Intra-epidermal Electrical Stimulation Research Articles

Comparison between intra-epidermal electrical and laser stimulation using direct intracranial recording of evoked potentials

It has long been argued that the intra-epidermal electrical stimulation (IES) can stimulate A-delta fibres. The IES directly stimulates free nerve endings, therefore bypassing the temperature conduction delay of around 20 ms needed for laser-induced activation. However, there is no direct evidence to prove its selectivity to A-delta; this hampers its clinical application in comparison to the laser stimulation, which is currently the gold standard in this field. Here, we performed direct intracranial recordings in response to both IES (10 pulses at 49 Hz; 0.2–0.3 mA) and laser stimulation (Nd:YAP; 80–100 mJ/mm 2 ). Seven (7) recording contacts were located in the posterior insula, 4 in the pericentral insula (posterior short gyrus 2, anterior long gyrus 1, central sulcus 1), 5 in the orbitofrontal cortex, 4 in the amygdala, 3 in the prefrontal cortex, and 2 in the perigenual anterior cingulate. Mean difference in peak latencies was 15.3 ms, consistent with peripheral heat transduction time. The amplitude of local insular responses was not significantly different between laser and intra-epidermal stimulation (97.7 ± 45.0 and 77.6 ± 33.0 μV, respectively; P = 0.24). However, when looking outside the insula, the magnitude of responses was significantly smaller for the IES-evoked potentials in the amygdala, perigenual cingulate and prefrontal/orbitofrontal cortices. We conclude that IES can effectively activate the A-delta system at non-nociceptive levels, and induce sizeable sensory insular responses; conversely, IES barely activates limbic, cingulate and prefrontal structures contributing to the cognitive and arousal value of the stimulus.

Augmented Pain Processing in Primary and Secondary Somatosensory Cortex in Fibromyalgia: A Magnetoencephalography Study Using Intra-Epidermal Electrical Stimulation.

The aim of this study was to investigate augmented pain processing in the cortical somatosensory system in patients with fibromyalgia (FM). Cortical evoked responses were recorded in FM (n = 19) and healthy subjects (n = 21) using magnetoencephalography after noxious intra-epidermal electrical stimulation (IES) of the hand dorsum (pain rating 6 on a numeric rating scale, perceptually-equivalent). In addition, healthy subjects were stimulated using the amplitude corresponding to the average stimulus intensity rated 6 in patients with FM (intensity-equivalent). Quantitative sensory testing was performed on the hand dorsum or thenar muscle (neutral site) and over the trapezius muscle (tender point), using IES (thresholds, ratings, temporal summation of pain, stimulus-response curve) and mechanical stimuli (threshold, ratings). Increased amplitude of cortical responses was found in patients with FM as compared to healthy subjects. These included the contralateral primary (S1) and bilateral secondary somatosensory cortices (S2) in response to intensity-equivalent stimuli and the contralateral S1 and S2 in response to perceptually-equivalent stimuli. The amplitude of the contralateral S2 response in patients with FM was positively correlated with average pain intensity over the last week. Quantitative sensory testing results showed that patients with FM were more sensitive to painful IES as well as to mechanical stimulation, regardless of whether the stimulation site was the hand or the trapezius muscle. Interestingly, the slope of the stimulus-response relationship as well as temporal summation of pain in response to IES was not different between groups. Together, these results suggest that the observed pain augmentation in response to IES in patients with FM could be due to sensitization or disinhibition of the cortical somatosensory system. Since the S2 has been shown to play a role in higher-order functions, further studies are needed to clarify the role of augmented S2 response in clinical characteristics of FM.

