Simultaneous measurement of intra-epidermal electric detection thresholds and evoked potentials for observation of nociceptive processing following sleep deprivation.

Sleep deprivation has been shown to increase pain intensity and decrease pain thresholds in healthy subjects. In chronic pain patients, sleep impairment often worsens the perceived pain intensity. This increased pain perception is the result of altered nociceptive processing. We recently developed a method to quantify and monitor altered nociceptive processing by simultaneous tracking of psychophysical detection thresholds and recording of evoked cortical potentials during intra-epidermal electric stimulation. In this study, we assessed the sensitivity of nociceptive detection thresholds and evoked potentials to altered nociceptive processing after sleep deprivation in an exploratory study with 24 healthy male and 24 healthy female subjects. In each subject, we tracked nociceptive detection thresholds and recorded central evoked potentials in response to 180 single- and 180 double-pulse intra-epidermal electric stimuli. Results showed that the detection thresholds for single- and double-pulse stimuli and the average central evoked potential for single-pulse stimuli were significantly decreased after sleep deprivation. When analyzed separated by sex, these effects were only significant in the male population. Multivariate analysis showed that the decrease of central evoked potential was associated with a decrease of task-related evoked activity. Measurement repetition led to a decrease of the detection threshold to double-pulse stimuli in the mixed and the female population, but did not significantly affect any other outcome measures. These results suggest that simultaneous tracking of psychophysical detection thresholds and evoked potentials is a useful method to observe altered nociceptive processing after sleep deprivation, but is also sensitive to sex differences and measurement repetition.

Nociceptive Intra-epidermal Electric Stimulation Evokes Steady-State Responses in the Secondary Somatosensory Cortex.

Recent studies have established the presence of nociceptive steady-state evoked potentials (SSEPs), generated in response to thermal or intra-epidermal electric stimuli. This study explores cortical sources and generation mechanisms of nociceptive SSEPs in response to intra-epidermal electric stimuli. Our method was to stimulate healthy volunteers (n = 22, all men) with 100 intra-epidermal pulse sequences. Each sequence had a duration of 8.5 s, and consisted of pulses with a pulse rate between 20 and 200 Hz, which was frequency modulated with a multisine waveform of 3, 7 and 13 Hz (n = 10, 1 excluded) or 3 and 7 Hz (n = 12, 1 excluded). As a result, evoked potentials in response to stimulation onset and contralateral SSEPs at 3 and 7 Hz were observed. The SSEPs at 3 and 7 Hz had an average time delay of 137 ms and 143 ms respectively. The evoked potential in response to stimulation onset had a contralateral minimum (N1) at 115 ms and a central maximum (P2) at 300 ms. Sources for the multisine SSEP at 3 and 7 Hz were found through beamforming near the primary and secondary somatosensory cortex. Sources for the N1 were found near the primary and secondary somatosensory cortex. Sources for the N2-P2 were found near the supplementary motor area. Harmonic and intermodulation frequencies in the SSEP power spectrum remained below a detectable level and no evidence for nonlinearity of nociceptive processing, i.e. processing of peripheral firing rate into cortical evoked potentials, was found.

Observing Altered Nociceptive Detection Thresholds in Patients With Persistent Spinal Pain Syndrome Type 2 With a Dorsal Root Ganglion Stimulator.

