Abnormalities of the Descending Inhibitory Nociceptive Pathway in Functional Motor Disorders.

BACKGROUND: Pain is a common disabling non-motor symptom affecting patients with functional motor disorders (FMD). OBJECTIVE: We aimed to explore ascending and descending nociceptive pathways with laser evoked potentials (LEPs) in FMD. METHODS: We studied a "bottom-up and top-down" noxious paradigm applying a conditioned pain modulation (CPM) protocol and recorded N2/P2 amplitude in 21 FMD and 20 controls following stimulation of both right arm and leg at baseline (BS) (bottom-up), during heterotopic noxious conditioning stimulation (HNCS) with ice test (top-down) and post-HNCS. RESULTS: We found a normal ascending pathway, but reduced CPM response (lower reduction of the N2/P2 amplitude) in FMD patients, by stimulating both upper and lower limbs. The N2/P2 amplitude ratio*100 (between the HNCS and BS) was significantly higher in patients with FMD than HC. CONCLUSIONS: Our results suggest that pain in FMD possibly reflects a descending pain inhibitory control impairment, therefore, providing a novel venue to explore the pathophysiology of pain in FMD. © 2024 International Parkinson and Movement Disorder Society.

Defect of the Endogenous Inhibitory Pain System in Idiopathic Restless Legs Syndrome: A Laser Evoked Potentials Study.

BACKGROUND: Restless legs syndrome (RLS) is a complex sensorimotor disorder. Symptoms worsen toward evening and at rest and are temporarily relieved by movement. Symptoms are perceived as painful in up to 45% of cases, and nociception system may be involved. OBJECTIVES: To assess the descending diffuse noxious inhibitory control in RLS patients. METHODS: Twenty-one RLS patients and twenty age and sex-matched healthy controls (HC) underwent a conditioned pain modulation protocol. Cutaneous heat stimuli were delivered via laser evoked potentials (LEPs) on the dorsum of the right hand (UL) and foot (LL). N2 and P2 latencies, N2/P2 amplitude and pain ratings (NRS) were recorded before (baseline), during, and after a heterotopic noxious conditioning stimulation (HNCS) application. The baseline/HNCS ratio was calculated for both UL and LL. RESULTS: N2 and P2 latencies did not vary between groups at each condition and limbs. Both groups showed a physiological N2/P2 amplitude and NRS reduction during the HNCS condition in UL and LL in comparison to baseline and post conditions (all, P < 0.003). Between-groups comparisons revealed a significant lower amplitude reduction in RLS at the N2/P2 amplitude during the HNCS condition only for LL (RLS, 13.6 µV; HC, 10.1 µV; P = 0.004). Such result was confirmed by the significant difference at the ratio (RLS, 69%, HC, 52.5%; P = 0.038). CONCLUSIONS: The lower physiological reduction during the HNCS condition at LL in RLS patients suggests a defect in the endogenous inhibitory pain system. Further studies should clarify the causal link of this finding, also investigating the circadian modulation of this paradigm. © 2023 International Parkinson and Movement Disorder Society.

Supraspinal facilitation to repetitive painful stimulation: a laser-evoked potential study.

To better characterize central modulation mechanisms involved in the processing of daily repetitive painful stimulation, laser-evoked potentials (LEPs) were recorded at and away from the conditioning area in healthy participants. In addition, we aimed to evaluate a repetitive painful stimulation paradigm that could be conducted in a shorter time frame than previous studies. Collectively, continuous pain rating, warm and heat pain threshold results suggest that sensitivity to pain was reduced 24 h after the shortened repeated painful stimulation. Laser-evoked potentials revealed a significant increase in the contralateral arm to where the conditioning stimulus was applied. This finding was specific to noxious conditioning (i.e., not seen in the control brush experiment). These results provide neurophysiological evidence of pain facilitation resulting from prolonged exposure to painful heat, potentially arising in supraspinal structures.NEW & NOTEWORTHY We provide evidence for supraspinal faciliation measured via laser-evoked potentails in response to a shortened and methodologically improved repetitive painful stimulation paradigm, serving the broader scientific community, insofar as providing a paradigm can feasibly be completed in a caldendar week. These findings provide new evidence using laser-evoked potentials indicating increased activation of the anterior cingulate cortex during prolonged pain processing.

Effects of spatial attention and limb position on the cortical interaction of bilateral noxious inputs.

