Premonitory Phase Research Articles

Insights from triggers and prodromal symptoms on how migraine attacks start: The threshold hypothesis.

The prodrome or premonitory phase is the initial phase of a migraine attack, and it is considered as a symptomatic phase in which prodromal symptoms may occur. There is evidence that attacks start 24-48 hours before the headache phase. Individuals with migraine also report several potential triggers for their attacks, which may be mistaken for premonitory symptoms and hinder migraine research. This review aims to summarize published studies that describe contributions to understanding the fine difference between prodromal/premonitory symptoms and triggers, give insights for research, and propose a way forward to study these phenomena. We finally aim to formulate a theory to unify migraine triggers and prodromal symptoms. For this purpose, a comprehensive narrative review of the published literature on clinical, neurophysiological and imaging evidence on migraine prodromal symptoms and triggers was conducted using the PubMed database. Brain activity and network connectivity changes occur during the prodromal phase. These changes give rise to prodromal/premonitory symptoms in some individuals, which may be falsely interpreted as triggers at the same time as representing the early manifestation of the beginning of the attack. By contrast, certain migraine triggers, such as stress, hormone changes or sleep deprivation, acting as a catalyst in reducing the migraine threshold, might facilitate these changes and increase the chances of a migraine attack. Migraine triggers and prodromal/premonitory symptoms can be confused and have an intertwined relationship with the hypothalamus as the central hub for integrating external and internal body signals. Differentiating migraine triggers and prodromal symptoms is crucial for shedding light on migraine pathophysiology and improve migraine management.

Intervening in the Premonitory Phase to Prevent Migraine: Prospects for Pharmacotherapy.

Migraine is a common brain condition characterised by disabling attacks of headache with sensory sensitivities. Despite increasing understanding of migraine neurobiology and the impacts of this on therapeutic developments, there remains a need for treatment options for patients underserved by currently available therapies. The first specific drugs developed to treat migraine acutely, the serotonin-5-hydroxytryptamine [5-HT1B/1D] receptor agonists (triptans), seem to require headache onset in order to have an effect, while early treatment during mild pain before headache escalation improves short-term and long-term outcomes. Some patients find treating in the early window once headache has started but not escalated difficult, and migraine can arise from sleep or in the early hours of the morning, making prompt treatment after pain onset challenging. Triptans may be deemed unsuitable for use in patients with vascular disease and in those of older age and may not be effective in a proportion of patients. Headache is also increasingly recognised as being just one of the many facets of the migraine attack, and for some patients it is not the most disabling symptom. In many patients, painless symptoms can start prior to headache onset and can reliably warn of impending headache. There is, therefore, a need to identify therapeutic targets and agents that may be used as early as possible in the course of the attack, to prevent headache onset before it starts, and to reduce both headache and non-headache related attack burden. Early small studies using domperidone, naratriptan and dihydroergotamine have suggested that this approach could be useful; these studies were methodologically less rigorousthan modern day treatment studies, of small sample size, and have not sincebeen replicated. The emergence of novel targeted migraine treatments more recently, specifically calcitonin gene-related peptide (CGRP) receptor antagonists (gepants), has reignited interest in this strategy, with encouraging results. This review summarises historical and emerging data in this area, supporting use of the premonitory phase as an opportunity to intervene as early as possible in migraine to prevent attack-related morbidity.

Color vision of people with headaches

The aim of the study is to obtain new data on possible changes in color vision of people with headaches. The object of the study is people who periodically experience primary headaches of different nature. The subject of the study is the specificity of perception of chromatic parameters of the environment and color sensitivity of people with headaches of different nature, quality, intensity and frequency. The data were collected using the Farnsworth-Munsell standard clinical color vision test (FM-100). The study involved 65 people aged 17 to 66 years. The results of the assessment of color vision in the experimental group were compared with the normative indicators and data obtained in the age-matched control group (N=40). Special attention was paid to discussing the possible causes of the identified disorders and analyzing the correlation between various aspects of headache with individual indicators of color sensitivity. The data analysis included calculating the total error (TES), as well as partial errors (PES) along the blue-yellow (B-Y) and red-green (R-G) axes. We also identified partial errors for individual tones. The study revealed a noticeable specificity in the perception of blue-green and blue shades of patients with severe, chronic and non-localized headaches. Since the detected color vision disorders appear to be temporary and are most likely typical of the premonitory phase of headaches, the results of this study may contribute to understanding of headache predictors. Since the identified changes relate to only one group of (blue) shades, the findings of the study can be used in the development of alternative treatment methods. In particular, in choosing the optimal color of tinted lenses, which are offered to patients to relieve headaches and reduce their frequency.

