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Higher burden of rare frameshift indels in genes related to synaptic transmission separate familial hemiplegic migraine from common types of migraine.

Familial hemiplegic migraine (FHM) is a rare form of migraine with aura that often has an autosomal dominant mode of inheritance. Rare mutations in the , and genes can all cause FHM revealing genetic heterogeneity in the disorder. Furthermore, only a small subset of the affected individuals has a causal mutation. We set out to investigate what differentiates patients with FHM with no mutation in any known FHM gene from patients with common types of migraine in both familial and sporadic cases.

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Use of Amitriptyline in the Treatment of Headache After Traumatic Brain Injury: Lessons Learned From a Clinical Trial.

The primary outcome of this study was to assess the efficacy and safety of preventive treatment with amitriptyline on headache frequency and severity after mild traumatic brain injury (mTBI).

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Long-Term Safety Evaluation of Ubrogepant for the Acute Treatment of Migraine: Phase 3, Randomized, 52-Week Extension Trial.

To evaluate the long-term safety and tolerability of ubrogepant for the acute treatment of migraine.

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Validation of the Temporomandibular Disorder Pain Screener in a Specialized Headache Center.

To investigate the sensitivity and specificity of the TMD pain screener in a headache population.

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Atypical functional connectivity between the anterior cingulate cortex and other brain regions in a Rat Model of Recurrent Headache.

We explored the atypical functional connectivity (FC) between the anterior cingulate cortex (ACC) and other brain areas in rats subjected to repeated meningeal nociception. The rat model was established by infusing an inflammatory soup (IS) through supradural catheters in conscious rats. Rats were subdivided according to the frequency of the IS infusions. FC analysis seeded on the ACC was performed on rats 21 days after IS infusion. Glyceryl trinitrate was injected following baseline scanning in the low-frequency IS (LF-IS) group and magnetic resonance imaging (MRI) data were acquired 1 hour after the injection. The rats exhibited nociceptive behavior after high-frequency IS (HF-IS) infusion. The ACC showed increased FC with the cerebellum in the IS groups. The medulla showed increased FC with the ACC in the ictal period in the LF-IS rats. Several areas showed increased FC with the ACC in the HF-IS group, including the pontine tegmentum, midbrain, thalamus, corpus callosum, hippocampus, and retrosplenial, visual, sensory, and motor cortices. This study indicated that the medulla participates in the early stage of a migraine attack and may be associated with the initiation of migraine. Sensitization of the trigeminal nociceptive pathway might contribute to the cutaneous allodynia seen in chronic migraine. Brain areas important for memory function may be related to the chronification of migraine. Electrophysiological studies should examine those migraine-related areas and provide new targets for migraine treatment and prevention.

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Primary Headaches and Sleep Disturbances: A Cause or a Consequence?

To evaluate the possible relationship between sleep disturbances and primary headaches.

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Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of Migraine: The ACHIEVE II Randomized Clinical Trial.

Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist under investigation for acute treatment of migraine.

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Lasmiditan inhibits calcitonin gene-related peptide release in the rodent trigeminovascular system.

Migraine headache pathophysiology involves trigeminovascular system activation, calcitonin gene-related peptide (CGRP) release and dysfunctional nociceptive transmission. Triptans are 5-HT1B/1D/(1F) receptor agonists that prejunctionally inhibit trigeminal CGRP release, but their vasoconstrictor properties limit their use in migraine patients with cardiovascular disease. In contrast, lasmiditan is a novel antimigraine and selective 5-HT1F receptor agonist devoid of vasoconstrictor properties. On this basis, the present study has investigated the modulation of trigeminal CGRP release by lasmiditan.For this purpose, we have comparatively analysed the inhibition of several components of the trigeminovascular system induced by lasmiditan and sumatriptan through: ex vivo KCl-induced CGRP release from isolated dura mater, trigeminal ganglion and trigeminal nucleus caudalis of mice; and in vivo dural vasodilation in the rat closed-cranial window model induced by endogenous (electrical stimulation, capsaicin) and exogenous CGRP.The ex vivo release of CGRP was similarly inhibited by sumatriptan and lasmiditan in all trigeminovascular system components. In vivo, i.v. lasmiditan or higher doses of sumatriptan significantly attenuated the vasodilatory responses to endogenous CGRP release, but not exogenous CGRP effects. These data suggest that lasmiditan prejunctionally inhibits CGRP release in peripheral and central trigeminal nerve terminals. Since lasmiditan is a lipophilic drug that crosses the blood-brain barrier, additional central sites of action remain to be determined.

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Issues Impacting Adverse Event Frequency and Severity: Differences Between Randomized Phase 2 and Phase 3 Clinical Trials for Lasmiditan.

We explore factors that may have contributed to differences in treatment-emergent adverse events in the phase 2 and phase 3 lasmiditan clinical trials.

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Remote Electrical Neuromodulation (REN) for the Acute Treatment of Migraine.

There is a significant unmet need for novel, effective, and well-tolerated acute migraine treatments. Remote electrical neuromodulation (REN) is a non-pharmacological, non-invasive, acute migraine treatment that stimulates upper arm peripheral nerves to induce conditioned pain modulation – an endogenous analgesic mechanism in which a conditioning stimulation inhibits pain in remote body regions. This review presents the method of action and the clinical data of REN and discusses its potential patient benefits. The clinically meaningful efficacy, together with a very favorable safety profile, suggests that REN may offer a promising alternative for the acute treatment of migraine and could be considered first-line treatment in some patients.

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