Migraine prodromes and migraine triggers.

Migraine is characterized by a well-defined premonitory phase occurring hours or even days before the headache. Also, many migraineurs report typical triggers for their headaches. Triggers, however, are not consistent in their ability to precipitate migraine headaches. When looking at the clinical characteristics of both premonitory symptoms and triggers, a shared pathophysiological basis seems evident. Both seem to have their origin in basic homeostatic networks such as the feeding/fasting, the sleeping/waking, and the stress response network, all of which strongly rely on the hypothalamus as a hub of integration and are densely interconnected. They also influence the trigeminal pain processing system. Additionally, thalamic and hormonal mechanisms are involved. Activity within all those networks is influenced by various endogenous and external factors and might even cyclically change dependent on physiological internal rhythms. This might affect the threshold for the generation of migraine headaches. Premonitory symptoms thus appear as the result of an already ongoing alteration within those networks, whereas triggers might in this special situation only be able to further stress the system over the threshold for attack generation as catalysts of a process already in motion.

Migraine: disease characterisation, biomarkers, and precision medicine.

Migraine is a disabling neurological disorder, diagnosis of which is based on clinical criteria. A shortcoming of these criteria is that they do not fully capture the heterogeneity of migraine, including the underlying genetic and neurobiological factors. This complexity has generated momentum for biomarker research to improve disease characterisation and identify novel drug targets. In this Series paper, we present the progress that has been made in the search for biomarkers of migraine within genetics, provocation modelling, biochemistry, and neuroimaging research. Additionally, we outline challenges and future directions for each biomarker modality. We also discuss the advances made in combining and integrating data from multiple biomarker modalities. These efforts contribute to developing precision medicine that can be applied to future patients with migraine.

Altered trigeminal pain processing on brainstem level in persistent idiopathic facial pain.

ABSTRACT: Persistent idiopathic facial pain (PIFP) is a poorly understood chronic pain syndrome of the face, formerly known as atypical facial pain. It is characterized by a constant painful sensation without neurological abnormalities and without clinically objectifiable cause. Similarities to neuropathic pain conditions have been discussed and are currently thought to be relevant for the pathophysiology of this disease. In this study, we aim to characterize the trigeminal pain processing in PIFP using functional magnetic resonance imaging of the brainstem. Twenty-five patients suffering from PIFP and 25 healthy controls underwent a standardized and well-established paradigm of painful stimulation of the trigeminal nerve using gaseous ammonia. Functional images were acquired within a 3T magnetic resonance imaging scanner using an optimized protocol for high-resolution echo planar brainstem imaging. Patients with PIFP show exclusively a stronger activation to painful stimulation in the spinal trigeminal nucleus when contrasted against healthy controls. Our data suggest that abnormal central pain processing plays a role in the pathophysiology of PIFP. An integration of these findings into neuropathic pain models might help to gain a better general understanding of the pathophysiology of PIFP.

The migraineur's brain networks: Continuous resting state fMRI over 30 days.

OBJECTIVE: The aim of the current study was to identify typical alterations in resting state connectivity within different stages of the migraine cycle and to thus explore task-free mechanisms of headache attack generation in migraineurs. BACKGROUND: Recent evidence in migraine pathophysiology suggests that hours and even days before headache certain changes in brain activity take place, ultimately leading to an attack. Here, we investigate changes before headache onset using resting state functional magnetic resonance imaging (fMRI). METHODS: Nine episodic migraineurs underwent daily resting state functional magnetic resonance imaging for a minimum period of 30 consecutive days, leading to a cumulative number of 282 total days scanned. Thus, data from 15 spontaneous headache attacks were acquired. This allows analysing not only the ictal and the interictal phase of migraine but also the preictal phase. ROI-to-ROI (region of interest) and ROI-to-voxel connectivity was calculated over the migraine cycle. RESULTS: Within the ROI-to-ROI analysis, the right nucleus accumbens showed enhanced functional connectivity to the left amygdala, hippocampus and gyrus parahippocampalis in the preictal phase compared to the interictal phase. ROI-to-voxel connectivity of the right accumbens with the dorsal rostral pons was enhanced during the preictal phase compared to interictally. Regarding custom defined ROIs, the dorsal pons was ictally functionally more strongly coupled to the hypothalamic area than interictally. CONCLUSIONS: This unique data set suggests that particularly connectivity changes in dopaminergic centres and between the dorsal pons and the hypothalamus are important within migraine attack generation and sustainment.

