Treatment of chronic migraine with transcutaneous stimulation of the auricular branch of the vagal nerve (auricular t-VNS): a randomized, monocentric clinical trial.

BACKGROUND: Aim of the study was assessment of efficacy and safety of transcutaneous stimulation of the auricular branch of the vagal nerve (t-VNS) in the treatment of chronic migraine. METHODS: A monocentric, randomized, controlled, double-blind study was conducted. After one month of baseline, chronic migraine patients were randomized to receive 25 Hz or 1 Hz stimulation of the sensory vagal area at the left ear by a handhold battery driven stimulator for 4 h/day during 3 months. Headache days per 28 days were compared between baseline and the last month of treatment and the number of days with acute medication was recorded The Headache Impact Test (HIT-6) and the Migraine Disability Assessment (MIDAS) questionnaires were used to assess headache-related disability. RESULTS: Of 46 randomized patients, 40 finished the study (per protocol). In the per protocol analysis, patients in the 1 Hz group had a significantly larger reduction in headache days per 28 days than patients in the 25 Hz group (-7.0 ± 4.6 vs. -3.3 ± 5.4 days, p = 0.035). 29.4 % of the patients in the 1 Hz group had a ≥50 % reduction in headache days vs. 13.3 % in the 25 Hz group. HIT-6 and MIDAS scores were significantly improved in both groups, without group differences. There were no serious treatment-related adverse events. CONCLUSION: Treatment of chronic migraine by t-VNS at 1 Hz was safe and effective. The mean reduction of headache days after 12 weeks of treatment exceeded that reported for other nerve stimulating procedures.

Excitatory and inhibitory purinergic control of neck muscle nociception in anaesthetized mice.

Tension-type headache is associated with noxious input from neck muscles. Due to the importance of purinergic mechanisms in muscle nociception, experimental studies typically inject alpha,beta-methyleneadenosine 5'-triphosphate (alpha,beta-meATP). In contrast to native adenosine 5'-triphosphate (ATP), alpha,beta-meATP has a narrow receptor profile and remains stable in tissue. The present study administered alpha,beta-meATP or ATP in semi-spinal neck muscles in anaesthetized mice (n = 65) in order to address different effects in neck muscle nociception. The jaw-opening reflex monitored the impact of neck muscle noxious input on brainstem processing. Injection of alpha,beta-meATP induced reflex facilitation in a dose-dependent manner. In contrast, only the lowest ATP dosage evoked facilitation. Preceding P2Y(1) receptor blockade revealed facilitation even under high-dosage ATP. Ongoing facilitation after alpha,beta-meATP injection neutralized under subsequent activation of P2Y(1) receptors. Results demonstrate opposing excitatory P2X and inhibitory P2Y effects of ATP in neck muscle nociception. These mechanisms may be involved in the pathophysiology of neck muscle pain in man.

Effects of short and prolonged transcutaneous vagus nerve stimulation on heart rate variability in healthy subjects.

The vagus nerve is strategically located in the body, and has multiple homeostatic and health-promoting effects. Low vagal activity predicts onset and progression of diseases. These are the reasons to activate this nerve. This study examined the effects of transcutaneous vagus nerve stimulation (t-VNS) on a main index of vagal activity, namely heart rate variability (HRV). In Study 1, we compared short (10min) left versus right ear t-VNS versus sham (no stimulation) in a within-subjects experimental design. Results revealed significant increases in only one HRV parameter (standard deviation of the RR intervals (SDNN)) following right-ear t-VNS. Study 2 examined the prolonged effects of t-VNS (1h) in the right ear. Compared to baseline, right-t-VNS significantly increased the LF and LF/HF components of HRV, and SDNN in women, but not in men. These results show limited effects of t-VNS on HRV, and are discussed in light of neuroanatomical and statistical considerations and future directions are proposed.

Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines.

Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode-skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to-baseline intensities of 1-2mA and during tACS at higher peak-to-peak intensities above 2mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low-intensity 'conventional' TES defined as <4mA, up to 60min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3-13A/m2 that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in Göttingen, Germany, on September 6-7, 2016 and were refined thereafter by email correspondence.

Modulation of vagal tone enhances gastroduodenal motility and reduces somatic pain sensitivity.