OBJECTIVES: There is a lack of clinically relevant measures for quantification of maladaptive mechanisms of the nociceptive system leading to chronic pain. Recently, we developed a method that tracks nociceptive detection thresholds (NDTs) using intraepidermal electrical stimulation. In this study, we explored the feasibility of using this NDT method in patients with persistent spinal pain syndrome type 2 (PSPS-T2) and its potential to enable observation of altered nociceptive processing induced by dorsal root ganglion (DRG) stimulation. In addition, we compared NDTs with quantitative sensory testing (QST) measurements and numeric rating scale (NRS). MATERIALS AND METHODS: A total of 12 patients with PSPS-T2 (seven men; 60.4 ± 12.3 years) experiencing chronic unilateral lower limb pain treated with DRG stimulation were included in the study. Both the NDT method and electrical and pressure QST methods were performed twice in the L5 dermatome on both the affected and the unaffected foot, once with the DRG stimulator turned off and, subsequently, once with the DRG stimulator turned on. RESULTS: The NDT method can be applied to patients with PSPS-T2. With the DRG stimulator turned off, NDTs on the affected side were significantly higher than on the unaffected side. This difference was no longer present once the DRG stimulator was turned on. Furthermore, DRG stimulation affected QST (electrical and pressure) values and NRS scores. Finally, NDTs showed larger contrasts between the sides than QST measures. CONCLUSIONS: The NDT method permitted observation of altered nociceptive function. The effect of DRG stimulation also was reflected in QST outcomes and NRS scores. The larger contrast between the sides for NDTs suggests that the NDT method might be valuable for future quantification of nociceptive dysfunction in chronic pain.

Feedforward and feedback pathways of nociceptive and tactile processing in human somatosensory system: A study of dynamic causal modeling of fMRI data.

Nociceptive and tactile information is processed in the somatosensory system via reciprocal (i.e., feedforward and feedback) projections between the thalamus, the primary (S1) and secondary (S2) somatosensory cortices. The exact hierarchy of nociceptive and tactile information processing within this 'thalamus-S1-S2' network and whether the processing hierarchy differs between the two somatosensory submodalities remains unclear. In particular, two questions related to the ascending and descending pathways have not been addressed. For the ascending pathways, whether tactile or nociceptive information is processed in parallel (i.e., 'thalamus-S1' and 'thalamus-S2') or in serial (i.e., 'thalamus-S1-S2') remains controversial. For the descending pathways, how corticothalamic feedback regulates nociceptive and tactile processing also remains elusive. Here, we aimed to investigate the hierarchical organization for the processing of nociceptive and tactile information in the 'thalamus-S1-S2' network using dynamic causal modeling (DCM) combined with high-temporal-resolution fMRI. We found that, for both nociceptive and tactile information processing, both S1 and S2 received inputs from thalamus, indicating a parallel structure of ascending pathways for nociceptive and tactile information processing. Furthermore, we observed distinct corticothalamic feedback regulations from S1 and S2, showing that S1 generally exerts inhibitory feedback regulation independent of external stimulation whereas S2 provides additional inhibition to the thalamic activity during nociceptive and tactile information processing in humans. These findings revealed that nociceptive and tactile information processing have similar hierarchical organization within the somatosensory system in the human brain.

Observation of Nociceptive Processing: Effect of Intra-Epidermal Electric Stimulus Properties on Detection Probability and Evoked Potentials.

Monitoring nociceptive processing is a current challenge due to a lack of objective measures. Recently, we developed a method for simultaneous tracking of psychophysical detection probability and brain evoked potentials in response to intra-epidermal stimulation. An exploratory investigation showed that we could quantify nociceptive system behavior by estimating the effect of stimulus properties on the evoked potential (EP). The goal in this work was to accurately measure nociceptive system behavior using this method in a large group of healthy subjects to identify the locations and latencies of EP components and the effect of single- and double-pulse stimuli with an inter-pulse interval of 10 or 40 ms on these EP components and detection probability. First, we observed the effect of filter settings and channel selection on the EP. Subsequently, we compared statistical models to assess correlation of EP and detection probability with stimulus properties, and quantified the effect of stimulus properties on both outcome measures through linear mixed regression. We observed lateral and central EP components in response to intra-epidermal stimulation. Detection probability and central EP components were positively correlated to the amplitude of each pulse, regardless of the inter-pulse interval, and negatively correlated to the trial number. Both central and lateral EP components also showed strong correlation with detection. These results show that both the observed EP and the detection probability reflect the various steps of processing of a nociceptive stimulus, including peripheral nerve fiber recruitment, central synaptic summation, and habituation to a repeated stimulus.

Healthy Pain-Free Individuals with a History of Distal Radius Fracture Demonstrate an Expanded Distribution of Experimental Referred Pain Toward the Wrist.

