See De Icco and Tassorelli (doi:) for a scientific commentary on this article.There are limited experimental approaches to study cranial allodynia in migraine. Akerman et al. report that nitroglycerine triggers cranial allodynia alongside migraine-like headache in patients, and dural-intracranial trigeminal neuronal hypersensitivity in rats, with both responding to abortive treatments. Using nitroglycerine thus represents a reliable translational approach to study allodynia in migraine.

Background Studying a spontaneous migraine attack is challenging, particularly the earliest components. Nitroglycerin is a potent, reliable and reproducible migraine trigger of the entirety of the migraine attack, making its use experimentally attractive. Methods Fifty-three subjects with migraine with a history of spontaneous premonitory symptoms were exposed to a 0.5 mcg/kg/min nitroglycerin infusion. Eighty-three percent (n = 44) developed typical premonitory and headache symptomatology. Fifty-seven percent (n = 25) were invited back to further study visits, during which they were re-exposed to nitroglycerin or placebo infusion in a double-blind randomised design. The phenotype of premonitory symptoms and headache was captured and compared to spontaneous attacks and between triggered attacks using agreement analysis. Results More premonitory symptoms were triggered with nitroglycerin than placebo (mean symptom difference = 4, t20 = 7.06, p < 0.001). The agreement in triggering for the most commonly reported premonitory symptoms (concentration difficulty and tiredness) was >66%. The retriggering agreement for all but one premonitory symptom was >60%. The agreement in timing to onset of premonitory symptoms was reliable across two triggered attacks. The agreement with spontaneous attacks and between attacks for headache and its associated symptoms, including laterality, was less reliable. Conclusions Nitroglycerin can reliably and reproducibly provoke premonitory symptomatology associated with migraine. This forms an ideal model to study the earliest manifestations of migraine attacks.

Objective.-To understand the changes in functional connectivity between brain areas of potential importance in migraine during different phases of the attack. Background.-Migraine is a symptomatically heterogeneous disorder. Understanding the possible changes in brain function and, therefore, neurobiology during different phases of the migraine attack is important in developing disease biomarkers and advancing therapeutics. Design.-Randomized, double-blind, placebo-controlled, multi-visit experimental study. Methods.-Subjects aged 18-50 years with migraine with and without aura (≤22 headache days per month) were recruited from across the UK using advertising, from both population and hospital clinic samples (n = 53). Consented subjects were randomized to a 0.5 µg/kg/min nitroglycerin infusion or to placebo over 20 minutes across different study visits, during the period February 2015-July 2017.* All subjects were exposed to a nitroglycerin infusion at least on 1 occasion at screening.** For those subjects who consented to participate in imaging visits (n = 25), structural T1, T2 and FLAIR sequences and resting state blood oxygen level dependant contrast (rsBOLD) time series, using a multiecho EPI sequence, were conducted over 30-40 minutes at baseline and rsBOLD during premonitory symptoms and migraine headache on a 3T General Electric MR750 MRI scanner. For the placebo visit, the imaging was conducted at the same times following infusion in the absence of symptoms. Results.-Montreal Neurological Institute (MNI) coordinates were used to characterize identified brain areas of connectivity change. Using repeated measures ANOVA models with time (visit number) and trigger substance (nitroglycerin/placebo) as factors, significant positive functional coupling was found between the thalami bilaterally and the right precuneus and cuneus regions during the nitroglycerin-triggered premonitory phase (T = 3.23, peak connectivity change at [−6, −68, 40] for left thalamus, P = 0.012 and [−4, −68, 40] for right thalamus, P = 0.019). The nitroglycerin-triggered premonitory phase was associated with a change in the direction of connectivity from positive to negative between the pons and the limbic lobe (T = 3.47, peak connectivity change at [2, 8, 50], P < 0.001). The headache phase of the nitroglycerin-triggered migraine attack was associated with ongoing negative functional coupling between the pons and the cingulate and frontal cortices, and positive functional coupling between the pons and the cerebellar tonsils and medulla (T = 3.47, peak connectivity change at [−8, −52, −58], P = 0.007).

This article focuses on the prevalence, phenotype, and proposed neurobiology of premonitory symptomatology in migraineurs as well as the scope of future research.