Bilateral noxious inputs interact in the brain to provide a better representation of physical threat. In the present study, we investigated the effects of spatial attention and limb position on this interaction. Painful laser stimuli were applied randomly on the right hand or on both hands, while varying spatial attention (focal or overall) and limb position (hands near or far from each other). Pain perception and laser-evoked potentials (N1, N2, P2) were compared between conditions in 27 healthy volunteers. Compared with unilateral stimulation, bilateral stimulation increased pain (p = .004), the N2 (p = .0015) and P2 (p < .001) amplitude. The effects on pain and the P2 were greater when hands were in the near compared with the far position (p < .05). The effect on pain was also greater for overall compared with focal pain rating (p = .003). In addition, the N1 amplitude was greater for bilateral stimulation when hands were in the far compared with the near position (p = .01). These results show that increased brain responses and pain for bilateral compared with unilateral noxious stimulation are modulated differentially by spatial attention and limb position. This suggests that the integration of noxious inputs occurs through partially independent pain-related processes, that it is modulated by limb position, and that it is partially independent of pain perception. We propose that this is necessary to produce coordinated, flexible and adapted defensive responses.

Neurophysiologic assessment of small fibre damage in chemotherapy-induced peripheral neuropathy.

OBJECTIVE: In patients with chemotherapy-induced peripheral neuropathy (CIPN), demonstration of small fibre (SF) damage is important to understand chronic late effects. METHODS: Thirty patients having complaints compatible with possible CIPN following treatment with oxaliplatin or docetaxel were compared with 27 healthy subjects. All subjects were evaluated with quantitative sensory testing (QST) assessing SF function and laser evoked potentials (LEP). In addition, SF-damage was assessed using cutaneous silent periods evoked with electrical (El-CSP) and laser (Ls-CSP) stimuli. RESULTS: For LEP, N2P2 amplitudes were significantly smaller in patients than controls in both upper (P = 0.007) and lower extremities (P = 0.002), and the N1 amplitude in upper extremities of patients were significantly smaller than in controls (P = 0.001). SF-QST, LEP, Ls-CSP, and El-CSP were abnormal in 10 (33.3%), 16 (53.3%), 19 (63.3%), and 24 (80%) of CIPN patients, respectively. CONCLUSIONS: In patients with possible CIPN, El-CSP and Ls-CSP were more often abnormal than LEP and QST. This is probably because El-CSP and Ls-CSP inform mainly about peripheral nociceptive fibres, while LEP and QST inform about peripheral and central nociceptive pathways together. SIGNIFICANCE: LEP and QST are established methods to detect SF-damage. El- and Ls-CSP might help clinicians in diagnosing SF-damage.

Inhibition of cortical somatosensory processing during and after low frequency peripheral nerve stimulation in humans.

OBJECTIVE: Transcutaneous low-frequency stimulation (LFS) elicits long-term depression-like effects on human pain perception. However, the neural mechanisms underlying LFS are poorly understood. We investigated cortical activation changes occurring during LFS and if changes were associated with reduced nociceptive processing and increased amplitude of spontaneous cortical oscillations post-treatment. METHODS: LFS was applied to the radial nerve of 25 healthy volunteers over two sessions using active (1 Hz) or sham (0.02 Hz) frequencies. Changes in resting electroencephalography (EEG) and laser-evoked potentials (LEPs) were investigated before and after LFS. Somatosensory-evoked potentials were recorded during LFS and source analysis was carried out. RESULTS: Ipsilateral midcingulate and operculo-insular cortex source activity declined linearly during LFS. Active LFS was associated with attenuated long-latency LEP amplitude in ipsilateral frontocentral electrodes and increased resting alpha (8-12 Hz) and beta (16-24 Hz) band power in electrodes overlying operculo-insular, sensorimotor and frontal cortical regions. Reduced ipsilateral operculo-insular cortex source activity during LFS correlated with a smaller post-treatment alpha-band power increase. CONCLUSIONS: LFS attenuated somatosensory processing both during and after stimulation. SIGNIFICANCE: Results further our understanding of the attenuation of somatosensory processing both during and after LFS.

Sexism-Related Stigma Affects Pain Perception.