OBJECTIVE: Nociception caused by injuries may sensitize central mechanisms causing expanded pain areas. After recovery, the status of such pain distribution and sensitivity mechanisms is unknown. The present study investigated whether individuals who have fully recovered from a distal radius fracture demonstrate increased pain sensitivity and expanded distribution of pressure-induced pain. DESIGN: Cross-sectional single-blinded study. SETTING: Clinical setting. SUBJECTS: Twenty-three pain-free individuals with a history of painful distal radius fracture and 22 nonfractured, age/gender-matched controls participated in two experimental sessions (day 0, day 1) 24 hours apart. METHODS: Pressure pain thresholds (PPTs) were recorded bilaterally at the extensor carpi radialis longus (ECRL), infraspinatus, and gastrocnemius muscles. Spatial distribution of pain was assessed following 60-second painful pressure stimulation at the ECRL (bilateral) and the infraspinatus muscles on the fractured or dominant side. Participants drew pain areas on a body map. After day 0 assessments, prolonged pain was induced by eccentric exercise of wrist extensors on the fractured/dominant side. RESULTS: Compared with controls, pressure-induced ECRL pain in the fracture group referred more frequently toward the distal forearm (P < 0.005) on day 0. Both groups showed larger pain areas on day 1 compared with day 0 (P < 0.005), although the fracture group showed a larger relative change between days (P < 0.005). The fracture group showed larger pain areas on the fracture side compared with the contralateral side on both days (P < 0.005). CONCLUSIONS: Prolonged pain and recovered prior painful injuries like fractures may sensitize pain mechanisms manifested as expanded pain distribution. Pressure-induced referred pain can be a simple pain biomarker for clinical use.

How Much Is Needed? Comparison of the Effectiveness of Different Pain Education Dosages in Patients with Fibromyalgia.

OBJECTIVE: To assess the effect of different dosages of pain neuroscience education (PNE) programs on central nociceptive processing in patients with fibromyalgia. Second, to compare the effects of different dosages of PNE programs on numerical pain rating scale (NPRS), disability, and psychological variables. DESIGN: Single-blind randomized controlled trial. SETTING: Three fibromyalgia centers in Spain (Valencia, Alcorcón, Alcalá de Henares). SUBJECTS: Seventy-seven patients with fibromyalgia. METHODS: Participants were randomized to four groups of PNE: 1) high-dose PNE (N = 20), 2) low-concentrated dose PNE (N = 20), 3) diluted low-dose PNE (N = 20), and (4) control treatment (N = 17), conducted in two 30-50-minute sessions in groups of four to six participants. Conditioned pain modulation (CPM), temporal summation (TS), and pressure pain thresholds (PPTs) were assessed at baseline and at three-month follow-up. Secondary outcome measures were the Fibromyalgia Impact Questionnaire, Pain Catastrophizing Scale, and Pain Anxiety Symptoms Scale. RESULTS: There were significant between-group differences for NPRS in favor of the groups receiving high-dose PNE, with a large effect size at three-month follow-up (P < 0.01, η2p = 0.170), but there were no significant differences between groups for the remaining variables (P > 0.05). All groups improved for central nociceptive processing, psychological variables, disability, and pain intensity (NPRS). CONCLUSIONS: In patients with fibromyalgia, higher dosages of PNE produced a larger improvement in pain severity at three-month follow-up than other dosages of PNE and biomedical education. However, PNE was not superior to biomedical education in the central nociceptive processing, disability, or psychological variables in patients with fibromyalgia.

Simultaneous tracking of psychophysical detection thresholds and evoked potentials to study nociceptive processing.

