Electro-acupuncture inhibits C-fiber-evoked WDR neuronal activity of the trigeminocervical complex: Neurophysiological hypothesis of a complementary therapy for acute migraine modeled rats.

INTRODUCTION: Acupuncture has become a relevant complementary and alternative treatment for acute migraine; however, the neurophysiological mechanism (C-fibers) underlying this effect remains unclear. C-fibers play a crucial role for diffuse noxious inhibitory controls (DNIC) at wide dynamic range (WDR) neurons in the trigeminocervical complex (TCC) in migraine attacks, and we supposed that this may be the mechanism of acupuncture analgesia. This study aimed to examine the neurophysiology of acupuncture intervention in an acute migraine rat model. METHODS: Inflammatory soup (IS) or saline was injected into the dura mater to establish a migraine and control model in rats. To explore the neurobiological mechanism of acupuncture for migraine, we implemented electro-acupuncture (EA), non-electric-stimulation acupuncture, and no-acupuncture in IS and saline injected rats, and recorded the single-cell extraneural neurophysiology of the atlas (C1) spinal dorsal horn neurons in the TCC. RESULTS: Our research shows that electro-acupuncture at GB8 (Shuaigu), located in the periorbital region receptive field of the trigeminal nerve, may rapidly reduce the C-fiber evoked WDR neuronal discharges of the TCC within 60 s. DISCUSSION: This study provides pioneering evidence of a potential neurobiological mechanism for the analgesic effect on migraine attacks achieved by electro-acupuncture intervention via DNIC. The data indicates that EA may become a crucial supplementary and alternative therapy for migraineurs that failed to respond to acute medications, e.g., fremanezumab, which achieves its analgesic effect via modulating Aσ-fibers, not C-fibers.

Effect of Paeonia lactiflora, a traditional Chinese herb, on migraines based on clinical application and animal behavior analyses.

BACKGROUND: Paeonia lactiflora (PL) was widely used for pain relief, but its effects on migraine headaches remain unclear. PURPOSE: The aim of the present study was to investigate the effects of PL on migraine headaches. METHODS: First, we found that PL was frequently used in Taiwan for headache treatment based on data from Taiwan's National Health Insurance Research Database. Migraine was induced through the intraperitoneal injection (i.p.) of nitroglycerin (NTG, 10 mg/kg) in rats. Pretreatment with PL was administered orally 30 min prior to the NTG i.p. Migraine headache behavior was observed by video-recordings. Finally, the rats were sacrificed and brain was removed for immunohistochemistry staining analysis. RESULTS: The frequency and total time spent rearing up and sniffing in exploratory behavior, and walking in locomotor behavior, were reduced in the NTG group compared with the control group (all p <  0.001). This reduction could be ameliorated by pretreatment with PL 1.0 g/kg (all p <  0.05). Total time spent in the light chamber was lower in the NTG group compared with the control group (p <  0.05); this could be ameliorated by pretreatment with 1.0 g/kg PL (p <  0.05). The rats in the NTG group spent longer time on the smooth surface than those in the control group (p <  0.001); this could be shortened by pretreatment with 0.5 and 1.0 g/kg PL (both p <  0.01). The traveling distance of rats in the NTG group was shorter than in the control group (p <  0.001); rats given 1.0 g/kg PL had a longer traveling distance than those in the NTG group (p <  0.01). Both c-fos and CGRP immunoreactive cells increased in the TNC in the NTG group compared with that of the control group (both p <  0.001); this increased could be reduced by pretreatment with PL 0.5 and 1.0 g/kg (both p <  0.05). CONCLUSION: Pretreatment with PL ameliorated migraine headache behaviors in the NTG-induced migraine rat model, suggesting pretreatment with PL is beneficial for migraine headache treatment. This effect of PL is related to the decrease of c-fos and CGRP in the TNC. However, still there are too many methodological limitations which need to be overcome in further experiments to support the data.

Advanced visual network and cerebellar hyperresponsiveness to trigeminal nociception in migraine with aura.

