Trigeminal nerve electrical stimulation: An effective arousal treatment for loss of consciousness.

BACKGROUND: To determine if trigeminal nerve electrical stimulation (TNS) would be an effective arousal treatment for loss of consciousness (LOC), we applied neuroscientific methods to investigate the role of potential brain circuit and neuropeptide pathway in regulating level of consciousness. METHODS: Consciousness behavioral analysis, Electroencephalogram (EEG) recording, Chemogenetics, Microarray analysis, Milliplex MAP rat peptide assay, Chromatin immune-precipitation (ChIP), Dual-luciferase reporter experiment, Western blot, PCR and Fluorescence in situ hybridization (FISH). RESULTS: TNS can markedly activate the neuronal activities of the lateral hypothalamus (LH) and the spinal trigeminal nucleus (Sp5), as well as improve rat consciousness level and EEG activities. Then we proved that LH activation and upregulated neuropeptide hypocretin are beneficial for promotion of consciousness recovery. We then applied gene microarray experiment and found hypocretin might be mediated by a well-known transcription factor Early growth response gene 1 (EGR1), and the results were confirmed by ChIP and Dual-luciferase reporter experiment. CONCLUSION: This study illustrates that TNS is an effective arousal strategy Treatment for LOC state via the activation of Sp5 and LH neurons and upregulation of hypocretin expression.

Electroacupuncture on Trigeminal Nerve-Innervated Acupoints Ameliorates Poststroke Cognitive Impairment in Rats with Middle Cerebral Artery Occlusion: Involvement of Neuroprotection and Synaptic Plasticity.

Poststroke cognitive impairment (PSCI) is a severe sequela of stroke. There are no effective therapeutic options for it. In this study, we evaluated whether electroacupuncture (EA) on the trigeminal nerve-innervated acupoints could alleviate PSCI and identified the mechanisms in an animal model. The male Sprague-Dawley rat middle cerebral artery occlusion (MCAO) model was used in our study. EA was conducted on the two scalp acupoints, EX-HN3 (Yintang) and GV20 (Baihui), innervated by the trigeminal nerve, for 14 sessions, daily. Morris water maze and novel object recognition were used to evaluate the animal's cognitive performance. Neuroprotection and synaptic plasticity biomarkers were analyzed in brain tissues. Ischemia-reperfusion (I/R) injury significantly impaired spatial and cognition memory, while EA obviously reversed cognitive deterioration to the control level in the two cognitive paradigms. Moreover, EA reversed the I/R injury-induced decrease of brain-derived neurotrophic factor, tyrosine kinase B, N-methyl-D-aspartic acid receptor 1, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, γ-aminobutyric acid type A receptors, Ca2+/calmodulin-dependent protein kinase II, neuronal nuclei, and postsynaptic density protein 95 expression in the prefrontal cortex and hippocampus. These results suggest that EA on the trigeminal nerve-innervated acupoints is an effective therapy for PSCI, in association with mediating neuroprotection and synaptic plasticity in related brain regions in the MCAO rat model.

Central effects of erenumab in migraine patients: An event-related functional imaging study.

OBJECTIVE: To determine whether erenumab, a new monoclonal antibody to the calcitonin gene-related peptide (CGRP) receptor, exerts functional central effects in migraineurs by performing functional imaging scans on patients treated with erenumab. METHODS: We conducted an fMRI study on 27 patients with migraine using a well-established trigeminal nociceptive paradigm, examining patients before and 2 weeks after administration of the CGRP receptor antibody erenumab 70 mg. RESULTS: Comparing both visit days in all patients (n = 27) revealed that erenumab leads to a decrease in activation in the right thalamus (i.e., contralateral to the stimulated side), right middle temporal gyrus, right lingual gyrus, left operculum, and several clusters on both sides of the cerebellum. Furthermore, when responders (n = 9) and nonresponders (n = 8) of the respective same headache state were compared, we found a significant reduction of hypothalamic activation after the administration of erenumab in responders only (t = 4.78; contrast estimate 29.79 [90% confidence interval 19.53-40.05]). This finding of reduced hypothalamic activation was confirmed when absolute headache days was used as a regressor. INTERPRETATION: These findings suggest that erenumab may not be an exclusively peripheral migraine treatment but has additional central effects. Whether this is due to secondary changes after peripheral modulation of sensory input or indeed represents a direct central mode of action is discussed.

