Migraine is a common neurological disorder with a diverse clinical phenotype that comprises more than just head pain. Premonitory (prodromal) symptoms can start hours to days before the onset of a migraine headache and can predict its onset in some individuals. Such symptomatology can include lethargy , yawning, light and sound sensitivity , thirst and cravings. This earliest phase of the migraine attack provides valuable insights into the neurobiology of the disorder, furthering our understanding of how and why these phenotypically heterogeneous symptoms are mediated. Improvements in our understanding of migraine could provide novel therapeutic opportunities, with the possibility of closing the therapeutic gap that remains owing to a lack of sufficiently effective and well-tolerated acute and preventive treatments. Improved understanding of disease mechanisms and potential therapeutic targets through benchto-bedside research into the premonitory phase is an exciting and emerging means of achieving this aim going forward. In this Review , we discuss the current evidence in the literature in relation to the phenotype and mediation of premonitory symptoms in migraine, and discuss the neurobiological insights gained from these studies.

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.

The observations here identify an entirely novel treatment strategy for migraine.

BackgroundThe premonitory stage of migraine attacks, when symptomatology outside of pain can manifest hours to days before the onset of the headache, is well recognised. Such symptoms have been reported in adults in a number of studies, and have value in predicting an impending headache. These symptoms have not been extensively studied in children. We aimed to characterise which, if any, of these symptoms are reported in children seen within a Specialist Headache Service.MethodsWe reviewed clinic letters from the initial consultation of children and adolescents seen within the Specialist Headache Service at Great Ormond Street Hospital between 1999 and 2015 with migraine in whom we had prospectively assessed clinical phenotype data. We randomly selected 100 cases with at least one premonitory symptom recorded in the letter. For these patients, the age at headache onset, presence of family history of headache, headache diagnosis, presence of episodic syndromes which may be associated with headache, developmental milestones, gestation at birth, mode of delivery and presence of premonitory symptoms occurring before or during headache were recorded.ResultsOf the 100 patients selected, 65 % were female. The age range of the patients was 18 months to 15 years at the time of headache onset. The most common diagnosis was chronic migraine in 58 %, followed by episodic migraine (29 %), New Daily Persistent Headache with migrainous features (8 %) and hemiplegic migraine (5 %). A history of infantile colic was noted in 31 % and was the most common childhood episodic syndrome associated with migraine. The most common premonitory symptoms recorded were fatigue, mood change and neck stiffness. The commonest number of reported premonitory symptoms was two.ConclusionPremonitory symptoms associated with migraine are reported in children as young as 18 months, with an overall clinical phenotype comparable to adults. Better documentation of this stage will aid parents and clinicians to better understand the phenotype of attacks, better recognise migraine and thus initiate appropriate management. Larger studies with a broader base are warranted to understand the extent and implications of these symptoms for childhood and adolescent migraine.

This article highlights the evidence behind the role of CGRP in migraine and the state of CGRP-based mechanism treatment development. We present a summary of the evidence base behind CGRP in migraine pathophysiology and the novel CGRP mechanism drugs and their potential future contribution to migraine management in our clinical practice.

Migraine is a complex disorder of the brain that is common and highly disabling. As understanding of the neural pathways has advanced, and it has become clear that the vascular hypothesis does not explain the disorder, new therapeutic avenues have arisen. One such target is calcitonin gene-related peptide (CGRP)-based mechanisms. CGRP is found within the trigeminovascular nociceptive system widely from the trigeminal ganglion to second-order and third-order neurons and in regulatory areas in the brainstem. Studies have shown CGRP is released during severe migraine attacks and the reversal of the attack with effective triptan treatment normalizes those levels. CGRP administration triggers migraine in patients, and CGRP receptor antagonists have been shown to abort migraine. Here, we review the current state of CGRP mechanism antagonist therapy as its research and development is increasing in migraine therapeutics. We discuss several recent trials, highlighting the evidence base behind these novel drugs, and their potential future contribution to migraine management.

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).