Functional connectivity of hypothalamus in chronic migraine with medication overuse.

OBJECTIVE: To investigate the functional connectivity of the hypothalamus in chronic migraine compared to interictal episodic migraine in order to improve our understanding of migraine chronification. METHODS: Using task-free fMRI and ROI-to-ROI analysis, we compared anterior hypothalamus intrinsic connectivity with the spinal trigeminal nucleus in patients with chronic migraine (n = 25) to age- and sex-matched patients with episodic migraine in the interictal phase (n = 22). We also conducted a seed-to-voxel analysis with anterior hypothalamus as a seed. RESULTS: All patients with chronic migraine had medication overuse. We found a significant connectivity (T = 2.08, p = 0.024) between anterior hypothalamus and spinal trigeminal nucleus in the chronic group, whereas these two regions were not connected in the episodic group. The strength of connectivity was not correlated with pain intensity (rho: 0.09, p = 0.655). In the seed-to-voxel analysis, three regions were more connected with the anterior hypothalamus in the chronic group: The spinal trigeminal nuclei (MNI coordinate x = 2, y = -44, z = -62), the right dorsal anterior insula (MNI coordinate x = 10, y = 10, z = 18), and the right caudate (MNI coordinate x = 12, y = 28, z = 6). However, these correlations were no longer significant after whole brain FWE correction. CONCLUSION: An increased functional connectivity between the anterior hypothalamus and the spinal trigeminal nucleus, as previously reported in preictal episodic migraine, was demonstrated in chronic migraine with medication overuse. This finding confirms a major role of the anterior hypothalamus in migraine and suggests that chronic migraineurs are locked in the preictal phase.

Blockade of 5-HT3 receptors with granisetron does not affect trigeminothalamic nociceptive transmission in rats: Implication for migraine.

One way to expand the existing range of anti-migraine drugs seems to be the search for pharmacological agents with anti-cephalalgic properties among medicines approved for clinical indications other than migraine. Numerous experimental and clinical data imply that selective serotonin 5-HT3 receptor antagonists can be considered as potential anti-migraine agents. Therefore, the objective of our work was to examine the impact of selective 5-HT3 receptor blockade with granisetron on migraine-related nociceptive transmission within the spinal trigeminal nucleus (STN) and the ventroposteromedial nucleus of the thalamus (VPM). Using an electrophysiological model of trigemino-durovascular nociception in anaesthetised male Wistar rats, we evaluated the effects of intravenous administration of granisetron on ongoing firing and dural electrical stimulation-evoked responses of the spinal trigeminal and thalamic cells. Granisetron did not substantially affect responses of the STN and VPM neurons to electrical stimulation of the dura mater as well as did not cause steady changes in ongoing firing of the spinal trigeminal cells. The results obtained argue against the use of 5-HT3 receptor antagonists for treating migraine. These data also lead to the conclusion that in the absence of sustained sensitisation of neurons along the trigemino-thalamo-cortical pathway the role of 5-HT3 receptor-dependent mechanisms in serotonergic modulation of trigeminovascular nociceptive transmission can hardly be considered crucial.

Inhibitory effect of high-frequency greater occipital nerve electrical stimulation on trigeminovascular nociceptive processing in rats.

Electrical stimulation of the greater occipital nerve (GON) has recently shown promise as an effective non-pharmacological prophylactic therapy for drug-resistant chronic primary headaches, but the neurobiological mechanisms underlying its anticephalgic action are not elucidated. Considering that the spinal trigeminal nucleus (STN) is a key segmental structure playing a prominent role in pathophysiology of headaches, in the present study we evaluated the effects of GON electrical stimulation on ongoing and evoked firing of the dura-sensitive STN neurons. The experiments were carried out on urethane/chloralose-anesthetized, paralyzed and artificially ventilated male Wistar rats. Extracellular recordings were made from 11 neurons within the caudal part of the STN that received convergent input from the ipsilateral facial cutaneous receptive fields, dura mater and GON. In each experiment, five various combinations of the GON stimulation frequency (50, 75, 100 Hz) and intensity (1, 3, 6 V) were tested successively in 10 min interval. At all parameter sets, preconditioning GON stimulation (250 ms train of pulses applied before each recording) produced suppression of both the ongoing activity of the STN neurons and their responses to electrical stimulation of the dura mater. The inhibitory effect depended mostly on the GON stimulation intensity, being maximally pronounced when a stimulus of 6 V was applied. Thus, the GON stimulation-induced inhibition of trigeminovascular nociceptive processing at the level of STN has been demonstrated for the first time. The data obtained can contribute to a deeper understanding of neurophysiological mechanisms underlying the therapeutic efficacy of GON stimulation in primary headaches.