Enhanced Thalamocortical Synaptic Transmission and Dysregulation of the Excitatory-Inhibitory Balance at the Thalamocortical Feedforward Inhibitory Microcircuit in a Genetic Mouse Model of Migraine.

Migraine is a complex brain disorder, characterized by attacks of unilateral headache and global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. The finding of enhanced excitatory, but unaltered inhibitory, neurotransmission at intracortical synapses in mouse models of familial hemiplegic migraine (FHM) suggested the hypothesis that dysregulation of the excitatory-inhibitory balance in specific circuits is a key pathogenic mechanism. Here, we investigated the thalamocortical (TC) feedforward inhibitory microcircuit in FHM1 mice of both sexes carrying a gain-of-function mutation in CaV2.1. We show that TC synaptic transmission in somatosensory cortex is enhanced in FHM1 mice. Due to similar gain of function of TC excitation of layer 4 excitatory and fast-spiking inhibitory neurons elicited by single thalamic stimulations, neither the excitatory-inhibitory balance nor the integration time window set by the TC feedforward inhibitory microcircuit was altered in FHM1 mice. However, during repetitive thalamic stimulation, the typical shift of the excitatory-inhibitory balance toward excitation and the widening of the integration time window were both smaller in FHM1 compared with WT mice, revealing a dysregulation of the excitatory-inhibitory balance, whereby the balance is relatively skewed toward inhibition. This is due to an unexpected differential effect of the FHM1 mutation on short-term synaptic plasticity at TC synapses on cortical excitatory and fast-spiking inhibitory neurons. Our findings point to enhanced transmission of sensory, including trigeminovascular nociceptive, signals from thalamic nuclei to cortex and TC excitatory-inhibitory imbalance as mechanisms that may contribute to headache, increased sensory gain, and sensory processing dysfunctions in migraine.SIGNIFICANCE STATEMENT Migraine is a complex brain disorder, characterized by attacks of unilateral headache and by global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. Here we provide insights into these mechanisms by investigating thalamocortical (TC) synaptic transmission and the function of the TC feedforward inhibitory microcircuit in a mouse model of a rare monogenic migraine. This microcircuit is critical for gating information flow to cortex and for sensory processing. We reveal increased TC transmission and dysregulation of the cortical excitatory-inhibitory balance set by the TC feedforward inhibitory microcircuit, whereby the balance is relatively skewed toward inhibition during repetitive thalamic activity. These alterations may contribute to headache, increased sensory gain, and sensory processing dysfunctions in migraine.

Is Electrical Nerve Stimulation the Answer for Management of Equine Headshaking?

Horses with trigeminal mediated headshaking (TMHS) have a decreased activation threshold of the trigeminal nerve and clinical signs are suspected to be a manifestation of trigeminal neuralgia. Electrical nerve stimulation (ENS) is used for management of neuralgia in humans and appears to work via gate control theory. Use of an equine specific percutaneous ENS program in over 130 TMHS horses has resulted in approximately 50% success return to previous work. Electroacupuncture may also be useful in the management TMHS. Optimization of ENS procedures for TMHS is likely to require a greater understanding of the etiopathogenesis of the aberrant neurophysiology.

Rationale for electrical parameter determination in external trigeminal nerve stimulation (eTNS) for migraine: A narrative review.

BACKGROUND: Migraine is a primary headache disorder involving dysregulation of central and peripheral pain pathways. Medical treatment is often limited by drug side effects, comorbidities and poor compliance. This makes neuromodulation an ideal option for migraine treatment. Cefaly® is a transcutaneous electrical neurostimulator designed specifically for migraine treatment. It results in external trigeminal nerve stimulation of the supraorbital and supratrochlear nerves. External trigeminal nerve stimulation is effective for acute and preventive migraine treatment and may result in normalization of dysregulated pain pathways. OBJECTIVE: Our objective was to provide a narrative review of the neuroanatomical and pathophysiological basis of external trigeminal nerve stimulation for migraine treatment and to provide the rationale behind the choice of the electrical parameters used for external trigeminal nerve stimulation. METHODS: We reviewed external trigeminal nerve stimulation clinical trial publications, basic science neurostimulation literature, publications describing pathophysiological mechanisms in migraine, and documentation used in the application for the Food and Drug Administration approval of external trigeminal nerve stimulation. RESULTS: The electrical parameters used for external trigeminal nerve stimulation were chosen to maximize safety and efficacy. Critical parameters include generator characteristics, pulse shape, pulse duration, pulse frequency and session duration and frequency. We explain the rationale behind determination of each parameter. There is evidence of dysregulated central and peripheral pathways in migraine and evidence that external trigeminal nerve stimulation may normalize function of these pathways. CONCLUSION: External trigeminal nerve stimulation is a safe and effective Food and Drug Administration-approved option for the acute and preventive treatment of migraine. The electrical parameters were optimized specifically for external stimulation of the trigeminal nerve to maximum safety, comfort and efficacy.