Phase dependent hypothalamic activation following trigeminal input in cluster headache.

BACKGROUND: Task-free imaging approaches using PET have shown the posterior hypothalamus to be specifically activated during but not outside cluster headache attacks. Evidence from task related functional imaging approaches however is scarce. METHODS: Twenty-one inactive cluster headache patients (episodic cluster headache out of bout), 16 active cluster headache patients (10 episodic cluster headache in bout, 6 chronic cluster headache) and 18 control participants underwent high resolution brainstem functional magnetic resonance imaging of trigeminal nociception using gaseous ammonia as a painful stimulus. RESULTS: Following trigeminonociceptive stimulation with ammonia there was a significantly stronger activation within the posterior hypothalamus in episodic cluster headache patients out of bout when compared to controls. When contrasting estimates of the pain contrast, active cluster headache patients where in between the two other groups but did not differ significantly from either. CONCLUSION: The posterior hypothalamus might thus be hyperexcitable in cluster headache patients outside the bout while excitability to external nociceptive stimuli decreases during in bout periods, probably due to frequent hypothalamic activation and possible neurotransmitter exhaustion during cluster attacks.

Longitudinal Neuroimaging over 30 Days: Temporal Characteristics of Migraine.

OBJECTIVE: Although migraine is defined by the headache and headache-associated symptoms, the true beginning of a migraine attack lies in the premonitory phase. To understand the generation of attacks, one needs to investigate the phase before headache starts. The premonitory phase of migraine is characterized by a well-described complex of symptoms. Its duration, however, is not clearly defined, and there are no biomarkers to help define when this phase starts. METHODS: Here, we used functional magnetic resonance imaging (MRI) to elucidate the duration of the premonitory phase in spontaneous human migraine attacks. Because migraine attacks are hardly predictable and thereby the premonitory phase is difficult to catch, we scanned 9 patients daily over a minimum period of 30 days using a well-established paradigm for functional MRI of trigeminal nociception. RESULTS: Seven patients were included in the analysis, thus providing cumulative data of 27 spontaneous human migraine attacks including scans before, during, and after migraine pain as well as interictal scans. As a response to painful trigeminal stimulation, activation of the hypothalamus was present within the last 48 hours before headache onset but not earlier. INTERPRETATION: Using hypothalamic activation as a potential marker for the premonitory phase of migraine in this unique dataset, our data corroborated a duration of 48 hours for the premonitory phase of migraine. We suggest applying this time criterion in future studies when focusing on this phase of the migraine cycle. ANN NEUROL 2020;87:646-651.

Current understanding of premonitory networks in migraine: A window to attack generation.

AIM: To describe neuronal networks underlying commonly reported migraine premonitory symptoms and to discuss how these might precipitate migraine pain. BACKGROUND: Migraine headache is frequently preceded by a distinct and well characterized premonitory phase including symptoms like yawning, sleep disturbances, alterations in appetite and food intake and hypersensitivity to certain external stimuli. Recent neuroimaging studies strongly suggest the hypothalamus as the key mediator of the premonitory phase and also suggested alterations in hypothalamic networks as a mechanism of migraine attack generation. When looking at the vast evidence from basic research within the last decades, hypothalamic and thalamic networks are most likely to integrate peripheral influences with central mechanisms, facilitating the precipitation of migraine headaches. These networks include sleep, feeding and stress modulating centers within the hypothalamus, thalamic pathways and brainstem centers closely involved in trigeminal pain processing such as the spinal trigeminal nucleus and the rostral ventromedial medulla, all of which are closely interconnected. CONCLUSION: Taken together, these networks represent the pathophysiological basis for migraine premonitory symptoms as well as a possible integration site of peripheral so-called "triggers" with central attack facilitating processes.