The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks.

Functional imaging using positron emission tomography and later functional magnetic resonance imaging revealed a particular brainstem area that is believed to be specifically activated in migraine during, but not outside of the attack, and consequently has been coined the 'migraine generator'. However, the pathophysiological concept behind this term is not undisputed and typical migraine premonitory symptoms such as fatigue and yawning, but also a typical association of attacks to circadian and menstrual cycles, all make the hypothalamus a possible regulating region of migraine attacks. Neuroimaging studies investigating native human migraine attacks however are scarce and for methodological but also clinical reasons there are currently no studies investigating the last 24 h before headache onset. Here we report a migraine patient who had magnetic resonance imaging every day for 30 days, always in the morning, to cover, using functional imaging, a whole month and three complete, untreated migraine attacks. We found that hypothalamic activity as a response to trigeminal nociceptive stimulation is altered during the 24 h prior to pain onset, i.e. increases towards the next migraine attack. More importantly, the hypothalamus shows altered functional coupling with the spinal trigeminal nuclei and the region of the migraine generator, i.e. the dorsal rostral pons during the preictal day and the pain phase of native human migraine attacks. These data suggest that although the brainstem is highly linked to the migraine biology, the real driver of attacks might be the functional changes in hypothalamo-brainstem connectivity.

A trigeminoreticular pathway: implications in pain.

Neurons in the caudalmost ventrolateral medulla (cmVLM) respond to noxious stimulation. We previously have shown most efferent projections from this locus project to areas implicated either in the processing or modulation of pain. Here we show the cmVLM of the rat receives projections from superficial laminae of the medullary dorsal horn (MDH) and has neurons activated with capsaicin injections into the temporalis muscle. Injections of either biotinylated dextran amine (BDA) into the MDH or fluorogold (FG)/fluorescent microbeads into the cmVLM showed projections from lamina I and II of the MDH to the cmVLM. Morphometric analysis showed the retrogradely-labeled neurons were small (area 88.7 µm(2)±3.4) and mostly fusiform in shape. Injections (20-50 µl) of 0.5% capsaicin into the temporalis muscle and subsequent immunohistochemistry for c-Fos showed nuclei labeled in the dorsomedial trigeminocervical complex (TCC), the cmVLM, the lateral medulla, and the internal lateral subnucleus of the parabrachial complex (PBil). Additional labeling with c-Fos was seen in the subnucleus interpolaris of the spinal trigeminal nucleus, the rostral ventrolateral medulla, the superior salivatory nucleus, the rostral ventromedial medulla, and the A1, A5, A7 and subcoeruleus catecholamine areas. Injections of FG into the PBil produced robust label in the lateral medulla and cmVLM while injections of BDA into the lateral medulla showed projections to the PBil. Immunohistochemical experiments to antibodies against substance P, the substance P receptor (NK1), calcitonin gene regulating peptide, leucine enkephalin, VRL1 (TPRV2) receptors and neuropeptide Y showed that these peptides/receptors densely stained the cmVLM. We suggest the MDH- cmVLM projection is important for pain from head and neck areas. We offer a potential new pathway for regulating deep pain via the neurons of the TCC, the cmVLM, the lateral medulla, and the PBil and propose these areas compose a trigeminoreticular pathway, possibly the trigeminal homologue of the spinoreticulothalamic pathway.

Cefalea en racimos ascendente: presentación de tres casos y revisión de la bibliografía / Ascending cluster headache: a description of three cases and a review of the literature

Introducción. Se sabe que la cefalea en racimos (CR) puede afectar a regiones extratrigeminales. En varios pacientes se ha descrito dolor occipital, incluso en el inicio de los ataques; sin embargo, las propuestas sobre variaciones topográficas de la CR sólo se han centrado, hasta el momento, en la distinción de localizaciones supra e infraorbitarias. Casos clínicos. Presentamos a tres pacientes que cumplían criterios diagnósticos de CR de la Clasificación Internacional de las Cefaleas, cuyos ataques se iniciaban con dolor leve o moderado en la región occipital. En los 10-30 minutos siguientes el dolor se desplazaba hacia delante de forma gradual, para instalarse finalmente en la región orbitaria. Una vez localizada en la región periocular, la cefalea adquiría características típicas de CR, con dolor intenso y síntomas autonómicos acompañantes. Conclusiones. La CR puede adoptar un patrón de progresión ascendente desde la región occipital. Es probable que este patrón clínico sea la expresión de ciertos mecanismos fisiopatológicos que implican al complejo trigémino-cervical. Estos mismos mecanismos podrían justificar la eficacia de determinados procedimientos terapéuticos en la CR, como el bloqueo del nervio occipital mayor o la neuroestimulación occipital (AU)