People with stigmatized characteristics tend to be devalued by others in a given society. The negative experiences related to stigma cause individuals to struggle as they would if they were in physical pain and bring various negative outcomes in the way that physical pain does. However, it is unclear whether stigma related to one's identity would affect their perception of physical pain. To address this issue, using sexism-related paradigms, we found that females had reduced pain threshold/tolerance in the Cold Pressor Test (Experiment 1) and an increased rating for nociceptive laser stimuli with fixed intensity (Experiment 2). Additionally, we observed that there was a larger laser-evoked N1, an early laser-evoked P2, and a larger magnitude of low-frequency component in laser-evoked potentials (LEPs) in the stigma condition than in the control condition (Experiment 3). Our study provides behavioral and electrophysiological evidence that sexism-related stigma affects the pain perception of females.

Posterior insular activity contributes to the late laser-evoked potential component in EEG recordings.

OBJECTIVE: Nociceptive activity in some brain areas has concordantly been reported in EEG source models, such as the anterior/mid-cingulate cortex and the parasylvian area. Whereas the posterior insula has been constantly reported to be active in intracortical and fMRI studies, non-invasive EEG and MEG recordings mostly failed to detect activity in this region. This study aimed to determine an appropriate inverse modeling approach in EEG recordings to model posterior insular activity, assuming the late LEP (laser evoked potential) time window to yield a better separation from other ongoing cortical activity. METHODS: In 12 healthy volunteers, nociceptive stimuli of three intensities were applied. LEP were recorded using 32-channel EEG recordings. Source analysis was performed in specific time windows defined in the grand-average dataset. Two distinct dipole-pairs located close to the operculo-insular area were compared. RESULTS: Our results show that posterior insular activity yields a substantial contribution to the latest part (positive component) of the LEP. CONCLUSIONS: Even though the initial insular activity onset is in the early LEP time window,modelingthe insular activity in the late LEP time window might result in better separation from other ongoing cortical activity. SIGNIFICANCE: Modeling the late LEP activity might enable to distinguish posterior insular activity.

Do nociceptive stimulation intensity and temporal predictability influence pain-induced corticospinal excitability modulation?

Temporal predictability and intensity of an impending nociceptive input both shape pain experience and modulate laser-evoked potentials (LEPs) amplitude. However, it remains unclear whether and how these two factors could influence pain-induced corticospinal excitability modulation. The current study investigated the influence of nociceptive stimulation intensity and temporal predictability on motor-evoked potentials (MEPs) modulation, in parallel to their effect on pain perception and LEPs amplitude. Twenty participants completed electroencephalographic and transcranial magnetic stimulation experiments during which two laser nociceptive stimulation intensities (high and low) were either unpredictably delivered (random delay) or preceded by a fixed-timing cue (fixed delay). The amplitude of the conditioned MEPs was significantly reduced only for the high nociceptive stimulation and was not affected by the temporal predictability of pain (despite the fact that temporal predictability modulated the amplitude of P2 LEP component amplitude). However, a posteriori analyses based on patterns of pain-induced MEPs modulation revealed that participants in which nociceptive stimulation resulted in an increase in corticospinal excitability were more affected by the predictability of pain (i.e. increasing corticospinal excitability even more when pain occurrence was predictable), regardless of the nociceptive stimulation intensity; whereas participants in which nociceptive stimulation resulted in a decrease in corticospinal excitability were sensitive to the intensity of the stimulation but not its predictability. These results suggest a potential influence of cognitive factors such as temporal predictability on the response of the motor system in the presence of pain for some participants, contributing to explain, at least in part, the high variability highlighted in a number of previous studies.

Pain in cervical dystonia: Evidence of abnormal inhibitory control.

INTRODUCTION: Several observations would suggest that dystonic pain is not simply muscular in origin. While ascending nociceptive pathways are normal in cervical dystonia, it is unknown whether descending inhibitory pain pathways are also normal. METHODS: We applied a conditioned pain modulation protocol and concomitantly recorded laser evoked potentials in patients with cervical dystonia (n = 15), blepharospasm (n = 15) and healthy volunteers (n = 15). RESULTS: During the application of a heterotopic noxious conditioning stimulation, patients with cervical dystonia, but not with blepharospasm, lacked the physiological reduction of the perceived intensity of a painful test stimulus as well as of the related evoked potential. This was observed in cervical dystonia patients regardless of the presence of clinical pain. CONCLUSIONS: Our results suggest that pain in CD is not simply muscular in origin but it also possibly reflects a dysfunction of the descending pain inhibitory control, thus providing a novel venue to explore the pathophysiology of pain in CD.