Measuring altered nociceptive processing involved in chronic pain is difficult due to a lack of objective methods. Potential methods to characterize human nociceptive processing involve measuring neurophysiological activity and psychophysical responses to well-defined stimuli. To reliably measure neurophysiological activity in response to nociceptive stimulation using EEG, synchronized activation of nerve fibers and a large number of stimuli are required. On the other hand, to reliably measure psychophysical detection thresholds, selection of stimulus amplitudes around the detection threshold and many stimulus-response pairs are required. Combining the two techniques helps in quantifying the properties of nociceptive processing related to detected and non-detected stimuli around the detection threshold.The two techniques were combined in an experiment including 20 healthy participants to study the effect of intra-epidermal electrical stimulus properties (i.e. amplitude, single- or double-pulse and trial number) on the detection thresholds and vertex potentials. Generalized mixed regression and linear mixed regression were used to quantify the psychophysical detection probability and neurophysiological EEG responses, respectively.It was shown that the detection probability is significantly modulated by the stimulus amplitude, trial number, and the interaction between stimulus type and amplitude. Furthermore, EEG responses were significantly modulated by stimulus detection and trial number. Hence, we successfully demonstrated the possibility to simultaneously obtain information on psychophysical and neurophysiological properties of nociceptive processing. These results warrant further investigation of the potential of this method to observe altered nociceptive processing.

High-frequency modulation of rat spinal field potentials: effects of slowly conducting muscle vs. skin afferents.

Long-term potentiation (LTP) in rat spinal dorsal horn neurons was induced by electrical high-frequency stimulation (HFS) of afferent C fibers. LTP is generally assumed to be a key mechanism of spinal sensitization. To determine the contribution of skin and muscle afferents to LTP induction, the sural nerve (SU, pure skin nerve) or the gastrocnemius-soleus nerve (GS, pure muscle nerve) were stimulated individually. As a measure of spinal LTP, C-fiber-induced synaptic field potentials (SFPs) evoked by the GS and by the SU were recorded in the dorsal horn. HFS induced a sustained increase of SFPs of the same nerve for at least 3 h, indicating the elicitation of homosynaptic nociceptive spinal LTP. LTP after muscle nerve stimulation (HFS to GS) was more pronounced (increase to 248%, P < 0.05) compared with LTP after skin nerve stimulation (HFS applied to SU; increase to 151% of baseline, P < 0.05). HFS applied to GS also increased the SFPs of the unconditioned SU (heterosynaptic LTP) significantly, whereas HFS applied to SU had no significant impact on the SFP evoked by the GS. Collectively, the data indicate that HFS of a muscle or skin nerve evoked nociceptive spinal LTP with large effect sizes for homosynaptic LTP (Cohen's d of 0.8-1.9) and small to medium effect sizes for heterosynaptic LTP (Cohen's d of 0.4-0.65). The finding that homosynaptic and heterosynaptic LTP after HFS of the muscle nerve were more pronounced than those after HFS of a skin nerve suggests that muscle pain may be associated with more extensive LTP than cutaneous pain.

Peripheral and central alterations affecting spinal nociceptive processing and pain at adulthood in rats exposed to neonatal maternal deprivation.

The nociceptive system of rodents is not fully developed and functional at birth. Specifically, C fibers transmitting peripheral nociceptive information establish synaptic connections in the spinal cord already during the embryonic period that only become fully functional after birth. Here, we studied the consequences of neonatal maternal deprivation (NMD, 3 h/day, P2-P12) on the functional establishment of C fiber-mediated neurotransmission in spinal cord and of pain-related behavior. In vivo recording revealed that C fiber-mediated excitation of spinal cord neurons could be observed at P14 only in control but not in NMD rats. NMD was associated with a strong alteration in the expression of growth factors controlling C nociceptor maturation as well as two-pore domain K+ channels known to set nociceptive thresholds. In good agreement, C-type sensory neurons from NMD animals appeared to be hypoexcitable but functionally connected to spinal neurons, especially those expressing TRPV1 receptors. In vivo and in vitro recordings of lamina II spinal neurons at P14 revealed that the NMD-related lack of C fiber-evoked responses resulted from an inhibitory barrage in the spinal cord dorsal horn. Eventually, C-type sensory-spinal processing could be recovered after a delay of about 10 days in NMD animals. However, animals remained hypersensitive to noxious stimulus up to P100 and this might be due to an excessive expression of Nav1.8 transcripts in DRG neurons. Together, our data provide evidence for a deleterious impact of perinatal stress exposure on the maturation of the sensory-spinal nociceptive system that may contribute to the nociceptive hypersensitivity in early adulthood.