Introduction. It has been previously shown that cluster headache (CH) can involve some extratrigeminal areas. Occipital pain has been recognized in several patients, even as the origin of the attacks. Nevertheless, the proposals of topographic variations of CH have been mainly focused on the location of pain in either supraorbital or infraorbital regions. Case reports. We report three patients fulfilling International Classification of Headache Disorders criteria for CH whose attacks started with mild or moderate headache at the occipital region and gradually moved forward over 10 to 30 minutes, finally reaching the ipsilateral orbital area. There the pain acquired typical CH features, with severe intensity and ipsilateral autonomic accompaniments. Conclusions. These descriptions of ascending CH probably reflect pathophysiological mechanisms involving the trigeminocervical complex, and also offer theoretical support for some new therapeutic approaches such as great occipital nerve blockades or occipital neurostimulation (AU)

Attack-related brainstem activation in a patient with SUNCT syndrome: an ictal fMRI study.

The authors report functional magnetic resonance imaging (fMRI) study data of a 60-year-old patient having short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome. Three consecutive pain attacks were detected during the imaging session and strong brainstem activation was found. It was concluded that the brainstem can be involved in the pain signal transmission in SUNCT syndrome.

Massaging over the greater occipital nerve reduces the intensity of migraine attacks: evidence for inhibitory trigemino-cervical convergence mechanisms.

Activation of the trigemino-cervical system constitutes one of the first steps in the genesis of migraine. The objective of this study was to confirm the presence of trigemino-cervical convergence mechanisms and to establish whether such mechanisms may also be of inhibitory origin. We describe a case of a 39-years-old woman suffering from episodic migraine who showed a significant improvement in her frontal headache during migraine attacks if the greater occipital nerve territory was massaged after the appearance of static mechanical allodynia (cortical sensitization). We review trigemino-cervical convergence and diffuse nociceptive inhibitory control (DNIC) mechanisms and suggest that the convergence mechanisms are not only excitatory but also inhibitory.

Massaging over the greater occipital nerve reduces the intensity of migraine attacks: evidence for inhibitory trigemino-cervical convergence mechanisms

Activation of the trigemino-cervical system constitutes one of the first steps in the genesis of migraine. The objective of this study was to confirm the presence of trigemino-cervical convergence mechanisms and to establish whether such mechanisms may also be of inhibitory origin. We describe a case of a 39-years-old woman suffering from episodic migraine who showed a significant improvement in her frontal headache during migraine attacks if the greater occipital nerve territory was massaged after the appearance of static mechanical allodynia (cortical sensitization). We review trigemino-cervical convergence and diffuse nociceptive inhibitory control (DNIC) mechanisms and suggest that the convergence mechanisms are not only excitatory but also inhibitory.

Ativação do sistema trigemino-cervical constitui um dos primeiros passos na gênese da crise de migrânea. O objetivo do estudo foi descrever um caso clínico que sugere a existência de mecanismos de convergência trigemino-cervical (CTC) e que esses possam ser do tipo inibitórios. Nós descrevemos o caso de mulher de 39 anos com migrânea episódica que mostrou significante melhora em sua cefaléia frontal durante suas crises quando realizava massagem sobre o território do nervo occipital maior ipsilateral a dor. A melhora clínica só ocorria quando a paciente apresentava alodinia mecânica estática (sensibilização cortical). Neste estudo nós revisamos os conceitos de CTC e de mecanismos de controle inibitório nociceptivo difuso (MCIN), sugerindo que este último é um elemento comprobatório da presença de CTC do tipo inibitório durante as crises de migrânea.

Pain and the primate thalamus.

