Pain-related Evoked Potentials Research Articles

Anodal transcutaneous spinal direct current stimulation influences the amplitude of pain-related evoked potentials in healthy subjects

It has already been described that transcutaneous spinal direct current stimulation (tsDCS) can selectively influence nociceptive evoked potentials. This study is the first aiming to prove an influence of tsDCS on pain-related evoked potentials (PREP) using concentric surface electrodes (CE), whose nociceptive specificity is still under discussion. 28 healthy subjects participated in this sham-controlled, double-blind cross-over study. All subjects underwent one session of anodal and one session of sham low-thoracic tsDCS. Before and after the intervention, PREP using CE, PREP-induced pain perception and somatosensory evoked potentials (SEP) were assessed on the right upper and lower limb. We found a decrease in PREP amplitude at the lower limb after sham stimulation, but not after anodal tsDCS, while SEP remained unchanged under all studied conditions. There was no difference between the effects of anodal tsDCS and sham stimulation on the studied parameters assessed at the upper limb. PREP-induced pain of the upper and lower limb increased after anodal tsDCS. The ability of influencing PREP using a CE at the spinal level in contrast to SEP suggests that PREP using CE follows the spinothalamic pathway and supports the assumption that it is specifically nociceptive. However, while mainly inhibitory effects on nociceptive stimuli have already been described, our results rather suggest that anodal tsDCS has a sensitizing effect. This may indicate that the mechanisms underlying the elicitation of PREP with CE are not the same as for the other nociceptive evoked potentials. The effects on the processing of different types of painful stimuli should be directly compared in future studies.

Acupuncture-Induced Changes in Nociception, Measured by Pain-Related Evoked Potentials: A Pilot Mechanistic Study.

Objective: The nociceptive system has been implicated in acupuncture analgesia, although acupuncture's precise mechanism of action remains unknown. Electric pain-related evoked potentials (PREPs) have emerged as an effective and reliable electrophysiologic method for evaluation of the human nociceptive system by electric stimulation of nociceptive Aδ and C fibers. This pilot mechanistic study aims to assess the feasibility of using advanced PREP techniques together with electroacupuncture and to use PREPs to characterize acupuncture's effect on nociception. Methods: Seven healthy volunteers underwent a previously designed electroacupuncture protocol using acupoints in the legs bilaterally, which has been demonstrated to induce systemic analgesia. Advanced PREP techniques involving tripolar stimulating electrode, varying interstimulus interval, and incorporating a cognitive task during PREPs were used. PREPs were assessed before electroacupuncture, during electroacupuncture, and 30 min after electroacupuncture. Subjective pain perception in response to the PREP-related electric pain stimuli delivered to the nondominant hand was assessed on the visual analog scale (VAS) at baseline, during electroacupuncture, and 30 min postelectroacupuncture. Results: Reliable PREP N1, P1, and N2 waves were obtained from all subjects at the following average latencies: N1 = 131.5 msec, P1 = 189.4 msec, and N2 = 231.1 msec. Electroacupuncture caused a significant reduction in PREP N1P1 wave amplitudes from 25.6 to 15.4 μV (p = 0.006) and electric pain perception on the VAS-from 2.86 to 2.14 (p = 0.008), compared to baseline. These effects were sustained at 30 min postacupuncture with N1P1 wave amplitude 17.2 μV (p = 0.030) and VAS 2.28 (p = 0.030), compared to baseline. Conclusions: Electroacupuncture causes significant changes in objective nociception, measured by PREP N1P1 wave amplitudes, and in subjective nociception, measured by the VAS, and these effects are sustained for 30 min after electroacupuncture. Planned future studies will involve chronic pain populations and will aim to assess acupuncture's longer term analgesic effects.

