Assessing thermal sensitivity using transient heat and cold stimuli combined with a Bayesian adaptive method in a clinical setting: A proof of concept study.

BACKGROUND: Quantitative sensory testing of thermal detection abilities is used as a clinical tool to assess the function of pain pathways. The most common procedure to assess thermal sensitivity, the 'method of limits', provides a quick but rough estimate of detection thresholds. Here, we investigate the potential of evaluating not only the threshold but also the slope of the psychometric functions for cold and warm detection. METHOD: A convenience sample of 15 patients with diabetes mellitus (DM) and 15 age-matched healthy controls (HC) was tested. Thirty brief (100 ms) stimuli of each modality were applied to the volar wrist and foot dorsum. Cold and warm stimuli were delivered with a Peltier thermode and a temperature-controlled CO2 laser, respectively. Stimulus intensities were dynamically selected using an adaptive Bayesian algorithm (psi method) maximizing information gain for threshold and slope estimation. ROC analyses were used to assess the ability of slopes, thresholds and the combination of both to discriminate between groups. RESULTS: Assessment of the slope and threshold of the psychometric function for thermal detection took about 10 min. The ability to detect warmth was not reduced in DM patients as compared to HC. Cold detection performance assessed using slope or threshold parameters separated DM from HC with good discriminative power. Discrimination was further increased when both parameters were used together (93% sensitivity and 87% specificity), indicating that they provide complementary information on patient status. CONCLUSION: The psi method may be an interesting alternative to the classical method of limits for thermal QST. SIGNIFICANCE: Current QST protocols provide an incomplete and potentially biased estimate of sensory detection performance. We propose a method that estimates the slope and the threshold of the psychometric function, defining heat and cold sensory detection performance, in only a few minutes. Furthermore, we provide preliminary evidence that combining slope and threshold parameters of cold detection performance leads to a better discriminative ability than relying solely on the threshold.

Fibromyalgia syndrome-A laser-evoked potentials study unsupportive of small nerve fibre involvement.

BACKGROUND: Fibromyalgia syndrome (FMS) is a chronic pain syndrome characterized by widespread pain and a variety of non-pain symptoms. Central sensitivity phenomena are found consistently in FMS. Additionally, several researchers proclaimed that a subgroup of FMS patients may present with unrecognized peripheral small fibre neuropathy (SFN). Laser-evoked brain potentials (LEP) are considered as a reliable method for the functional assessment of the thermo-nociceptive system, including the evaluation of SFN. OBJECTIVES: The aim of this retrospective study was to estimate the prevalence of thermo-nociceptive system dysfunction based on LEPs in FMS. METHODS: LEP recordings of 92 FMS patients and 39 age and gender-matched healthy controls were selected from a database collected between 2003 and 2012 with standardized settings for laser stimulation and EEG recording. The N1, N2 and P2 LEP components were identified and characterized by peak latency and amplitude. RESULTS: None of the FMS patients showed signs of loss of function of the nociceptive responses evoked by A δ-nociceptor activation, compared to healthy controls. 6.5% of the FMS patients had N2-P2 peak-to-peak amplitudes above the upper limit of the 99%-confidence interval. N2-P2 peak-to-peak amplitudes were negatively correlated with age, without age-related differences between groups. CONCLUSIONS: The characteristic signs of a damaged thermo-nociceptive system as revealed by LEPs were absent in this large cohort of FMS patients. SIGNIFICANCE: The present research does not support the hypothesis that small fibre neuropathy is a significant contributor to the pathophysiology of FMS.

Quickly responding C-fibre nociceptors contribute to heat hypersensitivity in the area of secondary hyperalgesia.