Noxious stimuli that are perceived as painful, are conveyed to the thalamus by the spinothalamic tract (STT) and the spinotrigeminothalamic tracts (vSTT), arising from the dorsal horn of the spinal cord and medulla, respectively. Most investigators have concluded that the thalamic terminus of these pathways include several nuclei of the somatosensory and intralaminar thalamus. Non-noxious stimuli are carried by the dorsal column/medial lemniscal or the trigeminothalamic pathways which terminate in much more restricted regions of the thalamus than do the STT and vSTT systems. Lesions of components of the somatosensory pathways result in profound changes in the circuitry of the recipient thalamic nuclei. Not only are there the expected losses of the injured axons and their synaptic terminations, but there is also a marked reduction of the intrinsic GABAergic circuitry, even though the GABAergic neurons contributing to the circuitry have not been injured directly by lesions of the afferent pathways. Such changes in the inhibitory circuitry observed in experimental animals may explain the abnormal bursting behavior of thalamic neurons found in patients with central deafferentation pain syndromes. One potential approach to treating chronic pain would be to selectively remove the neurons of the superficial dorsal horn (lamina I) that specifically respond to noxious stimuli (NS neurons). A toxin has been developed (SSP saporin) that binds to the substance P receptor of NS neurons, is internalized by the neuron and kills the cell. SSP saporin has been shown to be effective in rats, and we have recently demonstrated that it effectively causes lesions in NS neurons of the lumbar spinal cord in the monkey and reduces the animals' response to noxious cutaneous stimuli. The SSP-saporin administration to the lumbar spinal cord destroys a relatively small number of the total neurons that project into the somatosensory thalamus and does not lead to demonstrable changes in the inhibitory circuitry of the thalamus, in contrast to lesions of major pathways that lead to reductions in the thalamic inhibitory circuitry.

[Neurobiology of trigeminal pain]. / Neurobiologie de la douleur trigéminale.

The brainstem trigeminal complex integrates somatosensory inputs from orofacial areas and meninges. Recent studies have shown the existence of a double representation of pain within the brainstem, at the level of both caudalis and oralis subnuclei. Noxious messages are mainly conveyed by C-fibers that activate the subnucleus caudalis neurons. These neurons in turn activate the subnucleus oralis whose neurons share similar features with the deep spinal dorsal horn neurons. In contrast with the nearness of the laminar organization of the dorsal horn, the vertical organization of the trigeminal complex offers an easier access for the study of segmental mechanisms of nociceptive processing. This model allowed us to show the existence of subtle NMDA-related mechanisms of segmental nocious processing. The trigeminal complex conveys nociceptive messages to several brainstem and thalamic relays that activate a number of cortical areas responsible for pain sensations and reactions. Cortical processing is sustained by reciprocal interactions with thalamic areas and also by a direct modulation of their pre-thalamic relays. The dysfunction of these multiple modulatory mechanisms probably plays a key role in the pathophysiology of chronic trigeminal pain.

Sex differences in brainstem neural activation after injury to the TMJ region.

The basis for a higher prevalence of painful temporomandibular disorders (TMD) among women than men is not known. The present study used Fos-like immunoreactivity (Fos-LI) to quantify the pattern and magnitude of neural activation within the trigeminal brainstem complex of male and female rats caused by acute inflammatory injury to the temporomandibular joint (TMJ) region. Also, Fos-LI was assessed in animals given morphine, a preferential mu opioid receptor agonist, or U50,488H, a selective kappa opioid agonist, prior to TMJ injury to determine if opioid modulation of neural activation was similar in males and females. The general pattern of Fos-LI after TMJ injury was similar in males and females. This pattern was characterized by a high density of Fos-positive neurons in the dorsal paratrigeminal nucleus (dPa5), subnucleus interpolaris/caudalis transition region (Vi/Vc-vl), and in the superficial laminae at the subnucleus caudalis/upper cervical spinal cord (Vc/C2) junction ipsilateral to TMJ injury. In contrast to other regions the number of Fos-positive neurons produced at the Vc/C2 junction was proportional to the concentration of mustard oil injected into the TMJ region. In addition, proestrus females produced higher levels of Fos-LI at the Vc/C2 junction than diestrus females or males. Morphine caused a greater dose-related reduction in Fos-LI at the dPa5 and Vc/C2 junction in males than females. By contrast, U50,488H caused a dose-related reduction in Fos-LI only at the Vc/C2 junction of proestrus females. These results support the hypothesis that the Vc/C2 junction region plays a critical role in the integration of pain signals originating from the TMJ region and may underlie sex differences in sensory processing related to TMJ pain.

Spino (trigemino) parabrachiohypothalamic pathway: electrophysiological evidence for an involvement in pain processes.