P 17 Posttraumatic Headache – Pain Related Evoked Potentials (PREP) and Conditioned Pain Modulation (CPM) as possible biomarkers for identification of risk patients

Introduction : Posttraumatic headache (PTH) is one of the most common complications following traumatic brain injury (TBI)[1], though its underlying pathomechanisms have not been fully understood yet. An altered descending pain modulation seems to contribute to its development and persistence[2]. The aim of our study was to examine the pain processing in PTH-patients using pain-related evoked potentials after electrical stimulation (PREP) and conditioned pain modulation (CPM), based on their N1P1-amplitude as an objective readout. We chose a longitudinal design to analyse if PREP and CPM can be used as biomarkers for persisting PTH. Methods : We plan to recruit 30 patients with PTH and 20 healthy control subjects. Currently (October 2021) we have recruited 21 PTH-patients and 19 healthy control subjects. The patients were invited for follow-up sessions at 3 and 6 months after inclusion. The painful stimuli were applied at the dorsum of the right hand and above the right eyebrow with a concentric surface electrode while PREP were recorded over Cz and evoked pain was assessed on the numerical rating scale (NRS), as previously described [3]. For CPM we used the same electrode for painful cutaneous electric stimulation on the right hand as the test stimulus and the immersion of the left hand in a 10°C cold water bath as the conditioning stimulus. With the assessed data we calculated early and late CPM-effects for the subjective pain ratings and the objective N1-P1-amplitudes in the EEG, as recently reported[4]. Results : PTH-patients were on average 41.3 (± 10.7) years old, had a mean headache duration of 103 (± 265) weeks and a mean headache intensity of 5.9 (± 1.9) on the NRS (0-10). We currently present data at baseline. PREP parameters in both regions did not differ between PTH-patients and age-matched controls. The early CPM-effect based on PREP-amplitudes and the late CPM effect based on pain-rating were significantly less pronounced in patients than in controls. The early and late CPM effect for pain and amplitudes correlated significantly in both groups, but no significant correlation comparing CPM effects based on pain with the CPM effects based on amplitudes could be detected. Conclusions : Our preliminary results display a deficient endogenous pain modulation in PTH-patients also based on PREP-amplitude as an objective readout. The missing correlation between CPM-effects based on subjective pain ratings and PREP-amplitudes indicate different pathways involved in nociception and subjective pain perception. Further analysis of subgroups is planned after complete recruitment.

Diagnosing small fiber neuropathy in clinical practice: a deep phenotyping study.

Background and aims:Small fiber neuropathy (SFN) is increasingly suspected in patients with pain of uncertain origin, and making the diagnosis remains a challenge lacking a diagnostic gold standard.Methods:In this case–control study, we prospectively recruited 86 patients with a medical history and clinical phenotype suggestive of SFN. Patients underwent neurological examination, quantitative sensory testing (QST), and distal and proximal skin punch biopsy, and were tested for pain-associated gene loci. Fifty-five of these patients additionally underwent pain-related evoked potentials (PREP), corneal confocal microscopy (CCM), and a quantitative sudomotor axon reflex test (QSART).Results:Abnormal distal intraepidermal nerve fiber density (IENFD) (60/86, 70%) and neurological examination (53/86, 62%) most frequently reflected small fiber disease. Adding CCM and/or PREP further increased the number of patients with small fiber impairment to 47/55 (85%). Genetic testing revealed potentially pathogenic gene variants in 14/86 (16%) index patients. QST, QSART, and proximal IENFD were of lower impact.Conclusion:We propose to diagnose SFN primarily based on the results of neurological examination and distal IENFD, with more detailed phenotyping in specialized centers.

Role of Pain-Related Evoked Potential in the Diagnosis of Meralgia Paresthetica.

Introduction:Entrapment of the lateral femoral cutaneous nerve (LFCN) of thigh results in meralgia paresthetica (MP). Standard electrophysiological tests for MP are technically demanding and unreliable. We aimed to study the role of pain-related evoked potentials (PREP) in the diagnosis of MP.Methods:Patients with MP and normal volunteers were included. PREP was recorded by stimulating the skin over the lateral thigh 20 cm below the anterior-superior iliac spine and recording from the cortex at Cz.Results:A total of 28 subjects and 56 LFCNs were studied. 36 nerves had MP and 20 were normal. The mean PREP latency was 118 (8) ms among normal controls and 164 (10.8) ms in MP. The optimal cut-off point for the diagnosis of MP was 134 ms. Area under receiver operator characteristic curve was 0.97; sensitivity was 91.7% and specificity was 100%.Conclusion:PREP is reliable and easy to use electrophysiological test in establishing the diagnosis of MP.