BACKGROUND: Despite the growing body of advanced studies investigating the neuronal correlates of pain processing in patients with migraine without aura (MwoA), only few similar studies have been conducted in patients with migraine with aura (MwA). Therefore, we aimed to explore the functional brain response to trigeminal noxious heat stimulation in patients with MwA. METHODS: Seventeen patients with MwA and 15 age- and sex-matched healthy controls (HC) underwent whole-brain blood oxygen level-dependent (BOLD) fMRI during trigeminal noxious heat stimulation. To examine the specificity of any observed differences between patients with MwA and HC, the functional response of neural pathways to trigeminal noxious heat stimulation in patients with MwA was compared with 18 patients with MwoA. Secondary analyses investigated the correlations between BOLD signal changes and clinical parameters of migraine severity. RESULTS: We observed a robust cortical and subcortical pattern of BOLD response to trigeminal noxious heat stimulation across all participants. Patients with MwA showed a significantly increased activity in higher cortical areas known to be part of a distributed network involved in advanced visual processing, including lingual gyrus, inferior parietal lobule, inferior frontal gyrus and medial frontal gyrus. Moreover, a significantly greater cerebellar activation was observed in patients with MwA when compared with both patients with MwA and HC. Interestingly, no correlations were found between migraine severity parameters and magnitude of BOLD response in patients with MwA. CONCLUSION: Our findings, characterized by abnormal visual pathway response to trigeminal noxious heat stimulation, support the role of a functional integration between visual and trigeminal pain networks in the pathophysiological mechanisms underlying migraine with aura. Moreover, they expand the concept of "neurolimbic-pain network" as a model of MwoA including both limbic dysfunction and cortical dys-excitability. Indeed, we suggest a model of "neurolimbic-visual-pain network" in MwA patients, characterized by dysfunctional correlations between pain-modulating circuits not only with the cortical limbic areas but with advanced visual areas as well. Furthermore, the abnormal cerebellar response to trigeminal noxious heat stimulation may suggest a dysfunctional cerebellar inhibitory control on thalamic sensory gating, impinging on the advanced visual processing cortical areas in patients with MwA.

Afferent Fiber Remodeling in the Somatosensory Thalamus of Mice as a Neural Basis of Somatotopic Reorganization in the Brain and Ectopic Mechanical Hypersensitivity after Peripheral Sensory Nerve Injury.

Plastic changes in the CNS in response to peripheral sensory nerve injury are a series of complex processes, ranging from local circuit remodeling to somatotopic reorganization. However, the link between circuit remodeling and somatotopic reorganization remains unclear. We have previously reported that transection of the primary whisker sensory nerve causes the abnormal rewiring of lemniscal fibers (sensory afferents) on a neuron in the mouse whisker sensory thalamus (V2 VPM). In the present study, using transgenic mice whose lemniscal fibers originate from the whisker sensory principle trigeminal nucleus (PrV2) are specifically labeled, we identified that the transection induced retraction of PrV2-originating lemniscal fibers and invasion of those not originating from PrV2 in the V2 VPM. This anatomical remodeling with somatotopic reorganization was highly correlated with the rewiring of lemniscal fibers. Origins of the non-PrV2-origin lemniscal fibers in the V2 VPM included the mandibular subregion of trigeminal nuclei and the dorsal column nuclei (DCNs), which normally represent body parts other than whiskers. The transection also resulted in ectopic receptive fields of V2 VPM neurons and extraterritorial pain behavior on the uninjured mandibular region of the face. The anatomical remodeling, emergence of ectopic receptive fields, and extraterritorial pain behavior all concomitantly developed within a week and lasted more than three months after the transection. Our findings, thus, indicate a strong linkage between these plastic changes after peripheral sensory nerve injury, which may provide a neural circuit basis underlying large-scale reorganization of somatotopic representation and abnormal ectopic sensations.

[Intrinsic brain activity with pain]. / Intrinsische Hirnaktivität bei Schmerzen.

Besides the responses to nociceptive stimuli other neural function modes of the brain are necessary to obtain a comprehensive understanding of pain processing in humans. During a resting state without extrinsic stimulation the human brain generates spontaneous low frequency fluctuations of neural activity. This intrinsic activity does not reflect random background noise but is highly organized in several networks. Based on the findings of recent functional imaging studies, the role of these resting state networks in acute and chronic pain is discussed.

[Manual treatment of the cervical spinal column for tinnitus after acute hearing loss - a case report]. / Manualmedizinische Behandlung der Halswirbelsäule bei akutem Tinnitus nach Hörsturz - ein Fallbericht.

Tinnitus is one of the 20 most common reasons why patients aged 45-64 years consult a general practitioner in Germany. In the literature a correlation is claimed between disease patterns of the cervical spinal column and nuclei of cerebral nerves. In the case report presented here, a 30-year-old female patient with acute tinnitus after acute hearing loss was cured from her tinnitus after a single manual medical treatment at C0/C1, which supports the correlation claimed. If cervical spine diseases should therefore regularly be included in the differential diagnoses of acute tinnitus is a matter of further research.