Efficacy of ubrogepant for the treatment of migraine symptoms during the prodrome (premonitory phase): Results from the prodrome trial

Efficacy of ubrogepant for the treatment of migraine symptoms during the prodrome (premonitory phase): Results from the prodrome trial

B - 91 Cognition as a Premonitory Symptom of Migraine.

Migraine is often accompanied by premonitory symptoms (neurologic symptoms preceding migraine pain) which serve as "warning signs." Cognition changes are commonly described during the premonitory period (period preceding pain onset). Ecological momentary assessment can be utilized to understand if perceived cognitive changes are a symptom patients use as an indicator of the premonitory period. Participants with episodic migraine were recruited through a large urban health system and online advertising (n = 43). Individuals participated in a three-month, three-times-a-day electronic diary answering questions regarding migraine attack symptoms, including perception of being in a premonitory period, and the presence of premonitory symptoms, including "difficulty thinking or concentrating." The frequency of perceived cognitive difficulties was analyzed during the perceived premonitory period (endorsing "I think I might get a headache") vs. the perceived interictal period (endorsing "I do not anticipate a headache"). Cross tabs evaluated the frequencies of perceived cognitive difficulties during different migraine phases. Participants were predominantly White (n = 33, 76.7%), non-Hispanic (n = 33, 76.7%) women (n = 36, 83.7%). Thirty-three participants endorsed subjective cognitive difficulties at least once during the premonitory phase (n = 33; 76.75%). Difficulty thinking and concentrating was endorsed 35.16% of the time when participates also reported anticipating a headache in the morning and only 8.36% of the time when participants reported not anticipating a headache. Participants perceived cognitive decline as a premonitory symptom. Difficulty concentrating and thinking was endorsed more when participants anticipated getting a headache vs. when not. Assessing subjective cognitive decline as a premonitory symptom can guide individualized interventions for migraine and elucidate the relationship between cognition and migraine.

Improvement in Patient-Reported Outcomes When Ubrogepant Is Administered During the Migraine Prodrome (Premonitory Phase): Results From the PRODROME Trial (P9-12.001)

Improvement in Patient-Reported Outcomes When Ubrogepant Is Administered During the Migraine Prodrome (Premonitory Phase): Results From the PRODROME Trial (P9-12.001)

Efficacy of Ubrogepant for the Treatment of Migraine Symptoms During the Prodrome (Premonitory Phase): Results From the PRODROME Trial (S47.002)

Efficacy of Ubrogepant for the Treatment of Migraine Symptoms During the Prodrome (Premonitory Phase): Results From the PRODROME Trial (S47.002)

Ubrogepant for the Acute Treatment of Migraine When Administered During the Prodrome (Premonitory Phase): Results From a Phase 3, Randomized, Double-blind, Placebo-Controlled, Crossover Study (S47.001)

Ubrogepant for the Acute Treatment of Migraine When Administered During the Prodrome (Premonitory Phase): Results From a Phase 3, Randomized, Double-blind, Placebo-Controlled, Crossover Study (S47.001)

Characterizing Prodrome (Premonitory Phase) in Migraine: Results From the PRODROME Trial Screening Period (S41.009)

Characterizing Prodrome (Premonitory Phase) in Migraine: Results From the PRODROME Trial Screening Period (S41.009)

Study of the Mechanisms and Therapeutic Approaches of Migraine in Women and Pregnancy: A Literature Review.

Headache is a significant and debilitating health problem, affecting more than half of the population worldwide. Migraine is a type of headache that is strongly associated with women and accounts for the high number of years lived with disability among women. The pathophysiology of migraine attacks may begin with a premonitory phase, followed by an aura phase and migraine headache. In women, many factors influence the prevalence of migraine, and sex hormone fluctuations around the menstruation cycle were believed to impact the pathogenesis of migraine. The International Classification of Headache Disorders, 3rd edition identifies menstrual migraine as pure menstrual migraine without aura and menstrually related migraine without aura. While migraine without aura (MwoA) was clearly associated with menstruation, migraine with aura (MwA) was generally unrelated to menstruation. Studies suggested that estrogen withdrawal is a trigger for MwoA, but high estrogen states are a trigger for MwA. During pregnancy, the increase in estrogen hypothetically prevents migraine attacks. There are several strategies for managing menstrual migraine, from acute/abortive, mini-preventive, and continuous preventive treatment. Managing migraine during pregnancy follows a similar strategy, but the drugs' safety profile should be considered.