Pain-related evoked potentials in patients with large, mixed, and small fiber neuropathy

ObjectiveTo investigate A-delta fiber pathways in patients with large, mixed, and small fiber neuropathies using pain-related evoked potentials (PREP). MethodsWe prospectively examined consecutive and unselected 108 patients with neuropathies using PREP. Patients were stratified according to impaired fiber types in those with large fiber neuropathy (LFN, n = 23), mixed fiber neuropathy (MFN, n = 80), and small fiber neuropathy (SFN, n = 5). Additionally, medical history, nerve conduction studies, quantitative sensory testing (QST), and skin punch biopsy were applied. Data was compared with those of 49 healthy controls. ResultsPatients with MFN showed a distal loss of PREP (16/80, 20%) and prolonged PREP latencies after stimulation at the foot (MFN: 225.8 [135–293.6] ms, controls: 218 [135–394] ms, p < 0.05). Patients with demyelinating neuropathies had prolonged PREP latencies after stimulation at the hand (p < 0.05 each). QST showed an impairment of small and large fiber function in patients with MFN. PREP were mostly absent in patients at advanced stages of neuropathies: in 10/31 (30%) patients with no recordable sural nerve action potential (SNAP, preserved SNAP: 8/76, 10% missing) and in 4/17 (24%) patients with loss of distal epidermal innervation (preserved epidermal innervation: 7/60, 24%) PREP was not recordable. PREP peak-to-peak amplitude after stimulation at the face was lowered in patients with reduced proximal intraepidermal nerve fiber density (p < 0.02). ConclusionPREP is a useful screening method for A-delta fiber pathology also in patients with simultaneous large fiber pathology. Loss of PREP indicates advance stages of nerve fiber damage. SignificancePREP may be useful as a complementary method for detection of small fiber impairment also in patients with mixed fiber neuropathy and in advanced stages.

A ketogenic diet normalizes interictal cortical but not subcortical responsivity in migraineurs

BackgroundA short ketogenic diet (KD) treatment can prevent migraine attacks and correct excessive cortical response. Here, we aim to prove if the KD-related changes of cortical excitability are primarily due to cerebral cortex activity or are modulated by the brainstem.MethodsThrough the stimulation of the right supraorbital division of the trigeminal nerve, we concurrently interictally recorded the nociceptive blink reflex (nBR) and the pain-related evoked potentials (PREP) in 18 migraineurs patients without aura before and after 1-month on KD, while in metabolic ketosis. nBR and PREP reflect distinct brain structures activation: the brainstem and the cerebral cortex respectively. We estimated nBR R2 component area-under-the-curve as well as PREP amplitude habituation as the slope pof the linear regression between the 1st and the 2nd block of 5 averaged responses.ResultsFollowing 1-month on KD, the mean number of attacks and headache duration reduced significantly. Moreover, KD significantly normalized the interictal PREP habituation (pre: + 1.8, post: − 9.1, p = 0.012), while nBR deficit of habituation did not change.ConclusionsThe positive clinical effects we observed in a population of migraineurs by a 1-month KD treatment coexists with a normalization at the cortical level, not in the brainstem, of the typical interictal deficit of habituation. These findings suggest that the cerebral cortex may be the primary site of KD-related modulation.Trial registrationClinicalTrials.gov NCT03775252 (retrospectively registered, December 09, 2018).

Dyshidrosis is associated with reduced amplitudes in electrically evoked pain-related potentials in women with Fabry disease

ObjectiveTo investigate A-delta fiber conduction in mild to moderate Fabry disease (FD) patients using pain-related evoked potentials (PREP). MethodsIn this case-control study we prospectively investigated 58 patients with mild to moderate FD and compared data with those of healthy controls. Small fiber function (quantitative sensory testing, QST and sympathetic skin response, SSR), morphology (intraepidermal nerve fiber density, IENFD), and electrical conduction (PREP) were assessed and correlated with sweating as major autonomic function disturbed in FD. Patients were further stratified for gender, disease severity as reflected by renal and cardiac function, and genetics. ResultsAn- or hypohidrosis (i.e. dyshidrosis) was reported by 7/32 (22%) women and 15/26 (58%) men with FD (p < 0.01). QST showed small fiber impairment in female and male patients regardless of clinical symptoms, while SSR was obtained in all patients except one man with hypohidrosis. IENFD was reduced in 50% of FD patients, with no differences between groups with and without autonomic symptoms. However, PREP amplitudes were reduced independent of the stimulation site only in female patients with dyshidrosis (p < 0.01). Genetics had no influence on PREP parameters. ConclusionA-delta fiber conduction investigated using PREP is impaired in mild to moderately affected female FD patients with clinical signs of hypohidrosis. SignificanceSmall fiber assessment in FD is of diagnostic value already in mild to moderate stages of disease.

