Posttraumatic headache: pain related evoked potentials (PREP) and conditioned pain modulation (CPM) to assess the pain modulatory function.

Posttraumatic headache (PTH) is common following traumatic brain injury and impacts quality of life. We investigated descending pain modulation as one possible mechanism for PTH and correlated it to clinical measures. Pain-related evoked potentials (PREP) were recorded in 26 PTH-patients and 20 controls after electrical stimulation at the right hand and forehead with concentric surface electrodes. Conditioned pain modulation (CPM) was assessed using painful cutaneous electric stimulation (PCES) on the right hand as test stimulus and immersion of the left hand into 10 °C-cold water bath as conditioning stimulus based on changes in pain intensity and in amplitudes of PCES-evoked potentials. All participants completed questionnaires assessing depression, anxiety, and pain catastrophising. PTH-patients reported significantly higher pain ratings during PREP-recording in both areas despite similar stimulus intensity at pain threshold. N1P1-amplitudes during PREP and CPM-assessment were lower in patients in both areas, but statistically significant only on the hand. Both, PREP-N1-latencies and CPM-effects (based on the N1P1-amplitudes and pain ratings) were similar in both groups. Patients showed significantly higher ratings for anxiety and depression, which did not correlate with the CPM-effect. Our results indicate generalized hyperalgesia for electrical stimuli in both hand and face in PTH. The lacking correlation between pain ratings and EEG parameters indicates different mechanisms of pain perception and nociception.

EEG responses to standardised noxious stimulation during clinical anaesthesia: a pilot study.

Background: During clinical anaesthesia, the administration of analgesics mostly relies on empirical knowledge and observation of the patient's reactions to noxious stimuli. Previous studies in healthy volunteers under controlled conditions revealed EEG activity in response to standardised nociceptive stimuli even at high doses of remifentanil and propofol. This pilot study aims to investigate the feasibility of using these standardised nociceptive stimuli in routine clinical practice. Methods: We studied 17 patients undergoing orthopaedic trauma surgery under general anaesthesia. We evaluated if the EEG could track standardised noxious phase-locked electrical stimulation and tetanic stimulation, a time-locked surrogate for incisional pain, before, during, and after the induction of general anaesthesia. Subsequently, we analysed the effect of tetanic stimulation on the surgical pleth index as a peripheral, vegetative, nociceptive marker. Results: We found that the phase-locked evoked potentials after noxious electrical stimulation vanished after the administration of propofol, but not at low concentrations of remifentanil. After noxious tetanic stimulation under general anaesthesia, there were no consistent spectral changes in the EEG, but the vegetative response in the surgical pleth index was statistically significant (Hedges' g effect size 0.32 [95% confidence interval 0.12-0.77], P=0.035). Conclusion: Our standardised nociceptive stimuli are not optimised for obtaining consistent EEG responses in patients during clinical anaesthesia. To validate and sufficiently reproduce EEG-based standardised stimulation as a marker for nociception in clinical anaesthesia, other pain models or stimulation settings might be required to transfer preclinical studies into clinical practice. Clinical trial registration: DRKS00017829.

Pain-related evoked potentials with concentric surface electrodes in patients and healthy subjects: a systematic review.

Pain-related evoked potentials with concentric surface electrodes (PREP with CE) have been increasingly used in the diagnostics of polyneuropathies as well as in pain research. However, the study results are partly inconsistent regarding their utility to distinguish between normal and abnormal findings. The present systematic review aimed to summarise and compare study results, where PREP with CE were used in healthy subjects or patients and to identify possible influencing factors. We found 36 research articles, of which 21 investigated disorders in patients compared to healthy controls, while the other 15 focussed on basic research in healthy subjects. Patients with polyneuropathies showed the most consistent PREP results with similar prolonged latencies and reduced amplitude values. Findings in other patient groups or in healthy subjects were more heterogeneous. There was evidence for an influence by age and height as well as by central effects like emotions, which should be considered in further studies. Further systematic research analysing PREP results depending on individual and disease-specific factors is needed to develop optimal normative values.

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.

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

OBJECTIVE: To investigate A-delta fiber pathways in patients with large, mixed, and small fiber neuropathies using pain-related evoked potentials (PREP). METHODS: We 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. RESULTS: Patients 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). CONCLUSION: PREP 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. SIGNIFICANCE: PREP may be useful as a complementary method for detection of small fiber impairment also in patients with mixed fiber neuropathy and in advanced stages.

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.

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

BACKGROUND: A 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. METHODS: Through 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. RESULTS: Following 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. CONCLUSIONS: The 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 REGISTRATION: ClinicalTrials.gov NCT03775252 (retrospectively registered, December 09, 2018).

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

OBJECTIVE: To investigate A-delta fiber conduction in mild to moderate Fabry disease (FD) patients using pain-related evoked potentials (PREP). METHODS: In 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. RESULTS: An- 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. CONCLUSION: A-delta fiber conduction investigated using PREP is impaired in mild to moderately affected female FD patients with clinical signs of hypohidrosis. SIGNIFICANCE: Small fiber assessment in FD is of diagnostic value already in mild to moderate stages of disease.