Premonitory symptoms in migraine: a systematic review and meta-analysis of observational studies reporting prevalence or relative frequency

BackgroundObservational studies on the prevalence of premonitory symptoms in people with migraine, preceding the headache pain (or aura) phase, have shown conflicting results. We conducted a systematic review and meta-analysis to estimate the prevalence, and relative frequency among clinic populations, of premonitory symptoms in people with migraine, overall and of the multifarious individual symptoms, and to review the methodologies used to assess them.MethodsWe searched PubMed and Embase for studies published from database inception until 31st of May 2022. Two investigators independently screened titles, abstracts, and full texts. We retrieved observational studies that reported the prevalence/relative frequency of one or more premonitory symptoms in people with migraine. Two investigators independently extracted data and assessed risk of bias. Results were pooled using random-effects meta-analysis. Our main outcomes were the percentage of people with migraine who experienced at least one premonitory symptom and the percentages who experienced different individual premonitory symptoms. To describe our outcomes, we used the terms prevalence for data from population-based samples and relative frequency for data from clinic-based samples. We also descriptively and critically assessed the methodologies used to assess these symptoms.ResultsThe pooled estimated prevalence in population-based studies of at least one premonitory symptom was 29% (95% CI: 8–63; I2 99%) and the corresponding pooled estimated relative frequency in clinic-based studies was 66% (95% CI: 45–82; I2 99%). The data from clinic-based studies only supported meta-analysis of 11 of 96 individual symptoms, with relative frequency estimates ranging from 11 to 49%. Risk of bias was determined as high in 20 studies, moderate in seven, and low in two.ConclusionsThe substantial between-study heterogeneity demands cautious interpretation of our estimates. Studies showed wide methodological variations, and many lacked rigor. Overall, the evidence was insufficient to support reliable prevalence estimation or characterization of premonitory symptoms. More data are needed, of better quality, to confirm the existence of a distinctive premonitory phase of migraine, and its features. Methodological guidelines based on expert consensus are a prerequisite.

Exploring the neurobiology of the premonitory phase of migraine preclinically – a role for hypothalamic kappa opioid receptors?

BackgroundThe migraine premonitory phase is characterized in part by increased thirst, urination and yawning. Imaging studies show that the hypothalamus is activated in the premonitory phase. Stress is a well know migraine initiation factor which was demonstrated to engage dynorphin/kappa opioid receptors (KOR) signaling in several brain regions, including the hypothalamus. This study proposes the exploration of the possible link between hypothalamic KOR and migraine premonitory symptoms in rodent models.MethodsRats were treated systemically with the KOR agonist U-69,593 followed by yawning and urination monitoring. Apomorphine, a dopamine D1/2 agonist, was used as a positive control for yawning behaviors. Urination and water consumption following systemic administration of U-69,593 was also assessed. To examine if KOR activation specifically in the hypothalamus can promote premonitory symptoms, AAV8-hSyn-DIO-hM4Di (Gi-DREADD)-mCherry viral vector was microinjected into the right arcuate nucleus (ARC) of female and male KORCRE or KORWT mice. Four weeks after the injection, clozapine N-oxide (CNO) was administered systemically followed by the assessment of urination, water consumption and tactile sensory response.ResultsSystemic administration of U-69,593 increased urination but did not produce yawning in rats. Systemic KOR agonist also increased urination in mice as well as water consumption. Cell specific Gi-DREADD activation (i.e., inhibition through Gi-coupled signaling) of KORCRE neurons in the ARC also increased water consumption and the total volume of urine in mice but did not affect tactile sensory responses.ConclusionOur studies in rodents identified the KOR in a hypothalamic region as a mechanism that promotes behaviors consistent with clinically-observed premonitory symptoms of migraine, including increased thirst and urination but not yawning. Importantly, these behaviors occurred in the absence of pain responses, consistent with the emergence of the premonitory phase before the headache phase. Early intervention for preventive treatment even before the headache phase may be achievable by targeting the hypothalamic KOR.