Chapter 8 - Clinical neurophysiology of pain

Clinical neurophysiologic investigation of pain pathways in humans is based on specific techniques and approaches, since conventional methods of nerve conduction studies and somatosensory evoked potentials do not explore these pathways. The proposed techniques use various types of painful stimuli (thermal, laser, mechanical, or electrical) and various types of assessments (measurement of sensory thresholds, study of nerve fiber excitability, or recording of electromyographic reflexes or cortical potentials). The two main tests used in clinical practice are quantitative sensory testing and pain-related evoked potentials (PREPs). In particular, PREPs offer the possibility of an objective assessment of nociceptive pathways. Three types of PREPs can be distinguished depending on the type of stimulation used to evoke pain: laser-evoked potentials, contact heat evoked potentials, and intraepidermal electrical stimulation evoked potentials (IEEPs). These three techniques investigate both small-diameter peripheral nociceptive afferents (mainly Aδ nerve fibers) and spinothalamic tracts without theoretically being able to differentiate the level of lesion in the case of abnormal results. In routine clinical practice, PREP recording is a reliable method of investigation for objectifying the existence of a peripheral or central lesion or loss of function concerning the nociceptive pathways, but not the existence of pain. Other methods, such as nerve fiber excitability studies using microneurography, more directly reflect the activities of nociceptive axons in response to provoked pain, but without detecting or quantifying the presence of spontaneous pain. These methods are more often used in research or experimental study design. Thus, it should be kept in mind that most of the results of neurophysiologic investigation performed in clinical practice assess small fiber or spinothalamic tract lesions rather than the neuronal mechanisms directly at the origin of pain and they do not provide objective quantification of pain.

Cephalic and extracephalic neurophysiological effects of botulinum toxin type A in chronic migraine

The neurophysiological mechanisms underlying clinical efficacy of botulinum toxin type A (BTX-A) treatment of chronic migraine (CM) are still debated widely. We assessed the cephalic, and extra-cephalic effects of BTX-A injection in a group of 13 CM patients, by simultaneously recording the blink reflex (nBR), the trigemino-cervical reflex (nTCR), and the pain-related evoked potential (PREP) following stimulation of the right supraorbital nerve, and by recording the non-noxious somatosensory evoked potentials (SSEPs). Neurophysiological measurements were recorded before, and 1 month and 3 months after BTX-A. At month 3, BTX-A significantly reduced the mean headache days, severity of headache, and tablet intake. A significant increase in pain threshold was noted 3 months after treatment compared to baseline. We found that the initial nBR and nTCR lack of habituation was replaced by normal habituating response at 3 months. There were no variations in the initial PREP and SSEP after BTX-A, despite a trend for an increased habituation for PREP and lack of SSEP amplitudes. Our findings suggest that the responsiveness to a single session of BTX-A may be related to the blockage of sensitization of the nociceptive neurons in the dorsal horn, without an evident involvement of cortical circuitries.

Bilaterally prolonged latencies of pain-related evoked potentials in peripheral nerve injuries

