghki, 2003) and in earlier works ( Kakigi and Watanabe, 1996). Even the effect of a warm stimuli applied to a part of the body, such as the hand, has shown to activate the rostal anterior cingulate cortex, which is known to correlate with pleasant touch and emotions ( Rolls et al 2003Rolls et al , 2008). ...
In clinical practice, Osteopaths and Manual Therapists commonly direct treatment towards the diaphragm by the use of a ‘Diaphragm Release’. Currently, there is paucity within the literature to support the use of this technique, specifically in pain outcomes. This research aims to support a neurophysiological mechanism based upon the osteopathic principle “The body is a unit”. Demonstrating that directing treatment to distal tissue which is neurologically related can reduce pain in the originating spinal segments. This study investigated the immediate hypoalgesic effects of a ‘Diaphragm Release’ on pain pressure thresholds in the cervical spine. A single-blind, randomised, sham-controlled, repeated measures within subject, crossover design was conducted on 17 asymptomatic subjects. Pain pressure thresholds were measured bilaterally in the C4 paraspinal musculature, lateral end of the clavicle and upper third of the tibialis anterior before and after a ‘Diaphragm Release’. Results demonstrated a statistically significant hypoalgesic effect was only found in the spinal segment C4 in both the right (p= 0.016) and left (p= 0.004) sides. Averaging the hypoalgesic effect from both sides equates to a 17.17% change which is considered clinically significant, the effect magnitude was calculated to be small but educationally significant for the right (d= 0.26) and left (d= 0.40) sides. This study supports a novel neurophysiological mechanism, Regional Interdependent Inhibition, to induce a hypoalgesic state at segmentally related spinal segments, specifically C4. Suggesting that directing treatment towards the diaphragm, using a ‘Diaphragm Release’, could induce an immediate clinically and statistically significant hypoalgesic effect local to the fourth cervical segment due to its relationship with the phrenic nerve.
... selectively the conduction of myelinated fibres, pressure was applied to the left superficial branch of the radial nerve, at the level of the wrist (Magerl et al. 1999; Nahra & Plaghki, 2003; Mouraux et al. 2010). Participants were comfortably seated in a chair with the left forearm immobilized on an armrest in a neutral pronation/supination position with a handle bar in their left hand preventing any pronation or supination of the hand and forearm. ...
... A-fiber nerve conduction block. In order to block selectively the conduction of myelinated fibers, pressure was applied to the left superficial branch of the radial nerve, at the level of the wrist Nahra & Plaghki, 2003;Mouraux et al., 2010). Participants were comfortably seated in a chair with the left forearm immobilized on an armrest in a neutral pronation/supination position with a handle bar in their left hand preventing any pronation or supination of the hand and forearm. ...
Key points:
It is believed that secondary hyperalgesia (the increased sensitivity to mechanical nociceptive stimuli that develops after cutaneous tissue injury in the surrounding uninjured skin) is mediated by a subclass of nociceptors: the slowly adapting A-fibre mechano-heat nociceptors (AMH-type I). Here we tested this hypothesis. By using intense long-lasting heat stimuli, which are known to activate these slowly adapting AMH-type I nociceptors, we show that the perceived intensity elicited by these stimuli is not increased in the area of secondary hyperalgesia. Moreover, we show that during an A-fibre nerve conduction block the perception elicited by the long-lasting heat stimuli is significantly reduced in a time window that matches the response profile of the AMH-type I nociceptors. AMH-type I nociceptors contribute to the perception of sustained heat, but they do not mediate secondary hyperalgesia. Therefore, we propose that secondary hyperalgesia is mediated by high threshold mechanoreceptors.
Abstract:
Secondary hyperalgesia refers to the increase in sensitivity to mechanical nociceptive stimuli delivered outside the area of tissue injury. Previous studies have suggested that secondary hyperalgesia is mediated by a specific class of myelinated nociceptors: slowly adapting A-fibre mechano- and heat-sensitive (AMH) type I nociceptors. Here, we tested this hypothesis by examining whether long-lasting heat stimuli, which are known to activate AMH-type I nociceptors, elicit enhanced responses when delivered to the area of secondary hyperalgesia induced by high frequency electrical stimulation of the skin (HFS). Before and 20 min after HFS, sustained 30 s radiant heat stimuli were delivered to the area of increased mechanical pinprick sensitivity while participants continuously rated intensity of perception using an online visual analog scale (0-100 mm). After HFS, no significant enhancement of heat perception was observed in the area of increased pinprick sensitivity. To establish that myelinated nociceptors actually contribute to the perception of sustained heat, we conducted a second experiment in which sustained heat stimuli were presented before and during an A-fibre nerve conduction block, achieved by applying a rubber band with weights which compresses the superficial radial nerve against the radius. During the block, heat perception was significantly reduced 17-33 s after the onset of the heat stimulus (before: mean = 53 mm, during: mean = 31 mm; P = 0.03), matching the response profile of AMH-type I nociceptors. These results support the notion that AMH-type I nociceptors contribute to the perception of sustained heat, but also show that these afferents do not mediate secondary hyperalgesia.
... Free nerve endings of Aδ and C fibres are located in the epidermis, while mechanoreceptors of the tactile system in the upper layer of the dermis. Radiant heat stimulation by laser beams has been used in the study of nociception and pain perception in humans (Bromm et al 1983, Bragard et al 1996, Magerl et al 1999, Opsommer et al 2001, Nahra and Plaghki 2003, Churyukanov et al 2012. The reason for this trend is that laser stimulation, unlike conventional electrical stimulation, is able to stimulate Aδ-fibres selectively. ...
The in situ electric field in the peripheral nerve of the skin is investigated to discuss the selective stimulation of nerve fibres. Coaxial planar electrodes with and without intra-epidermal needle tip were considered as electrodes of a stimulator. From electromagnetic analysis, the tip depth of the intra-epidermal electrode should be larger than the thickness of the stratum corneum, the electrical conductivity of which is much lower than the remaining tissue. The effect of different radii of the outer ring electrode on the in situ electric field is marginal. The minimum threshold in situ electric field (rheobase) for free nerve endings is estimated to be 6.3 kV m−1. The possible volume for electrostimulation, which can be obtained from the in situ electric field distribution, becomes deeper and narrower with increasing needle depth, suggesting that possible stimulation sites may be controlled by changing the needle depth. The injection current amplitude should be adjusted when changing the needle depth because the peak field strength also changes. This study shows that intra-epidermal electrical stimulation can achieve stimulation of small fibres selectively, because Aβ-, Aδ-, and C-fibre terminals are located at different depths in the skin.
... 20,21 However, a consideration can be made against this hypothesis. Indeed, while laser-pain subjective sensation (VAS) is due to the activation of both Ad and C fibers, 22 the LEP waveforms are generated only by the Ad fiber inputs. Therefore, if the fMV stimulation reduced the C fiber activity, it would dampen the C fiber-related component of the laserpain subjective sensation. ...
Background
Nonpainful tactile and electrical stimulation of the large myelinated fibers reduces spontaneous pain and the amplitude of laser-evoked potentials (LEPs), which represent the most reliable technique to assess the nociceptive pathway function. Focal mechanical vibration stimulates the A afferents selectively; thus, it is conceivable its action on nociceptive pathways. AimThe aim of this study was to investigate the effect of vibratory stimuli, activating either both muscle and skin receptors or cutaneous afferents only on the LEPs and subjective laser-pain rating. Methods
Ten healthy volunteers were studied. The subjects were evaluated in two different sessions to test muscle and skin receptors or cutaneous afferents only. In each session, LEPs were recorded to stimulation of the dorsal hand skin in radial and ulnar territory bilaterally, while the vibratory stimulus was delivered on the radial territory of the right forearm. ResultsThe results showed a substantial stability of the potential N1 and N2/P2 after the two protocols, with a declining trend from the initial to the last test of the same session, probably due to habituation. Accordingly, the laser-pain perception did not change during the experimental setting. Conclusions
We conclude that a vibratory stimulus is ineffective in reducing the laser-evoked potentials and laser-pain perception.
