Interictal Dysfunction of a Brainstem Descending Modulatory Center in Migraine Patients

Background

The brainstem contains descending circuitry that can modulate nociceptive processing (neural signals associated with pain) in the dorsal horn of the spinal cord and the medullary dorsal horn. In migraineurs, abnormal brainstem function during attacks suggest that dysfunction of descending modulation may facilitate migraine attacks, either by reducing descending inhibition or increasing facilitation. To determine whether a brainstem dysfunction could play a role in facilitating migraine attacks, we measured brainstem function in migraineurs when they were not having an attack (i.e. the interictal phase).

Methods and Findings

Using fMRI (functional magnetic resonance imaging), we mapped brainstem activity to heat stimuli in 12 episodic migraine patients during the interictal phase. Separate scans were collected to measure responses to 41°C and noxious heat (pain threshold+1°C). Stimuli were either applied to the forehead on the affected side (as reported during an attack) or the dorsum of the hand. This was repeated in 12 age-gender-matched control subjects, and the side tested corresponded to that in the matched migraine patients. Nucleus cuneiformis (NCF), a component of brainstem pain modulatory circuits, appears to be hypofunctional in migraineurs. 3 out of the 4 thermal stimulus conditions showed significantly greater NCF activation in control subjects than the migraine patients.

Conclusions

Altered descending modulation has been postulated to contribute to migraine, leading to loss of inhibition or enhanced facilitation resulting in hyperexcitability of trigeminovascular neurons. NCF function could potentially serve as a diagnostic measure in migraine patients, even when not experiencing an attack. This has important implications for the evaluation of therapies for migraine.     

The relationship between levels of plasma-soluble urokinase plasminogen activator receptor (suPAR) and presence of migraine attack and aura

Migraine is one of the most common types of pain associated with sterile inflammatory conditions. Soluble urokinase plasminogen activator receptor (suPAR) is a potential novel inflammatory marker. We aim to determine the association between serum values of suPAR, procalcitonin, fibrinogen, and high-sensitivity C-reactive protein (hs-CRP) and migraine disease characteristics. The study involved a total of 60 migraine patients (33 patients in the interictal period, 27 patients in the attack period) and 30 healthy individuals. The serum values of suPAR were found to be significantly higher in migraine patients in the attack period than in migraine patients in the interictal period, and in healthy individuals (p?p?=?.001 for both). Significant differences were found between plasma levels of fibrinogen in migraine patients versus control subjects (p?相似文献   

Neuromagnetic Abnormality of Motor Cortical Activation and Phases of Headache Attacks in Childhood Migraine

The cerebral cortex serves a primary role in the pathogenesis of migraine. This aberrant brain activation in migraine can be noninvasively detected with magnetoencephalography (MEG). The objective of this study was to investigate the differences in motor cortical activation between attacks (ictal) and pain free intervals (interictal) in children and adolescents with migraine using both low- and high-frequency neuromagnetic signals. Thirty subjects with an acute migraine and 30 subjects with a history of migraine, while pain free, were compared to age- and gender-matched controls using MEG. Motor cortical activation was elicited by a standardized, validated finger-tapping task. Low-frequency brain activation (1∼50 Hz) was analyzed with waveform measurements and high-frequency oscillations (65–150 Hz) were analyzed with wavelet-based beamforming. MEG waveforms showed that the ictal latency of low-frequency brain activation was significantly delayed as compared with controls, while the interictal latency of brain activation was similar to that of controls. The ictal amplitude of low-frequency brain activation was significantly increased as compared with controls, while the interictal amplitude of brain activation was similar to that of controls. The ictal source power of high-frequency oscillations was significantly stronger than that of the controls, while the interictal source power of high-frequency oscillations was significantly weaker than that of controls. The results suggest that aberrant low-frequency brain activation in migraine during a headache attack returned to normal interictally. However, high-frequency oscillations changed from ictal hyper-activation to interictal hypo-activation. Noninvasive assessment of cortical abnormality in migraine with MEG opens a new window for developing novel therapeutic strategies for childhood migraine by maintaining a balanced cortical excitability.     