BACKGROUND: The parasympathetic nervous system, whose main neural substrate is the vagus nerve, exerts a fundamental antinociceptive role and influences gastrointestinal sensori-motor function. Our research question was to whether combined electrical and physiological modulation of vagal tone, using transcutaneous electrical vagal nerve stimulation (t-VNS) and deep slow breathing (DSB) respectively, could increase musculoskeletal pain thresholds and enhance gastroduodenal motility in healthy subjects. METHODS: Eighteen healthy subjects were randomized to a subject-blinded, sham-controlled, cross-over study with an active protocol including stimulation of auricular branch of the vagus nerve, and breathing at full inspiratory capacity and forced full expiration. Recording of cardiac derived parameters including cardiac vagal tone, moderate pain thresholds to muscle, and bone pressure algometry, conditioned pain modulation using a cold pressor test and a liquid meal ultrasonographic gastroduodenal motility test were performed. KEY RESULTS: Cardiac vagal tone increased during active treatment with t-VNS and DSB compared to sham (p = 0.009). In comparison to sham, thresholds to bone pain increased (p = 0.001), frequency of antral contractions increased (p = 0.004) and gastroduodenal motility index increased (p = 0.016) with active treatment. However, no effect on muscle pain thresholds and conditioned pain modulation was seen. CONCLUSIONS & INFERENCES: This experimental study suggests that this noninvasive approach with combined electrical and physiological modulation of vagal tone enhances gastroduodenal motility and reduces somatic pain sensitivity. These findings warrant further investigation in patients with disorders characterized with chronic pain and gastrointestinal dysmotility such as functional dyspepsia and irritable bowel syndrome.

Sensitization of trigeminal nociception specific for migraine but not pain of sinusitis.

Trigeminal pain processing was studied in 14 patients with unilateral migraine attacks and 14 age- and sex-matched patients with comparable unilateral headache from frontal sinusitis. Using a nociception-specific blink reflex method (nBR), a facilitation of nBR responses predominantly on the headache side was observed in migraine, but not in sinusitis. The facilitation of trigeminal nociception may be specific for migraine rather than a consequence of peripheral pain such as frontal sinusitis.

Acute migraine headache: possible sensitization of neurons in the spinal trigeminal nucleus?

OBJECTIVE: To investigate trigeminal sensory processing in patients with migraine using a novel "nociception-specific" blink reflex. METHODS: Seventeen patients with unilateral migraine headache were studied within 6 hours of onset. Blink reflexes were elicited with a standard stimulating electrode (standard blink reflex) and concentric stimulating electrode (nociception-specific blink reflex) during the acute migraine attack, after treatment with IV lysine acetylsalicylate (1,000 mg) or oral zolmitriptan (5 mg) and interictally. RESULTS: After standard stimulation, no differences were detected for the R1 and R2 onset latencies and areas under the curve (AUC) between the different time points and the headache and nonheadache side. Nociception-specific stimulation revealed a shortening of R2 onset latencies (44.3 +/- 5.4 ms for headache side vs 48.9 +/- 5.8 ms for nonheadache side) during the acute migraine attack compared with the headache-free interval (49.8 +/- 5.3 vs 49.8 +/- 4.5 ms). The AUC of the R2 increased on the headache side by 680% and on the nonheadache side by 230% compared with the headache-free interval. Drug treatment parallel to pain relief increased the onset latencies (zolmitriptan: 48.0 +/- 8.2 ms for headache side vs 52.3 +/- 7.6 ms for nonheadache side; lysine acetylsalicylate: 48.0 +/- 5.0 ms for headache side vs 51.2 +/- 5.6 ms for nonheadache side) and reduced the AUC of R2 (zolmitriptan by 45% and lysine acetylsalicylate by 48%). CONCLUSION: The data suggest temporary sensitization of central trigeminal neurons during acute migraine attacks.

Acetylsalicylic acid inhibits meningeal nociception in rat.