Functions of the temporomandibular system in extracranial chronic pain conditions: modulatory effects on nocifensive behavior in an animal model.

OBJECTIVE: Mastication may be able to activate endogenous pain inhibitory mechanisms and therefore lead to modulation of nociceptive processing. The purpose of this study was to examine the possible effect of food consistency on noxious input from the spinal system. METHODS: Three groups of adult male Sprague-Dawley rats were given an injection of complete Freund adjuvant in a hind paw 10 days after eating soft or hard food (one group received a saline injection-the control group [C]; the other group (D) received no injection). Nocifensive behavior was assessed with the use of the hot plate and tail flick assays at 1, 3, 6, and 12 hours and at 6.5 days after injection for groups A/B, and c-Fos activity was assessed in the brain after testing. Groups C/D had hot plate testing at 1 hour and 6.5 days. The data were analyzed by general linear modeling and 1-way analysis of variance. RESULTS: There was a small increase in the hot plate percent maximum possible effect (MPE) from -45.7 to -61.1 in group A over the length of the experiment, but a very small decrease for group B over the same period (-33.5 to -28.8). For the saline control group, there was a small increase toward 0 %MPE over the same time frame (-15.0 to 1.7). The %MPE differences were significant between groups A and C (P < .0005), but not significant between the other groups (F = 13.34, df = 2, P = .001, observed power = 99%). Using the pooled results (all time points), the differences between all groups were significant (P < .0005). There were no significant differences in the tail flick test. c-Fos was mainly observed in the raphe pallidus area with significant differences between groups A and B at 3 and 6 hours after injection of CFA (P = .027 and .022, respectively). CONCLUSIONS: The results of this study indicate that food consistency (hardness) influences nocifensive behavior in this animal model via a descending pathway operating at the supraspinal level.

Contact-Heat Evoked Potentials: Insights into Pain Processing in CRPS Type I.

Purpose: The pathophysiological mechanisms underlying the development of chronic pain in complex regional pain syndrome (CRPS) are diverse and involve both peripheral and central changes in pain processing, such as sensitization of the nociceptive system. The aim of this study was to objectively distinguish the specific changes occurring at both peripheral and central levels in nociceptive processing in individuals with chronic CRPS type I. Patients and Methods: Nineteen individuals with chronic CRPS type I and 16 age- and sex-matched healthy controls (HC) were recruited. All individuals underwent a clinical examination and pain assessment in the most painful limb, the contralateral limb, and a pain-free control area to distinguish between peripheral and central mechanisms. Contact-heat evoked potentials (CHEPs) were recorded after heat stimulation of the three different areas and amplitudes and latencies were analyzed. Additionally, quantitative sensory testing (QST) was performed in all three areas. Results: Compared to HC, CHEP amplitudes in CRPS were only increased after stimulation of the painful area (p=0.025), while no increases were observed for the pain-free control area (p=0.14). None of the CHEP latencies were different between the two cohorts (all p>0.23). Furthermore, individuals with CRPS showed higher pain ratings after stimulation of the painful limb compared to their contralateral limb (p=0.013). Lastly, compared to HC, mechanical (p=0.012) and thermal (p=0.046) sensitivity was higher in the painful area of the CRPS cohort. Conclusion: This study provides neurophysiological evidence supporting an intact thermo-nociceptive pathway with signs of peripheral sensitization, such as hyperexcitable primary afferent nociceptors, in individuals with CRPS type I. This is further supported by the observation of mechanical and thermal gain of sensation only in the painful limb. Additionally, the increased CHEP amplitudes might be related to fear-induced alterations of nociceptive processing.

Perinatal oxycodone exposure causes long-term sex-dependent changes in weight trajectory and sensory processing in adult mice.