Occipital Nerve Stimulation: An Alternative Treatment of Chronic Migraine.

This paper will examine the efficacy and safety of occipital nerve stimulation as a non-pharmacological alternative treatment for migraine. Migraine is characterized as a primary headache disorder with possible premonitory and aura phases, both of which vary greatly in symptomatology. The most common treatments for chronic migraine are pharmacological and are aimed at both acute relief (e.g., nonsteroidal anti-inflammatory drugs, triptans, and ergots) and prophylaxis (e.g., propranolol, valproic acid, and topiramate). For patients with medically refractory migraine, acute relief medication overuse can increase the risk of developing more severe and more frequent migraine attacks. Occipital nerve stimulation is a non-pharmacological alternative treatment for chronic migraine, which could eliminate the risk of adverse effects from acute relief medication overuse. Neurostimulation is thought to prevent pain by blocking signal transduction from small nociceptive fibers with non-painful signaling in larger adjacent fibers. Existing data from clinical trials support the overall safety and efficacy of occipital nerve stimulation for the treatment of chronic migraine. However, few large controlled, double-blinded studies have been conducted, due to both practical and ethical concerns. Currently, occipital nerve stimulation is available as an off-label use of neurostimulation for pain prevention but is not approved by the FDA specifically for the treatment of chronic migraine.

Intrinsic network connectivity reflects the cyclic trajectory of migraine attacks

BackgroundEpisodic migraine is considered to be cyclic in nature, triggered by the hypothalamus. To assess the natural trajectory of intrinsic networks over an entire migraine cycle, we designed a longitudinal intra-individual study using functional magnetic resonance imaging (fMRI). MethodsIntrinsic network connectivity was assessed for 12 migraineurs in 82 sessions including spontaneous, untriggered headache attacks and follow-up recordings towards the next attack. ResultsWe found cyclic changes in the visual, auditory, and somatosensory networks, in limbic networks (e.g. thalamo-insular, parahippocampal), and in the salience network (anterior insula and dorsal anterior cingulate cortex). Connectivity changes also extended to further cortical networks, such as the central executive network, the default mode network, as well as subcortical networks. Almost all of these network connectivity changes followed the trajectory of a linear increase over the pain-free interval that peaked immediately prior to the headache, and “dropped” to the baseline level during the headache. These network alterations are associated with a number of cortical functions that may explain the variety of ictal and pre-ictal physiological and psychological migraine symptoms. ConclusionOur results suggest that migraine disease is associated with widespread cyclic alterations of intrinsic networks that develop before the headache is initiated, i.e. during the interictal and premonitory phase. The increasing magnitude of connectivity within these networks towards the next attack may reflect an increasing effort to maintain network integrity.

The prevalence and characteristics of visceral autonomic symptoms among migraineurs: A population-based study.

There is limited evidence about visceral autonomic symptoms in the different phases of migraine attack. We evaluated the prevalence of these symptoms in migraineurs before, during, and after headache attacks. In addition, the association between migraine characteristics and visceral autonomic symptoms was investigated. A total of 605 participants who met the entry criteria were enrolled prospectively in this cross-sectional study. Participants were 18-60 years old and met the ICHD-3 criteria for migraine with or without aura. Information on the migraine symptoms was gathered from all participants in face-to-face interviews. A structured questionnaire was used to evaluate the related symptoms before, during, and after attacks. Migraine features of frequency, duration, and severity were also assessed. Considering all phases, the most commonly present visceral symptom was nausea (52.9%). About half of participants reported at least one visceral symptom before the onset of attacks. While, during and after attacks, 71% and 36% of participants reported such characteristics, respectively. Notably, the migraine headache in participants with visceral symptoms was longer during attacks compared to participants without them (24.4 ± 29.6 vs. 16.8 ± 19.8; P = 0.008). Additionally, subjects with positive visceral symptoms experienced more severe migraine attacks than participants without symptoms for both the premonitory (8 ± 1.7 vs. 7.6 ± 1.8; P = 0.02) and during-attack (8.01 ± 1.7 vs. 7.09 ± 1.9; P = 0.001) phases. This study demonstrated that visceral symptoms were common in migraine sufferers not only during attacks but also in the premonitory and postdrome phases. Positive visceral symptoms were also associated with more burdensome headache attacks. Therefore, recognizing the phenotypic presentation of associated symptoms of migraine, especially during the pre-attack phase, could aid in early implementation of optimal management.