Dopamine: what's new in migraine?

PURPOSE OF REVIEW: Dopamine has been implicated in the pathophysiology of migraine, although its exact role remains unclear. Recent data offer some new perspective on a possible role for dopaminergic mechanisms in migraine. This review aims to summarize our current understanding of dopamine in migraine. RECENT FINDINGS: Direct application of dopamine and dopamine receptor agonists onto trigeminocervical complex neurons inhibits their activation after nociceptive stimulation. The dopaminergic A11 nucleus of the hypothalamus has been identified as the likely source of this dopamine. Recent evidence has shown that the genes for dopamine beta-hydroxylase and the dopamine transporter SLC6A3 may play a role in migraine pathophysiology, and dopamine has also been implicated in menstrual migraine. SUMMARY: Dopamine is currently considered to contribute to the pathophysiology of migraine, and dopamine receptor antagonists are prescribed in the treatment of acute migraine. Laboratory data suggest that the role of dopamine in migraine is more complex, perhaps due to the multiple receptors and levels of the brain involved in the disorder. These data suggest a reappraisal of dopaminergic therapeutic targets in migraine as our understanding of the role of this important biogenic amine is better characterized.

The effects of ibuprofen and the neurokinin-1 receptor antagonist GR205171A on Fos expression in the ferret trigeminal nucleus following tooth pulp stimulation.

We have developed a model to study central changes following inflammation of the tooth pulp in the ferret and have examined Fos expression in the trigeminal nucleus following stimulation of non-inflamed and inflamed tooth pulps. The aim of this study was to establish the ability of this model to predict analgesic efficacy in clinical studies of inflammatory pain. We addressed this by assessing the effects of the neurokinin-1 receptor antagonist GR205171A and ibuprofen on Fos expression following stimulation of the inflamed pulp and comparing this with known analgesic efficacy. Adult ferrets were prepared under anaesthesia to allow tooth pulp stimulation, recording from the digastric muscle and intravenous injections at a subsequent experiment. In some animals pulpal inflammation was induced, by introducing human caries into a deep buccal cavity. After 5 days, animals were reanaesthetised, treated with vehicle, GR205171A or ibuprofen and the teeth were stimulated at ten times the threshold of the jaw-opening reflex. Stimulation of all tooth pulps induced ipsilateral Fos in trigeminal subnuclei caudalis and oralis. GR205171A had no significant effect on Fos expression in the trigeminal nucleus of animals with either non-inflamed or inflamed tooth pulps. Ibuprofen reduced Fos expression in the trigeminal nucleus and this effect was most marked in animals with pulpal inflammation. These results differ from those previously described using a range of other animal models, but agree with known clinical efficacy of neurokinin-1 receptor antagonists and ibuprofen. Therefore this model is likely to be of use in accurately predicting the analgesic efficacy of novel compounds.

In vivo quantification of spinal and bulbar motor neuron degeneration in the G93A-SOD1 transgenic mouse model of ALS by T2 relaxation time and apparent diffusion coefficient.

Magnetic resonance imaging (MRI) has provided important information in characterizing amyotrophic lateral sclerosis (ALS) in humans and in animal models. A frequently used animal model to study mechanisms of pathogenesis and the efficacy of drugs in ALS is a transgenic mouse over-expressing the human mutated G93A-superoxide dismutase 1 (G93A-SOD1). In our study, we applied MRI to find suitable progression markers, which can be used to monitor the development of ALS and to evaluate therapeutic approaches at early stages of the disease. Therefore, we generated parameter maps of the spin-spin relaxation time (T2) and the apparent diffusion coefficient (ADC) starting at day 70 after birth, i.e., before motor scores decline around day 90. Depending on the progression of the disease, G93A-SOD1 mice showed significantly increased values of T2 in the brain stem motor nuclei Nc. V (trigeminal nucleus), VII (facial nucleus), and XII (hypoglossal nucleus), and spinal cord compared to non-transgenic wild-type mice and transgenic mice over-expressing the non-mutated wild-type human SOD1 (tg-SOD1). Similar effects in these motor nuclei were revealed by ADC mapping. Furthermore, in the upper spinal cord, a dorsal-ventral difference with significantly higher T2 values in the ventral part was demonstrated by T2 mapping. While both T2 and ADC might prove useful as progression markers and enable the longitudinal non-invasive evaluation of ALS in G93A-SOD1 mice, the potential is limited by age-dependent effects in case of ADC mapping.