1. Parabrachiohypothalamic (PB-H) neurons (n = 71) were recorded with extracellular micropipettes in the parabrachial (PB) area and were antidromically driven from the ventromedial nucleus (VMH) or the retrochiasmatic area (RCh) of the hypothalamus, in the anesthetized rat. The spontaneous activity of these neurons was very low, (10th percentile < median frequency < 90th percentile were 0.01 < 0.2 < 7 Hz). The axons of these neurons exhibited a very slow conduction velocity in the range of 0.2-1.4 m/s, i.e., corresponding to thin unmyelinated fibers. 2. Most PB-H neurons (89%) were located in the mesencephalic division of the PB area (mPB) mainly in the superior lateral (mPBsl) and external lateral (mPBel) subnuclei. 3. These units were separated in three groups: 1) a group of nociceptive-specific (NS) neurons (49%) activated by mechanical and/or thermal (heat) cutaneous stimuli only in noxious range; 2) a group of inhibited neurons (7%), not activated by any of the mechanical or thermal cutaneous stimuli but inhibited, by at least one of these stimuli, which had to be in noxious range; and 3) a group of nonresponsive neurons (44%). 4. The NS neurons responded exclusively to mechanical (pinch or squeeze) and/or thermal (waterbath or waterjet > 44 degrees C) noxious stimuli with a rapid onset, a marked and sustained activation, and generally no afterdischarge. The magnitude of the responses was between 2 and 30 Hz with a mean value of 14.8 +/- 1.4 Hz (mean +/- SE, n = 49). These neurons exhibited a clear capacity to encode thermal stimuli in the noxious range: 1) the stimulus-response function was always positive and monotonic; 2) the slope of the mean curve increased up to a maximum (between 46 and 50 degrees C) then beyond the slope decreased; and 3) the mean threshold was 44.3 +/- 2.2 degrees C. 5. The excitatory receptive fields of the NS neurons were often large including all (22% of the population) or several (67% of the population) parts of the body. In the few remaining cases (11%) they were restricted to one part of the body. In addition, in several cases, noxious stimuli applied outside the excitatory receptive field were found to strongly inhibit the discharge of NS neurons. 6. Most NS neurons responded to intense transcutaneous electrical stimulation with two peaks of activation.(ABSTRACT TRUNCATED AT 400 WORDS)

An experimental model of deafferented pain in the cat.

Deafferentation hyperactivity, produced unilaterally in the neurons of the subnucleus caudalis of the spinal trigeminal nucleus (STNcd) in cats by left Gasserian ganglionectomy, was studied neurochemically and electrophysiologically. Analysis of neuronal activities on both sides of the STNcd was done 11-63 days after the denervation. On the denervated side, 37 (57%) of the 65 neurons identified showed deafferentation hyperactivity. Continuous and spontaneous firing of these hyperactive neurons were inhibited neither by the intraventricular administration of morphine or enkephalinamide nor by the electrical stimulation of periaqueductal gray. In contrast, the facilitation of the pain perceptive neuronal activities in the STNcd of the nondenervated side was remarkably inhibited, both by the administration of the same drugs and by periaqueductal gray stimulation. The deafferentation hyperactivity produced in this experiment in the STNcd of the denervated side might have a close physiological relationship to the deafferented pain of clinical patients.

Diffuse noxious inhibitory controls (DNIC): evidence for post-synaptic inhibition of trigeminal nucleus caudalis convergent neurones.

Activity produced by direct microelectrophoretic application of glutamate onto 19 convergent neurones in trigeminal nucleus caudalis, was strongly depressed during and after the application of heterotopic noxious conditioning stimuli: noxious heat (52 degrees C) applied to the tail, noxious pinches applied to the tail or hindpaws and intraperitoneal injections of bradykinin produced mean reductions in activity of 80-90%. The same noxious conditioning stimuli had no effect on the activities of any of 5 noxious-only or 5-non-noxious-only neurones. These effects were similar to those previously reported to influence peripherally evoked activities of nucleus caudalis convergent neurones and which have been termed diffuse noxious inhibitory controls (DNIC). It is therefore proposed that DNIC act on nucleus caudalis convergent neurones by a final post-synaptic inhibitory mechanism involving hyperpolarization of the neuronal membrane. Consistent with this hypothesis, it was also found that the noxious conditioning stimuli could restore firing of convergent neurones which had been excessively depolarised by large doses of glutamate.