... However, since A d fibre elicited first pain precedes C-fibre elicited second pain, due to the different conduction velocities of the two afferents (approximately 10 m/s for A d fibres and approximately 1 m/s for C-fibres), it can be easily distinguished when stimuli are applied at a remote location such as the hand dorsum (Plaghki and Mouraux, 2003). 'First pain' furthermore is more salient than 'second pain' (Nahra and Plaghki, 2003). Subjects in this study were therefore asked to rate the first sensation experienced during laser stimulation, which set the focus on the A d component. ...
BACKGROUND: Picturing the complexity of pain in human experimental settings has increased the predictivity for clinical pain but requires increasingly complex test batteries. This raises problems in studies in which time is objectively limited, for example by the course of action of an analgesic drug. We addressed the selection of a small yet comprehensive set of pain tests for the use in such a situation.
METHOD: Nineteen different pain measures from 'classical' pain models (n = 9) and a clinically established QST-pain test battery (n = 10), were obtained from 72 healthy volunteers (34 men). The nonparametric correlation structure among the various pain measures was analysed using Ward clustering.
RESULTS: Four clusters emerged, each consisting of highly correlated pain measures. The pain model groups emerged comprised (I) pain thresholds and tolerances to blunt pressure or electrical pain; (II) pain thresholds to thermal stimuli; (III) pain measures obtained following application of punctate mechanical, intranasal CO2 chemical or cutaneous laser heat stimuli; and (IV) detection thresholds to thermal stimuli. The first three clusters agreed with an immediate mechanistic interpretation as reflecting C-fibre mediated pain, thermal pain and Aδ -fibre mediated pain, respectively, whereas the last cluster contained non-painful measures and was disregarded.
CONCLUSIONS: When basing a selection of a small comprehensive set of pain models on the assumption that highly correlated pain measures account for redundant results and therefore, one member of each group suffices an economic yet comprehensive pain study, results suggest inclusion of established C-fibre, Aδ -fibre mediated and thermal pain measures.
... 20,21 However, a consideration can be made against this hypothesis. Indeed, while laser-pain subjective sensation (VAS) is due to the activation of both Ad and C fibers, 22 the LEP waveforms are generated only by the Ad fiber inputs. Therefore, if the fMV stimulation reduced the C fiber activity, it would dampen the C fiber-related component of the laserpain subjective sensation. ...
Our aim was to evaluate whether the focal application of a vibratory stimulation on the skin may change the laser evoked potentials (LEPs) and the laser- pain to pulses delivered on the same cutaneous area. In 10 healthy volunteers, LEPs were recorded after stimulation of the radial and ulnar dorsal hand territories, bilaterally. After each LEP recording, the subjects were asked to rate the laser-pain according to a 100-point VAS. All subjects were evaluated in two different sessions in order to test both effective and sham vibratory stimulation. In each session, the experiment included 2 times: (1) LEPs were recorded without any conditioning vibratory stimulus, (2) LEPs were recorded during effective or sham vibratory stimulation within the right radial territory. No difference in N2/P2 amplitude changes was found between the effective and the sham vibratory stimulation. Also the subjective perception of pain was not influenced by the simultaneous vibratory (effective or sham) stimulation. Our negative results suggest that focal vibratory stimuli, currently used for motor rehabilitation, are not effective as analgesic physical treatment.
... However, purportedly selective stimulation of C-and A-delta fibers by applying these slow and fast rates produced very similar patterns of pain summation and discrimination probably due to the failure of the experimental manipulation to activate the two fiber systems selectively. However, studies from other laboratories, using noxious laser stimulation, show that the sensation of pain produced by fast-rise stimulus is primarily, but not exclusively, a function of A-delta fiber activation (Nahra and Plaghki 2003). Furthermore, animal studies confirmed that highrate as compared with low-rate noxious skin heating evokes significant A-delta fiber mediation responses in the dorsal horn (Zachariou et al. 1997). ...
The underlying mechanism of spatial summation (SS) of pain, an essential component in pain perception and detection, is unknown. Because of the possible differential innervations by A-delta nociceptors and pain sensitivity of hairy and glabrous skin, a comparison of the SS characteristics between the two skin types could contribute to the elucidation of its subserving system and processing. The effect of sex on SS of pain was also evaluated due to the scarcity of information on the subject. Twenty-nine healthy subjects (13 males, 16 females) received four series of heat stimuli of various intensities, in hairy and glabrous skin of the hand using large (27 mm diameter) and small (12 mm) stimulation areas, and the perceived pain intensity (PPI) was rated. A fast temperature increase rate (70°/s) was used in order to selectively activate A-delta nociceptors. The effect of skin type, stimulation intensity and sex on SS and PPI was calculated. Skin type significantly affected PPI and SS of pain; values of both variables were significantly greater in hairy compared with glabrous skin. SS of pain gradually increased concomitantly with stimulation intensity magnitude, to a point when it became saturated in both skin types. Females exhibited greater SS in glabrous skin. It would appear that AMH-II nociceptive fibers in particular subserve SS of pain. Furthermore, SS is increased under stronger stimulation intensities, probably as defense mechanism against tissue damage. Sex differences in dynamic sensory processes such as SS are revealed only under conditions where the phenomenon is subtle (as in glabrous skin).
... Several methods to stimulate C-fibers by laser beams have been proposed based on the differential characteristics of A␦-and C-fibers [2]. A first proposed method exploits the fact that unmyelinated C-fibers are more resistant to ischemic compression block than myelinated fibers [3,4]. A second proposed method is based on the difference in the thermal activation threshold between A␦-and C-fibers, and heats the skin above the threshold of C-fibers but below the threshold of A␦-fibers [5,6]. ...
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.
... During the experiment, stimuli consisted of trains of three consecutive pulses separated by a 5-ms interpulse interval (Inui, Tsuji, & Kakigi, 2006). These stimuli were perceived as a pinprick sensation related to the activation of Aδ nociceptors (Bromm, Jahnke, & Treede, 1984;Nahra & Plaghki, 2003). The pinprick sensation was not necessarily qualified as painful. ...
The study tested whether nociceptive stimuli applied to a body limb can orient spatial attention in external space toward visual stimuli delivered close to that limb. Nociceptive stimuli were applied to either the left or the right hand. Task-relevant visual stimuli were delivered at the location adjacent to the stimulated hand (70% valid trials) or adjacent to the other hand (30% invalid trials). Visual stimuli were discriminated with shorter reaction times and elicited ERPs of greater magnitude in the valid as compared to the invalid trials. This enhancement affected the N1 component, suggesting that the location of the nociceptive cue modifies visual processing through a modulation of neural activity in the visual cortex. We hypothesize the existence of a common frame of reference able to coordinate the mapping of the space of the body and the mapping of the external space.
... Because the thermal activation threshold of at least a fraction of C-fibre afferents (eg, C-warm receptors) is lower than that of Ad-fibre afferents [3,6,24], it was expected that the skin temperature required to elicit Ad-fibre responses would be higher than the skin temperature required to elicit C-fibre responses. Hence, we expected that selective activation of C-fibres could be achieved using intermediate target skin temperatures, exceeding the threshold of C-fibre afferents, but remaining below the thermal activation threshold of Ad-fibres [6]. ...