Aerobic Exercise Reduces Pressure More Than Heat Pain Sensitivity in Healthy Adults.

OBJECTIVES: The hypoalgesic effects of exercise are well described, but there are conflicting findings for different modalities of pain; in particular for mechanical vs thermal noxious stimuli, which are the most commonly used in studies of exercise-induced hypoalgesia. The aims of this study were 1) to investigate the effect of aerobic exercise on pressure and heat pain thresholds that were well equated with regard to their temporal and spatial profile and 2) to identify whether changes in the excitability of nociceptive pathways-measured using laser-evoked potentials-accompany exercise-induced hypoalgesia. SUBJECTS: Sixteen healthy adults recruited from the University of New South Wales. METHODS: Pressure and heat pain thresholds and pain ratings to laser stimulation and laser-evoked potentials were measured before and after aerobic cycling exercise and an equivalent period of light activity. RESULTS: Pressure pain thresholds increased substantially after exercise (rectus femoris: 29.6%, d = 0.82, P < 0.001; tibialis anterior: 26.9%, d = 0.61, P < 0.001), whereas heat pain thresholds did not (tibialis anterior: 4.2%, d = 0.30, P = 0.27; foot: 0.44%, d = 0.02, P = 1). Laser-evoked potentials and laser heat pain ratings also changed minimally after exercise (d = -0.59 to 0.3, P > 0.06). CONCLUSIONS: This is the first investigation to compare the effects of exercise on pressure and heat pain using the same stimulation site and pattern. The results show that aerobic exercise reduces mechanical pain sensitivity more than thermal pain sensitivity.

Cortical integration of bilateral nociceptive signals: when more is less.

Integration of nociceptive information is essential to produce adapted responses, to promote body integrity and survival. However, how the brain integrates nociceptive inputs from different body areas remains unknown. The aim of this study was to examine the cortical integration of bilateral nociceptive inputs evoked by laser heat stimuli. Sixteen healthy volunteers (8 F, 8 M; age: 25.5 ± 4.3) were recruited to participate in one session during which painful laser stimuli were applied to their hands with 2 Nd:YAP laser systems. Electroencephalographic activity was recorded to measure laser-evoked potentials and event-related spectral perturbations. Twenty nociceptive stimuli were applied in each of the 4 counterbalanced conditions: (1) right hand, (2) left hand, and both hands with (3) attention to the right or (4) attention to the left. Compared with unilateral conditions, N2 and P2 peak amplitude as well as gamma oscillation power were decreased in bilateral conditions (P < 0.05), but these effects were not affected by the direction of attention (P > 0.1). By contrast, pain was not significantly different in any condition (P > 0.05). These findings show that although more nociceptive inputs reach the brain with multiple nociceptive stimuli, their sensory representation is decreased while pain perception remains unchanged. These interactions between cerebral processing of nociceptive information from different body regions could support coordinated behavioral responses when pain origins from multiple sources.

Need for Thorough Standardization of CO2 Laser Evoked Potential Procedure.

PURPOSE: The objective of this study was to determine normative values of laser evoked potentials and anthropometric correlations in a healthy middle-aged working population. METHODS: In 51 subjects, CO2 laser stimulation was applied bilaterally onto dorsal surface of the feet, hands, and neck using constant duration of stimulus and beam diameter, changing just the intensity of stimulation. Amplitudes and latencies of the laser evoked potential negative-positive complex were recorded, and relationship with height, age and gender was statistically analyzed. RESULTS: There was a significant correlation between the latencies obtained for feet, hands, and height. P2 amplitudes for feet, hands, and neck, and negative-positive pk-pk amplitudes for hands and neck correlated negatively with age. The values obtained did not differ significantly between male and female gender, except for N2 latencies for hands. CONCLUSIONS: Clinically useful reference values for laser evoked potentials in a healthy middle-aged population were provided, which are interesting from the physiological point of view.

Small fibre neuropathy in mitochondrial diseases explored with sudoscan.