KEY POINTS: A recent animal study showed that high frequency electrical stimulation (HFS) of C-fibres induces a gliogenic heterosynaptic long-term potentiation at the spinal cord that is hypothesized to mediate secondary hyperalgesia in humans. Here this hypothesis was tested by predominantly activating C-fibre nociceptors in the area of secondary mechanical hyperalgesia induced by HFS in humans. It is shown that heat perception elicited by stimuli predominantly activating C-fibre nociceptors is greater, as compared to the control site, after HFS in the area of secondary mechanical hyperalgesia. This is the first study that confirms in humans the involvement of C-fibre nociceptors in the changes in heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS. ABSTRACT: It has recently been shown that high frequency electrical stimulation (HFS) of C-fibres induces a gliogenic heterosynaptic long-term potentiation (LTP) at the spinal cord in animals, which has been hypothesized to be the underlying mechanism of secondary hyperalgesia in humans. Here we tested this hypothesis using a method to predominantly activate quickly responding C-fibre nociceptors in the area of secondary hyperalgesia induced by HFS in humans. HFS was delivered to one of the two volar forearms in 18 healthy volunteers. Before, 20 min and 45 min after HFS, short-lasting (10 ms) high-intensity CO2 laser heat stimuli delivered to a very small area of the skin (0.15 mm2 ) were applied to the area of increased mechanical pinprick sensitivity at the HFS-treated arm and the homologous area of the contralateral control arm. During heat stimulation the electroencephalogram, reaction times and intensity of perception (numerical rating scale 0-100) were measured. After HFS, we observed a greater heat sensitivity, an enhancement in the number of detected trials, faster reaction times and an enhancement of the N2 wave of C-fibre laser-evoked potentials at the HFS-treated arm compared to the control arm. This is the first study that confirms in humans the involvement of C-fibre nociceptors in enhanced heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS.

Aδ and not C fibers mediate thermal hyperalgesia to short laser stimuli after burn injury in man.

It remains unclear which nerve fibers are responsible for mediating hyperalgesia after skin injury. Here, we examined the role of Aδ and C fibers in inflammatory hyperalgesia after a first-degree burn injury. A CO2 laser delivered ultrafast short constant-temperature heat pulses to the upper part of the lower leg to stimulate selectively the relatively fast-conducting thinly myelinated Aδ and the slowly conducting unmyelinated C fibers. Participants were asked to respond as fast as possible whenever they detected a thermal stimulus. Thresholds and reaction times to selective Aδ and C fiber activations were measured in the conditioned and the surrounding intact skin, at pre-injury, and 1 hour and 24 hours after injury. First-degree burn injury caused a significant decrease in Aδ fiber detection thresholds and a significant increase in the proportion of Aδ-fiber-mediated responses in the inflamed area 24 hours, but not 1 hour, after burn injury. No changes in heat perception were observed in the intact skin surrounding the injury. No group differences in C-fiber-mediated sensations were observed. Our findings indicate that quickly adapting Aδ fibers but not quickly adapting C fibers are sensitized when activated by short and ultrafast heat stimuli after skin burn injury. Our results further show that this change occurs between 1 hour and 24 hours after injury and that it does not extend to the skin surrounding the injury.

NRP-1 Receptor Expression Mismatch in Skin of Subjects with Experimental and Diabetic Small Fiber Neuropathy.

The in vivo cutaneous nerve regeneration model using capsaicin is applied extensively to study the regenerative mechanisms and therapeutic efficacy of disease modifying molecules for small fiber neuropathy (SFN). Since mismatches between functional and morphological nerve fiber recovery are described for this model, we aimed at determining the capability of the capsaicin model to truly mimic the morphological manifestations of SFN in diabetes. As nerve and blood vessel growth and regenerative capacities are defective in diabetes, we focused on studying the key regulator of these processes, the neuropilin-1 (NRP-1)/semaphorin pathway. This led us to the evaluation of NRP-1 receptor expression in epidermis and dermis of subjects presenting experimentally induced small fiber neuropathy, diabetic polyneuropathy and of diabetic subjects without clinical signs of small fiber neuropathy. The NRP-1 receptor was co-stained with CD31 vessel-marker using immunofluorescence and analyzed with Definiens® technology. This study indicates that capsaicin application results in significant loss of epidermal NRP-1 receptor expression, whereas diabetic subjects presenting small fiber neuropathy show full epidermal NRP-1 expression in contrast to the basal expression pattern seen in healthy controls. Capsaicin induced a decrease in dermal non-vascular NRP-1 receptor expression which did not appear in diabetic polyneuropathy. We can conclude that the capsaicin model does not mimic diabetic neuropathy related changes for cutaneous NRP-1 receptor expression. In addition, our data suggest that NRP-1 might play an important role in epidermal nerve fiber loss and/or defective regeneration and that NRP-1 receptor could change the epidermal environment to a nerve fiber repellant bed possibly through Sem3A in diabetes.