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.
... Quality assessment procedure using labels As a final part of the second series of experiments, each of the four stimuli that had been used during the VAS procedure was presented again. Each of the stimuli was repeated five times, after which the subject was asked to fill in a questionnaire based on the labels used by Mouraux et al. (2010) and Nahra and Plaghki (2003). Contrary to the VASs, which were presented with English labels, the questions were presented in German. ...
Studies of the interaction between mechanoception and nociception would benefit from a method for stimulation of both modalities at the same location. For this purpose, we developed an electrical stimulation device. Using two different electrode geometries, discs and needles, the device is capable of inducing two distinct stimulus qualities, dull and sharp, at the same site on hairy skin. The perceived strength of the stimuli can be varied by applying stimulus pulse trains of different lengths. We assessed the perceived stimulus qualities and intensities of the two electrode geometries at two levels of physical stimulus intensity. In a first series of experiments, ten subjects participated in two experimental sessions. The subjects reported the perceived quality and intensity of four different stimulus classes on visual analogue scales (VASs). In a second series, we added a procedure in which subjects assigned descriptive labels to the stimuli. We assessed the reproducibility of the VAS scores by calculating intraclass correlation coefficients. The results showed that subjects perceived stimuli delivered through the disc electrodes as dull and those delivered through the needles as sharp. Increasing the pulse train length increased the perceived stimulus intensities without decreasing the difference in quality between the electrode types. The intraclass correlation coefficients for the VAS scores ranged from .75 to .95. The labels that were assigned for the two electrode geometries corresponded to the descriptors for nociception and touch reported by other researchers. We concluded that our device is capable of reliably inducing tactile and nociceptive sensations of controllable intensity at the same skin site.
Electronic supplementary material
The online version of this article (doi:10.3758/s13428-012-0216-y) contains supplementary material, which is available to authorized users.
... This result is in line with earlier observations of a decreased sensitivity to painful experimental (heat) stimuli in depressed patients [4,6,7,17,18]. While acute concomitant A-and C-fiber stimulation is dominated by the A-fiber input [22,25,29] , we documented that reduced perceptibility is related not only to the A-fibers, but is also related to a reduced sensitivity to C-fiber input in DP. Therefore, we conclude that the impaired perception of laser-heat stimuli in depressed subjects is, at least in part, based on a clear deficit of the processing of C-fiber input. ...
Depression and clinical pain have been shown being strongly associated with each other. However, recent studies have demonstrated that depressed patients are less sensitive to experimental pain than healthy individuals. Reasons for this phenomenon are still elusive. The study investigates whether cutaneous C- and/or Aδ-fibers might contribute to this phenomenon. C- and Aδ-fiber systems were assessed in 12 depressed patients and 12 sex- and age-matched healthy controls using stimulation of tiny skin areas by laser heat stimuli. Detection and pain thresholds as well as proportions of trials associated with C- and Aδ-fiber stimulation as well as of non-perceived trials were compared between groups. Patients showed elevated pain thresholds and significantly less C-fiber responses. They also failed significantly more often to recognize the noxious laser-heat stimuli. Thus, higher pain thresholds to experimental stimuli in depressed patients are not only associated with reduced perception of cutaneous Aδ-, but also with decreased perception of selective C-fiber input. The physiological underpinnings of the phenomenon remain elusive and should be examined in the future to understand whether it is based on changes in the periphery or in central processing or both.
... This study did not use methods to investigate Ad-and C-LEPs Fig. 2. Grand averages of laser-evoked brain potentials for Ad-fibre stimulation. Controls (black) and patients (grey) are displayed; note that N2 and P2 components are labelled at Cz. Axes cross at 0. separately; therefore, the results are mainly influenced by Ad-fibre activity [42,48]. ...
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 first staircase converged toward the threshold (50% detection rate) for detecting any sensation. Because (1) the thermal activation threshold of C-fibers is lower than that of myelinated A-fibers and (2) the conduction velocity of unmyelinated C-fibers is much lower than that of myelinated A-fibers (Bromm and Treede, 1984;Bjerring and Arendt-Nielsen, 1988;Mouraux et al., 2003;Nahra and Plaghki, 2003;Mouraux and Plaghki, 2007), the threshold estimated using this first staircase can be assumed to reflect the detection threshold of C-fiber mediated sensations (i.e., "second pain"). The second staircase converged toward the threshold (50% detection rate) for detecting the stimulus with a RT 650 ms. ...
The periodic presentation of a sensory stimulus induces, at certain frequencies of stimulation, a sustained electroencephalographic response known as steady-state evoked potential (SS-EP). In the somatosensory, visual, and auditory modalities, SS-EPs are considered to constitute an electrophysiological correlate of cortical sensory networks resonating at the frequency of stimulation. In the present study, we describe and characterize, for the first time, SS-EPs elicited by the selective activation of skin nociceptors in humans. The stimulation consisted of 2.3-s-long trains of 16 identical infrared laser pulses (frequency, 7 Hz), applied to the dorsum of the left and right hand and foot. Two different stimulation energies were used. The low energy activated only C-nociceptors, whereas the high energy activated both Aδ- and C-nociceptors. Innocuous electrical stimulation of large-diameter Aβ-fibers involved in the perception of touch and vibration was used as control. The high-energy nociceptive stimulus elicited a consistent SS-EP, related to the activation of Aδ-nociceptors. Regardless of stimulus location, the scalp topography of this response was maximal at the vertex. This was noticeably different from the scalp topography of the SS-EPs elicited by innocuous vibrotactile stimulation, which displayed a clear maximum over the parietal region contralateral to the stimulated side. Therefore, we hypothesize that the SS-EPs elicited by the rapid periodic thermal activation of nociceptors may reflect the activation of a network that is preferentially involved in processing nociceptive input and may thus provide some important insight into the cortical processes generating painful percepts.
... However, since A d fiber elicited first pain precedes the C fiber elicited second pain due to the different conduction velocities of the two afferents (,10 m/s for A d and ,1 m/s for C fibers), it can be easily distinguished when the stimulus is applied at a remote location such as the back of the hand [15]. Furthermore, ''first pain'' is more salient than ''second pain'' [16]. Therefore, in the present study, subjects were asked to rate and choose descriptors for the first sensation they experienced when being stimulated by the laser, which set the focus on the A d component. ...
A(δ) and C fibers are the major pain-conducting nerve fibers, activate only partly the same brain areas, and are differently involved in pain syndromes. Whether a stimulus excites predominantly A(δ) or C fibers is a commonly asked question in basic pain research but a quick test was lacking so far.
Of 77 verbal descriptors of pain sensations, "pricking", "dull" and "pressing" distinguished best (95% cases correctly) between A(δ) fiber mediated (punctate pressure produced by means of von Frey hairs) and C fiber mediated (blunt pressure) pain, applied to healthy volunteers in experiment 1. The sensation was assigned to A(δ) fibers when "pricking" but neither "dull" nor "pressing" were chosen, and to C fibers when the sum of the selections of "dull" or "pressing" was greater than that of the selection of "pricking". In experiment 2, with an independent cohort, the three-descriptor questionnaire achieved sensitivity and specificity above 0.95 for distinguishing fiber preferential non-mechanical induced pain (laser heat, exciting A(δ) fibers, and 5-Hz electric stimulation, exciting C fibers).
A three-item verbal rating test using the words "pricking", "dull", and "pressing" may provide sufficient information to characterize a pain sensation evoked by a physical stimulus as transmitted via A(δ) or via C fibers. It meets the criteria of a screening test by being easy to administer, taking little time, being comfortable in handling, and inexpensive while providing high specificity for relevant information.