A spatiotemporal signature of cortical pain relief by tactile stimulation: An MEG study

Recently, the cortical mechanisms of tactile-induced analgesia have been investigated; however, spatiotemporal characteristics have not been fully elucidated. The insular–opercular region integrates multiple sensory inputs, and nociceptive modulation by other sensory inputs occurs in this area. In this study, we focused on the insular–opercular region to characterize the spatiotemporal signature of tactile-induced analgesia using magnetoencephalography in 11 healthy subjects. Aδ (intra-epidermal electrical stimulation) inputs were modified by Aβ (mechanical tactile stimulation) selective stimulation, either independently or concurrently, to the right forearm. The optimal inter-stimulus interval (ISI) for cortical level modulation was determined after comparing the 40-, 60-, and 80-ms ISI conditions, and the calculated cortical arrival time difference between Aδ and Aβ inputs. Subsequently, we adopted a 60-ms ISI for cortical modulation and a 0-ms ISI for spinal level modulation. Source localization using minimum norm estimates demonstrated that pain-related activity was located in the posterior insula, whereas tactile-related activity was estimated in the parietal operculum. We also found significant inhibition of pain-related activity in the posterior insula due to cortical modulation. In contrast, spinal modulation was observed both in the posterior insula and parietal operculum. Subjective pain, as evaluated by the visual analog scale, also showed significant reduction in both conditions. Therefore, our results demonstrated that the multisensory integration within the posterior insula plays a key role in tactile-induced analgesia.

テーピングが痛覚関連体性感覚誘発電位に及ぼす影響

Taping is widely used in sports medicine to prevent injury, protect affected sites post injury and relieve pain. However, it is not clear whether taping affects the perception of noxious stimulation because in previous studies, it was difficult to selectively activate Aδ fibers. A recently developed, useful, new tool named intra-epidermal electrical stimulation (IES) can preferentially activate Aδ fibers. We aimed to clarify the effect of taping on pain-related somatosensory evoked potentials (pSEPs) using IES. We recorded pSEPs following IES of the right medial forearm in twelve healthy volunteers. pSEPs were recorded from 9 electrodes on the scalp under control, elastic-taping and white-taping conditions. Under the control condition, subjects relaxed on a comfortable reclining seat without taping, whereas under the taping conditions, they were subjected to taping along the forearm with tension (elastic-taping) and without tension (white-taping). Subjects were asked to assign a visual analog scale (VAS) score after each session. The peak amplitudes of N2-P2 were significantly lower under the elastic-taping and white-taping conditions than those under the control condition. VAS was significantly lower elastic-taping condition than those under the control and white-taping conditions. Moreover, there was a significant positive correlation between the amplitude of N2-P2 and VAS. We revealed that taping along the forearm decreased pSEPs and subjective pain perception under the white-taping and elastic-taping conditions. The underlying mechanism of pain relief was the distraction effect in both taping conditions. In addition, elastic-taping with tension changes afferent inputs mainly from the skin, and this might more effectively decrease the subjective pain perception than that achieved under the white-taping condition.

Effect of temporal stimulus properties on the nociceptive detection probability using intra-epidermal electrical stimulation.

Chronic pain disorders can be initiated and maintained by malfunctioning of one or several mechanisms underlying the nociceptive function. Although several quantitative sensory testing methods exist to characterize the nociceptive function, it remains difficult to distinguish the contributions of individual mechanisms. Intra-epidermal electrical stimulation of nociceptive fibers allows defining stimuli with temporal properties within the timescale of these mechanisms. Here, we studied the effect of stimulus properties on the psychophysical detection probability. A psychophysical detection experiment was conducted including 30 healthy human participants. Participants were presented with electrical stimuli having various temporal properties. The pulse-width was varied for single pulse stimuli (either 420 or 840 μs), and the inter-pulse interval for double pulse stimuli (10, 50, or 100 ms). Generalized linear mixed models were used to obtain estimates of thresholds and slopes of the psychophysical function. The 840-μs single pulse resulted in a lower threshold and steeper slope of the psychophysical function than the 420-μs single pulse. Moreover, a double-pulse stimulus resulted in a lower threshold and steeper slope than single pulse stimuli. The slopes were similar between the double pulse stimuli, but thresholds slightly increased with increasing inter-pulse intervals. In the present study, it was demonstrated that varying the temporal properties of intra-epidermal electrical stimuli results in variations in nociceptive processing. The estimated thresholds and slopes corresponding to the selection of temporal properties suggest that contributions of peripheral and central nociceptive mechanisms can be reflected in psychophysical functions.