Placement and Anchoring of Trigeminal Neurostimulation Electrodes: Technical Report.

BACKGROUND: Peripheral neurostimulation (PNS) for medically refractory trigeminal and craniofacial pain is an emerging alternative to traditional surgical approaches. Technical problems with craniofacial PNS have included electrode migration and erosion, limiting the utility and cost-effectiveness of this procedure. OBJECTIVE: To review our institutional surgical technique for trigeminal PNS implantation, focusing on a novel technique for electrode anchoring. METHODS: Consecutive cases of permanent craniofacial PNS placement by a single surgeon over 36 months were reviewed for surgical technique and technical outcomes. Electrodes were placed percutaneously with open anchoring to the pericranium at a separate parietal incision. RESULTS: Sixteen systems (53 electrodes) were implanted in 14 patients. Median follow-up was 13 months (range, 5-29 months). Electrode placement was successful in all cases with no intraoperative complications. There was 1 lead migration (6.3% per patient; 1.8% per lead) and no cases of erosion. Two patients (14.3%) required explant for infection, 1 of whom was successfully reimplanted. Three patients (21.4%) underwent surgical revision other than for infection. CONCLUSIONS: We present an improved method for craniofacial PNS surgery which introduces a separate incision for electrode anchoring at the parietal boss. This technique simplifies the procedure and greatly reduces rates of erosion and migration, improving patient comfort and satisfaction.

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.

The enigma of site of action of migraine preventives: no effect of metoprolol on trigeminal pain processing in patients and healthy controls.

BACKGROUND: Beta-blockers are a first choice migraine preventive medication. So far it is unknown how they exert their therapeutic effect in migraine. To this end we examined the neural effect of metoprolol on trigeminal pain processing in 19 migraine patients and 26 healthy controls. All participants underwent functional magnetic resonance imaging (fMRI) during trigeminal pain twice: Healthy subjects took part in a placebo-controlled, randomized and double-blind study, receiving a single dose of metoprolol and placebo. Patients were examined with a baseline scan before starting the preventive medication and 3 months later whilst treated with metoprolol. RESULTS: Mean pain intensity ratings were not significantly altered under metoprolol. Functional imaging revealed no significant differences in nociceptive processing in both groups. Contrary to earlier findings from animal studies, we did not find an effect of metoprolol on the thalamus in either group. However, using a more liberal and exploratory threshold, hypothalamic activity was slightly increased under metoprolol in patients and migraineurs. CONCLUSIONS: No significant effect of metoprolol on trigeminal pain processing was observed, suggesting a peripheral effect of metoprolol. Exploratory analyses revealed slightly enhanced hypothalamic activity under metoprolol in both groups. Given the emerging role of the hypothalamus in migraine attack generation, these data need further examination.

Acupuncture modulates the abnormal brainstem activity in migraine without aura patients.

Migraine is a common neurological disease with a high prevalence and unsatisfactory treatment options. The specific pathophysiological mechanisms of migraine remain unclear, which restricts the development of effective treatments for this prevalent disorder. The aims of this study were to 1) compare the spontaneous brain activity differences between Migraine without Aura (MwoA) patients and healthy controls (HCs), using amplitude of low-frequency fluctuations (ALFF) calculation method, and 2) explore how an effective treatment (verum acupuncture) could modulate the ALFF of MwoA patients. One hundred MwoA patients and forty-six matched HCs were recruited. Patients were randomized to four weeks' verum acupuncture, sham acupuncture, and waiting list groups. Patients had resting state BOLD-fMRI scan before and after treatment, while HCs only had resting state BOLD-fMRI scan at baseline. Headache intensity, headache frequency, self-rating anxiety and self-rating depression were used for clinical efficacy evaluation. Compared with HCs, MwoA patients showed increased ALFF in posterior insula and putamen/caudate, and reduced ALFF in rostral ventromedial medulla (RVM)/trigeminocervical complex (TCC). After longitudinal verum acupuncture treatment, the decreased ALFF of the RVM/TCC was normalized in migraine patients. Verum acupuncture and sham acupuncture have different modulation effects on ALFF of RVM/TCC in migraine patients. Our results suggest that impairment of the homeostasis of the trigeminovascular nociceptive pathway is involved in the neural pathophysiology of migraines. Effective treatments, such as verum acupuncture, could help to restore this imbalance.