3D-Neuronavigation In Vivo Through a Patient's Brain During a Spontaneous Migraine Headache

A growing body of research, generated primarily from MRI-based studies, shows that migraine appears to occur, and possibly endure, due to the alteration of specific neural processes in the central nervous system. However, information is lacking on the molecular impact of these changes, especially on the endogenous opioid system during migraine headaches, and neuronavigation through these changes has never been done. This study aimed to investigate, using a novel 3D immersive and interactive neuronavigation (3D-IIN) approach, the endogenous µ-opioid transmission in the brain during a migraine headache attack in vivo. This is arguably one of the most central neuromechanisms associated with pain regulation, affecting multiple elements of the pain experience and analgesia. A 36 year-old female, who has been suffering with migraine for 10 years, was scanned in the typical headache (ictal) and nonheadache (interictal) migraine phases using Positron Emission Tomography (PET) with the selective radiotracer [¹¹C]carfentanil, which allowed us to measure µ-opioid receptor availability in the brain (non-displaceable binding potential - µOR BP_ND). The short-life radiotracer was produced by a cyclotron and chemical synthesis apparatus on campus located in close proximity to the imaging facility. Both PET scans, interictal and ictal, were scheduled during separate mid-late follicular phases of the patient''s menstrual cycle. During the ictal PET session her spontaneous headache attack reached severe intensity levels; progressing to nausea and vomiting at the end of the scan session. There were reductions in µOR BP_ND in the pain-modulatory regions of the endogenous µ-opioid system during the ictal phase, including the cingulate cortex, nucleus accumbens (NAcc), thalamus (Thal), and periaqueductal gray matter (PAG); indicating that µORs were already occupied by endogenous opioids released in response to the ongoing pain. To our knowledge, this is the first time that changes in µOR BP_ND during a migraine headache attack have been neuronavigated using a novel 3D approach. This method allows for interactive research and educational exploration of a migraine attack in an actual patient''s neuroimaging dataset.     

The effects of double-shifts (15.5 hours) on sleep, fatigue and health

The aim of the present study was to investigate how "double-shifts" (15.5 hours) affects sleep, fatigue and self-rated health. The study was carried out on male construction workers of which 80% were long-distance commuters. The schedule involved two work periods and each work period involved two double shifts in a row. The subjects filled in a sleep/wake diary at 8 times across a year and a questionnaire at 3 times. They also wore an actigraph during one shift cycle. The results showed that sleepiness, and to a certain extent, mental fatigue increased during double shifts and accumulated across days. The short rest time (8.5 hours) between days caused insufficient sleep and approximately 5.5 hours of sleep was obtained between double shifts. Questionnaire data showed that complaints of insufficient sleep, exhaustion on awakening and pain symptoms increased across the year. It was concluded that a shift system involving double shifts has a negative effect on fatigue, recovery and health-related well-being.     

Circadian variations in the clinical presentation of headaches among migraineurs: A study using a smartphone headache diary

Migraines occur within certain time frames. Nevertheless, information regarding circadian variation in the clinical presentation of migraine is limited. We investigated circadian variations in the clinical presentation of migraine using a smartphone headache diary (SHD). We enrolled adult participants with the diagnosis of migraine according to the third beta edition of the International Classification of Headache Disorders. Participants were asked to log in to the SHD every day for 90 days to record the occurrence of headaches. We compared the occurrence and clinical presentation of headaches during four 6-hour quadrants per day (00:00–05:59, 06:00–11:59, 12:00–17:59, and 18:00–23:59). Migraine-type headache was defined as a headache attack that fulfilled all criteria of migraine, except for the criterion regarding typical headache duration. Eighty-two participants kept a dairy for at least 50% of the study period and recorded 1491 headache attacks. Among the 1491 headache attacks, 474 (31.8%) were classified as migraine-type headaches and 1017 (68.2%) were classified as non-migraine-type headaches. All headaches, migraine-type headaches and non-migraine-type headaches occurred most frequently between 06:00 and 11:59, and least frequently between 18:00 and 23:59, and between 00:00 and 05:59. Migrainous headache characteristics, such as unilateral pain, pulsating quality, severe headache intensity, aggravation by movement, nausea, photophobia, and phonophobia presented most frequently between 06:00 and 11:59, and least frequently between 18:00 and 23:59, and 00:00 and 05:59 among 1491 all headache attacks. Headache clinical presentation as well as headache occurrence exhibited circadian periodicity among migraineurs.