Depressive symptoms during the different phases of a migraine attack: A prospective diary study

BackgroundThe relationship between migraine and depression has been thoroughly investigated, indicating a bidirectional comorbidity. The exact temporal relationship between acute depressive symptoms (mood changes) and the various phases of the migraine attack has not yet been examined. MethodsWe performed a prospective diary study in n = 487 participants with migraine. Participants filled out a daily diary on migraine and acute depressive symptoms during a 1-month period. We randomly selected one migraine attack per participant, consisting of six days around an attack, including the interictal, premonitory, ictal, and postdromal phases. Acute depressive symptoms covered five major items from the DSM-5 classification. Primary analysis was performed using a mixed model with post-hoc testing. We also tested whether lifetime depression influenced the presence of acute depressive symptoms. ResultsDuring a migraine headache day, patients scored higher on acute depressive symptoms than on all other days of the migraine attack (p < 0.001). There were no early warning signs for an upcoming headache attack through acute depressive symptomatology. Migraine patients with lifetime depression scored overall higher during the migraine attack than those without lifetime depression (p < 0.001). LimitationsMigraine attacks were based on self-reported migraine and one migraine attack per patient was randomly selected. ConclusionWe now clearly demonstrate that during the migraine headache phase, but not in the prodromal phase, patients report increased depressive symptomatology. No evidence was found for mood changes as an early warning sign for an upcoming migraine attack.

Bench to bedside understanding of migraine pathophysiology

Migraine is a common, complex brain disorder whose pathophysiology is being unravelled by bench to bedside and back iterative advances [ [1] Goadsby P.J. Holland P.R. Martins-Oliveira M. Hoffmann J. Schankin C. Akerman S. Pathophysiology of Migraine- A disorder of sensory processing. Physiol. Rev. 2017; 97: 553-622 Google Scholar ]. Migraine consists of overlapping, parallel “phases” that offer insights into brain areas for laboratory exploration. Pain in migraine involves the activation, or perception of activation, of the pain-producing innervation of intracranial structures, notably the dura mater. The first, ophthalmic division, can be activated by direct stimulation in experimental animals to activate pathways of potential interest. Second order activation occurs in the trigemiinocervical complex that projects, with decussation, in the quintothalamic tract to the neurons of the ventroposteromedial thalamus. Triptans, serotonin 5-HT1B/1D receptor agonists, gepants, calcitonin gene-related peptide (CGRP) receptor antagonists, and ditans, 5-HT1F receptor agonists, each reduce nociceptive signalling in this pathway, and are effective in the acute treatment of migraine. Blockade of the pathway with monoclonal antibodies directed at the peptide, or its canonical receptor, are effective in the preventive treatment of migraine. Remarkably, gepants can have both acute attack effects and preventive effects in migraine. Brain imaging has demonstrated activations in the region of the hypothalamus in migraineurs in the premonitory phase in nitrogylcerin-triggered attacks or in spontaneous attacks. Given premonitory symptoms such as somnolence, yawning, thirst and polyuria, diencephalic structures offer a target for further bench-based studies. Understanding migraine neurobiology has generated new therapies and is likely to continue to do.

Hypothalamic structural integrity and temporal complexity of cortical information processing at rest in migraine without aura patients between attacks