Although acetylsalicylic acid (ASA) is one of the most commonly administered drugs in the treatment of acute headaches, the sites of its action and the mechanisms of its therapeutic efficacy are still unclear. In this study using extracellular recording we examined the effects of ASA on spontaneous and mechanically evoked activities of neurons within the medullary dorsal horn with input from the parietal dura mater in rat. Their dural receptive fields were identified by von Frey filaments and found to be mainly located at the medial meningeal artery. All units showed spontaneous activity and had convergent input from the face. Neuronal activities were recorded before and after intravenously applied ASA (30 mg/kg) in 13 and saline in four units. Systemic application of ASA inhibited spontaneous and mechanically evoked activity within 15 min after application. Additionally, neuronal activities were recorded before, during and after topical application of ASA (1 mg/ml) onto the parietal dura mater in 5 units. Topically applied ASA inhibited the mechanically evoked activity, whereas the spontaneous activity remained unchanged. It is concluded, that there are different effects of systemic and topical ASA on trigeminal neuronal activity, which may be due to both central and peripheral mechanisms.

The effect of multiple stimuli on the modulation of the 'nociceptive' blink reflex.

The 'nociceptive' blink reflex is a method of examining human trigeminal pain pathways. We explored temporal summation of this reflex by using a train of pulses, rather than a single pulse, and remote activation of diffuse noxious inhibitory control (DNIC), to improve reliability, flexibility and nociceptive specificity of this technique. The R2 component of the nociceptive blink reflex response (nR2) was assessed in 28 healthy volunteers using between 1 and 7 pulses per stimulus train (inter-pulse interval 5 ms). The effect of DNIC on single-, double-, and triple-pulse nR2 was investigated. Compared to single pulses, double and triple pulses increased the sensation of pain, reduced the tactile and pain thresholds, and facilitated the blink reflex responses (reduced onset latency, increased magnitude and persistence of nR2). The maximal reflex facilitation was achieved using a triple pulse. Higher pulse numbers had no additional facilitatory effect. Activation of the DNIC system using heterotopic pain suppressed the nR2 evoked by double and triple stimulation by 16 and 42%, respectively, but not the nR2 from a single pulse. Stimulation with double and triple pulses may be more suitable to study influences on nociceptive pathways than single pulses and may widen the methodological flexibility of the nociceptive blink reflex technique. This technique may be useful in studying the trigeminal nociceptive system with particular reference to primary headache disorders and their neuropharmacology.

Meningeal nociception: electrophysiological studies related to headache and referred pain.

Headaches, which are usually referred to characteristic sites of the skull, are believed to involve meningeal nociceptors located in the dura mater encephali. Animal experiments show that these meningeal nociceptors are polymodal and usually highly sensitive to mechanical stimulation. These properties are also characteristic for the second order neurons in the spinal trigeminal nucleus, most of which receive convergent input from facial receptive sites. Sensitization of primary and secondary neurons by chemical irritants to mechanical stimuli may be an important mechanism in the generation of headaches. The convergent input from extracranial structures, which seems to be differentially organized in rodents and man, may explain the typical features of referred headache. Targets for analgesics used in the therapy of headaches (non-steroidal antiinflammatory drugs, 5-HT(1) receptor agonists) are probably meningeal nociceptors and different sites of the central trigeminal nociceptive and antinociceptive pathways.

Convergence of nociceptive and non-nociceptive input onto the medullary dorsal horn in man.

Referred pain arising in orofacial pain states is probably due to convergence of different somatosensory input onto the medullary dorsal horn (MDH). To examine convergence between nociceptive and non-nociceptive input onto the MDH, the blink reflex (BR) was applied. R1- and R2-components can be evoked by innocuous stimuli, but only the R2 is elicited by painful heat. The BR was elicited by innocuous electrical stimuli applied to the supraorbital nerve. A conditioning painful heat pulse which did not evoke any BR was homotopically applied to the left forehead preceding the electrical stimulus by 75 ms. While R1 remained unchanged, the R2 was facilitated by about 30%. This study demonstrates a convergence of low-threshold mechanoreceptive and nociceptive inputs onto interneurons of the MDH in man.

Are 'neutral cells' in the rostral ventro-medial medulla subtypes of on- and off-cells?