The dorsolateral prefrontal network is involved in pain perception in knee osteoarthritis patients

Functional MRI (fMRI) studies have been used to investigate how the brain processes noxious stimuli in osteoarthritis (OA) and to identify the cortical location of pain perception. However, no consensus has been reached regarding brain activity associated with pain-induced conditions in OA patients. We examined cerebral responses using intra-epidermal electrical stimulation of the . knee in knee OA patients. To replicate the pain of knee OA in terms of predictability, acute pain generated by electrical stimulation was provided simultaneously with displayed images in this study. We used fMRI to identify differences in response between healthy subjects and knee OA patients and explored the modulating cortico-subcortical and cortico-cortical pathways using psychophysiological interaction (PPI) analysis. Our results show that chronic pain results in a different brain activation profile in the DLPFC and the pain matrix in knee OA patients. Abnormal brain connectivity between the DLPFC and the pain matrix is induced by chronic pain in knee OA patients.

Cortical responses to C-fiber stimulation by intra-epidermal electrical stimulation: An MEG study

Intra-epidermal electric stimulation (IES) is an alternative to laser stimulation for selective activation of cutaneous Aδ-fibers. IES is based on the fact that nociceptive fiber terminals are located in the epidermis, whereas receptors of other fibers end deep in the dermis. IES can selectively stimulate C-fibers if the electrode structure and stimulation parameters are carefully selected. However, stable selective stimulation of C-fibers using IES has proven difficult and cannot currently be used in clinical settings. The purpose of the present study was to determine if IES performed using a modified electrode reliably stimulates C-fibers. Magnetoencephalographic responses to IES to the foot were measured in seven healthy subjects. IES elicited somatosensory evoked fields in all subjects. The mean peak latency was 1327±116ms in the opercular region contralateral to the stimulated side, 1318±90ms in the opercular region ipsilateral to the stimulated side, and 1350±139ms in the primary somatosensory cortex. These results indicate that IES performed using the modified electrode can selectively stimulate C-fibers and may be a useful tool for pain research as well as clinical evaluation of peripheral small fiber function.

The respiratory cycle modulates brain potentials, sympathetic activity, and subjective pain sensation induced by noxious stimulation

To test the hypothesis that a respiratory cycle influences pain processing, we conducted an experimental pain study in 10 healthy volunteers. Intraepidermal electrical stimulation (IES) with a concentric bipolar needle electrode was applied to the hand dorsum at pain perceptual threshold or four times the perceptual threshold to produce first pain during expiration or inspiration either of which was determined by the abrupt change in an exhaled CO2 level. IES-evoked potentials (IESEPs), sympathetic skin response (SSR), digital plethysmogram (DPG), and subjective pain intensity rating scale were simultaneously recorded. With either stimulus intensity, IES during expiration produced weaker pain feeling compared to IES during inspiration. The mean amplitude of N200/P400 in IESEPs and that of SSR were smaller when IES was applied during expiration. The magnitude of DPG wave gradually decreased after IES, but a decrease in the magnitude of DPG wave was less evident when IES was delivered during expiration. Regardless of stimulus timing or stimulus intensity, pain perception was always concomitant with appearance of IESEPs and SSR, and changes in DPG. Our findings suggest that pain processing fluctuates during normal breathing and that pain is gated within the central nervous system during expiration.

Evaluation of nociceptive Aδ- and C-fiber dysfunction with lidocaine using intraepidermal electrical stimulation