Abbreviations: SHD: smartphone headache diary; ICHD-3 beta: the third edition beta version of the International Classification of Headache Disorders     

Elevated S100B and Neuron Specific Enolase Levels in Patients with Migraine-without Aura: Evidence for Neurodegeneration?

Although migraine has mainly been considered as a benign disease, there is cumulative evidence of silent changes in the brain, brainstem, or cerebellum and subtle subclinical cerebellar dysfunction. In this study, in order to investigate a possible neuronal and/or glial damage at the cellular level in migraine, we measured and compared serum levels of S100B which is a protein marker of glial damage or activation, and neuron specific enolase (NSE) which is a marker of neuronal damage, in migraine patients and control subjects. Serum levels of S100B and NSE were measured in blood samples from 41 patients with migraine-without aura taken during a migraine attack (ictal) and in the attack-free period between migraine attacks (interictal) and 35 age- and sex-matched controls. Patients with migraine-without aura had significantly higher ictal serum levels of S100B and NSE (P < 0.05, for both) than control subjects; whereas in the interictal phase, there was a significant increment only in S100B levels (P < 0.05) compared to controls. On the other hand, serum levels of S100B and NSE in ictal and interictal blood samples did not differ significantly. The findings of increased ictal serum S100B and NSE levels together with increased interictal levels of S100B suggested that migraine might be associated with glial and/or neuronal damage in the brain and a prolonged disruption of blood–brain barrier. Increased interictal serum levels of S100B might point out to an insidious and slow damaging process in migraine patients.     

IMMUNE RESPONSE TO PARASITISM REDUCES RESISTANCE OF DROSOPHILA MELANOGASTER TO DESICCATION AND STARVATION

Abstract In natural populations, organisms experience simultaneously biotic (e.g., competitors and parasites) and abiotic (e.g., temperature and humidity) stresses. Thus, species must have the capacity to respond to combinations of stressors. How does interaction between biotic and abiotic stress affect organismal performance? To address this question, I studied stress resistance of adult Drosophila melanogaster that survived parasitic attack (as larvae) by the parasitoid Asobara tabida. To determine the impact of genotype on stress resistance, I measured survival under desiccation and starvation of flies within isofemale (genetic) lines. Survivors of parasitism had slightly reduced survivorship compared to unparasitized relatives when both were unstressed, and this difference was exacerbated by desiccation and starvation. These results indicate multiple stressors can compound each other's individual negative effects on fitness. Moreover, isofemale lines differed in their sensitivity to environmental stress and to parasitism. Consequently, genotypic differences in sensitivity to stress may reflect differences in investment priorities between traits that promote survival over other life‐history characters.     

Analysis of Trigger Factors in Episodic Migraineurs Using a Smartphone Headache Diary Applications

Background

Various stimuli can trigger migraines in susceptible individuals. We examined migraine trigger factors by using a smartphone headache diary application.

Method

Episodic migraineurs who agreed to participate in our study downloaded smartphone headache diary application, which was designed to capture the details regarding headache trigger factors and characteristics for 3 months. The participants were asked to access the smartphone headache diary application daily and to confirm the presence of a headache and input the types of trigger factors.

Results

Sixty-two participants kept diary entries until the end of the study. The diary data for 4,579 days were analyzed. In this data set, 1,099 headache days (336 migraines, 763 non-migraine headaches) were recorded; of these, 772 headache events had with trigger factors, and 327 events did not have trigger factors. The common trigger factors that were present on headache days included stress, fatigue, sleep deprivation, hormonal changes, and weather changes. The likelihood of a headache trigger was 57.7% for stress, 55.1% for sleep deprivation, 48.5% for fatigue, and 46.5% for any trigger. The headaches with trigger factors were associated with greater pain intensity (p<0.001), headache-related disability (p<0.001), abortive medication use (p = 0.02), and the proportion of migraine (p < 0.001), relative to those without trigger factors. Traveling (odd ratios [OR]: 6.4), hormonal changes (OR: 3.5), noise (OR: 2.8), alcohol (OR: 2.5), overeating (OR: 2.4), and stress (OR:1.8) were significantly associated with migraines compared to non-migraine headaches. The headaches that were associated with hormonal changes or noise were more often migraines, regardless of the preventive medication. The headaches due to stress, overeating, alcohol, and traveling were more often migraines without preventive medication, but it was not evident with preventive medication.