RATIONALE: In utero opioid exposure is associated with lower weight and a neonatal opioid withdrawal syndrome (NOWS) at birth, along with longer-term adverse neurodevelopmental outcomes and mood disorders. While NOWS is sometimes treated with continued opioids, clinical studies have not addressed if long-term neurobehavioral outcomes are worsened with continued postnatal exposure to opioids. In addition, pre-clinical studies comparing in utero only opioid exposure to continued post-natal opioid administration for withdrawal mitigation are lacking. OBJECTIVES: Here, we sought to understand the impact of continued postnatal opioid exposure on long term behavioral consequences. METHODS: We implemented a rodent perinatal opioid exposure model of oxycodone (Oxy) exposure that included Oxy exposure until birth (short Oxy) and continued postnatal opioid exposure (long Oxy) spanning gestation through birth and lactation. RESULTS: Short Oxy exposure was associated with a sex-specific increase in weight gain trajectory in adult male mice. Long Oxy exposure caused an increased weight gain trajectory in adult males and alterations in nociceptive processing in females. Importantly, there was no evidence of long-term social behavioral deficits, anxiety, hyperactivity, or memory deficits following short or long Oxy exposure. CONCLUSIONS: Our findings suggest that offspring with prolonged opioid exposure experienced some long-term sequelae compared to pups with opioid cessation at birth. These results highlight the potential long-term consequences of opioid administration as a mitigation strategy for clinical NOWS symptomology and suggest alternatives should be explored.

Cortical networks underlying successful control of nociceptive processing using real-time fMRI.

Real-time fMRI (rt-fMRI) enables self-regulation of neural activity in localized brain regions through neurofeedback. Previous studies showed successful up- and down-regulation of neural activity in the anterior cingulate cortex (ACC) and the insula (Ins) during nociceptive stimulation. Such self-regulation capacity is, however, variable across subjects, possibly related to the ability of cognitive top-down control of pain. Moreover, how specific brain areas interact to enable successful regulation of nociceptive processing and neurofeedback-based brain modulation is not well understood. A connectivity analysis framework in the frequency domain was used to examine the up- or down-regulation in the ACC and Ins and pain intensity and unpleasantness ratings were assessed. We found that successful up- and down-regulation was mediated by the ACC and by its functional connectivity with the Ins and secondary somatosensory cortex. There was no significant relationship between successful up- or downregulation and pain ratings. These findings demonstrate functional interactions between brain areas involved in nociceptive processing during regulation of ACC and Ins activity, and the relevance of the frequency domain connectivity analysis for real-time fMRI. Moreover, despite successful neural regulation, there was no change in pain ratings, suggesting that pain is a complex perception, which may be more difficult to modify than other sensory or emotional processes.

Real-time estimation of perceptual thresholds based on the electroencephalogram using a deep neural network.

BACKGROUND: Perceptual thresholds are measured in scientific and clinical setting to evaluate performance of the nervous system in essential tasks such as vision, hearing, touch, and registration of pain. Current procedures for estimating perceptual thresholds depend on the analysis of pairs of stimuli and participant responses, relying on the commitment and cognitive ability of subjects to respond accurately and consistently to stimulation. Here, we demonstrate that it is possible to measure the threshold for the perception of nociceptive stimuli based on non-invasively recorded brain activity alone using a deep neural network. NEW METHOD: For each stimulus, a trained deep neural network performed a 2-interval forced choice procedure, in which the network had to choose which of two time intervals in the electroencephalogram represented post-stimulus brain activity. Network responses were used to estimate the perceptual threshold in real-time using a psychophysical method of limits. COMPARISON WITH EXISTING METHODS: Network classification was able to match participants in reporting stimulus perception, resulting in average network-estimated perceptual thresholds that matched perceptual thresholds based on participant reports. RESULTS: The neural network successfully separated trials containing brain responses from trials without and could consistently estimate perceptual thresholds in real-time during a Go-/No-Go procedure and a counting task. CONCLUSION: Deep neural networks monitoring non-invasively recorded brain activity are now able to accurately predict stimulus perception and estimate the perceptual threshold in real-time without any verbal or motor response from the participant.

The selective 5-HT1F receptor agonist lasmiditan inhibits trigeminal nociceptive processing: Implications for migraine and cluster headache.