Background Non-painful symptoms in migraine following headache resolution can last up to days. Studying the postdrome is important to appreciate the morbidity associated with migraine. Methods Fifty-three subjects ( n = 53) with migraine were studied in an experimental setting, collecting historical phenotypic information on the postdrome in their spontaneous attacks, and also associated with nitroglycerin-triggered attacks, while being observed prospectively. In a separate headache clinic-based cohort of migraineurs ( n = 42), who were age and sex-matched to the experimental group, the same phenotypic data were extracted from their clinic records. Spontaneous and nitroglycerin-triggered attack phenotypes, and experimental and clinical cohort phenotypes were compared using agreement analysis. Results In the experimental group, 100% had a postdrome with their triggered attack, while 98% reported a postdrome in their spontaneous attacks. In the clinical group, 79% had reported a postdrome. In the experimental group, there was good agreement between spontaneous and nitroglycerin-triggered tiredness, hunger, mood change, sensory sensitivities and vertigo and with similarity in premonitory and postdrome phenotypes experienced in the same individual. Conclusions The migraine postdrome is common and symptomatically similar to the premonitory phase. The nitroglycerin model and migraine abortive agents can be used to study the postdrome experimentally. Systematic questioning of symptoms, as well as collateral histories from direct observers of migraine attacks, are likely to enhance symptomatic capture of the migraine postdrome, and aid understanding of attack mediation, abortion and neurobiology.

Objective To study the agreement between self-reported trigger factors and early premonitory symptoms amongst a group of migraineurs in both spontaneous and pharmacologically provoked attacks. Methods Fifty-three subjects with migraine with and without aura, with ≤ 22 headache days/month, with spontaneous premonitory symptoms associated with migraine attacks were recruited nationally. A detailed history was taken by a study investigator to confirm diagnosis and extended phenotyping was performed to identify patient-reported triggers for migraine attacks, premonitory symptom phenotype and headache characteristics, using a standardised physician-administered questionnaire. The same subjects were exposed to a 0.5 mcg/kg/min nitroglycerin infusion over 20 min, to determine if similar migraine symptoms could be triggered. The triggered attacks were phenotyped in the same way as spontaneous ones. Percentage agreement and Cohen’s kappa measure of agreement were used to identify concordance between patient-reported triggers and the corresponding spontaneous and triggered premonitory symptoms. Percentage agreement of > 60% and/or a kappa value > 0.3 with P < 0.05 were considered significant. Results There was statistically significant agreement between perception of light as a migraine trigger and spontaneous premonitory photophobia; perception of sound as a trigger and triggered premonitory phonophobia; skipping meals as a trigger and spontaneous premonitory food cravings; and food triggers and spontaneous premonitory food cravings. There was good agreement between stress and premonitory triggered mood change. Conclusions At least some patient-reported triggers, such as light, sound, foods and skipping meals, may represent early brain manifestations of the premonitory phase of the migraine attack.

The disability related to migraine is not limited to the headache phase and pans out to include the postdrome phase. The migraine postdrome needs to be studied more as this may improve our overall understanding of migraine mechanisms and also treat the concurrent symptoms better.

Cranial hypersensitivity is a prominent symptom of migraine, exhibited as migraine headache exacerbated with physical activity, and cutaneous facial allodynia and hyperalgesia. The underlying mechanism is believed to be, in part, activation and sensitization of dural-responsive trigeminocervical neurons. Validated preclinical models that exhibit this phenotype have great utility for understanding putative mechanisms and as a tool to screen therapeutics. We have previously shown that nitroglycerin triggers cranial allodynia in association with migraine-like headache, and this translates to neuronal cranial hypersensitivity in rats. Furthermore, responses in both humans and rats are aborted by triptan administration, similar to responses in spontaneous migraine. Here, our objective was to study the nitroglycerin model examining the effects on therapeutic targets with newly approved treatments, specifically gepants and ditans, for the acute treatment of migraine. Using electrophysiological methods, we determined changes to ongoing firing and somatosensory-evoked cranial sensitivity, in response to nitroglycerin, followed by treatment with a calcitonin gene-related peptide receptor antagonist, gepant (olcegepant), a 5-HT1F receptor agonist, ditan (LY344864), and an NK1 receptor antagonist (GR205171). Nitroglycerin induced activation of migraine-like central trigeminocervical neurons, and intracranial and extracranial neuronal hypersensitivity. These responses were aborted by olcegepant and LY344864. However, GR205171, which failed in clinical trial for both abortive and preventive treatment of migraine, had no effect. These data support the nitroglycerin model as a valid approach to study cranial hypersensitivity and putative mechanisms involved in migraine and as a screen to dissect potentially efficacious migraine therapeutic targets.