Visual processing in migraineurs depends on the migraine cycle.

We investigated changes of after-image duration in migraineurs and healthy controls (HCs) and throughout the migraine cycle to depict changes in the excitatory/inhibitory equilibrium within the visual cortex. Forty-seven episodic (EMs) and 39 chronic migraineurs (CMs; interictal) were compared to 34 HCs for visual after-image duration. Additionally, seven EMs were investigated every consecutive day over 20 to 32 days using the identical paradigm throughout the migraine cycle. Interictally, the after-image duration was shorter compared to HCs, but significantly longer in the ictal compared to interictal phase. These data suggest an altered excitatory/inhibitory equilibrium in migraineurs, which oscillates over the migraine cycle. ANN NEUROL 2019;85:280-283.

Visual stimulation leads to activation of the nociceptive trigeminal nucleus in chronic migraine.

OBJECTIVE: The visual system has often been described to be sensitized in migraineurs, with light being perceived as aversive or even painful. One possible explanation for this altered perception is crosslinks between the visual and the trigeminonociceptive system. Visual stimulation in chronic migraineurs on the level of the brainstem might lead to enhanced activity within the spinal trigeminal nucleus (sTN) as the main site of trigeminal pain processing within this area. METHODS: Eighteen episodic migraineurs (EM), 17 chronic migraineurs (CM), and 19 healthy controls (HC) underwent one session of high-resolution brainstem imaging during which a rotating checkerboard was presented repeatedly as a visual stimulus. Data were analyzed using SPM12 and MATLAB with the classic first-level-second-level approach of SPM. Analyses of variance were used for group comparisons. RESULTS: CM showed enhanced activation within the sTN as compared to HC. In addition, we observed enhanced activity within the right superior colliculus in CM as compared to HC. When comparing all migraineurs with headaches during scanning with all migraineurs without headaches during scanning and HC, we also found the sTN to be more strongly activated during headaches. CONCLUSION: Our data provide evidence for the existence of visual-nociceptive integration on brainstem level in chronic migraineurs.

Linear and inverted U-shaped dose-response functions describe estrogen effects on hippocampal activity in young women.

In animals, 17-beta-estradiol (E2) enhances hippocampal plasticity in a dose-dependent, monotonically increasing manner, but this relationship can also exhibit an inverted U-shaped function. To investigate E2's dose-response function in the human hippocampus, we pharmacologically increased E2 levels in 125 naturally cycling women (who were in their low-hormone menstruation phase) to physiological (equivalent to menstrual cycle peak) and supraphysiological (equivalent to levels during early pregnancy) concentrations in a placebo-controlled design. Twenty-four hours after first E2 intake, we measured brain activity during encoding of neutral and negative pictures and then tested recognition memory 24 h after encoding. Here we report that E2 exhibits both a monotonically increasing relationship with hippocampal activity as well as an inverted U-shaped relationship, depending on the hippocampal region. Hippocampal activity exhibiting a U-shaped relationship inflects at supraphysiological E2 levels, suggesting that while E2 within physiological ranges stimulates hippocampal activity, supraphysiological ranges show opposite effects.

Hypothalamus as a mediator of chronic migraine: Evidence from high-resolution fMRI.

OBJECTIVE: To identify pathophysiologic mechanisms of migraine chronification using a recently standardized protocol for high-resolution brainstem imaging of trigeminal nociceptive stimulation. METHODS: Eighteen episodic migraineurs (EMs), 17 chronic migraineurs (CMs), and 19 healthy controls (HCs) underwent painful ammonia stimulation of the left nostril in a 3T MRI scanner. Functional images were acquired with a brainstem-optimized protocol for high-resolution echo-planar imaging. RESULTS: We detected a significantly stronger activation of the anterior right hypothalamus in CMs compared to HCs. To exclude the headache as a prime mediator of the hypothalamic activations, we compared all migraineurs with headaches (EMs and CMs) with all migraineurs without headaches (EMs and CMs) and HCs in a second analysis and found a more posterior region of the hypothalamus to be more activated bilaterally during headaches. CONCLUSIONS: Our data corroborate the fact that the hypothalamus plays a crucial role in the pathophysiology of migraine chronification and acute pain stage of migraineurs. While the more posterior part of the hypothalamus seems to be important for the acute pain stage, the more anterior part seems to play an important role in attack generation and migraine chronification.