BACKGROUND AND PURPOSE: Lasmiditan is a novel selective 5-HT1F receptor agonist, recently approved for acute treatment of migraine. 5-HT1F receptors are widely expressed in the CNS and trigeminovascular system. Here, we have explored the therapeutic effects of 5-HT1F receptor activation in preclinical models of migraine and cluster headache. EXPERIMENTAL APPROACH: Electrical stimulation of the dura mater or the superior salivatory nucleus in anaesthetised rats evoked trigeminovascular or trigeminal-autonomic reflex activation at the level of the trigeminocervical complex. Additionally, cranial autonomic manifestations in response to trigeminal-autonomic reflex activation were measured, via anterior choroidal blood flow alterations. These responses were then challenged with lasmiditan. We explored the tissue distribution of mRNA for 5-HT1F receptors in human post-mortem tissue and of several 5-HT1 receptor subtypes in specific tissue beds. KEY RESULTS: Lasmiditan dose-dependently reduced trigeminovascular activation in a preclinical model of migraine. Lasmiditan also reduced superior salivatory nucleus-evoked activation of the trigeminal-autonomic reflex, but had no effect on cranial autonomic activation. mRNA profiling in human tissue showed expression of the 5-HT1F receptor in several structures relevant for migraine and cluster headache. CONCLUSION AND IMPLICATIONS: Our data suggest that lasmiditan acts, at least in part, as an anti-migraine agent by reducing trigeminovascular activation. Furthermore, our results highlight a clear action for lasmiditan in a preclinical model of cluster headache. Given the proven translational efficacy of this model, our data support the potential utility of lasmiditan as a therapeutic option for the acute treatment of cluster headache attacks. LINKED ARTICLES: This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.

Sensorimotor Integration and Pain Perception: Mechanisms Integrating Nociceptive Processing. A Systematic Review and ALE-Meta Analysis.

Pain treatment services and clinical indicators of pain chronicity focus on afferent nociceptive projections and psychological markers of pain perception with little focus on motor processes. Research supports a strong role for the motor system both in terms of pain related disability and in descending pain modulation. However, there is little understanding of the neurological regions implicated in pain-motor interactions and how the motor and sensory systems interact under conditions of pain. We performed an ALE meta-analysis on two clinical cohorts with atypical sensory and motor processes under conditions of pain and no pain. Persons with sensory altered processing (SAP) and no pain presented with greater activity in the precentral and supplementary motor area relative to persons with self-reported pain. In persons with motor altered processing (MAP), there appeared to be a suppression of activity in key pain regions such as the insula, thalamus, and postcentral gyrus. As such, activation within the motor system may play a critical role in dampening pain symptoms in persons with SAP, and in suppressing activity in key pain regions of the brain in persons with MAP. Future research endeavors should focus on understanding how sensory and motor processes interact both to understand disability and discover new treatment avenues.

Event-related potentials evoked by skin puncture reflect activation of Aß fibers: comparison with intraepidermal and transcutaneous electrical stimulations.