OBJECTIVE: Polyneuropathy in mitochondrial diseases (MDs) is relatively common and widely investigated, but few data are instead reported about small fibres involvement. METHODS: In order to investigate the involvement of small fibres in MDs we performed extensive neurophysiological test (nerve conduction studies; sympathetic skin response; sudoscan) in 27 patients with genetic diagnosis of MD (7 m.3243A > G; 4 m.8344A > G; 9 single mtDNA deletion; 7 multiple mtDNA deletions). RESULTS: NCS showed a polyneuropathy in 11/27 cases (41%). The incidence was very high in POLG1 (100%), m.8344A > G (75%) and m.3243A > G (43%), while only 11% of patients with single deletion had evidence of large fibres involvement. Sympathetic skin response was abnormal only in three patients (one progressive external ophthalmoplegia with single mtDNA deletion; one patient with m.3243A > G mutation; one patient with POLG1 mutation). Sudoscan revealed the presence of an autonomic small fibres dysfunction in 9/27 cases (33%), most of them (7/9) carrying a single mtDNA deletion. Sudoscan data were also confirmed in a sub-group of patients by laser evoked potentials study. Considering only patients with single mtDNA deletion 7/9 (78%) showed abnormal results at sudoscan. CONCLUSIONS: Small fibre neuropathy is another feature to investigate in mitochondrial diseases and seems specifically associated with the presence of single mtDNA deletion. SIGNIFICANCE: The correct identification through specific neurophysiological tests of small fibres involvement in MDs represents another tile in this challenging diagnosis.

Laser evoked potential amplitude and laser-pain rating reduction during high-frequency non-noxious somatosensory stimulation.

OBJECTIVE: To investigate the mechanism subtending the analgesic effect of high frequency non-painful somatosensory stimulation. METHODS: Laser evoked potentials (LEPs) and laser-pain rating were obtained from healthy subjects to stimulation of different parts of the body. LEPs were recorded at baseline and during non-painful electrical stimulation of the superficial branch of the right radial nerve (RRES). RESULTS: RRES reduced N2/P2 LEP amplitude to right radial (F(8,10) = 82.4, p < 0.001), left radial (F(8,10) = 22.2, p < 0.001), and right ulnar (F(8,10) = 7.2, p = 0.008) stimulation, while the N2/P2 amplitude to left ulnar territory stimulation remained unchanged (F(8,10) = 3.6, p = 0.07). The laser-pain rating was reduced by RRES to bilateral radial territory stimulation (p < 0.05). In a control experiment, laser-pain rating and LEPs to left foot stimulation were not modified by RRES (p > 0.05). CONCLUSIONS: Our study confirms that the non-nociceptive afferents dampen the nociceptive input. The spatial pattern of this interaction suggests that, when conditioning higher frequency non-painful stimulation is used, the inhibition takes place at the spinal cord. SIGNIFICANCE: Our experimental design reproduces what happens when non-painful somatosensory stimuli are used to reduce pain, such as rubbing a wound or during transcutaneous electrical nerve stimulation. Therefore, in these situations the analgesia is likely to occur at the spinal cord level.

Somatosensory function is impaired in patients with idiopathic REM sleep behaviour disorder.

BACKGROUND: Idiopathic REM sleep behaviour disorder (iRBD) has been recognised as a significant biomarker for developing a neurodegenerative alpha-synucleinopathy, which is why iRBD is considered to be a prodromal state for alpha-synucleinopathies including Parkinson's disease (PD). Many patients with PD suffer from complaints of pain and present impaired somatosensory function. We hypothesized that pain perception and somatosensory function could be altered already in a preclinical stage of PD including iRBD. Hence, the objective of this study was to investigate pain perception and somatosensory function in patients with iRBD. METHODS: Quantitative sensory testing (QST), laser evoked potentials (LEPs), and conditioned pain modulation (CPM) testing were performed in 13 iRBD patients without any clinical signs of PD or narcolepsy (11 males, 2 females, mean age 65.2 years) and 15 gender- and age-matched healthy control subjects (12 males, 3 females, mean age 65.8 years). RESULTS: Thermal detection thresholds were higher in the iRBD group compared with the control group (cold detection threshold (CDT) p = 0.020, thermal sensory limen (TSL) p = 0.001), indicating an impaired temperature sensation in iRBD patients. The N2/P2 LEPs amplitude was smaller in iRBD patients than controls, but not statistically significant (p = 0.053). CONCLUSIONS: This study found an impaired somatosensory function in iRBD patients, suggesting that somatosensory impairment might be an early feature in the neurodegenerative process of PD.