Automated PGP9.5 immunofluorescence staining: a valuable tool in the assessment of small fiber neuropathy?

BACKGROUND: In this study we explored the possibility of automating the PGP9.5 immunofluorescence staining assay for the diagnosis of small fiber neuropathy using skin punch biopsies. The laboratory developed test (LDT) was subjected to a validation strategy as required by good laboratory practice guidelines and compared to the well-established gold standard method approved by the European Federation of Neurological Societies (EFNS). To facilitate automation, the use of thinner sections. (16 µm) was evaluated. Biopsies from previously published studies were used. The aim was to evaluate the diagnostic performance of the LDT compared to the gold standard. We focused on technical aspects to reach high-quality standardization of the PGP9.5 assay and finally evaluate its potential for use in large scale batch testing. RESULTS: We first studied linear nerve fiber densities in skin of healthy volunteers to establish reference ranges, and compared our LDT using the modifications to the EFNS counting rule to the gold standard in visualizing and quantifying the epidermal nerve fiber network. As the LDT requires the use of 16 µm tissue sections, a higher incidence of intra-epidermal nerve fiber fragments and a lower incidence of secondary branches were detected. Nevertheless, the LDT showed excellent concordance with the gold standard method. Next, the diagnostic performance and yield of the LDT were explored and challenged to the gold standard using skin punch biopsies of capsaicin treated subjects, and patients with diabetic polyneuropathy. The LDT reached good agreement with the gold standard in identifying small fiber neuropathy. The reduction of section thickness from 50 to 16 µm resulted in a significantly lower visualization of the three-dimensional epidermal nerve fiber network, as expected. However, the diagnostic performance of the LDT was adequate as characterized by a sensitivity and specificity of 80 and 64 %, respectively. CONCLUSIONS: This study, designed as a proof of principle, indicated that the LDT is an accurate, robust and automated assay, which adequately and reliably identifies patients presenting with small fiber neuropathy, and therefore has potential for use in large scale clinical studies.

Respiratory hypoalgesia? Breath-holding, but not respiratory phase modulates nociceptive flexion reflex and pain intensity.

Several observations suggest that respiratory phase (inhalation vs. exhalation) and post-inspiratory breath-holds could modulate pain and the nociceptive reflex. This experiment aimed to investigate the role of both mechanisms. Thirty-two healthy participants received supra-threshold electrocutaneous stimulations to elicit both the Nociceptive Flexion Reflex (NFR) and pain, either during spontaneous inhalations or exhalations, or during three types of instructed breath-holds: following exhalation, at mid-inhalation and at full-capacity inhalation. Whether the electrocutaneous stimulus was applied during inhalation or exhalation did not affect the NFR or pain. Self-reported pain was reduced and the NFR was increased during breath-holding compared to spontaneous breathing. Whereas the type of breath-hold did not impact on self-reported pain, breath-holds at full-capacity inhalation and following exhalation were associated with a lower NFR amplitude compared to breath-holds at mid-inhalation. The present findings confirm that breath-holding can modulate pain (sensitivity) and suggest that both attentional distraction and changes in vagal activity may underlie the observed effects.

Biological inflammatory markers mediate the effect of preoperative pain-related behaviours on postoperative analgesics requirements.

BACKGROUND: The predictive value of an individual's attitude towards painful situations and the status of his immune system for postoperative analgesic requirements are not well understood. These may help the clinician to anticipate individual patient's needs. METHODS: Sixty patients, who underwent a laparoscopic cholecystectomy under standardised general anaesthesia, were included. The total analgesic requirements during the first 48 h were the primary endpoint (unitary dosage, UD). The individual's attitude towards imaginary painful situations was measured with the Situational Pain Scale (SPS). The emotional status was assessed by the Hospital Anxiety and Depression Scale (HADS) and the inflammatory status by the neutrophil-to-lymphocyte ratio (NLR). RESULTS: Univariate analyses revealed a significant association between UD and SPS, HADS and NLR. A negative relationship between SPS and NLR (NLR = 0.820-0.180*SPS;R(2) = 0.211;P < 0.001) and a positive relationship between SPS and HADS (HADS = 14.8 + 1.63*SPS; R(2) = 0.159;P = 0.002) were observed. A multiple linear regression analysis showed that the contribution of NLR to the UD was the most effective. A mediation analysis showed a complete mediation of the effect of SPS on UD (R(2) = 0.103;P = 0.012), by the NLR (SPS on NLR: R(2) = 0.211;P = <0.001), the HADS (SPS on HADS: R(2) = 0.159;P = 0.002). The variance in UD explained by the SPS was indirect and amounts to 46% through NLR and to 34% through HADS. CONCLUSIONS: In this series, preoperative pain-related attitudes (SPS) were associated with the postoperative analgesic requirements (UD) after a cholecystectomy. Eighty per cent of this effect was mediated by the HADS and the NLR.