Objective
To compare nociceptive event-related brain potentials elicited by a high-speed contact-thermode vs. an infrared CO2 laser stimulator.
Methods
Contact heat-evoked potentials (CHEPs) and CO2 laser-evoked potentials (LEPs) were recorded in healthy volunteers using a high-speed contact-thermode (>200°C/s) and a temperature-controlled CO2 laser. In separate experiments, stimuli were matched in terms of target surface temperature (55°C) and intensity of perception. A finite-element model of skin heat transfer was used to explain observed differences.
Results
For 55°C stimuli, CHEPs were reduced in amplitude and delayed in latency as compared to LEPs. For perceptually matched stimuli (CHEPs: 62°C; LEPs: 55°C), amplitudes were similar, but CHEPs latencies remained delayed. These differences could be explained by skin thermal inertia producing differences in the heating profile of contact vs radiant heat at the dermo-epidermal junction.
Conclusions
Provided that steep heating ramps are used, and that target temperature is matched at the dermo–epidermal junction, contact and radiant laser heat stimulation elicit responses of similar magnitude. CHEPs are delayed compared to LEPs.
Significance
CHEPs could be used as an alternative to LEPs for the diagnosis of neuropathic pain. Dedicated normative values must be used to account for differences in skin thermal transfer.
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.
Electrical stimulation of small fibres is gaining attention in the diagnosis of peripheral neuropathies, such as diabetes mellitus, and pain research. However, it is still challenging to characterise the electrical characteristics of axons in small fibres (Aδ and C fibres). In particular, in vitro measurement for human Aδ-fibre is difficult due to the presence of myelin and ethical reason. In this study, we investigate the in vivo electrical characteristics of the human Aδ-fibre to derive strength–duration (S–D) curves from the measurement. The Aδ-fibres are stimulated using coaxial planar electrodes with intraepidermal needle tip. For human volunteer experiments, the S–D curve of Aδ-fibre is obtained in terms of injected electrical current. With the computational analysis, the standard deviation of the S–D curve is mostly attributed to the thickness of the stratum corneum and depth of the needle tip, in addition to the fibre thickness. Then, we derive electrical parameters of the axon in the Aδ-fibre based on a conventional fibre model. The parameters derived here would be important in exploring the optimal stimulation condition of Aδ-fibres.
It is well known that pain sensation exhibits physiological and psychological features and is influenced by many factors such as the strength of the noxious stimulus, state of the organism, and environmental variables. As engineers, we want to know the different features of skin thermal pain and how they are induced. This will be helpful for engineers to apply engineering methods to solve biological and neural problems. In this chapter we mainly discuss the physiological features of pain sensation, and psychological features are not included in this chapter.
It has been hypothesised that the human cortical responses to nociceptive and non-nociceptive somatosensory inputs differ. Supporting this view, somatosensory-evoked potentials (SEPs) elicited by thermal nociceptive stimuli have been suggested to originate from areas 1 and 2 of the contralateral primary somatosensory (S1), operculo-insular and cingulate cortices; whereas the early components of non-nociceptive SEPs mainly originate from area 3b of S1. However, to avoid producing a burn lesion, and sensitise or fatigue nociceptors, thermonociceptive SEPs are typically obtained by delivering a small number of stimuli using a large and variable inter-stimulus interval (ISI). In contrast, the early components of non-nociceptive SEPs are usually obtained by applying many stimuli at a rapid rate. Hence, previously reported differences between nociceptive and non-nociceptive SEPs could be due to differences in signal-to-noise ratio and/or differences in the contribution of cognitive processes related, for example, to arousal and attention. Here, using intra-epidermal electrical stimulation to selectively activate Aδ-nociceptors at a fast and constant 1-s ISI, we found that the nociceptive SEPs obtained using a long ISI are no longer identified, indicating that these responses are not obligatory for nociception. Furthermore, using a blind source-separation, we found that, unlike the obligatory components of non-nociceptive SEPs, the obligatory components of nociceptive SEPs do not receive a significant contribution from a contralateral source possibly originating from S1. Instead, they were best explained by sources compatible with bilateral operculo-insular and/or cingulate locations. Taken together, our results indicate that the obligatory components of nociceptive and non-nociceptive SEPs are fundamentally different.
Adequate observation techniques are required to explore changes in the nociceptive system in pain
patients. In this thesis neurophysiological observation methods of nociceptive system are explored. The
focus is to explore the merits of electrocutaneous single pulse (SP) and pulse train (PT) stimulation as
observation techniques of the nociceptive system.
It is shown that in healthy subjects both SP and PT influence evoked potentials (EPs) and subjective
ratings; however not all EP components were changed by both methods. For both SP and PT the
amplitude of several EP components were inhibited by a heterotopic noxious conditioning stimulus.
Results of lumbosacral radicular patients showed that similar EP components were modulated by SP
and PT in both patients and healthy subjects. However EP amplitudes were larger or smaller in patients.
In this thesis we showed that both SP and PT methods influence EP components and subjective ratings
differently. The results shed some light on the link between neurophysiology of nociception and the
recorded EPs. We concluded that different ways of processing are involved in both SP and PT method.
PT is less dependent on stimulus location, which can be of interest for further research to changes in
the nociceptive system of pain patients. Results of patients suggest that the methods can be used to
measure changes in the central pain processing in patients. To further analyse changes in the
nociceptive system in pain patients different measurement protocols can be formulated based on the SP
and PT methods depending on the research question.
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.
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.
Partial nerve injury leads to peripheral neuropathic pain. This injury results in conducting/uninterrupted (also called uninjured) sensory fibres, conducting through the damaged nerve alongside axotomised/degenerating fibres. In rats seven days after L5 spinal nerve axotomy (SNA) or modified-SNA (added loose-ligation of L4 spinal nerve with neuroinflammation-inducing chromic-gut), we investigated a) neuropathic pain behaviours and b) electrophysiological changes in conducting/uninterrupted L4 dorsal root ganglion (DRG) neurons with receptive fields (called: L4-receptive-field-neurons). Compared to pretreatment, modified-SNA rats showed highly significant increases in spontaneous-foot-lifting duration, mechanical-hypersensitivity/allodynia, and heat-hypersensitivity/hyperalgesia, that were significantly greater than after SNA, especially spontaneous-foot-lifting. We recorded intracellularly in vivo from normal L4/L5 DRG neurons and ipsilateral L4-receptive-field-neurons. After SNA or modified-SNA, L4-receptive-field-neurons showed the following: a) increased percentages of C-, Ad-, and Ab-nociceptors and cutaneous Aa/b-low-threshold mechanoreceptors with ongoing/spontaneous firing; b) spontaneous firing in C-nociceptors that originated peripherally; this was at a faster rate in modified-SNA than SNA; c) decreased electrical thresholds in A-nociceptors after SNA; d) hyperpolarised membrane potentials in A-nociceptors and Aa/b-low-threshold-mechanoreceptors after SNA, but not C-nociceptors; e) decreased somatic action potential rise times in C- and A-nociceptors, not Aa/b-low-threshold-mechanoreceptors. We suggest that these changes in subtypes of conducting/uninterrupted neurons after partial nerve injury contribute to the different aspects of neuropathic pain as follows: spontaneous firing in nociceptors to ongoing/spontaneous pain; spontaneous firing in Aa/b-low-threshold-mechanoreceptors to dysesthesias/paresthesias; and lowered A-nociceptor electrical thresholds to A-nociceptor sensitization, and greater evoked pain.