ObjectiveCross-sectional study to test the applicability of pain-related evoked potentials (PREP) for the diagnosis of peripheral nerve injuries (PNI). IntroductionPatients with generalized polyneuropathies show prolonged latencies and decreased amplitudes of PREP indicating an impairment of A-delta fibers. Although these fibers are frequently affected in PNI, it is unclear, if PREP-testing detects PNI comparable to Nerve Conduction Studies (NCS). Methods23 patients with PNI of one upper limb underwent bilateral PREP-testing (using concentric surface electrodes) and NCS. 41 healthy controls underwent PREP-testing only. We determined pain thresholds, N1-latencies and N1P1-amplitudes of PREP and analyzed them for group and side-to-side differences. Small-fiber function was evaluated using thermal detection thresholds of Quantitative Sensory Testing (QST). N1-latencies above a cut-off calculated by ROC-analysis were defined as abnormal in order to compare detection rates of PREP and NCS. ResultsPatients with PNI showed bilaterally prolonged N1-latencies (ipsilateral: 167.0 ± 40.7 ms vs. 141.2 ± 20.5 ms / contralateral: 160.0 ± 41.0 ms vs. 140.2 ± 23.9 ms) without a significant side-to-side difference. Pain thresholds were increased on the affected side only (4.6 ± 5.2 mA vs. 2.4 ± 1.4 mA (controls)). N1P1-amplitudes did not differ between patients and controls. 7 (32%) patients showed prolonged N1-latencies (>176 ms) of PREP. NCS were abnormal in 16 (73%) cases. 13 (59%) patients showed thermal hypoesthesia in QST. ConclusionContrary to our expectations, we found bilaterally prolonged N1-latencies and normal N1P1-amplitudes in patients with PNI. Our findings support the hypothesis of a bilateral generation of PREP and indicate that PREP are not suitable for the diagnosis of PNI.

The Availability of Quantitative Assessment of Pain Perception in Patients With Diabetic Polyneuropathy.

ObjectiveTo evaluate the usefulness of the quantitative assessment of pain perception (QAPP) in diabetic polyneuropathy (DPN) patients.MethodsThirty-two subjects with DPN were enrolled in this study. The subjects’ pain perception was assessed quantitatively. Current perception threshold (CPT) and pain equivalent current (PEC) were recorded. All patients were tested with a nerve conduction study (NCS) for evaluation of DPN and pain-related evoked potential (PREP) for evaluation of small fiber neuropathy (SFN) on bilateral upper and lower limbs. All patients were asked to participate in tests such as visual analogue scale (VAS) and SF-36 Health Survey Version 2 to evaluate their subjective pain and quality of life, respectively.ResultsThe PEC of QAPP showed significant correlations with VAS (p=0.002) and physical function surveyed with SF-36 Health Survey Version 2 (p=0.035). The results of QAPP had no correlation with NCS, but there was a significant relationship between the CPT of QAPP and PREP (p=0.003).ConclusionThe QAPP may be useful not only in providing objective evaluations of subjective pain in patients with DPN but also in the assessment of diabetic SFN.

T84. Reduced amplitudes of pain-related evoked potentials in patients with neuropathic pain and normal small nerve fiber function and morphology

Cortical pain-related evoked potentials (PREP) are elicited by activation of the Aδ-fibers using cutaneous electrical stimulation and objectively reflect the Aδ-pathways. PREP were applied in an unselected patient population with acral neuropathic pain to explore its diagnostic usefulness in detecting small fiber impairment compared to quantitative sensory test (QST) and skin punch biopsy. Thirty-two patients (13 male and 19 female, median age 50 years, range 26–83) suffering from acral neuropathic pain were examined clinically and with nerve conduction studies, QST, skin punch biopsy and PREP. The study cohort consisted of 16 patients with small fiber neuropathy (SFN), 18 patients with mixed fiber neuropathy (MFN, i.e. large and small fiber neuropathy), and 8 patients with acral neuropathic pain without signs of a large fiber neuropathy or SFN. QST and skin biopsy were pathological in terms of elevated thermal thresholds and reduced distal skin innervation in patients with SFN and MFN, while patients with acral neuropathic pain had normal findings. PREP was the only method showing a pathological finding, namely reduced peak-to-peak amplitudes also in patients with acral neuropathic pain (p < 0.05). PREP was the only method revealing small fiber dysfunction in patients suffering from acral neuropathic pain with otherwise normal QST and skin biopsy. As a non-invasive test giving reproducible results, PREP may contribute to the diagnostic portfolio of small fiber tests in patients with neuropathic pain.