ObjectiveTo investigate whether intraepidermal electrical stimulation (IES) can evaluate nociceptive Aδ- and C-fiber dysfunctions of an experimental model of small-fiber neuropathy (SFN) with transdermal lidocaine. MethodsLidocaine tape or placebo was applied to the dorsum of the feet in 14 healthy subjects. Reaction time (RT), sensory threshold, and evoked potentials (EPs) were measured using IES before, and 30 and 60min after lidocaine/placebo application. ResultsAll subjects felt pricking sensations following Aδ-fiber stimulation, and light painful sensations such as pricking, tingling, or burning following C-fiber stimulation using IES. RT was divided bimodally between Aδ- and C-fiber stimulations. At 30min, lidocaine increased the sensory threshold and decreased the amplitude of EPs in both fiber stimulations. At 60min, lidocaine’s effects were greater for C fibers than for Aδ fibers. The sensory threshold and amplitude of EPs were unchanged among placebo sessions. ConclusionsIES demonstrated differential effects of transdermal lidocaine on nociceptive Aδ and C fibers, and elucidated the pathophysiology of the experimental model of SFN. SignificanceIES has advantages in terms of cost, convenience, and invasiveness. It may have potential for a clinical tool to elucidate the pathophysiology of patients with SFN, including the differences between Aδ and C fibers.

Short trains of intra-epidermal electrical stimulation to elicit reliable behavioral and electrophysiological responses to the selective activation of nociceptors in humans

Currently, the study of nociception in humans relies mainly on thermal stimulation of heat-sensitive nociceptive afferents. To circumvent some limitations of thermal stimulation, it was proposed that intra-epidermal electrical stimulation (IES) could be used as an alternative method to activate nociceptors selectively. The selectivity of IES relies on the fact that it can generate a very focal electrical current and, thereby, activate nociceptive free nerve endings located in the epidermis without concomitantly activating non-nociceptive mechanoreceptors located more deeply in the dermis. However, an important limitation of IES is that it is selective for nociceptors only when very low current intensities are used. At these intensities, the stimulus generates a very weak percept, and the signal-to-noise ratio of the elicited evoked potentials (EPs) is very low. To circumvent this limitation, it was proposed that the strength of the nociceptive afferent volley could be increased through temporal summation, using short trains of repeated IES. Here, we characterized the intensity of perception and EPs elicited by trains of 2, 3 and 4 IES delivered using a 5-ms inter-stimulus interval. We found that both the intensity of perception and the magnitude of EPs significantly increased with the number of pulses. In contrast, the latency of the elicited EPs was not affected by the number of pulses, indicating that temporal summation did not affect the type of activated fibers and, therefore, that trains of IES can be used to increase the reliability of stimulus-evoked responses while still preserving its selectivity for nociceptors.

Unmasking the obligatory components of nociceptive event-related brain potentials

It has been hypothesized that the human cortical responses to nociceptive and nonnociceptive somatosensory inputs differ. Supporting this view, somatosensory-evoked potentials (SEPs) elicited by thermal nociceptive stimuli have been suggested to originate from areas 1 and 2 of the contralateral primary somatosensory (S1), operculo-insular, and cingulate cortices, whereas the early components of nonnociceptive SEPs mainly originate from area 3b of S1. However, to avoid producing a burn lesion, and sensitize or fatigue nociceptors, thermonociceptive SEPs are typically obtained by delivering a small number of stimuli with a large and variable interstimulus interval (ISI). In contrast, the early components of nonnociceptive SEPs are usually obtained by applying many stimuli at a rapid rate. Hence, previously reported differences between nociceptive and nonnociceptive SEPs could be due to differences in signal-to-noise ratio and/or differences in the contribution of cognitive processes related, for example, to arousal and attention. Here, using intraepidermal electrical stimulation to selectively activate Aδ-nociceptors at a fast and constant 1-s ISI, we found that the nociceptive SEPs obtained with a long ISI are no longer identified, indicating that these responses are not obligatory for nociception. Furthermore, using a blind source separation, we found that, unlike the obligatory components of nonnociceptive SEPs, the obligatory components of nociceptive SEPs do not receive a significant contribution from a contralateral source possibly originating from S1. Instead, they were best explained by sources compatible with bilateral operculo-insular and/or cingulate locations. Taken together, our results indicate that the obligatory components of nociceptive and nonnociceptive SEPs are fundamentally different.