Objectives
Electric peripheral nerve stimulation (PNS) is a neuromodulatory therapy in pain patients. The efficacy of this neurosurgical pain treatment is controversial because its antinociceptive effect in humans has not been objectively proven so far.
Materials and Methods
Noxious infrared laser stimulation of the left hand dorsum evoked cortical potentials (LEP) by selective excitation of Aδ-fiber nociceptors in 15 healthy volunteers under control and PNS conditions. LEP were recorded before, during, and after electric Aβ-fiber stimulation (PNS) of the left superficial radial nerve. In the control session LEP were recorded without PNS. Laser stimulus intensity ratings, LEP latencies, and amplitudes were statistically analyzed (anova).
Results
During PNS, LEP amplitudes (p < 0.001) and laser intensity ratings (p < 0.05) significantly decreased, and LEP latencies significantly increased (p < 0.05). Under control conditions LEP and intensity ratings remained unchanged.
Conclusions
The electrophysiologic data provide evidence that electric stimulation of peripheral Aβ-fibers reliably suppresses Aδ-fiber nociceptive processing in human volunteers.
Compound action potentials of both myelinated (A) and non-myelinated (C) fibres in the common peroneal nerve of rabbits were studied during and after acute, graded compression of the nerve at 200 or 400 mmHg applied for 2 h or during ischaemia created by nitrogen inhalation or aortic occlusion. Compression of the nerve at 200 mmHg blocked the AI component (large myelinated fibres) after about 23 min, while compression at 400 mmHg shortened this time to 11 min. The A2 component (thinner myelinated fibres) had a lower conduction velocity and a higher resistance to compression. There was just a slight decrease in conduction velocity of the non-myelinated fibres when the nerves were compressed at 200 mmHg for 2 h. However, compression at 400 mmHg for 2 h induced a marked deterioration of amplitude and conduction velocity of the C-fibres. There was an incomplete restitution of function of A- and C-fibres during 2 h of recovery. The thinner myelinated fibres were more susceptible to deprivation of oxygen than the thicker ones, while non-myelinated fibres differed in response according to method of ischaemia induction. It is concluded that non-myelinated fibres are very resistant to compression and a very high pressure (greater than 400 mmHg) is needed to affect these fibres.
Pain and detection thresholds to short CO2 laser pulses were studied in healthy human subjects. Pain thresholds were significantly higher than detection thresholds in both hairy and glabrous skin; in the glabrous skin both thresholds were higher in the hairy skin. The range from detection threshold to pain threshold was larger in the glabrous skin. The minimal energy per surface area needed to produce any sensation (detection) or pain sensation decreased with increasing stimulus surface, and this spatial summation effect was to equal magnitude in the hairy and the glabrous skin. With decreasing stimulus pulse duration (from 45 to 15 msec) the detection and pain thresholds were elevated: this effect was stronger on pain thresholds. With increasing adapting skin temperature, less energy was needed to produce any sensation (detection) or pain sensation. The effect of adapting skin temperature was equal on pain and detection thresholds. The conduction velocity of fibers mediating laser evoked first sensations was in the thin fiber range (less than 10 msec), according to a reaction time study. The results suggest that short CO2 laser pulses produce both non-pain and pain sensations, but that both these sensations are based on the activation of the same primary afferent fiber population of slowly conducting nociceptive fibers. Central summation of primary afferent impulses is needed to elicit a liminal non-painful sensation, and an increased number of impulses in the same fibers produces pain.
We recorded laser-evoked potentials (LEPs) from 20 normal subjects by stimulating the skin with pulses from an infrared CO2 laser. The conduction velocity of the peripheral afferent fibers mediating the LEPs averaged 14.9 m/sec. The amplitude of the LEP components correlated significantly with perceived stimulus intensity. During repetitive constant intensity stimulation, the peak-to-peak LEP amplitude decreased 38% during a distraction task and 42% during drowsiness and was absent during stage 2 sleep, indicating a modulation of responsiveness to laser stimulation during distraction and decreased states of arousal. Normative data revealed considerable intersubject variability in LEP latencies and amplitudes. Analysis of intrasubject lateralized (side-to-side) differences revealed that the relative peak-to-peak amplitude was less variable than that of the N or P components. For clinical applications using 3 S.D.s to define the normal range, a lateral interpeak amplitude difference greater than 28% would suggest focal or lateralized sensory abnormality in an individual patient. Vigilance and attentiveness to the stimuli should be monitored during the acquisition of LEPs.
Tissue injury induces enhanced pain sensation to light touch and punctate stimuli in adjacent, uninjured skin (secondary hyperalgesia). Whereas hyperalgesia to light touch (allodynia) is mediated by A-fibre low-threshold mechanoreceptors, hyperalgesia to punctate stimuli may be mediated by A- or C-fibre nociceptors. To disclose the relative contributions of A- and C-fibres to the hyperalgesia to punctate stimuli, the superficial radial nerve was blocked by pressure at the wrist in nine healthy subjects. Secondary hyperalgesia was induced by intradermal injection of 40 microg capsaicin, and pain sensitivity in adjacent skin was tested with 200 micron diameter probes (35-407 mN). The progress of conduction blockade was monitored by touch, cold, warm and first pain detection and by compound sensory nerve action potential. When A-fibre conduction was blocked completely but C-fibre conduction was fully intact, pricking pain to punctate stimuli was reduced by 75%, but burning pain to capsaicin injection remained unchanged. In normal skin without A-fibre blockade, pain ratings to the punctate probes increased significantly by a factor of two after adjacent capsaicin injection. In contrast, pain ratings to the punctate probes were not increased after capsaicin injection when A-fibre conduction was selectively blocked. However, hyperalgesia to punctate stimuli was detectable immediately after block release, when A-fibre conduction returned to normal. In conclusion, the pricking pain to punctate stimuli is predominantly mediated by A-fibre nociceptors. In secondary hyperalgesia, this pathway is heterosynaptically facilitated by conditioning C-fibre input. Thus, secondary hyperalgesia to punctate stimuli is induced by nociceptive C-fibre discharge but mediated by nociceptive A-fibres.
Temperature thresholds were determined in 16 patients with probable or definite multiple sclerosis, in six patients with possible but unconfirmed multiple sclerosis and in 34 healthy subjects, using the method of limits and the thermal sensory limen (TSL) of the MarStock technique. A significant proportion of the patients had thresholds outside the 2.5 SD range for normal subjects, both for warmth detection threshold and TSL. In addition, 10 patients with probable or definite multiple sclerosis and one patient with possible multiple sclerosis reported a paradoxical heat sensation, i.e. a sensation of warmth elicited by a cold stimulus. This illusion was almost exclusively observed with the alternating warm and cold stimuli of the TSL procedure. In contrast to experimental nerve block or peripheral demyelinating neuropathy, where paradoxical heat sensation has been described by various authors, in the patients with multiple sclerosis the demyelination sites were located in the central nervous system. The observation that multiple sclerosis patients had paradoxical heat sensation in addition to threshold abnormalities supports the view that supraspinal sites are important for the integration of temperature sensation.