P1-4-01. Evaluation of small fiber involvement using pain-related evoked potentials in patients with type 1 and type 2 diabetes

The pathophysiology of diabetic neuropathy presumably differs between type1 and type 2 diabetes mellitus (T1DM and T2DM), and neuropathic pain is more frequent in patients with T2DM than T1DM. To investigate difference in small fiber involvement, we studied painrelated evoked potentials (PREPs) using intraepidermal electrical stimulation (IES) selective to A-delta-fibers and C-fibers in patients with T1DM (n = 20) and T2DM (n = 20). IES was applied in the back of hand and foot, and PREPs were recorded from the Cz electrode referenced to the linked earlobes. We evaluated the thresholds, and PREP latencies and amplitudes. Nerve conduction studies were performed in the ipsilateral limbs. There were no significant differences in age and hemoglobin A1c levels between the groups, but disease duration was significantly longer in T1DM. In nerve conduction study, patients with T1DM showed significantly more severe large fiber dysfunction in the lower extremity, however less pain/paresthesia than T2DM patients. PREPs study showed no significant differences in all the parameters between T1DM and T2DM. Diabetic neuropathy in T1DM showed relatively mild small fiber involvement compared with large fiber dysfunction, and this characteristic pattern might be related to the difference in the pathophysiology or neuropathic symptoms.

58. Clinical efficacy of short-lasting ketogenic diet in migraine might be due to a general normalization of cortical hyperresponsivity rather than to a direct modulation of the brainstem activity

We previously reported that a short-lasting period of ketogenic diet (KD) regimen can help to prevent migraine and can normalize its interictally abnormal cortical hyperresponsivity. Here, we aimed to verify whether cerebral cortex is the primary site of KD-related changes or if the latter are the expression of ketones ability to modulate brainstem subcortical structures. We simultaneously recorded the nociceptive specific blink (nBR, a marker of the brainstem trigeminal activity) and cortical pain-related evoked potentials (PREP) elicited by the stimulation of right the supraorbital division of the trigeminal nerve in 18 migraine without aura patients before and after 1-month of KD, during ketogenesis. We measured nBR R2 component as well as PREP amplitude habituations over 2 blocks of 5 averaged responses. We confirmed the ability of 1-month KD of significantly decreasing mean attack frequency and duration. KD significantly induced normalization of the interictally reduced PREP habituation (pre: +1.8, post: −9.1), while nBR habituation remained unchanged. Here, we provided evidence that the clinical efficacy of a short-lasting KD regimen in migraine can be principally due to a general normalization of the interictal cortical dysfunction, and not to a direct modulation of the subcortical brainstem activation.

Evaluation of an automated analysis for pain-related evoked potentials

Abstract This paper presents initial steps towards an auto-mated analysis for pain-related evoked potentials (PREP) to achieve a higher objectivity and non-biased examination as well as a reduction in the time expended during clinical daily routines. While manually examining, each epoch of an en-semble of stimulus-locked EEG signals, elicited by electrical stimulation of predominantly intra-epidermal small nerve fibers and recorded over the central electrode (Cz), is in-spected for artifacts before calculating the PREP by averag-ing the artifact-free epochs. Afterwards, specific peak-latencies (like the P0-, N1 and P1-latency) are identified as certain extrema in the PREP’s waveform. The proposed automated analysis uses Pearson’s correlation and low-pass differentiation to perform these tasks. To evaluate the auto-mated analysis’ accuracy its results of 232 datasets were compared to the results of the manually performed examina-tion. Results of the automated artifact rejection were compa-rable to the manual examination. Detection of peak-latencies was more heterogeneous, indicating some sensitivity of the detected events upon the criteria used during data examina-tion.

S65 Neurophysiological data favoring a central mechanism of trigeminal neuralgia

Current opinion is that TN is caused by a proximal compression of the trigeminal nerve root by a ectasic blood vessel leading to mechanical twist of nerve fibers and secondary demyelination. These changes lower the excitability threshold of affected fibers and promote inappropriate ephaptic propagation towards adjacent fibers. Not all patients have a nerve vessel conflict and 25% of people without any clinical signs of TN did show a nerve vessel contact. Possible involvement of central factors, suggesting a central facilitation and resulting hyperexcitability of the trigeminal system sustained by peripheral as well as central mechanisms were discussed. Sensitisation of second order wide dynamic range (WDR) neurons was discussed as additional pathophysiological mechanism. Since these WDR neurons receive convergent information from tactile (A-beta) and nociceptive (A-delta and C) fibers, their sensitisation could facilitate nociceptive input while promoting the perception of pain in response to tactile stimuli (i.e., allodynia). Central facilitation was demonstrated in TN patients with additional constant dull background pain besides their typical TN attacks using pain-related evoked potentials (PREP) and nociceptive blink reflex (nBR) [4]. Borsook et al. (2007) reported increased fMRI activation of a single TN patient in the primary somatosensory cortex, insula, anterior cingulate, and thalamus to further support cortical involvement [28]. Structural changes of the cortical grey matter was also reported to further support a central origin of the disease.