Hypothalamus as a mediator of chronic migraine: Evidence from high-resolution fMRI.

OBJECTIVE: To identify pathophysiologic mechanisms of migraine chronification using a recently standardized protocol for high-resolution brainstem imaging of trigeminal nociceptive stimulation. METHODS: Eighteen episodic migraineurs (EMs), 17 chronic migraineurs (CMs), and 19 healthy controls (HCs) underwent painful ammonia stimulation of the left nostril in a 3T MRI scanner. Functional images were acquired with a brainstem-optimized protocol for high-resolution echo-planar imaging. RESULTS: We detected a significantly stronger activation of the anterior right hypothalamus in CMs compared to HCs. To exclude the headache as a prime mediator of the hypothalamic activations, we compared all migraineurs with headaches (EMs and CMs) with all migraineurs without headaches (EMs and CMs) and HCs in a second analysis and found a more posterior region of the hypothalamus to be more activated bilaterally during headaches. CONCLUSIONS: Our data corroborate the fact that the hypothalamus plays a crucial role in the pathophysiology of migraine chronification and acute pain stage of migraineurs. While the more posterior part of the hypothalamus seems to be important for the acute pain stage, the more anterior part seems to play an important role in attack generation and migraine chronification.

Cervical spine disorders and its association with tinnitus: The "triple" hypothesis.

Subjective tinnitus and cervical spine disorders (CSD) are among the most common complaints encountered by physicians. Although the relationship between tinnitus and CSD has attracted great interest during the past several years, the pathogenesis of tinnitus induced by CSD remains unclear. Conceivably, CSD could trigger a somatosensory pathway-induced disinhibition of dorsal cochlear nucleus (DCN) activity in the auditory pathway; furthermore, CSD can cause inner ear blood impairment induced by vertebral arteries hemodynamic alterations and trigeminal irritation. In genetically -predisposed CSD patients with reduced serotoninergic tone, signals from chronically stimulated DCNs could activate specific cortical neuronal networks and plastic neural changes resulting in tinnitus. Therefore, an early specific tailored CSD treatments and/or boosting serotoninergic activity may be required to prevent the creation of 'tinnitus memory circuits' in CSD patients.

Valproate Attenuates Nitroglycerin-Induced Trigeminovascular Activation by Preserving Mitochondrial Function in a Rat Model of Migraine.

BACKGROUND Migraine is a chronic disease that interferes with life quality and work productivity. Valproate shows protective effects against migraine, yet the underlying mechanisms are unclear. This study aimed to evaluate the potential effect of valproate on migraine using a rat model of nitroglycerin-induced trigeminovascular activation, as well as to explore the underlying mechanism. MATERIAL AND METHODS Intraperitoneal injection of nitroglycerin was conducted to induce trigeminovascular activation in rats. To explore the protective effect of valproate, a low dose (100 mg/kg) or a high dose (200 mg/kg) of valproate was intraperitoneally injected into rats, and then the levels of 5-hydroxytryptamine and nitric oxide in the peripheral blood were examined. The mtDNA copy number and the protein levels of peroxisome proliferator-activated receptor-γ coactivator 1α, mitochondrial transcription factor A, and peroxisome proliferator-activated receptor-γ in the spinal trigeminal nucleus were detected to evaluate the biogenesis of mitochondria. The mitochondrial energy metabolism was determined by the mitochondrial membrane potential and the levels of adenosine triphosphate, cytochrome C oxidase, and reactive oxygen species. RESULTS Valproate attenuated nitroglycerin-induced trigeminovascular activation in rats, with reduced scratching behavior and restored 5-hydroxytryptamine and nitric oxide levels. Moreover, the mitochondrial energy metabolism and the biogenesis of mitochondria were preserved by valproate in nitroglycerin-treated rats. CONCLUSIONS The protective effect of valproate against migraine may be achieved through the modulation of mitochondrial biogenesis and function. Our study provides evidence for the potential use of valproate in the treatment of migraine.