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

OBJECTIVE: Cross-sectional study to test the applicability of pain-related evoked potentials (PREP) for the diagnosis of peripheral nerve injuries (PNI). INTRODUCTION: Patients 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). METHODS: 23 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. RESULTS: Patients with PNI showed bilaterally prolonged N1-latencies (ipsilateral: 167.0 ±â€¯40.7 ms vs. 141.2 ±â€¯20.5 ms / contralateral: 160.0 ±â€¯41.0 ms vs. 140.2 ±â€¯23.9 ms) without a significant side-to-side difference. Pain thresholds were increased on the affected side only (4.6 ±â€¯5.2 mA vs. 2.4 ±â€¯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. CONCLUSION: Contrary 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.

Capsaicin 8% patch reversibly reduces A-delta fiber evoked potential amplitudes.

INTRODUCTION: The capsaicin 8% patch is a treatment option in patients with localized peripheral neuropathic pain. Better understanding of its mechanisms of action and knowledge on predictive biomarkers for a treatment response is warranted. OBJECTIVES: To use electrically evoked pain-related potentials for investigation of A-delta fiber conduction after capsaicin 8% patch treatment. METHODS: We studied 11 healthy controls at the dorsal hand and the foot and 12 patients with neuropathic pain at the area affected by neuropathic pain before and 2 hours after application of a capsaicin 8% patch (Qutenza). Patients were additionally phenotyped using quantitative sensory testing and skin biopsy. RESULTS: Peak-to-peak N1-P1 amplitudes (PPA) were reduced after Qutenza application by a median of 60% in 6/11 controls and by 33% in patients with neuropathic pain compared with baseline; they were increased in 3 controls that did not develop capsaicin-induced pain. Patients with elevated cold detection thresholds more often had reduced PPA after Qutenza than those with normal cold detection threshold. Patients with reduced PPA after capsaicin application and with capsaicin-induced pain were more likely to achieve pain reduction on Qutenza. CONCLUSION: The capsaicin 8% patch induces a reduction in A-delta PPA in healthy persons and in patients with neuropathic pain adding to the mechanistic understanding of its effect.

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.

Amplitudes of Pain-Related Evoked Potentials Are Useful to Detect Small Fiber Involvement in Painful Mixed Fiber Neuropathies in Addition to Quantitative Sensory Testing - An Electrophysiological Study.

To investigate the usefulness of pain-related evoked potentials (PREP) elicited by electrical stimulation for the identification of small fiber involvement in patients with mixed fiber neuropathy (MFN). Eleven MFN patients with clinical signs of large fiber impairment and neuropathic pain and ten healthy controls underwent clinical and electrophysiological evaluation. Small fiber function, electrical conductivity and morphology were examined by quantitative sensory testing (QST), PREP, and skin punch biopsy. MFN was diagnosed following clinical and electrophysiological examination (chronic inflammatory demyelinating neuropathy: n = 6; vasculitic neuropathy: n = 3; chronic axonal -neuropathy: n = 2). The majority of patients with MFN characterized their pain by descriptors that mainly represent C-fiber-mediated pain. In QST, patients displayed elevated cold, warm, mechanical, and vibration detection thresholds and cold pain thresholds indicative of MFN. PREP amplitudes in patients correlated with cold (p < 0.05) and warm detection thresholds (p < 0.05). Burning pain and the presence of par-/dysesthesias correlated negatively with PREP amplitudes (p < 0.05). PREP amplitudes correlating with cold and warm detection thresholds, burning pain, and par-/dysesthesias support employing PREP amplitudes as an additional tool in conjunction with QST for detecting small fiber impairment in patients with MFN.

Small fibre pathology in patients with fibromyalgia syndrome.

Fibromyalgia syndrome is a clinically well-characterized chronic pain condition of high socio-economic impact. Although the pathophysiology is still unclear, there is increasing evidence for nervous system dysfunction in patients with fibromyalgia syndrome. In this case-control study we investigated function and morphology of small nerve fibres in 25 patients with fibromyalgia syndrome. Patients underwent comprehensive neurological and neurophysiological assessment. We examined small fibre function by quantitative sensory testing and pain-related evoked potentials, and quantified intraepidermal nerve fibre density and regenerating intraepidermal nerve fibres in skin punch biopsies of the lower leg and upper thigh. The results were compared with data from 10 patients with monopolar depression without pain and with healthy control subjects matched for age and gender. Neurological and standard neurophysiological examination was normal in all patients, excluding large fibre polyneuropathy. Patients with fibromyalgia syndrome had increased scores in neuropathic pain questionnaires compared with patients with depression and with control subjects (P < 0.001 each). Compared with control subjects, patients with fibromyalgia syndrome but not patients with depression had impaired small fibre function with increased cold and warm detection thresholds in quantitative sensory testing (P < 0.001). Investigation of pain-related evoked potentials revealed increased N1 latencies upon stimulation at the feet (P < 0.001) and reduced amplitudes of pain-related evoked potentials upon stimulation of face, hands and feet (P < 0.001) in patients with fibromyalgia syndrome compared to patients with depression and to control subjects, indicating abnormalities of small fibres or their central afferents. In skin biopsies total (P < 0.001) and regenerating intraepidermal nerve fibres (P < 0.01) at the lower leg and upper thigh were reduced in patients with fibromyalgia syndrome compared with control subjects. Accordingly, a reduction in dermal unmyelinated nerve fibre bundles was found in skin samples of patients with fibromyalgia syndrome compared with patients with depression and with healthy control subjects, whereas myelinated nerve fibres were spared. All three methods used support the concept of impaired small fibre function in patients with fibromyalgia syndrome, pointing towards a neuropathic nature of pain in fibromyalgia syndrome.