Of generators, networks and migraine attacks.

PURPOSE OF REVIEW: One of the most discussed topics in migraine pathophysiology is where migraine attacks originate. Although recent evidence suggests central attack generating loci, there is an ongoing debate about the involved centres of the brain and brainstem. RECENT FINDINGS: Recent neuroimaging studies focussing on the preictal stage of migraine attacks suggest a predominant role of the hypothalamus and its functional connectivity shortly before the beginning of migraine headaches. In interictal migraineurs, changes in resting state functional connectivity of the dorsal pons and the hypothalamus have been found. SUMMARY: Based on the clinical presentation of the premonitory phase of migraine, the hypothalamus and changes within the dopaminergic system have been discussed as likely candidates for attack generation. Neuroimaging studies however suggested the dorsal pons as attack generator. Taking into account the recent findings of hypothalamic involvement and changing connectivity in the preictal stage, the available evidence suggests that the idea of a single migraine generator within the human brain is probably too simplistic. More likely, spontaneous oscillations of complex networks lead to activity changes in certain subcortical and brainstem areas. This in turn might constitute functional changes of descending pain-modulating pathways, and thus the generation of migraine pain.

Functional Neuroimaging in Migraine: Chances and Challenges.

Functional neuroimaging studies are an indispensable tool in headache research and have greatly contributed to our understanding of migraine pathophysiology. The past two decades have identified the brainstem as the target region of interest in migraine pathophysiology: Recent evidence suggests that certain areas of the central nervous system and especially the brainstem periodically change activity during different stages of the migraine cycle. Additionally, the number of resting-state functional MRI studies in migraine has increased greatly in recent years. Three future trends in migraine neuroimaging can be identified: brainstem optimized functional imaging, longitudinal approaches tracking biological changes through the migraine cycle, and optimized resting-state fMRI. Consequently, we face a lot of difficulties regarding image noise and artifacts, organizational details, and data interpretation. Optimized neuroimaging studies and new approaches will continue to greatly contribute to our pathophysiological understanding of migraine.

Chronic migraine: risk factors, mechanisms and treatment.

Chronic migraine has a great detrimental influence on a patient's life, with a severe impact on socioeconomic functioning and quality of life. Chronic migraine affects 1-2% of the general population, and about 8% of patients with migraine; it usually develops from episodic migraine at an annual conversion rate of about 3%. The chronification is reversible: about 26% of patients with chronic migraine go into remission within 2 years of chronification. The most important modifiable risk factors for chronic migraine include overuse of acute migraine medication, ineffective acute treatment, obesity, depression and stressful life events. Moreover, age, female sex and low educational status increase the risk of chronic migraine. The pathophysiology of migraine chronification can be understood as a threshold problem: certain predisposing factors, combined with frequent headache pain, lower the threshold of migraine attacks, thereby increasing the risk of chronic migraine. Treatment options include oral medications, nerve blockade with local anaesthetics or corticoids, and neuromodulation. Well-defined diagnostic criteria are crucial for the identification of chronic migraine. The International Headache Society classification of chronic migraine was recently updated, and now allows co-diagnosis of chronic migraine and medication overuse headache. This Review provides an up-to-date overview of the classification of chronic migraine, basic mechanisms and risk factors of migraine chronification, and the currently established treatment options.

The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks.