Transcranial magnetic stimulation and potential cortical and trigeminothalamic mechanisms in migraine.

A single pulse of transcranial magnetic stimulation has been shown to be effective for the acute treatment of migraine with and without aura. Here we aimed to investigate the potential mechanisms of action of transcranial magnetic stimulation, using a transcortical approach, in preclinical migraine models. We tested the susceptibility of cortical spreading depression, the experimental correlate of migraine aura, and further evaluated the response of spontaneous and evoked trigeminovascular activity of second order trigemontothalamic and third order thalamocortical neurons in rats. Single pulse transcranial magnetic stimulation significantly inhibited both mechanical and chemically-induced cortical spreading depression when administered immediately post-induction in rats, but not when administered preinduction, and when controlled by a sham stimulation. Additionally transcranial magnetic stimulation significantly inhibited the spontaneous and evoked firing rate of third order thalamocortical projection neurons, but not second order neurons in the trigeminocervical complex, suggesting a potential modulatory effect that may underlie its utility in migraine. In gyrencephalic cat cortices, when administered post-cortical spreading depression, transcranial magnetic stimulation blocked the propagation of cortical spreading depression in two of eight animals. These results are the first to demonstrate that cortical spreading depression can be blocked in vivo using single pulse transcranial magnetic stimulation and further highlight a novel thalamocortical modulatory capacity that may explain the efficacy of magnetic stimulation in the treatment of migraine with and without aura.

Neuromodulation of Electrically Induced Hyperalgesia in the Trigeminocervical System.

OBJECTIVE: Trigeminal and cervical afferents converge on neurons of the trigeminocervical complex and may significantly alter the function of these neurons. This interaction may have implications for the pathophysiology and treatment of primary headache disorders. Therefore, the aim of this work was to study pain modulatory mechanisms within the trigeminocervical complex. SUBJECTS: We used an electrical pain model challenging pro- and antinociceptive systems in 19 healthy volunteers. METHODS: Transcutaneous supraorbital noxious electrical low-frequency stimulation (0.5 Hz), known to induce both hyperalgesia due to central sensitization (as a marker of pain facilitation) and habituation (as a marker of pain inhibition), was combined with different noxious stimulation paradigms applied to the innervation territory of upper cervical afferents. We investigated the effects of concurrent stimulation in the cervical/extratrigeminal system on habituation profiles, hyperalgesic area, pain, and detection thresholds in the trigeminal system. RESULTS: It was previously shown that conditioning 20-Hz noxious electrical stimuli may provoke centrally mediated sensory decline that possesses heterotopic antihyperalgesic properties. Occipital and forearm costimulation at a frequency of 20 Hz had no significant modulating effect on supraorbital pain adaptation, hyperalgesic area, or pain perception. Effects for trigeminal stimulation were independent of occipital stimulus intensity. Furthermore, for single occipital stimulation at 0.5 and 20 Hz, no somatosensory changes could be demonstrated within the trigeminal system. CONCLUSION: Trigeminal nociception stayed unchanged despite of occipital costimulation.

[Pathophysiology of cluster headache]. / Physiopathologie de l'algie vasculaire de la face (AVF).

The aetiology of cluster headache is partially unknown. Three areas are involved in the pathogenesis of cluster headache: the trigeminal nociceptive pathways, the autonomic system and the hypothalamus. The cluster headache attack involves activation of the trigeminal autonomic reflex. A dysfunction located in posterior hypothalamic gray matter is probably pivotal in the process. There is a probable association between smoke exposure, a possible genetic predisposition and the development of cluster headache.

Unirhinal Olfactory Testing for the Diagnostic Workup of Mild Cognitive Impairment.