O3-D-12. Pain-related evoked potentials with intra-epidermal stimulation in healthy controls

Intra-epidermal electrical stimulation has been recently developed to stimulate A δ - and C-fibers selectively and non-invasively. To establish measurement system of pain-related evoked potential (PREP) using intra-epidermal electrical stimulation (IES), we examined 36 healthy controls (18 males; age, 20–70 yrs). The electrical stimulation using IES was applied to the dorsum of hand, wrist and foot. PREPs were recorded from the Cz electrode referenced to the linked earlobes (A1–A2) of the International 10–20 electrode system. A negative wave (N2) was recorded after stimulation to A δ and C fiber in the arm and leg clearly and reproducibly. Stimulation by IES was not painful and tolerable in all the subjects. Age and gender did not significantly affect amplitudes or latency of evoked potentials. IES can be applied in a clinical setting and PREP recordings could be useful to investigate pathophysiology of neuropathic pain.

Somatotopic representation of pain in the primary somatosensory cortex (S1) in humans

ObjectiveIn contrast to tactile inputs, the organization and processing of nociceptive inputs in the primary somatosensory cortex (S1) remain largely unexplored. Few studies have examined the arrangement of nociceptive inputs in S1. The aim of this study was to investigate the representation of nociceptive inputs in the human cortex, including the somatosensory and posterior parietal cortices, from widely separated cutaneous sites. MethodsWe examined the somatotopic organization of the nociceptive system in S1, opercularandposteriorparietalcortices by measuring the magnetoencephalographic responses (somatosensory-evoked magnetic fields) of four healthy controls in response to intraepidermal electrical stimulation applied to the face, neck, back, elbow, wrist, hand, finger, knee, and foot, which selectively activated the Aδ fibers. ResultsMagnetoencephalography demonstrated clear somatotopy in the S1 responses to noxious stimuli, with the foot representation in the extreme posteromedial position of S1 and the facial area in the extreme anterolateral position. There was little evidence of any clear somatotopic organization in the secondary somatosensory and posterior parietal cortices. ConclusionThese findings suggest that the nociceptive system uses the large body surface map in S1. SignificanceThis is the first MEG study to demonstrate the cortical representation of nociceptive inputs in the human S1. We showed that widely separated cutaneous sites clearly supported Penfield’s homunculus.

Steady-state evoked potentials to tag specific components of nociceptive cortical processing

Studies have shown that the periodic repetition of a stimulus induces, at certain stimulation frequencies, a sustained electro-cortical response of corresponding frequency, referred to as steady-state evoked potential (SSEP). Using infrared laser stimulation, we recently showed that SSEPs can be used to explore nociceptive cortical processing. Here, we implemented a novel approach to elicit such responses, using a periodic intra-epidermal electrical stimulation of cutaneous Aδ-nociceptors (Aδ-SSEPs). Using a wide range of frequencies (3-43 Hz), we compared the scalp topographies and temporal dynamics of these Aδ-SSEPs to the Aβ-SSEPs elicited by non-nociceptive transcutaneous electrical stimulation, as well as to the transient ERPs elicited by the onsets of the 10-s stimulation trains, applied to the left and right hand. At 3 Hz, we found that the topographies of Aβ- and Aδ-SSEPs were both maximal at the scalp vertex, and resembled closely that of the late P2 wave of transient ERPs, suggesting activity originating from the same neuronal populations. The responses also showed marked habituation, suggesting that they were mainly related to unspecific, attention-related processes. In contrast, at frequencies >3 Hz, the topographies of Aβ- and Aδ-SSEPs were markedly different. Aβ-SSEPs were maximal over the contralateral parietal region, whereas Aδ-SSEPs were maximal over midline frontal regions, thus indicating an entrainment of distinct neuronal populations. Furthermore, the responses showed no habituation, suggesting more obligatory and specific stages of sensory processing. Taken together, our results indicate that Aβ- and Aδ-SSEPs offer a unique opportunity to study the cortical representation of nociception and touch.