BACKGROUND: Recently, event-related potentials (ERPs) evoked by skin puncture, commonly used for blood sampling, have received attention as a pain assessment tool in neonates. However, their latency appears to be far shorter than the latency of ERPs evoked by intraepidermal electrical stimulation (IES), which selectively activates nociceptive Aδ and C fibers. To clarify this important issue, we examined whether ERPs evoked by skin puncture appropriately reflect central nociceptive processing, as is the case with IES. METHODS: In Experiment 1, we recorded evoked potentials to the click sound produced by a lance device (click-only), lance stimulation with the click sound (click+lance), or lance stimulation with white noise (WN+lance) in eight healthy adults to investigate the effect of the click sound on the ERP evoked by skin puncture. In Experiment 2, we tested 18 heathy adults and recorded evoked potentials to shallow lance stimulation (SL) with a blade that did not reach the dermis (0.1 mm insertion depth); normal lance stimulation (CL) (1 mm depth); transcutaneous electrical stimulation (ES), which mainly activates Aß fibers; and IES, which selectively activates Aδ fibers when low stimulation current intensities are applied. White noise was continuously presented during the experiments. The stimulations were applied to the hand dorsum. In the SL, the lance device did not touch the skin and the blade was inserted to a depth of 0.1 mm into the epidermis, where the free nerve endings of Aδ fibers are located, which minimized the tactile sensation caused by the device touching the skin and the activation of Aß fibers by the blade reaching the dermis. In the CL, as in clinical use, the lance device touched the skin and the blade reached a depth of 1 mm from the skin surface, i.e., the depth of the dermis at which the Aß fibers are located. RESULTS: The ERP N2 latencies for click-only (122 ± 2.9 ms) and click+lance (121 ± 6.5 ms) were significantly shorter than that for WN+lance (154 ± 7.1 ms). The ERP P2 latency for click-only (191 ± 11.3 ms) was significantly shorter than those for click+lance (249 ± 18.6 ms) and WN+lance (253 ± 11.2 ms). This suggests that the click sound shortens the N2 latency of the ERP evoked by skin puncture. The ERP N2 latencies for SL, CL, ES, and IES were 146 ± 8.3, 149 ± 9.9, 148 ± 13.1, and 197 ± 21.2 ms, respectively. The ERP P2 latencies were 250 ± 18.2, 251 ± 14.1, 237 ± 26.3, and 294 ± 30.0 ms, respectively. The ERP latency for SL was significantly shorter than that for IES and was similar to that for ES. This suggests that the penetration force generated by the blade of the lance device activates the Aß fibers, consequently shortening the ERP latency. CONCLUSIONS: Lance ERP may reflect the activation of Aß fibers rather than Aδ fibers. A pain index that correctly and reliably reflects nociceptive processing must be developed to improve pain assessment and management in neonates.

Multisine frequency modulation of intra-epidermal electric pulse sequences: A novel tool to study nociceptive processing.

A sustained sensory stimulus with a periodic variation of intensity creates an electrophysiological brain response at associated frequencies, referred to as the steady-state evoked potential (SSEP). The SSEPs elicited by the periodic stimulation of nociceptors in the skin may represent activity of a brain network that is primarily involved in nociceptive processing. Exploring the behavior of this network could lead to valuable insights regarding the pathway from nociceptive stimulus to pain perception. We present a method to directly modulate the pulse rate of nociceptive afferents in the skin with a multisine waveform through intra-epidermal electric stimulation. The technique was demonstrated in healthy volunteers. Each subject was stimulated using a pulse sequence modulated by a multisine waveform of 3, 7 and 13 Hz. The EEG was analyzed for the presence of the base frequencies and associated (sub)harmonics. Topographies showed significant central and contralateral SSEP responses at 3, 7 and 13 Hz in respectively 7, 4 and 3 out of the 9 participants included for analysis. As such, we found that intra-epidermal stimulation with a multisine frequency modulated pulse sequence can generate nociceptive SSEPs. The possibility to stimulate the nociceptive system using multisine frequency modulated pulses offers novel opportunities to study the temporal dynamics of nociceptive processing.

Transcranial Static Magnetic Field Stimulation over the Primary Motor Cortex Induces Plastic Changes in Cortical Nociceptive Processing.

Transcranial static magnetic field stimulation (tSMS) is a novel and inexpensive, non-invasive brain stimulation (NIBS) technique. Here, we performed non-invasive modulation of intra-epidermal electrical stimulation-evoked potentials (IES-EPs) by applying tSMS or sham stimulation over the primary motor (M1) and somatosensory (S1) cortices in 18 healthy volunteers for 15 min. We recorded EPs after IES before, right after, and 10 min after tSMS. The IES-EP amplitude was significantly reduced immediately after tSMS over M1, whereas tSMS over S1 and sham stimulation did not affect the IES-EP amplitude. Thus, tSMS may affect cortical nociceptive processing. Although the results of intervention for experimental acute pain in healthy subjects cannot be directly translated into the clinical situation, tSMS may be a potentially useful NIBS method for managing chronic pain, in addition to standard of care treatments.