The classification of cells in the rostral ventromedial medulla (RVM) is based on the response pattern to noxious tail heat: on-cell activity increased, off-cell activity decreased, and activity of neutral cells is unaffected by noxious heat tail stimulation. It is generally assumed that on-, off- and neutral cells respond equally to noxious stimulation applied anywhere on the body surface, but so far this assumption has not been systematically examined. In the present study the effects of thermal and mechanical stimuli applied to the tail, the extremities and the orofacial region on the extracellularly recorded activity of 14 neutral cells were investigated in lightly anesthetized rats. Although the neutral cells did not respond to noxious tail heat, all of them responded to most of the other stimuli in an on- or off-manner. Especially cell responses to pinch stimuli applied to the skin of the ear, the forehead and the nose differed from the neutral behavior. The fact that the neutral cells in the present study responded in an off- or on-manner by applying noxious stimuli different from noxious tail heat suggests that these cells are possibly subtypes of on- and off-cells in the RVM.

Neither a general flexor nor a withdrawal pattern of nociceptive reflexes evoked from the human foot.

In humans motor reactions to noxious radiant heat stimulation of the sole and the dorsum of the foot do not resemble a locally specific pattern of multiple modular withdrawal reflexes but rather a general flexion reflex pattern with a few exceptions which did neither fit a withdrawal nor a flexion reflex pattern. The partly observed excitatory feed back to foot extensors from nociceptive afferents of the foot sole is functionally discussed as a foot stabilizing mechanism under particular conditions.

Afferent input to the medullary dorsal horn from the contralateral face in rat.

Sensory deficits on the contralateral face in Wallenberg's lateral medullary syndrome (WS) may be due to an involvement of the crossing contralateral trigeminothalamic tract. Alternatively, neurons within the medullary dorsal horn (MDH) get input from the contralateral face. MDH neurons supplying the supraorbital nerve area in rat were recorded by electrophysiological techniques. In this first study on contralateral projections, about 60% of the neurons received excitatory afferent input from the contralateral face as well as the ipsilateral supraorbital area. Thus, contralateral sensory deficits in WS may be due to an involvement of these neurons.

Characterization of blink reflex interneurons by activation of diffuse noxious inhibitory controls in man.

The blink reflex consists of an early, pontine R1-component and a late, medullary R2-component. R1 and R2 can be evoked by innocuous stimuli, but only the R2 also by painful heat, suggesting that the R2 is mediated by wide dynamic range neurons (WDR) of the spinal trigeminal nucleus. Remote noxious stimuli suppress the activity in WDR neurons via activation of diffuse noxious inhibitory controls (DNIC), whereas low-threshold mechanoreceptive neurons (LTM) are unaffected. In order to characterize the trigeminal interneurons of R1 and R2 we investigated the modulation of the blink reflex by remote painful heat. The blink reflex was elicited in 11 healthy subjects by innocuous electrical pulses applied to the left supraorbital nerve. The remote, painful heat stimuli were applied by a Peltier type thermode to the left volar forearm. Remote painful heat of 44 to 46 degreesC significantly suppressed the R2 by 15% (p<0.01), while the R1 remained unchanged. These results provide further evidence that the R2 is mediated by medullary WDR neurons and the R1 by pontine LTM neurons.

Nociceptive masseter inhibitory reflexes evoked by laser radiant heat and electrical stimuli.

Electrical stimulation of the mental nerve evokes two suppression periods SP1 and SP2 in masseter muscle activity bilaterally. In order to investigate a possible nociceptive origin of the suppression periods, we compared the reflex responses evoked by electrical stimulation and by selective activation of nociceptors in hairy skin using painful infrared laser stimuli. The SP was elicited during more than 90% maximal voluntary contraction. Thresholds for detection, pain, and SP in the mental nerve area were determined by the method of limits. A suppression period was evoked by laser stimuli in nine of ten subjects bilaterally. The mean onset latency was 46.9 ms, the mean duration 58.9 ms. The electrical threshold of SP1 (9 mA) was 7.7 x I(0), about 20% smaller than I(P), and significantly higher than I(SP2) (4.7 mA). The onset latencies and durations were 11.7 ms and 21 ms for SP1, and 45 ms and 42.7 ms for SP2 (stimulus intensity 2 x I(P)). The mean difference in onset latencies between laser SP and electrically evoked SP1 was 35.1 +/- 6.2 ms, which closely matches the nociceptor response latency to a laser heat pulse. Based on the threshold and the onset latency we conclude that at least SP1 and laser SP are nociceptive in origin and mediated by group III fibers.