The effect of heterotopic noxious conditioning stimulation on Aδ-, C- and Aß-fibre brain responses in humans.

Human studies have shown that heterotopic nociceptive conditioning stimulation (HNCS) applied to a given body location reduces the percept and brain responses elicited by noxious test stimuli delivered at a remote body location. It remains unclear to what extent this effect of HNCS relies on the spinal-bulbar-spinal loop mediating the effect of diffuse noxious inhibitory controls (DNICs) described in animals, and/or on top-down cortical mechanisms modulating nociception. Importantly, some studies have examined the effects of HNCS on the brain responses to nociceptive input conveyed by Aδ-fibres. In contrast, no studies have explored the effects of HNCS on the responses to selective nociceptive C-fibre input and non-nociceptive Aß-fibre input. In this study, we measured the intensity of perception and event-related potentials (ERPs) to stimuli activating Aδ-, C- and Aß-fibres, before, during and after HNCS, obtained by immersing one foot in painful cold water. We observed that (i) the perceived intensity of nociceptive Aδ- and C-stimuli was reduced during HNCS, and (ii) the ERPs elicited by Aδ- and Aß- and C-stimuli were also reduced during HNCS. Importantly, because Aß-ERPs are related to primary afferents that ascend directly through the dorsal columns without being relayed at spinal level, the modulation of these responses may not be explained by an influence of descending projections modulating the transmission of nociceptive input at spinal level. Therefore, our results indicate that, in humans, HNCS should be used with caution as a direct measure of DNIC-related mechanisms.

Psychophysical and electrophysiological evidence for nociceptive dysfunction in complex regional pain syndrome.

The aim of this study was to assess the function of the thermo-nociceptive system in 25 patients with long-lasting, medium-to-severe refractory complex regional pain syndrome (CRPS)-1 using behavioral (detection rates and reaction times) and electrophysiological (event-related brain potentials) responses to brief (50 milliseconds) and intense (suprathreshold for Aδ-nociceptors) carbon dioxide laser stimuli delivered to the affected and contralateral limbs, and by comparing these responses to the responses obtained in the left and right limbs of age- and sex-matched healthy controls. Compared with healthy controls and compared with the contralateral limb, the detection rate of pricking pain related to the activation of Aδ-fibers was markedly reduced at the affected limb. Furthermore, reaction times were substantially prolonged (>100 milliseconds in 84% of patients and >300milliseconds in 50% of patients). Finally, the N2 and P2 waves of laser-evoked brain potentials were significantly reduced in amplitude, and their latencies were significantly increased. Taken together, our results show that in the majority of patients with chronic CRPS-1, thermo-nociceptive pathways are dysfunctional. A number of pathological mechanisms involving the peripheral nervous system and/or the central nervous system could explain our results. However, the primary or secondary nature of these observed changes remains an open question.

Reliable EEG responses to the selective activation of C-fibre afferents using a temperature-controlled infrared laser stimulator in conjunction with an adaptive staircase algorithm.

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.

Shielding cognition from nociception with working memory.