Functional imaging using positron emission tomography and later functional magnetic resonance imaging revealed a particular brainstem area that is believed to be specifically activated in migraine during, but not outside of the attack, and consequently has been coined the 'migraine generator'. However, the pathophysiological concept behind this term is not undisputed and typical migraine premonitory symptoms such as fatigue and yawning, but also a typical association of attacks to circadian and menstrual cycles, all make the hypothalamus a possible regulating region of migraine attacks. Neuroimaging studies investigating native human migraine attacks however are scarce and for methodological but also clinical reasons there are currently no studies investigating the last 24 h before headache onset. Here we report a migraine patient who had magnetic resonance imaging every day for 30 days, always in the morning, to cover, using functional imaging, a whole month and three complete, untreated migraine attacks. We found that hypothalamic activity as a response to trigeminal nociceptive stimulation is altered during the 24 h prior to pain onset, i.e. increases towards the next migraine attack. More importantly, the hypothalamus shows altered functional coupling with the spinal trigeminal nuclei and the region of the migraine generator, i.e. the dorsal rostral pons during the preictal day and the pain phase of native human migraine attacks. These data suggest that although the brainstem is highly linked to the migraine biology, the real driver of attacks might be the functional changes in hypothalamo-brainstem connectivity.

Physiological brainstem mechanisms of trigeminal nociception: An fMRI study at 3T.

The brainstem is a major site of processing and modulation of nociceptive input and plays a key role in the pathophysiology of various headache disorders. However, human imaging studies on brainstem function following trigeminal nociceptive stimulation are scarce as brainstem specific imaging approaches have to address multiple challenges such as magnetic field inhomogeneities and an enhanced level of physiological noise. In this study we used a viable protocol for brainstem fMRI of standardized trigeminal nociceptive stimulation to achieve detailed insight into physiological brainstem mechanisms of trigeminal nociception. We conducted a study of 21 healthy participants using a nociceptive ammonia stimulation of the left nasal mucosa with an optimized MR acquisition protocol for high resolution brainstem echoplanar imaging in combination with two different noise correction techniques. Significant BOLD responses to noxious ammonia stimulation were observed in areas typically involved in trigeminal nociceptive processing such as the spinal trigeminal nuclei (sTN), thalamus, secondary somatosensory cortex, insular cortex and cerebellum as well as in a pain modulating network including the periaqueductal gray area, hypothalamus (HT), locus coeruleus and cuneiform nucleus (CNF). Activations of the left CNF were positively correlated with pain intensity ratings. Employing psychophysiological interaction (PPI) analysis we found enhanced functional connectivity of the sTN with the contralateral sTN and HT following trigeminal nociception. We also observed enhanced functional connectivity of the CNF with the RVM during painful stimulation thus implying an important role of these two brainstem regions in central pain processing. The chosen approach to study trigeminal nociception with high-resolution fMRI offers new insight into human pain processing and might thus lead to a better understanding of headache pathophysiology.

Efficacy of interventions used by physiotherapists for patients with headache and migraine-systematic review and meta-analysis.