Warfarin as a therapeutic option in the control of chronic cluster headache: a report of three cases.

Chronic cluster headache remains refractory to medical therapy in at least 30% of those who suffer from this condition. The lack of alternative medical therapies that are as effective as, or more effective than, lithium carbonate makes new therapies necessary for this highly disabling condition. Based on a previous report, we gave oral anticoagulants to three patients with chronic cluster headache. Two of them remained cluster headache-free while taking warfarin. In the third patient, the use of warfarin for three weeks initially increased the frequency and intensity of cluster headache attacks but subsequently induced a prolonged remission. In spite of the paucity of data available, oral anticoagulation appears to be a promising therapy for chronic cluster headache.

[Neurophysiological background of pain in the orofacial area: review of the literature]. / Az orofaciális terület fájdalmainak neurofiziológiai háttere. Osszefoglaló referátum.

The article presents an overview on the peripheral and central neural mechanisms underlying pain in the orofacial area. First a definition of pain and a description of general aspects of orofacial pain are presented. Characteristics of acute and chronic pain are also described. The study highlights the sense organs, the molecular mechanisms and categories of primary afferents involved in peripheral events of orofacial pain. After describing the brain-stem nuclei participating in trigeminal pain and their functional role, primary afferents involved in nociceptive sensation from the tooth pulp, explanations of dentinal sensitivity and differences between the brain-stem endings of primary afferents among different species are discussed in details. The role of higher brain centres, with a special emphasis on the thalamus and somatosensory cortex in the development of orofacial pain sensation is considered. The last section provides a review about how the activities of nociceptive neurons are controlled by higher brain centres and neurochemicals involved in pain transmission.

Unitary hypothesis for multiple triggers of the pain and strain of migraine.

Migraine headache is triggered by and associated with a variety of hormonal, emotional, nutritional, and physiological changes. The perception of migraine headache is formed when nociceptive signals originating in the meninges are conveyed to the somatosensory cortex through the trigeminal ganglion, medullary dorsal horn, and thalamus. Is there a common descending pathway accounting for the activation of meningeal nociceptors by different migraine triggers? We propose that different migraine triggers activate a wide variety of brain areas that impinge on parasympathetic neurons innervating the meninges. According to this hypothesis, migraine triggers such as perfume, stress, or awakening activate multiple hypothalamic, limbic, and cortical areas, all of which contain neurons that project to the preganglionic parasympathetic neurons in the superior salivatory nucleus (SSN). The SSN, in turn, activates postganglionic parasympathetic neurons in the sphenopalatine ganglion, resulting in vasodilation and local release of inflammatory molecules that activate meningeal nociceptors. Are there ascending pathways through which the trigeminovascular system can induce the wide variety of migraine symptoms? We propose that trigeminovascular projections from the medullary dorsal horn to selective areas in the midbrain, hypothalamus, amygdala, and basal forebrain are functionally positioned to produce migraine symptoms such as irritability, loss of appetite, fatigue, depression, or the quest for solitude. Bidirectional trafficking by which the trigeminovascular system can activate the same brain areas that have triggered its own activity in the first place provides an attractive network of perpetual feedback that drives a migraine attack for many hours and even days.

Migrainous vertigo: development of a pathogenetic model and structured diagnostic interview.

PURPOSE OF REVIEW: Vestibular symptoms occur frequently in patients with migraine. This review refines recently proposed diagnostic criteria for migraine-related vestibular symptoms, and develops a pathophysiological model for the interface between migraine and the vestibular system. RECENT FINDINGS: The epidemiological link between migraine and vestibular symptoms and signs suggests shared pathogenetic mechanisms. Links between the vestibular nuclei, the trigeminal system, and thalamocortical processing centers provide the basis for the development of a pathophysiological model of migraine-related vertigo. During the last year, several studies have increased understanding of the relationship between migraine and vestibular symptoms. A study of motion sickness and allodynia in migraine patients supports the importance of central mechanisms of sensitization for migraine-related vestibular symptoms. A study has demonstrated effective treatment of vertigo with migraine therapy. The identification of migrainous vertigo, however, is hampered by a lack of standardized assessment criteria for both clinical and research practices. The application of published criteria for the diagnosis of migrainous vertigo allows the development of a standardized, structured assessment interview. SUMMARY: An understanding of the relationship between migraine and the vestibular system increases knowledge of the pathogenesis of both migraine and vertigo. In addition, studies have identified successful treatment, with standard migraine therapies, of vestibular symptoms in patients with both migraine and vertigo. The use of a standardized assessment tool to identify this unique population of patients will help future studies to test both the pathological model and effective treatment options.