Conclusion

Smartphone headache diary application is an effective tool to assess migraine trigger factors. The headaches with trigger factors had greater severity or migraine features. The type of triggers and the presence of preventive medication influenced the headache characteristics; hence, an investigation of trigger factors would be helpful in understanding migraine occurrences.     

Diencephalic and brainstem mechanisms in migraine

Migraine is a common and complex brain disorder. Although it is clear that head pain is a key manifestation of the disorder for most patients, what drives the activation of neuronal pain pathways in susceptible patients is less obvious. There is growing evidence that migraine pathophysiology may, in part, include dysfunction of subcortical structures. These include diencephalic and brainstem nuclei that can modulate the perception of activation of the trigeminovascular system, which carries sensory information from the cranial vasculature to the brain. Dysfunction of these nuclei, and their connections to other key brain centres, may contribute to the cascade of events that results in other symptoms of migraine - such as light and sound sensitivity - thus providing a comprehensive explanation of the neurobiology of the disorder.     

Footballer's Migraine

Classical migraine, including incapacitating visual field defects, repeatedly developed in five young men immediately after blows to the head while playing football and in no other circumstances. A similar condition occurred in a professional boxer and an isolated attack in a boy footballer. Prophylactic treatment with ergotamine tartrate may not be wholly successful and it may be necessary to give up the sport. Any unitary theory of causation of attacks of migraine must account for prodromal symptoms immediately after head injury.     

Changes in cerebral blood flow during a migraine attack.

Regional cerebral blood flow studies during a typical prodromal phase of a migraine attack in a young woman showed a global decrease of cerebral blood flow in the carotid artery territory. These studies were repeated during the subsequent headache phase of the same attack and hemispheric blood flow increased considerably. Ergotamine tartrate was then administered intramuscularly which brought definite relief of symptoms but no change in cerebral blood flow. Carotid angiography performed immediately afterwards showed retrograde filling of the proximal portion of the basilar artery, which suggested that the brain stem was the site of hyper-perfusion. These findings illustrate certain features underlying both the pathophysiology of migraine itself and its response to ergotamine preparations.     

Migraine prodromes separated from the aura: complete migraine.

Detailed questioning of 50 patients with uncomplicated migraine has shown that 17 had symptoms that preceded the headache phase by several hours. These prodromes consisted of changes in mood, behaviour, wakefulness, appetite, bowel activity, or fluid balance. The term "complete migraine" is proposed for attacks that include prodromal symptoms, whose occurrence implies an initial diffuse cerebral or hypothalamic disturbance.     

Primary Somatosensory Cortices Contain Altered Patterns of Regional Cerebral Blood Flow in the Interictal Phase of Migraine

The regulation of cerebral blood flow (CBF) is a complex integrated process that is critical for supporting healthy brain function. Studies have demonstrated a high incidence of alterations in CBF in patients suffering from migraine with and without aura during different phases of attacks. However, the CBF data collected interictally has failed to show any distinguishing features or clues as to the underlying pathophysiology of the disease. In this study we used the magnetic resonance imaging (MRI) technique—arterial spin labeling (ASL)—to non-invasively and quantitatively measure regional CBF (rCBF) in a case-controlled study of interictal migraine. We examined both the regional and global CBF differences between the groups, and found a significant increase in rCBF in the primary somatosensory cortex (S1) of migraine patients. The CBF values in S1 were positively correlated with the headache attack frequency, but were unrelated to the duration of illness or age of the patients. Additionally, 82% of patients reported skin hypersensitivity (cutaneous allodynia) during migraine, suggesting atypical processing of somatosensory stimuli. Our results demonstrate the presence of a disease-specific functional deficit in a known region of the trigemino-cortical pathway, which may be driven by adaptive or maladaptive functional plasticity. These findings may in part explain the altered sensory experiences reported between migraine attacks.     