The hypothalamus has been attributed an important role during the premonitory phase of a migraine attack. Less is known about the role played by the hypothalamus in the interictal period and its relationship with the putative neurocognitive networks previously identified in the pathophysiology of migraine. Our aim was to test whether the hypothalamic microstructure would be altered during the interictal period and whether this co-existed with aberrant connectivity at cortical level. We collected multimodal MRI data from 20 untreated patients with migraine without aura between attacks (MO) and 20 healthy controls (HC) and studied fractional anisotropy, mean (MD), radial (RD), and axial diffusivity of the hypothalamus ROI as a whole from diffusion tensor imaging (DTI). Moreover, we performed an exploratory analysis of the same DTI metrics separately for the anterior and posterior hypothalamic ROIs bilaterally. From resting-state functional MRI, we estimated the Higuchi’s fractal dimension (FD), an index of temporal complexity sensible to describe non-periodic patterns characterizing BOLD signature. Finally, we correlated neuroimaging findings with migraine clinical features. In comparison to HC, MO had significantly higher MD, AD, and RD values within the hypothalamus. These findings were confirmed also in the exploratory analysis on the sub-regions of the hypothalamus bilaterally, with the addition of lower FA values on the posterior ROIs. Patients showed higher FD values within the salience network (SN) and the cerebellum, and lower FD values within the primary visual (PV) network compared to HC. We found a positive correlation between cerebellar and SN FD values and severity of migraine. Our findings of hypothalamic abnormalities between migraine attacks may form part of the neuroanatomical substrate that predisposes the onset of the prodromal phase and, therefore, the initiation of an attack. The peculiar fractal dimensionality we found in PV, SN, and cerebellum may be interpreted as an expression of abnormal efficiency demand of brain networks devoted to the integration of sensory, emotional, and cognitive information related to the severity of migraine.

Hypothalamic functional MRI activity in the initiation phase of spontaneous and glyceryl trinitrate-induced migraine attacks.

The hypothalamus has been suggested to be important in the initiation cascade of migraine attacks based on clinical and biochemical observations. Previous imaging studies could not disentangle the changes due to the attack and those due to the trigger compound. With a novel approach, we assessed hypothalamic neuronal activity in early premonitory phases of glyceryl‐trinitrate (GTN)‐induced and spontaneous migraine attacks. We measured the hypothalamic blood oxygen level‐dependent (BOLD) response to oral glucose ingestion with 3T‐functional magnetic resonance imaging (MRI) in 27 women, 16 with migraine without aura and 11 controls group matched for age and body mass index (BMI), on 1 day without prior GTN administration and on a second day after GTN administration (to coincide with the premonitory phase of an induced attack). Interestingly, subgroups of patients with and without GTN‐triggered attacks could be compared. Additionally, five migraineurs were investigated in a spontaneous premonitory phase. Linear mixed models were used to study between‐ and within‐group effects. Without prior GTN infusion, the BOLD response to glucose was similar in migraine participants and controls (P = .41). After prior GTN infusion, recovery occurred steeper and faster in migraineurs (versus Day 1; P < .0001) and in those who developed an attack versus those who did not (P < .0001). Prior GTN infusion did not alter the glucose‐induced response in controls (versus baseline; P = .71). Just before spontaneous attacks, the BOLD‐response recovery was also faster (P < .0001). In this study, we found new and direct evidence of altered hypothalamic neuronal function in the immediate preclinical phase of both GTN‐provoked and spontaneous migraine attacks.

Source Mechanisms of Laboratory Earthquakes During Fault Nucleation and Formation

AbstractIdentifying deformation and pre‐failure mechanisms preceding faulting is key for fault mechanics and for interpreting precursors to fault rupture. This study presents the results of a new and robust derivation of first motion polarity focal mechanism solutions (FMS) applied to acoustic emission (AE). FMS are solved using a least squares minimization of the fit between projected polarity measurements and the deviatoric stress field induced by dilatational (T‐type), shearing (S‐type), and compressional (C‐type) sources. 4 × 10 cm cylindrical samples of Alzo Granite (AG, porosity &lt;1%) and Darley Dale Sandstone (DDS, porosity ≈14%) underwent conventional triaxial tests in order to investigate the relationships between increasing confining pressure (5, 10, 20, and 40 MPa), deformation and failure mode, and role of microstructural features. Results highlight that S‐type events occur in very low numbers with poor spatial correlation to fault structure. Instead, deformation is driven by a complex interplay between compactant (C‐type) and dilatant (T‐type) regions of deformation. C‐type events are the earliest precursor related to crack nucleation and T‐type events mark new cracks opening, with the onset of fracture growth characterized by periodic cycles of coalescence. For AG a single sequence is able to lead to dynamic failure, while for DDS several cycles are needed for coalescence to take place due to the competition between dilatant and compactant deforming regions induced by multiple fracture nucleation sites. The occurrence of C‐ and S‐type events is also consistent with a quasi‐static premonitory phase, or foreshock, before a critical nucleation length allows the development of a planar localization.