Neuroplasticity induced by tooth pulp stimulation in trigeminal subnucleus oralis involves NMDA receptor mechanisms.

We have recently demonstrated that application of the mustard oil (MO), a small-fiber excitant and inflammatory irritant, to the rat maxillary molar tooth pulp induces significant increases in jaw muscle electromyographic (EMG) activity and neuroplastic changes in trigeminal (V) subnucleus caudalis. Since subnucleus oralis (Vo) as well as caudalis receives projections from molar pulp afferents and is also an integral brain stem relay of afferent input from orofacial structures, we tested whether MO application to the exposed pulp induces neuroplastic changes in oralis neurons and whether microinjection of MK-801, a noncompetitive NMDA antagonist, into the Vo influences the pulp/MO-induced neuroplastic changes in chloralose/urethan-anesthetized rats. Single neuronal activity was recorded in Vo, and neurons classified as low-threshold mechanoreceptive (LTM), wide dynamic range (WDR), nociceptive-specific (NS), deep (D), or skin/mucosa and deep (S + D). The spontaneous activity, mechanoreceptive field (RF) size, mechanical threshold, and response to suprathreshold mechanical stimuli applied to the neuronal RF were assessed prior to and throughout a 40- to 60-min period after MO application to the maxillary molar pulp. In animals pretreated with saline microinjection (0.3 microl) into the Vo, MO application to the pulp produced a significant increase in spontaneous activity, expansion of the pinch or deep RF, decrease in the mechanical threshold, and increase in response to suprathreshold mechanical stimuli of the nociceptive (WDR, NS, and S + D) neurons except for those nociceptive neurons having their RF only in the intraoral region. The pulpal application of MO did not produce any significant neuroplastic changes in LTM neurons. Furthermore, in animals pretreated with MK-801 microinjection (3 microg/0.3 microl) into the Vo, MO application to the pulp did not produce any significant changes in the RF and response properties of nociceptive neurons. In other animals pretreated with saline (0.3 microl) or MK-801 (3 microg/0.3 microl) microinjected into the Vo, mineral oil application to the pulp did not produce any significant changes in RF and response properties of nociceptive neurons. These findings indicate that the application of MO to the tooth pulp can induce significant neuroplastic changes in oralis nociceptive neurons and that central NMDA receptor mechanisms may be involved in these neuroplastic changes.

Evidence for subnucleus interpolaris in craniofacial muscle pain mechanisms demonstrated by intramuscular injections with hypertonic saline.

The subnucleus interpolaris (Vi) has been identified as a major recipient for trigeminal ganglionic input from jaw muscles, and contains neurons with nociceptive properties similar to those in the subnucleus caudalis (Vc). Therefore, Vi may be another important site for processing craniofacial muscle nociception. The aims of present study were to define functional properties of Vi neurons that receive input from masseter muscle afferents by characterizing their responses to electrical, mechanical, and to chemical stimulation of the muscle. Ninety cells were identified as masseter muscle units in 11 adult cats. Most of these units (79%) received additional inputs from orofacial skin. Following the intramuscular injection of 5% hypertonic saline, 49% of the cells showed a significant modulation of either the resting discharge and/or responses to innocuous mechanical stimulation on their cutaneous receptive fields (RFs). The most common response to saline injection was an induction or facilitation of resting discharge which declined as an exponential decay function, returning to pre-injection level within 3-4 min. Forty-five percent of the muscle units that were tested with mechanical stimulation (13/29) showed a prolonged inhibition of mechanically-evoked responses. In most cases (8/13), the inhibitory response was accompanied by initial facilitation. The observations that Vi contained a population of neurons that receive small diameter muscle afferent inputs, responded to noxious mechanical stimulation on the muscle and to a chemical irritant that is known to produce pain in humans provide compelling evidence for the involvement of Vi in craniofacial muscle pain mechanisms.

The tension headache, migraine headache continuum: a hypothesis.

There is evidence in the literature that tension-type and migraine headaches do not exist as discrete pathophysiologic entities but form a continuum. The mechanisms for tension and migraine headaches are discussed and the evidence for this continuum, both basic scientific and clinical, is reviewed. A model for chronic headaches based on this evidence and based on clinical observations by the author is presented. Clinical and research implications of this model and means of testing the model are discussed.