THE OBJECTIVE of this investigation was the examination of dermal, subdermal, fascial, and periosteal pain endings accessible from the surface of the body and a comparison of these with the better-known pricking-pain endings located subepithelially. Criteria for comparison were the subjective sensations evoked by comparable stimuli to the skin surface, to deep endings, or to nerves supplying these endings in their course below the skin; the spatial distributions of endings, and the relative thresholds—and therefore the fiber-size groupings— of the nerve fibers mediating the different sensations. Size groups of fibers innervating pain endings were determined by applying differential-pressure and procaine blocks to the peripheral nerves supplying the various sensory endings of the hand, arm, and leg of the human subject. We served as subjects, after considerable training in the discrimination of the effects of painful stimulation of various sorts. Deep endings have been studied recently, by means of mechanical stimulation,
: Changes in perception of pure thermal stimuli delivered to the hand at threshold intensity were observed during ischemic nerve block in 27 healthy subjects in order to study the significance of unmyelinated cutaneous cold receptors for thermal sensibility. Paresthesias and an increasing feeling of numbness were followed by a sudden change in cold sensation which developed a clearly dysesthetic quality. When complete motor block was reached and no myelinated axon functions were left, cold stimuli were still clearly but abnormally perceived. Warm sensation was little affected during the whole course of nerve block. The results indicate that the information from unmyelinated low threshold cold receptors alone leads to a dysesthetic cold sensation which normally is suppressed by the activity of myelinated cold afferents. Obviously these receptors are not needed for the discrimination of minor cold stimuli but they seem to be essential for the perception of the first burning cold pain.
In Part I, this Focus article describes characteristics of laser-evoked brain potentials (LEPs) in human pain and examines some of the methodological inconsistencies. Evidence both cautioning and supporting the use of LEPs is contrasted. A host of neurological mechanisms clearly illustrates the relation of LEPs and pain processing: Lasers elicit selectively the cutaneous receptors of thin afferent fibers, the anterolateral spinal tract, and the lateral tracts of the brainstem. Implication for clinical use is briefly suggested. We raise three contending issues: (1) measurement standard, (2) association and dissociation of the LEP amplitude and pain, and (3) dynamic spatiotemporal specificity of LEPs. We conclude that LEPs may reflect nociceptive processing but may not be the entire pain experience. We emphasize the proper use of LEPs in understanding the mechanisms of nociceptive activation in pain experience. To achieve this, we address the technological advance required in studying the dynamic spatiotemporal specificity of LEPs and human pain.
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.
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.
Psychophysical experiments were carried out on 6 huma subjects to determine how first and second pain are influenced by peripheral receptor mechanisms and by central nervous system inhibitory and facilitatory mechanisms. For these experiments, brief natural painful stimuli delivered to the hand were a train of 4-8 constant waveform heat pulses generated by a contact thermode (peak temp. = 51-5% C). The magnitude of first and second pain sensations was estimated using cross-modality matching procedures and reaction times were determined. The latter confirmed the relationship between first and second pain and impulse conduction in Adelta and C noxious heat afferents, respectively. The intensity of first pain decreased with each successive heat pulse when the interpulse interval was 80 sec or less. This decrease was most likely the result of heat induced suppression of Adelta heat nociceptors since it did not occur if the probe location changed between successive heat pulses. In contrast, second pain increased in intensity with each successive heat pulse if the interval was 3 sec or less. This summation was most likely due to central nervous system summation mechanisms since it also occurred after blockage of first pain by ulnar nerve compression and when the location of the thermode changed between heat pulses. These observations and their interpretations are supported by our recording of responses of singlt Adelta heat nociceptive afferents, C polymodal nociceptive afferents, and "warm" afferents of rhsus monkeys to similar trains of noxious heat pulses. Their responses to these heat pulses show a progressive suppression. Furthermore, previous studies have shown that wide dynamic range dorsal horn neurons show summated responses to repeated volleys in C fibers (greater than 1/3 sec). These spinal cord summation mechanisms could account for the summation of second pain.
In awake human subjects, neural responses in cutaneous nerves to electrical stimulation were recorded with intrafascicular tungsten micro-electrodes. Changes in the activity of individual fibre groups during blocking procedures were recorded and correlated with simultaneous alterations in the perception of standardized stimuli. Light touch sensibility in hairy skin was mediated by A-beta-gamma fibres, cold and pinprick by A-delta fibres and warmth and dull pain by C fibres.
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.
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.
The effect of compression-ischaemia nerve block on psychophysical thresholds for warm sensation and heat-induced pain was studied on 19 normal human volunteers. Although those two sensory submodalities should be predicted to block simultaneously, based on the fact that both are served by unmyelinated primary afferents, it was actually found that warm sensation was much more vulnerable to compression-ischaemia than heat-induced pain. This is interpreted as resulting from different summation requirements for each of the two sensory modalities; sensation of warmth depends on spatial summation to a larger extent than heat-induced pain. Such differential vulnerability is in line with recent clinical studies reporting deterioration of warm sensation associated with preservation of heat pain in peripheral nerve disorders caused by diabetes, ageing and other neuropathic processes.
Late components of cerebral potentials evoked by brief heat pulses applied to various skin sites were used to monitor the afferent pathways of pain and temperature sensitivity. Radiation at 10.6 micron wave length generated by a CO2 laser stimulator predominantly activates superficial cutaneous A delta and C nociceptors and elicits late and ultralate cerebral potentials. This paper deals with the investigation of the component structure and topography of the A delta fibre mediated late potentials, which were compared with the corresponding late potentials in response to standard electrical nerve stimuli. In the upper limb both stimulus types evoked a large positive potential (nerve: 260 msec, skin: 390 msec latency), preceded by a negativity (nerve: 140 msec, skin: 250 msec). Whereas these components were always maximal at the vertex, an earlier negativity appeared over the somatosensory projection area (nerve: 70 msec, skin: 170 msec). After stimulation of the lower limb all latencies were delayed by 20-30 msec. As a rule, the heat-evoked potentials appeared about 100 msec later than the corresponding potentials after electrical nerve stimulation. Similarities in interpeak latencies and scalp topography indicated similar cerebral processing.
Changes in thermal sensibility for warmth, cold, heat pain and cold pain during nerve compression block of impulse conduction in myelinated fibres were studied in 20 healthy subjects. When mainly unmyelinated fibres were conducting, after 30-36 min of nerve compression, the pain threshold, induced by cold stimulation, was shifted towards higher temperatures (from 19.1 degrees C to 22.8 degrees C, mean values). Furthermore, the sensation of cold pain became more unpleasant and had a hot burning rather than a cold quality. These results indicate that a change in central decoding of the afferent input has occurred, possibly due to lack of inhibition normally exerted by concomitant activation of myelinated fibres. Whereas dramatic changes in the sensation of cold pain were observed during the course of nerve compression, no alteration in heat pain threshold was seen. This implies that heat pain threshold in hairy skin is due to activation of C nociceptor fibres without any significant contribution from myelinated nociceptor fibres. Furthermore, no gating from heat-sensitive myelinated fibre input was evident on heat pain threshold.
The introduction of lasers in pain research has made it possible to activate the nociceptive system without activating mechanosensitive afferents. In the present study the reaction times to painless and painful laser stimuli were studied to investigate if the reaction time to experimental pain is reproduceable. CO2 and argon lasers were used for stimulation, and the influence of stimulus (intensity and duration) and skin parameters (temperature, thickness, and reflectance) on reaction time were investigated. When these parameters were controlled the reaction times to painful CO2 and argon laser stimulation were within the same range (350-450 ms), and the intra-individual variability minimal (6.9%). The reaction time was used to estimate peripheral conduction velocity (10 m.s-1) for the activated fibre population when distinct pain was perceived. Determination of reaction times to non-painful and painful stimuli may be suitable ways to assess the functioning of thermal and nociceptive pathways.