Recent advances in understanding migraine mechanisms, molecules and therapeutics

Migraine is a complex, disabling disorder of the brain that manifests itself as attacks of often severe, throbbing head pain with sensory sensitivity to light, sound and head movement. There is a clear familial tendency to migraine, which has been well defined in a rare autosomal dominant form of familial hemiplegic migraine (FHM). FHM mutations so far identified include those in CACNA1A (P/Q voltage-gated Ca(2+) channel), ATP1A2 (N(+)-K(+)-ATPase) and SCN1A (Na(+) channel) genes. Physiological studies in humans and studies of the experimental correlate--cortical spreading depression (CSD)--provide understanding of aura, and have explored in recent years the effect of migraine preventives in CSD. Therapeutic developments in migraine have come by targeting the trigeminovascular system, with the most-recent being the proof-of-principle study of calcitonin gene-related peptide (CGRP) receptor antagonists in acute migraine. To understand the basic pathophysiology of migraine, brain imaging studies have firmly established reproducible changes in the brainstem in regions that include areas that are involved in sensory modulation. These data lead to the view that migraine is a form of sensory dysmodulatio--a system failure of normal sensory processing.     

Early warning signs of an acute myocardial infarction and their influence on symptoms during the acute phase,with comparisons by gender

Background: Identifying early warning signs of an acute myocardial infarction (AMI) may aid in the early diagnosis of coronary artery disease.Objectives: This study was conducted to assess early warning signs (prodromal symptoms) of AMI, with comparisons made by gender. Another aim was to determine whether these early warning signs had any influence on the patients' acute symptoms of AMI.Methods: This was a multicenter, cross-sectional study of Norwegian patients (aged ≤75 years) hospitalized with their first AMI. A self-administered questionnaire was used to gather information on prodromal symptoms, defined as pain in the chest, pain in the shoulder or back, radiating pain or numbness in the arms, dyspnea, and fatigue. Symptoms were reported for the year before AMI and during the acute stage. Logistic regression analyses were used to examine the association between prodromal symptoms and acute symptoms and the effect of medical history (hypertension, diabetes, and hypercholesterolemia).Results: The self-administered questionnaire had a 72% response rate; the study included 149 women and 384 men diagnosed with first-time AMI. Symptoms occurring during the year before AMI included pain in the chest in 45% (240/533), shoulder or back pain in 51% (270/533), arm pain in 38% (205/533), dyspnea in 33% (176/533), and fatigue in 62% (330/533). There were no statistically significant gender differences. The risk of experiencing chest symptoms in the acute phase was >5 times higher in women who had experienced prodromal symptoms in the chest (adjusted odds ratio [OR] = 5.11; 95% CI, 1.38-18.88) and nearly 3 times higher in men (OR = 2.80; 95% CI, 1.17–6.70). The risk of experiencing shoulder or back pain was almost 5 times higher in men with prodromal shoulder or back pain (OR = 4.96; 95% CI, 3.01–8.19), but no statistically significant association was found in women. The risk of experiencing radiating arm pain or numbness in the acute phase was more than doubled in women with prodromal arm pain (OR = 2.68; 95% CI, 1.19–6.20) and more than tripled in men with prodromal arm pain (OR = 3.11; 95% CI, 1.90–5.07). The risk of experiencing dyspnea in the acute phase was more than doubled in women with prodromal dyspnea (OR = 2.67; 95% CI, 1.25–5.71) and >5 times higher in men with prodromal dyspnea (OR = 5.73; 95% CI, 3.42–9.62). Finally, the risk of fatigue was almost tripled in women (OR = 2.97; 95% CI, 1.28–6.85) and more than doubled in men (OR = 2.51; 95% CI, 1.54–4.11). Hypertensive women, but not men, were less likely to experience chest symptoms in the acute phase (OR = 0.29; 95% CI, 0.10–0.82).Conclusions: Almost half of the study patients (45%) experienced prodromal chest symptoms the year before their first AMI. These prodromal symptoms predicted the symptoms that occurred during the acute stage of AMI, with some differences between the sexes.     

Stress-Induced Allodynia – Evidence of Increased Pain Sensitivity in Healthy Humans and Patients with Chronic Pain after Experimentally Induced Psychosocial Stress

Background

Experimental stress has been shown to have analgesic as well as allodynic effect in animals. Despite the obvious negative influence of stress in clinical pain conditions, stress-induced alteration of pain sensitivity has not been tested in humans so far. Therefore, we tested changes of pain sensitivity using an experimental stressor in ten female healthy subjects and 13 female patients with fibromyalgia.