AIM: We aimed to conduct a systematic review evaluating the effectiveness of interventions used by physiotherapists on the intensity, frequency and duration of migraine, tension-type (TTH) and cervicogenic headache (CGH). METHODS: We performed a systematic search of electronic databases and a hand search for controlled trials. A risk of bias analysis was conducted using the Cochrane risk of bias tool (RoB). Meta-analyses present the combined mean effects; sensitivity analyses evaluate the influence of methodological quality. RESULTS: Of 77 eligible trials, 26 were included in the RoB assessment. Twenty trials were included in meta-analyses. Nineteen out of 26 trials had a high RoB in >1 domain. Meta-analyses of all trials indicated a reduction of TTH ( ITALIC! p < 0.0001; mean reduction -1.11 on a 0-10 visual analog scale (VAS); 95% CI -1.64 to -0.57) and CGH ( ITALIC! p = 0.0002; mean reduction -2.52 on a 0-10 VAS; 95% CI -3.86 to -1.19) pain intensity, CGH frequency ( ITALIC! p < 0.00001; mean reduction -1.34 days per month; 95% CI -1.40 to -1.28), and migraine ( ITALIC! p = 0.0001; mean reduction -22.39 hours without relief; 95% CI -33.90 to -10.88) and CGH ( ITALIC! p < 0.00001; mean reduction -1.68 hours per day; 95% CI -2.09 to -1.26) duration. Excluding high RoB trials increased the effect sizes and reached additional statistical significance for migraine pain intensity ( ITALIC! p < 0.00001; mean reduction -1.94 on a 0-10 VAS; 95% CI -2.61 to -1.27) and frequency ( ITALIC! p < 0.00001; mean reduction -9.07 days per month; 95% CI -9.52 to -8.62). DISCUSSION: Results suggest a statistically significant reduction in the intensity, frequency and duration of migraine, TTH and CGH. Pain reduction and reduction in CGH frequency do not reach clinically relevant effect sizes. Small sample sizes, inadequate use of headache classification, and other methodological shortcomings reduce the confidence in these results. Methodologically sound, randomized controlled trials with adequate sample sizes are required to provide information on whether and which physiotherapy approach is effective. According to Grading of Recommendations Assessment, Development and Evaluation (GRADE), the current level of evidence is low.

Photo-, osmo- and phonophobia in the premonitory phase of migraine: mistaking symptoms for triggers?

BACKGROUND: Certain environmental stimuli are frequently reported as typical triggers of migraine pain. Whether these so-called triggers are independent precipitators of migraine pain or mere symptoms of the premonitory phase of migraine remains to be elucidated. METHODS: In this retrospective cohort study of 1010 migraine patients of a tertiary headache center we assessed the frequency of common trigger factors, premonitory symptoms and accompanying symptoms as well as basic headache characteristics and demographic data. RESULTS: Premonitory symptoms with an onset of 2 or more hours prior to the headache were present in 38.9% of migraine patients, the most frequent being a tense neck, phonophobia and difficulty concentrating. There was a clear overlap of certain trigger factors and the presence of corresponding premonitory symptoms: flickering or bright light as a trigger was associated with higher frequency of photophobia in the premonitory phase. The same applied to the presence of food craving and osmophobia in the premonitory phase and certain foods or odours as trigger factors. CONCLUSIONS: Our data thus support the view that commonly reported trigger factors of migraine are not so much independent precipitators of migraine pain, but that they are most likely just misinterpreted results of enhanced attention to certain stimuli mediated by typical premonitory symptoms of migraine pain.

Migraine trait symptoms in migraine with and without aura.

OBJECTIVES: The aim of the study was to determine whether various transient sensory and neuropsychological symptoms (SNS) were associated with migraine using a custom questionnaire. METHODS: In this hypothesis-generating case-control study, the frequencies of transient SNS in 219 patients with migraine (149 without aura and 70 with aura) were compared with 161 age- and sex-matched healthy controls using a custom questionnaire. Patients from a tertiary academic headache center in Hamburg were contacted by regular mail. Healthy controls without a history of migraine were recruited by means of a screening questionnaire and consecutively approached by e-mail. RESULTS: The presence of both migraine and aura was associated with significantly higher frequencies of autokinesis, metamorphopsia, dyschromatopsia, cinematographic vision, illusionary visual spread, and synesthesia (for all comparisons: corrected p < 0.05). Double vision, inverted 2- and 3-dimensional vision, and altered perception of body weight and size were found more often in patients with migraine without aura than in those with aura. In contrast, aura was associated with the occurrence of visual splitting and corona phenomenon (for all comparisons: corrected p < 0.05). No relevant association with migraine was found for micropsia and macropsia, teleopsia and pelopsia, inverted vision, out-of-body experience, Doppelgänger phenomenon, complex visual hallucinations, and altered perception of body position in space. CONCLUSIONS: The observed SNS seem to belong to a physiologic spectrum of multisensory phenomena. Some of these phenomena were significantly accentuated in patients with migraine and may therefore be termed migraine trait symptoms. However, these results will have to be confirmed in a prospective study with face-to-face interviews.