Because pain often signals the occurrence of potential tissue damage, nociceptive stimuli have the capacity to capture attention and interfere with ongoing cognitive activities. Working memory is known to guide the orientation of attention by maintaining goal priorities active during the achievement of a task. This study investigated whether the cortical processing of nociceptive stimuli and their ability to capture attention are under the control of working memory. Event-related brain potentials (ERPs) were recorded while participants performed primary tasks on visual targets that required or did not require rehearsal in working memory (1-back vs 0-back conditions). The visual targets were shortly preceded by task-irrelevant tactile stimuli. Occasionally, in order to distract the participants, the tactile stimuli were replaced by novel nociceptive stimuli. In the 0-back conditions, task performance was disrupted by the occurrence of the nociceptive distracters, as reflected by the increased reaction times in trials with novel nociceptive distracters as compared to trials with standard tactile distracters. In the 1-back conditions, such a difference disappeared suggesting that attentional capture and task disruption induced by nociceptive distracters were suppressed by working memory, regardless of task demands. Most importantly, in the conditions involving working memory, the magnitude of nociceptive ERPs, including ERP components at early latency, were significantly reduced. This indicates that working memory is able to modulate the cortical processing of nociceptive input already at its earliest stages, and could explain why working memory reduces consequently ability of nociceptive stimuli to capture attention and disrupt performance of the primary task. It is concluded that protecting cognitive processing against pain interference is best guaranteed by keeping out of working memory pain-related information.

Psychophysics of a nociceptive test in the mouse: ambient temperature as a key factor for variation.

BACKGROUND: The mouse is increasingly used in biomedical research, notably in behavioral neurosciences for the development of tests or models of pain. Our goal was to provide the scientific community with an outstanding tool that allows the determination of psychophysical descriptors of a nociceptive reaction, which are inaccessible with conventional methods: namely the true threshold, true latency, conduction velocity of the peripheral fibers that trigger the response and latency of the central decision-making process. METHODOLOGY/PRINCIPAL FINDINGS: Basically, the procedures involved heating of the tail with a CO(2) laser, recording of tail temperature with an infrared camera and stopping the heating when the animal reacted. The method is based mainly on the measurement of three observable variables, namely the initial temperature, the heating rate and the temperature reached at the actual moment of the reaction following random variations in noxious radiant heat. The initial temperature of the tail, which itself depends on the ambient temperature, very markedly influenced the behavioral threshold, the behavioral latency and the conduction velocity of the peripheral fibers but not the latency of the central decision-making. CONCLUSIONS/SIGNIFICANCE: We have validated a psychophysical approach to nociceptive reactions for the mouse, which has already been described for rats and Humans. It enables the determination of four variables, which contribute to the overall latency of the response. The usefulness of such an approach was demonstrated by providing new fundamental findings regarding the influence of ambient temperature on nociceptive processes. We conclude by challenging the validity of using as "pain index" the reaction time of a behavioral response to an increasing heat stimulus and emphasize the need for a very careful control of the ambient temperature, as a prevailing environmental source of variation, during any behavioral testing of mice.

Thermal detection thresholds of Aδ- and C-fibre afferents activated by brief CO2 laser pulses applied onto the human hairy skin.

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.

Tactile roughness discrimination of the finger pad relies primarily on vibration sensitive afferents not necessarily located in the hand.

This study aims to investigate the relative contribution of remote mechanoreceptors to perception of roughness and spatial acuity. We examined two unilateral pathological conditions affecting differently innervation of the index finger: unilateral carpal tunnel syndrome (n=12) and surgically repaired complete traumatic median nerve section at the wrist following surgical repair (n=4). We employed a control condition consisting of ring-block anesthesia of the entire index in 10 healthy subjects to model pathological denervation of the fingertip. Spatial acuity and the ability to discern roughness were assessed using a grating orientation task and a roughness discrimination task, respectively. In patients with carpal tunnel syndrome, we observed a significant reduction of spatial resolution acuity but an intact ability to discriminate roughness with the fingertip. For patients with traumatic median nerve section there was no recovery with the grating orientation task up to 20 months post surgery but a progressive and full recovery with the roughness discrimination task between 6 and 9 months. Finally, in the anesthetic ring bloc group, the nerve block completely disrupted performances in grating orientation task, but unexpectedly left unaffected performances in the roughness discrimination task. Taken together, these lines of evidence support the view that the neural mechanisms underlying tactile roughness discrimination differ from those involved in spatial resolution acuity. Vibrotaction is necessary and sufficient for the perception of fine textures and, when the innervation of the fingerpad is compromised, information about textures can be captured and encoded by remote mechanoreceptors located in more proximal tissues where the innervation is intact.

Nociceptive steady-state evoked potentials elicited by rapid periodic thermal stimulation of cutaneous nociceptors.

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 Aß-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.

Asymptomatic small fiber neuropathy in diabetes mellitus: investigations with intraepidermal nerve fiber density, quantitative sensory testing and laser-evoked potentials.