The effect of tourniquet-induced ischemia on human thermal thresholds was studied. After the development of the A-fibre block (= a sharp elevation of cool threshold) the heat-pain threshold was still uninfluenced. This result supports previous evidence indicating that C-fibres mediate the liminal heat pain sensation. Thus, the quantitative determination of cutaneous heat pain thresholds provides a rather selective method for testing C-fibre mediated pain sensitivity, at least when a contact thermostimulator with a slow or moderate rise of stimulus temperature is used. The second aim of this study was to examine whether ischemia or mechanical pressure is the cause of the tourniquet-induced block of A-fibres. This was studied by varying the mechanical pressure and the amount of ischemia. With increased ischemia (with muscle work) the A-fibre block (increased cool threshold) came earlier, but this finding was not significant.
In awake human subjects, electrically induced A and C fibre responses were recorded from skin nerves with percutaneously inserted tungsten microelectrodes. By studying the influence of preferential blocking manoeuvres upon the nerve response, attempts were made to correlate activity in A and C fibres with sensation. Following injection of Lidocaine of a low concentration between the stimulating and recording sites the C waves were abolished before the A deflections. When mainly A fibre activity was recorded, weak electric skin shocks were still felt as a tactile sensation. A strong stimulus was perceived as a short, sometimes sharp blow but the prolonged pain had disappeared. The reverse order of blocking of the neural peaks occurred on application of pressure on the nerve between the stimulating and recording sites. The preferential blocking of the A response was accompanied by an impaired discrimination of weak stimuli. Stronger skin stimuli evoked sensations related to pain when mainly C fibre activity was recorded. Signs of fatigue in peripheral C fibre structures were observed during high frequency stimulation, and the reduction of the C response was accompanied by a decrease in the experience of burning pain. Centripetally conducted mass-activity in C fibres was distinguished from reflex activity in sympathethic fibres by differences in latencies and response patterns to repetitive stimuli applied inside and outside the innervation zone of the fascicle recorded from.
The simultaneous recording of afferent A and C discharges together with sympathetic reflex activity seems valuable in studying reactions to cutaneous timuli in conscious man.
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)
Changes in perception of pure thermal stimuli delivered to the hand at threshold intensity were observed during ischemic nerve block in 27 healthy subjects in order to study the significance of unmyelinated cutaneous cold receptors for thermal sensibility. Paresthesias and an increasing feeling of numbness were followed by a sudden change in cold sensation which developed a clearly dysesthetic quality. When complete motor block was reached and no myelinated axon functions were left, cold stimuli were still clearly but abnormally perceived. Warm sensation was little affected during the whole course of nerve block. The results indicate that the information from unmyelinated low threshold cold receptors alone leads to a dysesthetic cold sensation which normally is suppressed by the activity of myelinated cold afferents. Obviously these receptors are not needed for the discrimination of minor cold stimuli but they seem to be essential for the perception of the first burning cold pain.
The peripheral neural contributions to the magnitude of pain sensations elicited by heat stimulations of the skin and the increased pain to heat following a mild heat injury to the skin were studied by comparing psychophysical measures of pain in humans with impulse activity elicited by heat in single nociceptive afferents in the monkey. Human subjects made continuous magnitude ratings of pain elicited by short-duration stimuli of 39-51°C delivered before and at varying intervals of time following a heat injury induced by a conditioning stimulus (CS) of 50°C and 100 s duration. The same stimuli were delivered to the receptive fields in hairy and glabrous skin of C-fiber and A-fiber mechanoheat nociceptors (CMHs and AMHs, respectively). For heat stimulations of normal skin, that is, uninjured skin stimulated prior to the CS, pain thresholds ranged from 41 to 49°C. For most subjects, magnitude scaling functions for pain relating the maximum rating of pain elicited by each stimulus to stimulus temperature were slightly positively accelerating. The median maximum pain rating increased as a positively accelerating function of stimulus temperature. Threshold responses of CMH nociceptors in normal skin ranged from 41 to 51°C, while those of AMH nociceptors were generally greater than 51°C. The intensity-response functions of CMH nociceptors relating the total number of impulses elicited by each stimulus to stimulus temperature varied in shape, but the mean intensity-response function increased as a positively accelerating function of stimulus temperature. Therefore, the mean number of impulses elicited in CMHs in hairy and in glabrous skin of the monkey increased linearly with the median pain ratings in humans for hairy and glabrous skin, respectively. Within 5-10 min after the CS, pain thresholds were lower, and magnitude ratings of pain elicited by suprathreshold stimuli were greater than pre-CS values (hyperalgesia). Parallel changes were seen in the increased responses and/or lowered thresholds (sensitization) of most CMHs. While threshold changes in most CMHs in both types of skin paralleled changes in pain threshold following heat injury, only CMHs in hairy skin and not those in glabrous skin were sensitized a sufficient amount to contribute to increased magnitude ratings of pain following the development of hyeralgesia. In hyperalgesic skin, the median maximum pain rating increased as a negatively accelerating function of stimulus temperature, with the greatest increases over normal in pain ratings occurring in response to stimuli of 43-45°C in hairy skin and 47-49°C in glabrous skin with little if any increase in the magnitude of pain elicited by the highest stimulus of 51°C. In contrast, the impulse discharges of most CMH nociceptors exhibited the greatest increases in response to stimuli of 47-49°C. Since, in addition, the overall amount of sensitization of glabrous skin CMHs was not significant, the increases in CMH responses following a heat injury to either type of skin were not in proportion to increases in magnitude ratings of pain at each stimulus temperature. Evidence from control experiments indicated it was unlikely that the magnitude scaling of heat pain in normal skin and the changes in magnitude scaling following the development of hyperalgesia after heat injury depended on activity in AMH nociceptors, low-threshold thermoreceptors, or regional changes in blood flow. The results of these experiments suggest that activity in CMH nociceptors is a major peripheral determinant of heat pain sensation in normal skin and also contributes to the hyperalgesia following heat injury to the skin. If the magnitude of heat pain in normal skin is coded in the mean impulse discharge of CMH nociceptors as the data suggest, then the same neural code, at least as revealed in the responses of nociceptors in the monkey, does not fully account for the magnitude of change in pain sensation in humans following mild heat injury. Candidate explanations for certain mismatches between human sensory and monkey neural events are discussed.
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.
Monkeys and human subjects were exposed to a series of thermal stimuli before and after a 53 degrees C, 30-second burn to
the glabrous skin of the hand. The responses of C- and A-fiber nociceptive afferents in the monkeys and subjective responses
by the humans were compared. The burn resulted in increased sensitivity of the A fibers, decreased sensitivity of the C fibers,
and increased pain sensibility (hyperalgesia) in the human subjects.
1. Responses to ramped or stepped temperature stimuli were obtained from fifty-three cutaneous C fibre mechano-heat nociceptors (CMHs) in the hairy skin of the pentobarbitone-morphine anaesthetized monkey. A three-layer heat transfer model was developed to describe the temperature distribution within the skin and to estimate receptor depth and heat threshold. 2. Surface heat threshold, defined as the surface temperature when the first action potential occurs, increased as: (a) the rate of temperature rise for the ramped stimuli increased from 0.095 to 5.8 degrees C s-1; (b) the duration of stepped heat stimuli decreased from 30 to 1 s; and (c) the base temperature of stepped heat stimuli decreased from 38 to 35 degrees C. These results suggest that the heat threshold for CMHs is determined by the temperature at the depth of the receptor. 3. Receptor depth estimates from responses to ramped stimuli ranged from 20 to 570 microns with a mean of 201 microns. The estimated mean receptor heat threshold was 40.4 +/- 2.2 degrees C (+/- S.D.). No correlation was observed between depth and thermal or mechanical threshold. The average receptor depth and threshold, estimated from the responses to stepped heat stimuli, were 150 microns and 40.2 degrees C, respectively. 4. We conclude that: (a) the receptor endings of CMHs occur in the epidermis and dermis; (b) temperature at the level of the receptor determines threshold; (c) temperature at the receptor ending is much lower than skin surface temperature at threshold; and (d) the tight distribution of receptor heat thresholds suggests a uniform transducer mechanism for heat in CMHs.
