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Cluster headache, a primary headache disorder, consists of short (15-180 minutes), frequent (up to eight a day), unilateral attacks of facial pain with associated ipsilateral autonomic features and restlessness. The attacks are suspected to be one of the most painful human experiences, and the disorder is associated with a high rate of suicidal ideation. Proper diagnosis is key, as some of the most effective treatments, such as high flow oxygen gas, are rarely used in other headache disorders. Yet diagnostic delay is typically years for this disorder, as it is often confused with migraine and trigeminal neuralgia, and secondary causes may be overlooked. This review covers the clinical, pathophysiologic, and therapeutic features of cluster headache. Recent updates in diagnosis include the redefinition of chronic cluster headache (remission periods lasting less than three months instead of the previous one month), and recent advances in management include new treatments for episodic cluster headache (galcanezumab and non-invasive vagus nerve stimulation).
Learn More >Migraine is characterized by an increased sensitivity to visual stimuli that worsens during attacks. Recent evidence has shown that feedforward volleys carrying incoming visual information induce high frequency (gamma) oscillations in the visual cortex, while feedback volleys arriving from higher order brain areas induce oscillatory activity at lower frequencies (theta/alpha/low-beta). We investigated visually induced high (feedforward) and low (feedback) frequency activations in healthy subjects and various migraine patients. Visual evoked potentials from 20 healthy controls and 70 migraine patients (30 inter-ictal and 20 ictal episodic migraineurs, 20 chronic migraineurs) were analysed in the frequency domain. We compared power in the theta-alpha-low beta and gamma range between groups, and searched for correlations between the low-to-high frequency activity ratio and number of monthly headache and migraine days. Compared to healthy controls, inter-ictal migraine patients had increased visually induced low frequency (feedback) activity. Conversely, ictal and chronic migraine patients showed an augmented gamma band (feedforward) power. The low-frequency-to-gamma (feedback/feedforward) activity ratio correlated negatively with monthly headache days and tended to do so with migraine days. Our findings show that visual processing is differentially altered depending on migraine cycle and type. Feedback control from higher order cortical areas predominates interictally in episodic migraine while migraine attacks and chronic migraine are associated with enhanced incoming afferent activity, confirming their similar electrophysiological profile. The presence of headache is associated with proportionally higher gamma (feedforward) activities. Perspective: This study provides an insight into the pathophysiology of migraine headache from the perspective of cortical sensory processing dynamics. Patients with migraine present alterations in feedback and feedforward visual signalling that differ with the presence of headache.
Learn More >Cortical spreading depression (CSD) is a wave of transient network hyperexcitability leading to long lasting depolarization and block of firing, which initiates focally and slowly propagates in the cerebral cortex. It causes migraine aura and it has been implicated in the generation of migraine headache. Cortical excitability can be modulated by cholinergic actions, leading in neocortical slices to the generation of rhythmic synchronous activities (UP/DOWN states). We investigated the effect of cholinergic activation with the cholinomimetic agonist carbachol on CSD triggered with 130 mM KCl pulse injections in acute mouse neocortical brain slices, hypothesizing that the cholinergic-induced increase of cortical network excitability during UP states could facilitate CSD. We observed instead an inhibitory effect of cholinergic activation on both initiation and propagation of CSD, through the action of muscarinic receptors. In fact, carbachol-induced CSD inhibition was blocked by atropine or by the preferential M1 muscarinic antagonist telenzepine; the preferential M1 muscarinic agonist McN-A-343 inhibited CSD similarly to carbachol, and its effect was blocked by telenzepine. Recordings of spontaneous excitatory and inhibitory post-synaptic currents in pyramidal neurons showed that McN-A-343 induced overall a decrease of the excitatory/inhibitory ratio. This inhibitory action may be targeted for novel pharmacological approaches in the treatment of migraine with muscarinic agonists.
Learn More >Inconsistent findings from migraine neuroimaging studies have limited attempts to localize migraine symptomatology. Novel brain network mapping techniques offer a new approach for linking neuroimaging findings to a common neuroanatomical substrate and localizing therapeutic targets. In this study, we attempted to determine whether neuroanatomically heterogeneous neuroimaging findings of migraine localize to a common brain network. We used meta-analytic coordinates of decreased grey matter volume in migraineurs as seed regions to generate resting state functional connectivity network maps from a normative connectome (n = 1000). Network maps were overlapped to identify common regions of connectivity across all coordinates. Specificity of our findings was evaluated using a whole-brain Bayesian spatial generalized linear mixed model and a region of interest analysis with comparison groups of chronic pain and a neurologic control (Alzheimer's disease). We found that all migraine coordinates (11/11, 100%) were negatively connected (t ≥ ±7, P < 10-6 family-wise error corrected for multiple comparisons) to a single location in left extrastriate visual cortex overlying dorsal V3 and V3A subregions. More than 90% of coordinates (10/11) were also positively connected with bilateral insula and negatively connected with the hypothalamus. Bayesian spatial generalized linear mixed model whole-brain analysis identified left V3/V3A as the area with the most specific connectivity to migraine coordinates compared to control coordinates (voxel-wise probability of ≥90%). Post hoc region of interest analyses further supported the specificity of this finding (ANOVA P = 0.02; pairwise t-tests P = 0.03 and P = 0.003, respectively). In conclusion, using coordinate-based network mapping, we show that regions of grey matter volume loss in migraineurs localize to a common brain network defined by connectivity to visual cortex V3/V3A, a region previously implicated in mechanisms of cortical spreading depression in migraine. Our findings help unify migraine neuroimaging literature and offer a migraine-specific target for neuromodulatory treatment.