This study aimed at evaluating the performance of a battery of morphological and functional tests for the assessment of small nerve fiber loss in asymptomatic diabetic neuropathy (DNP). Patients diagnosed for ≥10 years with type 1 (n = 10) or type 2 (n = 13) diabetes mellitus (DM) without conventional symptoms or signs of DNP were recruited and compared with healthy controls (n = 18) and patients with overt DNP (n = 5). Intraepidermal nerve fiber density (IENFd) was measured with PGP9.5 immunostaining on punch skin biopsies performed at the distal leg. Functional tests consisted of quantitative sensory testing (QST) for light-touch, cool, warm and heat pain detection thresholds and brain-evoked potentials with electrical (SEPs) and CO(2) laser stimulation [laser-evoked potentials (LEPs)] of hand dorsum and distal leg using small (0.8 mm(2)) and large (20 mm(2)) beam sizes. Results confirmed a state of asymptomatic DNP in DM, but only at the distal leg. Defining a critical small fiber loss as a reduction of IENFd ≤-2 z scores of healthy controls, this state prevailed in type 2 (30%) over type 1 DM (10%) patients despite similar disease duration and current glycemic control. LEPs with the small laser beam performed best in terms of sensitivity (91%), specificity (83%) and area-under-the ROC curve (0.924). Although this performance was not statically different from that of warm and cold detection threshold, LEPs offer an advantage over QST given that they bypass the subjective report and are therefore unbiased by perceptual factors.

The pain matrix reloaded: a salience detection system for the body.

Neuroimaging and neurophysiological studies have shown that nociceptive stimuli elicit responses in an extensive cortical network including somatosensory, insular and cingulate areas, as well as frontal and parietal areas. This network, often referred to as the "pain matrix", is viewed as representing the activity by which the intensity and unpleasantness of the perception elicited by a nociceptive stimulus are represented. However, recent experiments have reported (i) that pain intensity can be dissociated from the magnitude of responses in the "pain matrix", (ii) that the responses in the "pain matrix" are strongly influenced by the context within which the nociceptive stimuli appear, and (iii) that non-nociceptive stimuli can elicit cortical responses with a spatial configuration similar to that of the "pain matrix". For these reasons, we propose an alternative view of the functional significance of this cortical network, in which it reflects a system involved in detecting, orienting attention towards, and reacting to the occurrence of salient sensory events. This cortical network might represent a basic mechanism through which significant events for the body's integrity are detected, regardless of the sensory channel through which these events are conveyed. This function would involve the construction of a multimodal cortical representation of the body and nearby space. Under the assumption that this network acts as a defensive system signaling potentially damaging threats for the body, emphasis is no longer on the quality of the sensation elicited by noxious stimuli but on the action prompted by the occurrence of potential threats.

Multimodal therapeutic assessment of peripheral nerve stimulation in neuropathic pain: five case reports with a 20-year follow-up.

Neuropathic pain following peripheral nerve lesion is highly resistant to conventional pain treatments but may respond well to direct electrical peripheral nerve stimulation (PNS). In the 1980s, we treated a series of 11 peripheral neuropathic pain patients with PNS. A first outcome assessment, conducted after a 52-month follow-up, revealed that the majority of the patients were significantly improved. Here, we present the results of a second and more comprehensive follow-up, conducted after more than 20years of PNS usage. Of the six patients still using PNS, five participated in a multimodality assessment of the long-term efficacy of PNS. Home evaluations showed reduced pain ratings and improved quality-of-life during active periods of stimulation. Quantitative sensory testing confirmed the neuropathic character of the pain complaints. PNS had no significant overall effect on tactile detection, cool, warmth, cold pain and heat pain thresholds. Laser-evoked potentials showed an enlarged N2-P2 complex during active PNS. Positron Emission Tomography revealed that PNS decreased activation in the pain matrix at rest and during thermal stimulation. PNS led to increased blood flow not only in primary somatosensory cortex, but also in anterior cingulate and insular cortices, suggesting that besides activation of the dorsal column lemniscal system, other mechanisms may play a role in its analgesic effects. These data show that PNS can provide truly long-term pain relief in carefully selected patients and they provide some objective quantitative data in support of this. They encourage the planning of future prospective studies in a larger cohort of patients.