Cortical excitability in migraine: Contributions of magnetic resonance imaging

Migraine is characterized by symptoms related to cortical hyperexcitability such as photophobia, phonophobia, osmophobia and allodynia. One-third of migraineurs experience aura, whose neurophysiological substrate is thought to be cortical spreading depression (CSD). Functional magnetic resonance imaging (MRI) has shown the migraine aura to be characterized by cerebral hyperactivity/hyperperfusion followed by hypometabolism/hypoperfusion spreading along the occipital cortex with the same spatiotemporal organization as the experimentally triggered CSD. The link between migraine aura and headache remains undetermined. Neuroimaging studies have failed to show a leakage of the blood–brain barrier, which was suspected to occur during CSD and to cause the stimulation of trigeminal nociceptive receptors. However, recent studies have highlighted the involvement of neuroglial inflammation and other studies have suggested that a common central network plays a role in the link between CSD and migraine pain. Finally, MRI has made it possible to study the contribution of metabolites such as glutamic acid, γ-amino-butyric acid and sodium in the pathophysiology of hyperexcitability in migraine.     

From neuroimaging to clinical setting: what have we learned from migraine pain?

In the last 15 years, the neuroimaging of patients suffering from migraine with or without aura has improved our understanding of the mechanisms underlying the pathophysiology of the disease. A great number of studies based on modern imaging techniques, such as structural imaging and functional imaging emphasize that in migraine patients suffering from repetitive pain attacks, both significant abnormalities of function and diffuse structural changes of brain white and gray matter become striking features of the disease. The hypothesis that migraine pain is due to a global brain disorder with substantial brainstem involvement leading to secondary blood flow changes in the posterior circulation is reinforced by several elegant studies. Clinical application of functional imaging findings in migraine is yet to be considered, since the specificity of some results has to be determined. Nevertheless, functional MRI techniques have a vast potential for exploring the pathophysiology of pain in migraine patients.     

The pain in migraine beyond the pain of migraine

Migraine is a complex and often disabling brain disorder that affects about 15 % of the population. The diagnosis of migraine is based on clinical features as proposed by the International Headache Society criteria but they are somewhat subjective and arbitrary. Functional neuroimaging of patients with migraine has been recently employed to study the underlying pathophysiology of headache. These studies have suggested that migraine involves functional and structural plasticity of both central and peripheral nervous system. Insights into the fundamental physiology of migraine have been limited by the lack of methods available to detect the pathophysiological background of critical moment of migraine attack onset that is greatly different from the onset of pain or pain phase of a migraine attack. In order to overcome methodological caveats in detecting "migraine origin" or a "migraine generator", functional brain imaging has been lately dominated by experimental acute-pain research. Along this research line functional imaging using experimental pain stimulation have greatly improved our knowledge about physiological or dysfunctional neuronal activity pattern in patients with migraine, but at the same time, it is important to emphasize that experimental pain is different from spontaneous migraine pain.     

Genes, proteases, cortical spreading depression and migraine: impact on pathophysiology and treatment

Migraine headaches have a complex pathophysiology; both vascular and neuronal mechanisms have been proposed. One possible scenario begins with a series of destabilising events within the brain that trigger cortical spreading depression (CSD). CSD can cause both migraine aura and trigeminal activation which, in turn, promotes neuropeptide release and triggers peripheral and central mechanisms that promote headache and autonomic activation. Susceptibility to CSD and to migraine is, in part, genetically determined. The best evidence to date comes from certain subtypes of migraine with aura in which point mutations in genes controlling translocation of calcium, sodium and potassium have been implicated. This review briefly summarises recent migraine research that supports CSD as an upstream driver of the migraine attack as well as an activator of the trigemino-vascular system.     

Physiopathology of Migraine: What Have We Learned from Functional Imaging?

Purpose of Review

This review aims to provide an overview of the most recent and significant functional neuroimaging studies which have clarified the complex mechanisms underlying migraine pathophysiology.

Recent Findings

The recent data allow us to overcome the concept of a migraine generator suggesting that functional networks abnormalities may lead to changes in different brain area activities and consequent reduced migraine thresholds susceptibility, likely associated with higher migraine severity and burden.

Summary

Although functional magnetic resonance imaging studies have allowed recognition of several migraine mechanisms, its pathophysiology is not completely understood and is still a matter of research. Nevertheless, in recent years, functional magnetic resonance imaging studies have allowed us to implement our knowledge of migraine pathophysiology. The pivotal role of both the brainstem and the hippocampus in the first phase of a migraine attack, the involvement of limbic pathway in the constitution of a migrainous pain network, the disrupted functional connectivity in cognitive brain networks, as well as the abnormal function of the visual network in patients with migraine with aura are the main milestones in migraine imaging achieved through functional imaging advances. We believe that further studies based on combined functional and structural techniques and the investigation of the different phases of migraine cycle may represent an efficient methodological approach for comprehensively looking into the migrainous brain secrets.

     

Cortical spreading depression and calcitonin gene-related peptide: A brief review of current progress

Although detailed disease mechanisms of migraine remain poorly understood, migraine is known to have a complex pathophysiology with both vascular and neuronal mechanisms. The neuronal mechanisms of migraine may be attributed to cortical spreading depression (CSD); consequently, CSD has been widely studied for understanding the pathophysiology of migraine. Well validated CSD models have been developed for evaluating anti-migraine drugs. Neuropeptides, mainly, calcitonin gene-related peptide (CGRP), have been proposed as an emerging class of effective drugs against migraine headache. The central role of this neuropeptide has led to research into CSD for understanding disease mechanisms of migraine. This review briefly summarizes our current understanding of CSD and CGRP involvement in CSD. Although CSD can also worsen strokes, this brief paper has excluded the possible connection between the neuropeptide and CSD associated with them. Instead it has focused solely on CGRP in CSD associated with migraine.     