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)
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.
It has been suggested that ageing may have a differential effect on C fibre-mediated protopathic/tonic pain versus epicritic/phasic pain perception mediated by A delta fibres. The present study attempted to independently assess age-related changes in the function of A delta- and C-nociceptive fibres by examining CO2 laser-induced thermal pain thresholds before, during and after a compression block of the superficial radial nerve in 15 young and 15 healthy elderly adult subjects. Nerve block efficacy was monitored via measures of cold, warm and mechanical threshold, and simple reaction time. During nerve compression block, reaction time and mechanical threshold increased, cold sensation became impaired while warm sensation remained unaffected throughout the test in both groups. With respect to pain sensitivity, young adults exhibited significant increases in thermal pain threshold during A-fibre block while pain threshold remained relatively stable across the 3 test periods in the elderly group. It would appear that elderly adults rely predominantly on C-fibre input when reporting pain whereas younger adults utilise additional input from A delta fibres. Subsequent analysis revealed that during pre- and post-block periods, older adults exhibited a significant elevation in thermal pain threshold; however, when A delta-fibre function was impaired and only C-fibre information was available, both groups responded similarly. These findings support the notion of a differential age-related change in A-fibre-mediated epicritic pain perception versus C-fibre-mediated protopathic pain.
Temperature thresholds were determined in 16 patients with probable or definite multiple sclerosis, in six patients with possible but unconfirmed multiple sclerosis and in 34 healthy subjects, using the method of limits and the thermal sensory limen (TSL) of the MarStock technique. A significant proportion of the patients had thresholds outside the 2.5 SD range for normal subjects, both for warmth detection threshold and TSL. In addition, 10 patients with probable or definite multiple sclerosis and one patient with possible multiple sclerosis reported a paradoxical heat sensation, i.e. a sensation of warmth elicited by a cold stimulus. This illusion was almost exclusively observed with the alternating warm and cold stimuli of the TSL procedure. In contrast to experimental nerve block or peripheral demyelinating neuropathy, where paradoxical heat sensation has been described by various authors, in the patients with multiple sclerosis the demyelination sites were located in the central nervous system. The observation that multiple sclerosis patients had paradoxical heat sensation in addition to threshold abnormalities supports the view that supraspinal sites are important for the integration of temperature sensation.
Psychophysical visual analog scaling can be used to reveal critical determinants of the neural processing underlying non-painful and painful heat sensations produced by radiant and contact heat stimulation. This study determined the stimulus-response (S-R) functions of cutaneous non-painful and painful heat stimuli delivered by an infra-red CO2 laser or by a contact thermode in a series of experiments in healthy volunteers. In experiments 1 (n = 12), with the rating scale anchored at pain threshold, the S-R curve for brief (60 ms) laser pulse stimulation with a beam diameter of 10 mm was a negatively accelerating function. Transformation of laser stimulus intensity (W) into temperatures (degree C) did not change the form of the S-R curve. In experiment 2 (n = 9), using the same laser stimulus parameters as in experiment 1, but without an anchored rating scale, the form of the S-R relationship did not change. In experiment 3 (n = 9), increases of the laser pulse duration up to 5 s and the beam diameter up to 18 mm produced linear S-R curves. In contrast, in experiment 4 (n = 21), the S-R curve for cutaneous contact heat stimuli applied for 5 s with an 18 mm diameter probe was best described by a positively accelerating power function with an exponent greater than 2.0. These experiments have (1) characterized the S-R functions for different parameters of infra-red laser stimulation of the skin, and (2) have shown that the form of the S-R function for innocuous and noxious heat sensation is influenced strongly by the physical conditions of heat stimulus application, including mechanical contact with the skin.
This study was designed to estimate and compare nerve conduction velocity (NCV) of cutaneous heat-sensitive C-fibres obtained using two methods. The first is a method based on reaction times to different rates of temperature change produced by a large contact thermode (Thermotest). The second is a novel method based on ultra-late-evoked brain potentials to CO2 laser stimuli with tiny beam sections (< 0.25 mm2), allowing selective and direct activation of very slow conducting afferents. Both methods were applied on three sites of the right leg (foot, knee and thigh) of ten healthy subjects. When based on the reaction times to contact heat, NCV estimations were 0.4 +/- 0.22 m/s for the proximal segment (knee-thigh) and 0.6 +/- 0.23 m/s for the distal segment (foot-knee). When based on the difference in latency of the ultra-late positivity of laser-evoked brain potentials, NCV estimations were respectively 1.4 +/- 0.77 m/s and 1.2 +/- 0.55 m/s. For both methods, the difference in NCV between proximal and distal limb segments was not significant. Although both methods give NCV estimations within the range of C-fibres, the systematic difference between NCV obtained from each method may result from the activation of subpopulations of C-fibres with different NCV depending on the method of stimulation (low-threshold thermal receptors by the thermode and thermal nociceptors by the CO2 laser). Considering the difficulty of investigating peripheral fibres with slow conduction velocities (C-fibres) in humans, the methods used in the present study may be useful tools in both experimental and clinical situations.
The authors reviewed basic and clinical reports of pain-related somatosensory evoked potentials (SSEP) after high-intensity electrical stimulation [pain SSEP(E)] and painful laser stimulation [pain SSEP(L)]. The conduction velocity of peripheral nerves for both pain SSEP(E) and pain SSEP(L) is approximately 10 to 15 m/second, in a range of Adelta fibers. The generator sources are considered to be the secondary somatosensory cortex and insula, and the limbic system, including the cingulate cortex, amygdala, or hippocampus of the bilateral hemispheres. The latencies and amplitudes are clearly affected by vigilance, attention-distraction, and various kinds of stimulation applied simultaneously with pain. Abnormalities of pain SSEP(L) reflect an impairment of pain-temperature sensation, probably relating to dysfunction of A5 fibers of the peripheral nerve and spinothalamic tract. In contrast, conventional SSEP after nonpainful electrical stimulation reflects an impairment of tactile, vibratory, and deep sensation, probably relating to dysfunction of Aalpha or Abeta fibers of the peripheral nerve and dorsal column. Therefore, combining the study of pain SSEP(L) and conventional SSEP is useful to detect physiologic abnormalities, and sometimes subclinical abnormalities, of patients with peripheral and central nervous system lesions.
Perception and neurophysiological correlates of brief infrared laser pulses:influence of cutaneous stimulation area Doctoral Dissertation Direct isolation of ultra-late (C-fibre) evoked brain potentials by CO 2 laser stimulation of tiny cutaneous surface areas in man
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Similarity of threshold temper-atures for first pain sensation, laser-evoked potentials, and noci-ceptor activation
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Treede R-D, Meyer RA, Lesser RP. Similarity of threshold temper-atures for first pain sensation, laser-evoked potentials, and noci-ceptor activation. In: Gebhart GF, Hammond DL, Jensen TS, editors. Proceedings of the 7th World Congress on Pain. Seattle: IASP Press; 1994. p. 857–65.
The logit transformation with special references to its use in bioassay. London: Griffin; 1972 Variability of laser-evoked potentials: attention, arousal, and lateralized differences
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Thermal sensibility changes during ischaemic nerve block
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Perception and neurophysiological correlates of brief infrared laser pulses:influence of cutaneous stimulation area
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