Evaluation of afferent pain pathways in adrenomyeloneuropathic patients.

OBJECTIVE: Patients with adrenomyeloneuropathy may have dysfunctions of visual, auditory, motor and somatosensory pathways. We thought on examining the nociceptive pathways by means of laser evoked potentials (LEPs), to obtain additional information on the pathophysiology of this condition. METHODS: In 13 adrenomyeloneuropathic patients we examined LEPs to leg, arm and face stimulation. Normative data were obtained from 10 healthy subjects examined in the same experimental conditions. We also examined brainstem auditory evoked potentials (BAEPs), pattern reversal full-field visual evoked potentials (VEPs), motor evoked potentials (MEPs) and somatosensory evoked potentials (SEPs). RESULTS: Upper and lower limb MEPs and SEPs, as well as BAEPs, were abnormal in all patients, while VEPs were abnormal in 3 of them (23.1%). LEPs revealed abnormalities to stimulation of the face in 4 patients (30.7%), the forearm in 4 patients (30.7%) and the leg in 10 patients (76.9%). CONCLUSIONS: The pathologic process of adrenomyeloneuropathy is characterized by a preferential involvement of auditory, motor and somatosensory tracts and less severely of the visual and nociceptive pathways. This non-inflammatory distal axonopathy preferably damages large myelinated spinal tracts but there is also partial involvement of small myelinated fibres. SIGNIFICANCE: LEPs studies can provide relevant information about afferent pain pathways involvement in adrenomyeloneuropathic patients.

[Small fiber neuropathy]. / La neuropathie des petites fibres.

Small fiber neuropathy (SFN) is still unknown. Characterised by neuropathic pain, it typically begins by burning feet, but could take many other expression. SFN affects the thinly myelinated Aδ and unmyelinated C-fibers, by an inherited or acquired mechanism, which could lead to paresthesia, thermoalgic disorder or autonomic dysfunction. Recent studies suggest the preponderant role of ion channels such as Nav1.7. Furthermore, erythromelalgia or burning mouth syndrome are now recognized as real SFN. Various aetiologies of SFN are described. It could be isolated or associated with diabetes, impaired glucose metabolism, vitamin deficiency, alcohol, auto-immune disease, sarcoidosis etc. Several mutations have recently been identified, like Nav1.7 channel leading to channelopathies. Diagnostic management is based primarily on clinical examination and demonstration of small fiber dysfunction. Laser evoked potentials, Sudoscan®, cutaneous biopsy are the main test, but had a difficult access. Treatment is based on multidisciplinary management, combining symptomatic treatment, psychological management and treatment of an associated etiology.

Effects of external trigeminal nerve stimulation (eTNS) on laser evoked cortical potentials (LEP): A pilot study in migraine patients and controls.

Background Transcutaneous external supraorbital nerve stimulation has emerged as a treatment option for primary headache disorders, though its action mechanism is still unclear. Study aim In this randomized, sham-controlled pilot study we aimed to test the effects of a single external transcutaneous nerve stimulation session on pain perception and cortical responses induced by painful laser stimuli delivered to the right forehead and the right hand in a cohort of migraine without aura patients and healthy controls. Methods Seventeen migraine without aura patients and 21 age- and sex-matched controls were selected and randomly assigned to a real or sham external transcutaneous nerve stimulation single stimulation session. The external transcutaneous nerve stimulation was delivered with a self-adhesive electrode placed on the forehead and generating a 60 Hz pulse at 16 mA intensity for 20 minutes. For sham stimulation, we used 2 mA intensity. Laser evoked responses were recorded from 21 scalp electrodes in basal condition (T0), during external transcutaneous nerve stimulation and sham stimulation (T1), and immediately after these (T2). The laser evoked responses were analyzed by LORETA software. Results The real external transcutaneous nerve stimulation reduced the trigeminal N2P2 amplitude in migraine and control groups significantly in respect to placebo. The real stimulation was associated with lower activity in the anterior cingulate cortex under trigeminal laser stimuli. The pattern of LEP-reduced habituation was reverted by real and sham transcutaneous stimulation in migraine patients. Conclusions The present results could suggest that the external transcutaneous nerve stimulation may interfere with the threshold and the extent of trigeminal system activation, with a mechanism of potential utility in the resolution and prevention of migraine attacks.