Electrophysiological brainstem investigations in obstructive sleep apnoea syndrome.

Phasic inspiratory genioglossus activity prevents pharyngeal airway collapse in healthy subjects during sleep and is diminished or absent in obstructive sleep apnoea syndrome (OSAS), thus leading to pharyngeal obstruction. Case reports of OSAS after pontomedullary lesions indicate that impaired inspiratory genioglossal activity may result from brainstem lesions. We therefore investigated brainstem functions in 18 awake patients with OSAS using brainstem auditory evoked potentials, blink reflex, masseter reflex, masseter inhibitory reflex (in 11 of 18 patients), magnetic evoked potentials of the tongue and electrooculography with vestibular testing. Fifteen of 18 patients showed no electrophysiological abnormalities. One patient had a left pontine and two patients a bilateral pontomesencephalic lesion, although a causal connection with OSAS was not conclusively confirmed. Our results do not support the assumption of a relevant structural brainstem lesion in OSAS patients with normal neurological findings.

Optimized stimulation and recording parameters of human 'nociception specific' blink reflex recordings.

OBJECTIVE: Few non-invasive methods are available for studying trigeminal nociception in humans. The 'nociception specific' blink reflex (nBR) is elicited by a preferential stimulation of trigeminal nociceptive fibers and is highly sensitive to changes in trigeminal nociception. The aim of this study was to establish its optimal stimulation parameters. METHODS: The inter-individual variability of R2 responses (41 healthy subjects), symmetry of R2 responses after right vs. left sided stimulation (25 subjects), optimal stimulation parameters (3 groups, each 16 subjects) and re-test reliability over time (15 subjects) were studied. RESULTS: The nBR had a R2 response with a latency of 44.7+/-7.3ms, but no R1 response. The mean difference of R2 latencies (right vs. left sided stimulation) was 0.4+/-2.1(SD)ms, the mean ratio of the R2 response areas (RA) was 1.05+/-0.39 (SD). Thus, lateral differences of onset latencies greater than 4.6ms (0.4+4.2 (2SD)) or >1.83-fold (1.05+0.78 (2SD)) of RA can be assumed as outside of normal range. Long inter-block intervals of 7min minimized the cumulative habituation of R2 RAs to 23%, onset latencies remained constant. Re-test reliability over 4 weeks was high both for latencies (Crohnbach's alpha=0.85) and RAs (alpha=0.94). CONCLUSIONS: The nBR with the established stimulation parameters could be used for studying trigeminal nociception.

A new method to increase nociception specificity of the human blink reflex.

OBJECTIVE: The medullary R2 response of the blink reflex can be elicited by innocuous and noxious stimuli. The purpose of this study was to elicit a nociception specific R2 response with a new surface electrode. METHODS: In 10 healthy subjects the blink reflex was elicited using a standard (10-15 mA) and a new concentric surface electrode type (0.6-1.6 mA) which produces a pin-prick-like pain. RESULTS: After topical local anaesthesia with lignocaine/prilocaine R1 was unchanged, R2 was attenuated by 12% after standard stimulation but was almost abolished (-91%) with the new electrode type. CONCLUSION: Stimulation with low stimulus intensities but electrode-dependent high current density allows preferential depolarization of superficial nociceptive A-delta fibres. This new method is less traumatic than others and is useful in the study of trigeminal nociception.

Cerebral potentials are not evoked by activation of Golgi tendon organ afferents in human abductor hallucis muscle.

The earliest components of the somatosensory evoked potentials (SSEP) are generated by excitation of the fastest low-threshold, thick myelinated group I afferents. Ib afferents belonging to this group innervate Golgi tendon organs and are excited almost selectively by a muscle twitch. Contraction of the abductor hallucis muscle was evoked by intramuscularly placed teflon insulated needle electrodes in ten healthy volunteers. We failed to demonstrate any cortical activity (over Cz' vs. Fz) following isolated muscle contractions. Our results do not point to a significant projection of group Ib afferents to the human somatosensory cortex at least with the small numbers of fibers activated by intramuscular stimulation of abductor hallucis muscle.