BACKGROUND: Olfactory dysfunction is associated with Alzheimer's disease (AD), and already present at pre-dementia stage. OBJECTIVES: Based on the assumption that early neurodegeneration in AD is asymmetrical and that olfactory input is primarily processed in the ipsilateral hemisphere, we assessed whether unirhinal psychophysical and electrophysiological assessment of olfactory function can contribute to the diagnostic workup of mild cognitive impairment (MCI). METHODS: Olfactory function of 13 MCI patients with positive amyloid PET, 13 aged-matched controls (AC) with negative amyloid PET and 13 patients with post-infectious olfactory loss (OD) was assessed unirhinally using (1) psychophysical testing of olfactory detection, discrimination and identification performance and (2) the recording of olfactory event-related brain potentials. Time-frequency analysis was used to enhance the signal-to-noise ratio of the electrophysiological responses. Psychophysical and electrophysiological assessment of auditory and trigeminal chemosensory function served as controls. RESULTS: As compared to AC and OD, MCI patients exhibited a significant asymmetry of olfactory performance. This asymmetry efficiently discriminated between MCI and AC (sensitivity: 85% , specificity: 77% ), as well as MCI and OD (sensitivity: 85% , specificity: 70% ). There was also an asymmetry of the electrophysiological responses, but not specific for MCI. In both MCI and OD, olfactory stimulation of the best nostril elicited significantly more activity than stimulation of the worse nostril, between 3-7.5 Hz and 1.2-2.0 s after stimulus onset. Trigeminal and auditory psychophysical testing did not show any difference between groups. CONCLUSION: MCI patients exhibit a marked asymmetry of behavioral olfactory function, which could be useful for the diagnostic workup of MCI.

Response characteristics of pruriceptive and nociceptive trigeminoparabrachial tract neurons in the rat.

We tested the possibility that the trigeminoparabrachial tract (VcPbT), a projection thought to be importantly involved in nociception, might also contribute to sensation of itch. In anesthetized rats, 47 antidromically identified VcPbT neurons with receptive fields involving the cheek were characterized for their responses to graded mechanical and thermal stimuli and intradermal injections of pruritogens (serotonin, chloroquine, and ß-alanine), partial pruritogens (histamine and capsaicin), and an algogen (mustard oil). All pruriceptive VcPbT neurons were responsive to mechanical stimuli, and more than half were additionally responsive to thermal stimuli. The majority of VcPbT neurons were activated by injections of serotonin, histamine, capsaicin, and/or mustard oil. A subset of neurons were inhibited by injection of chloroquine. The large majority of VcPbT neurons projected to the ipsilateral and/or contralateral external lateral parabrachial and Kölliker-Fuse nuclei, as evidenced by antidromic mapping techniques. Analyses of mean responses and spike-timing dynamics of VcPbT neurons suggested clear differences in firing rates between responses to noxious and pruritic stimuli. Comparisons between the present data and those previously obtained from trigeminothalamic tract (VcTT) neurons demonstrated several differences in responses to some pruritogens. For example, responses of VcPbT neurons to injection of serotonin often endured for nearly an hour and showed a delayed peak in discharge rate. In contrast, responses of VcTT neurons endured for roughly 20 min and no delayed peak of firing was noted. Thus the longer duration responses to 5-HT and the delay in peak firing of VcPbT neurons better matched behavioral responses to stimulation in awake rats than did those of VcTT neurons. The results indicate that VcPbT neurons may have important roles in the signaling of itch as well as pain.

Neuromodulation in cluster headache.

Medically refractory chronic cluster headache (CH) is a severely disabling headache condition for which several surgical procedures have been proposed as a prophylactic treatment. None of them have been evaluated in controlled conditions, only open studies and case series being available. Destructive procedures (radiofrequency lesioning, radiosurgery, section) and microvascular decompression of the trigeminal nerve or the sphenopalatine ganglion (SPG) have induced short-term improvement which did not maintain on long term in most of the patients. They carried a high risk of complications, including severe sensory loss and neuropathic pain, and consequently should not be proposed in first intention.Deep brain stimulation (DBS), targeting the presumed CH generator in the retro-hypothalamic region or fibers connecting it, decreased the attack frequency >50 in 60 % of the 52 patients reported. Complications were infrequent: gaze disturbances, autonomic disturbances, and intracranial hemorrhage (2).Occipital nerve stimulation (ONS) was efficient (decrease of attack frequency >50 %) in about 70 % of the 60 patients reported, with a low risk of complications (essentially hardware related). Considering their respective risks, ONS should be proposed first and DBS only in case of ONS failure.New on-demand chronically implanted SPG stimulation seemed to be efficient to abort CH attacks in a pilot controlled trial, but its long-term safety needs to be further studied.