S6-2 Selective stimulation of cutaneous nociceptors by intra-epidermal electrical stimulation

S6-2 Selective stimulation of cutaneous nociceptors by intra-epidermal electrical stimulation

P2-10 Pain threshold of diabetic patients: An investigation using intraepidermal electrical stimulation

P2-10 Pain threshold of diabetic patients: An investigation using intraepidermal electrical stimulation

Low intensity intra-epidermal electrical stimulation can activate Aδ-nociceptors selectively

In the past 30 years, the study of nociception has relied mostly on thermal stimulation to activate nociceptors selectively. However, thermal stimulation suffers from some important limitations. For this reason, investigators have proposed intra-epidermal electrical stimulation (IES) as an alternative method to activate nociceptors selectively. This method relies on the fact that nociceptors are located mainly in the epidermis, while non-nociceptive fibres terminate more deeply in the dermis. Therefore, provided that the difference in receptor depth is sufficient, electric currents spatially restricted to the epidermal layers might activate nociceptors selectively. Here, we examined whether or not IES provides a fully selective nociceptive input. In a first experiment, we used capsaicin to induce a selective denervation of capsaicin-sensitive nociceptors, and thereby test whether the responses to IES are mediated by this population of afferent fibres. We found that capsaicin abolishes both the behavioural and the electrophysiological responses to IES applied at twice the perceptual threshold. In a second experiment, we applied a nerve pressure block to the superficial radial nerve to induce a temporally dissociated impairment of Aβ-, Aδ- and C-fibre afferents, and thereby determine the fibre populations contributing to the responses elicited by IES. We found that the time course of the blockade of the responses to IES follows closely the time course of the blockade of Aδ-fibres, but not of Aβ-fibres. Taken together, our results provide converging evidence that Aδ-nociceptors can be activated selectively using IES, provided that low intensities of stimulation are used.

The characteristics of no-go potentials with intraepidermal stimulation

The objective of this study was to investigate whether no-go potentials during go/no-go tasks were observed after painful stimulation using intraepidermal electrical stimulation. Event-related potentials were recorded by stimulating the medial or lateral side of the left-hand dorsum. Peak amplitudes of N2 and P3 were significantly larger in no-go trials than in go trials at frontocentral electrodes during go/no-go task, but the differences were not found during rest control and choice reaction time tasks. These characteristics of no-go-related potentials were very similar to event-related potential waveforms during visual, auditory, and somatosensory go/no-go tasks. We suggest that cortical activities relating to response inhibitory processing are not dependent on the sensory modality used.

Selective Stimulation of C Fibers by an Intra-Epidermal Needle Electrode in Humans

We recorded evoked potentials (EPs) induced by intra-epidermal electrical stimulation using a needle electrode with specific parameters. We identified the fibers activated by this specific stimulation by assessing the conduction velocity (CV) of the peripheral nerve. The EPs were recorded from the Cz electrode (vertex) of the International 10-20 system in ten healthy male subjects. The dorsum of the left hand and forearm were stimulated with an intensity of 0.01 mA above the sensory threshold. The mean P1 latency of EPs for the hand and forearm were 1007 ± 88 and 783 ± 80 ms, respectively, and the CV estimated from the latency of P1 was 1.5 ± 0.7 m/s. The CV indicated that the fibers activated by the stimulation were C fibers. Since the method of stimulation is convenient and non-invasive, it should be useful for investigating the functions of small fibers.

A transition from unimodal to multimodal activations in four sensory modalities in humans: an electrophysiological study

BackgroundTo investigate the long-latency activities common to all sensory modalities, electroencephalographic responses to auditory (1000 Hz pure tone), tactile (electrical stimulation to the index finger), visual (simple figure of a star), and noxious (intra-epidermal electrical stimulation to the dorsum of the hand) stimuli were recorded from 27 scalp electrodes in 14 healthy volunteers.ResultsResults of source modeling showed multimodal activations in the anterior part of the cingulate cortex (ACC) and hippocampal region (Hip). The activity in the ACC was biphasic. In all sensory modalities, the first component of ACC activity peaked 30–56 ms later than the peak of the major modality-specific activity, the second component of ACC activity peaked 117–145 ms later than the peak of the first component, and the activity in Hip peaked 43–77 ms later than the second component of ACC activity.ConclusionThe temporal sequence of activations through modality-specific and multimodal pathways was similar among all sensory modalities.