High test-retest-reliability of pain-related evoked potentials (PREP) in healthy subjects

Pain-related evoked potentials (PREP) is an established electrophysiological method to evaluate the signal transmission of electrically stimulated A-delta fibres. Although prerequisite for its clinical use, test-retest-reliability and side-to-side differences of bilateral stimulation in healthy subjects have not been examined yet. We performed PREP twice within 3–14days in 33 healthy subjects bilaterally by stimulating the dorsal hand. Detection (DT) and pain thresholds (PT) after electrical stimulation, the corresponding pain ratings, latencies of P0, N1, P1 and N2 components and the corresponding amplitudes were assessed. Impact of electrically induced pain intensity, age, sex, and arm length on PREP was analysed. MANOVA, t-Test, interclass correlation coefficient (ICC), standard error of measurement (SEM), smallest real difference (SRD), Bland-Altmann-Analysis as well as ANCOVA were used for statistical analysis.Measurement from both sides on both days resulted in mean N1-latencies from 142.39±18.12ms to 144.03±16.62ms and in mean N1P1-amplitudes from 39.04±12.26μV to 40.53±12.9μV. Analysis of a side-to-side effect showed for the N1-latency a F-value of 0.038 and for the N1P1-amplitude of 0.004 (p>0.8). We found intraclass correlation coefficients (ICC) from 0.88 to 0.93 and a standard error of measurement (SEM)<10% of mean values for all measurements concerning the N1-Latency and N1P1-amplitude.Intraclass correlation coefficients, standard error of measurement and Bland-Altman-Analyses revealed excellent test-retest-reliability for N1-latency and N1P1-amplitude without systematic error and there was no side-to-side effect on PREP. N1-latency (r=0.35, p<0.05) and N1P1-amplitude (r=−0.45, p<0.05) correlated with age and additionally N1-latency correlated with arm length (r=0.45, p<0.001). In contrast, pain intensity during the stimulation had no effect on both N1-latency and N1P1-amplitude.In summary, PREP showed high test-retest-reliability and negligible side-to-side differences concerning the commonly used parameters N1-latency and N1P1-amplitude.

Pain-related evoked potentials after intraepidermal electrical stimulation to Aδ and C fibers in patients with neuropathic pain

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.

13. Which is the best evoked potential technique for assessing the nociceptive system? Preliminary results of a neurophysiological study in healthy humans

Laser evoked potentials (LEPs) and contact heat evoked potentials (CHEPs) are widely agreed method for investigating the nociceptive system. Concentric electrodes (CE) have also recently been introduced to measure pain-related evoked potentials (PREPs) and, thereby, to assess the nociceptive system in patients. Although some authors have reported that low intensity CE stimulation, evoking pinprick sensation, selectively activates nociceptive fibres, the CE reliability in the assessment of nociceptive system is still unclear. In this study we aimed to verify whether low and high intensity CE stimulations selectively activates nociceptive fibres. To do so we recorded LEPs, CHEPs and PREPs before and after capsaicin-induced skin denervation. To date, we have enrolled 6 healthy subjects. All subjects underwent a baseline recording of LEPs, CHEPs and PREPs after stimulation of the right forearm. For PREP recording we used both low intensity stimulation, evoking a distinct pinprick sensation and high intensity stimulation, evoking an electrical painless sensation. After the baseline evoked potential recordings, we applied an 8% capsaicin plaster on the right forearm. After one-two weeks, we recorded LEPs, CHEPs and PREPs after stimulation of the capsaicin-induced denervated forearm skin. In a small skin area spared by evoked potential stimulations we have also collected a skin biopsy for assessing the skin denervation. While LEPs and CHEPs were suppressed after topical application of capsaicin, low and high intensity PREPs did not differ before and after capsaicin-induced skin denervation. The skin biopsy documented the skin denervation induced by the capsaicin plaster. Our data indicate that both low and high intensity CE stimulation elicit PREPs after skin denervation, thus suggesting that the CE stimulation probably coactivates non-nociceptive fibres.