Learn More >Most centrally-acting migraine preventive drugs suppress frequency and velocity of cortical spreading depression (CSD). The purpose of the current study was to determine how the new class of peripherally acting migraine preventive drug (i.e., the anti-CGRP-mAbs) affect CSD – an established animal model of migraine aura, which affects about 1/3 of people with migraine – when allowed to cross the blood brain barrier (BBB). Using standard electrocorticogram recording techniques and rats in which the BBB was intentionally compromised, we found that when the BBB was opened, the anti-CGRP-mAb fremanezumab did not prevent the induction, occurrence or propagation of a single wave of CSD induced by a pinprick, but that both fremanezumab and its isotype were capable of slowing down the propagation velocity of CSD and shortening the period of profound depression of spontaneous cortical activity that followed the spreading depolarization. Fremanezumab's inability to completely block the occurrence of CSD in animals in which the BBB was compromised suggests that CGRP may not be involved in the initiation of CSD, at least not to the extent that it can prevent its occurrence. Similarly, we cannot conclude that CGRP is involved in the propagation velocity or the neuronal silencing period (also called cortical recovery period) that follows the CSD because similar effects were observed when the isotype was used. These finding call for caution with interpretations of studies that claim to show direct CNS effects of anti-CGRP-mAbs.
Learn More >Migraine is a common neurological problem associated with the highest burden amongst neurological conditions in terms of years lived with disability. Medications can be used as prophylaxis or rescue medicines, but are costly and not always effective. A range of psychological interventions have been developed to manage migraine.
Learn More >Although TWIK-related spinal cord K (TRESK) channel is expressed in all primary afferent neurons in trigeminal ganglia (TG) and dorsal root ganglia (DRG), whether TRESK activity regulates trigeminal pain processing is still not established. Dominant-negative TRESK mutations are associated with migraine but not with other types of pain in humans, suggesting that genetic TRESK dysfunction preferentially affects the generation of trigeminal pain, especially headache. Using TRESK global knockout mice as a model system, we found that loss of TRESK in all TG neurons selectively increased the intrinsic excitability of small-diameter nociceptors, especially those that do not bind to isolectin B4 (IB4). Similarly, loss of TRESK resulted in hyper-excitation of the small IB4 dural afferent neurons but not those that bind to IB4 (IB4). Compared with wild-type littermates, both male and female TRESK knockout mice exhibited more robust trigeminal nociceptive behaviors, including headache-related behaviors; whereas their body and visceral pain responses were normal. Interestingly, neither the total persistent outward current nor the intrinsic excitability was altered in adult TRESK knockout DRG neurons, which may explain why genetic TRESK dysfunction is not associated with body and/or visceral pain in humans. We reveal for the first time that, among all primary afferent neurons, TG nociceptors are the most vulnerable to the genetic loss of TRESK. Our findings indicate that endogenous TRESK activity regulates trigeminal nociception, likely through controlling the intrinsic excitability of TG nociceptors. Importantly, we provide evidence that genetic loss of TRESK significantly increases the likelihood of developing headache. TRESK K channel is expressed in all primary afferent neurons in trigeminal ganglia (TG) and dorsal root ganglia (DRG), but dominant-negative TRESK mutations are only associated with migraine but not with other types of pain in humans. In TRESK global knockout mice, we found that ubiquitous loss of TRESK selectively increased the intrinsic excitability of small-diameter TG nociceptors without affecting DRG neuronal excitability. Compared with wild-type littermates, TRESK knockout mice exhibited more robust trigeminal pain, especially headache-related behaviors; whereas their body and visceral pain responses were normal. This recapitulates the clinical manifestations of human TRESK mutations. Our results indicate that endogenous TRESK activity regulates trigeminal nociception, and genetic loss of TRESK significantly increases the likelihood of developing headache.
Learn More >To review the new drug class of calcitonin gene-related peptide antagonists (monoclonal antibodies) and their clinical relevance in migraine prophylaxis. A literature search was performed in PubMed (January 2009 to November 2019) using the terms (CGRP), , and for clinical trials and studies. Reports from human studies in English were evaluated for clinical evidence supporting pharmacology, efficacy, and adverse events. Initial pharmacokinetic and preclinical studies were excluded. In chronic and episodic migraine, prophylaxis with injections of monoclonal antibodies antagonizing CGRP reduced monthly migraine days with minimal clinically significant adverse events. In addition, there is evidence supporting efficacy in refractory migraine despite optimal prophylaxis. This is the first target-specific migraine prophylaxis treatment to show efficacy with minimal adverse effects. A higher drug cost is a barrier but is balanced by improved quality of life. Current therapies have limited efficacy and tolerability because of poor side effect profiles. CGRP antagonists represent a shift to more precise migraine treatments. Monoclonal antibodies inhibiting CGRP are effective in migraine prophylaxis with minimal adverse effects. Targeting CGRP is a novel clinical strategy in managing migraine.
Learn More >Previous attempts to develop a pragmatic human model for testing new anti-migraine drugs, have failed. Calcitonin gene-related peptide (CGRP) induces a mild headache in healthy volunteers and migraine-like headache in migraine patients. The induced headache must respond to already established migraine treatment for validation. Thus, the objective of the study was to test the effect of sumatriptan against CGRP-induced symptoms in an attempt to validate CGRP-induced headache as a model for drug testing.
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