Methods

Multiple sensory aspects of pain were evaluated in all participants with the help of the quantitative sensory testing protocol before (60 min) and after (10 and 90 min) inducing psychological stress with a standardized psychosocial stress test (“Trier Social Stress Test”).

Results

Both healthy subjects and patients with fibromyalgia showed stress-induced enhancement of pain sensitivity in response to thermal stimuli. However, only patients showed increased sensitivity in response to pressure pain.

Conclusions

Our results provide evidence for stress-induced allodynia/hyperalgesia in humans for the first time and suggest differential underlying mechanisms determining response to stressors in healthy subjects and patients suffering from chronic pain. Possible mechanisms of the interplay of stress and mediating factors (e.g. cytokines, cortisol) on pain sensitivity are mentioned. Future studies should help understand better how stress impacts on chronic pain conditions.     

Interrelated hypoalgesia,creep, and muscle fatigue following a repetitive trunk flexion exposure

Repetitive trunk flexion can damage spinal tissues, however its association with low back pain in the workplace may be confounded by factors related to pain sensitivity. Muscle fatigue, exercise-induced hypoalgesia, and creep-induced neuromuscular changes following repetitive trunk flexion may all affect this assumed exposure-pain relationship. This study’s purpose was to determine how mechanical pain sensitivity in the low back is affected by a repetitive trunk flexion exposure and identify factors associated with changes in low back pain sensitivity. Pressure pain thresholds, perceptions of sub-threshold stimuli, and muscle fatigue in the trunk and tibia, as well as lumbar spine creep were tracked in 37 young healthy adults before and up to 40 min after a 10-min repetitive trunk flexion exposure. Pressure pain thresholds (p = 0.033), but not perceptions of sub-threshold stimuli (p > 0.102) were associated with approximately a 12.5% reduction in pain sensitivity 10 min after completing the exposure, while creep and local muscle fatigue effects were only observed immediately following the exposure. Creep and fatigue interactions and the corresponding tibial measure co-varied with individual low back pressure pain thresholds. The net hypoalgesic effects of repetitive trunk flexion have the potential to partially mask possibly injurious loads, which could contribute to the severity or incidence of lower back injuries related to these exposures.     

偏头痛患者体感刺激下脑电信号的功能连接（英文）

目的 偏头痛是一种复杂的脑功能障碍性疾病,全球范围内患病率为14.4%。功能连接测量两个神经信号之间的统计学相互依赖性,不同的功能连接反映了大脑区域协同工作的不同模式。因此,研究不同脑区的功能连接对于理解偏头痛的病理生理机制具有十分重要的意义。以往基于脑电图对偏头痛患者脑功能连接的分析主要集中在视觉和疼痛刺激。本文尝试研究偏头痛患者在发作间期对体感刺激的皮质反应,以进一步了解偏头痛的神经功能障碍,为偏头痛的预防和治疗提供线索。方法 招募23例无先兆偏头痛患者,10例有先兆偏头痛患者,28名健康对照者。所有受试者均进行详细的基本资料和病史采集,完善量表评估,在正中神经体感刺激下进行脑电图记录。计算68个脑区的相干性作为功能连接,并评估功能连接与临床参数的相关性。结果 在正中神经体感刺激下,无先兆偏头痛和有先兆偏头痛患者的脑电功能连接与对照组相比存在差异,异常的脑电功能连接主要位于感觉辨别、疼痛调节、情绪认知和视觉处理等区域。无先兆偏头痛和有先兆偏头痛患者的大脑皮层对体感刺激可能具有相同的反应方式。偏头痛患者的功能连接异常与临床特征之间存在相关性,可以部分反映偏头痛的严重程度。结论 本研究...     

Left and right brain hemispheres in the regulation of pain sensitivity biorhythms in mice during stress

The foot-shock effects on ultradian and circadian rhythms of pain sensitivity in the SHR mice were studied after unilateral brain cortex hemisphere inactivation by means of the Leao spreading depression. Under acute painful stress, the left hemisphere partially loses its synchronizing effect on circadian rhythm and supports the 12-hour and particularly 6-hour periodicities. The left hemisphere effect dominates in intact animals under stress. The right hemisphere under the same conditions mainly loses its activating effect on circadian rhythm and supports the 8- and 16-hour periodicities. The right hemisphere effect dominates in animals under stress operated 2-3 days prior to the experiment.