Migraine: What Imaging Reveals

Although migraine symptomatology is well-defined, our understanding of migraine pathophysiology is incomplete. Structural and functional brain imaging can contribute to a greater understanding of migraine pathophysiology. Recent neuroimaging studies demonstrate that migraine is associated with structural and functional alterations of brain regions commonly implicated in pain processing. This review summarizes recent brain structural and functional imaging findings in migraine and highlights those that are associated with characteristics such as the presence or absence of aura, associated cognitive dysfunction, sex-differences (male vs. female migraineurs), age, and disease burden.     

Arguments against the role of cortical spreading depression in migraine

Cortical spreading depression (CSD) is a wave of increased electrocortical activity and vasodilation, followed by sustained decreased activity and prolonged vasoconstriction. Although the discovery of CSD has been ascribed to Leão, rather than vasoconstriction, he only observed a depression of neural activity combined with vasodilation, with much weaker stimulation than used by his followers. There is a longstanding belief that CSD underlies migraine aura, with its positive symptoms such as mosaic patterns and its negative symptoms such as scotoma, and a similar propagation speed and vasoreaction pattern. However, there are many arguments against this theory. CSD is difficult to evoke in man, and electroencephalography (EEG) readings are not flattened during migraine (as opposed to EEG during CSD). Moreover, in contrast to CSD, migraine can occur bilaterally, and is not accompanied by a disrupted blood–brain barrier, increased cerebral metabolism, or cerebral cell swelling. Calcitonin gene-related peptide, which is thought to be characteristic of migraine pain, is increased in the blood from the external jugular vein during migraine in humans, but not during CSD in cats or rats. Moreover, CSD does not explain the appearance of premonitory symptoms or allodynia, long before the actual onset of aura. In addition, there is a variation in the pain mechanisms of migraine and CSD, and in their reaction to transcranial magnetic stimulation and several pharmacologic interventions. Finally, the origin of putative CSD in migraine is currently unknown.     

Cortical spreading depression modulates synaptic transmission of the rat lateral amygdala

Clinical and pathophysiological evidence connects migraine and the amygdala. Cortical spreading depression (CSD) plays a causative role in the generation of aura symptoms. However, the role of CSD in the pathophysiology of other symptoms of migraine needs to be investigated. An in vitro brain slice technique was used to investigate CSD effects on tetanus-induced long-term potentiation (LTP) in the lateral amygdala (LA) of the combined rat amygdala–hippocampus–cortex slices. More than 75% of CSD induced in temporal cortex propagated to LA. Induction of CSD in combined amygdala–hippocampus–cortex slices in which CSD propagated from neocortex to LA significantly augmented LTP in LA. LTP was inhibited when CSD travelled only in the neocortical tissues. Separation of the amygdala from the remaining neocortical part of the slice, in which CSD propagation was limited to the neocortex, increased LTP close to the control levels. Pharmacological manipulations of the slices, in which CSD reached LA, revealed the involvement of NMDA and AMPA glutamate subreceptors as well as dopamine D2 receptors in the enhancement of LTP in LA. However, neither blocking of GABA receptors nor activation of dopamine D1 receptors affected LTP in these slices. The results indicate the disturbances of LA synaptic transmission triggered by propagation of CSD. This perturbation of LA synaptic transmission induced by CSD may relate to some symptoms occurring during migraine attacks.     

Perspective of pathophysiology and treatment of migraine

Migraine is a most common neurological disease that affects nearly 10% of the general population. Although the pathophysiology of migraine is obscure, cortical spreading depression (CSD) is believed to be a phenomenon underlying migraine auras. On the other hand, the activation of the trigemino-vascular system is considered to be related to headaches. Furthermore, satellite ganglion cells located around the neurons in the trigeminal ganglion may contribute to migraine headaches. Besides, CSD has also been reported to activate the trigemino-vascular system, which subsequently causes migraine headaches. The present review discusses the recent findings of migraine pathophysiology, and mentions some newly developed calcitonin gene-related peptide (CGRP) receptor antagonists, which have revealed the efficaciousness for acute migraine attacks.     

Migraine: new molecular mechanisms.

Migraine is an episodic headache disorder affecting more than 10% of the general population. Migraine arises from a primary brain dysfunction that leads to activation and sensitization of the trigeminovascular system. A major incompletely understood issue in the neurobiology of migraine concerns the molecular and cellular mechanisms that underlie the primary brain dysfunction and lead to activation and sensitization of the trigeminovascular system, thus generating and maintaining migraine pain. Here the author reviews recent discoveries that have advanced our understanding of these mechanisms toward a unifying pathophysiological hypothesis, in which cortical spreading depression (CSD), the phenomenon underlying migraine aura, assumes a key role. In particular, the author discusses the main recent findings in the genetics and neurobiology of familial hemiplegic migraine and the insights they provide into the molecular and cellular mechanisms that may lead to the increased susceptibility of CSD in migraineurs.     

Clinical relevance of cortical spreading depression in neurological disorders: migraine,malignant stroke,subarachnoid and intracranial hemorrhage,and traumatic brain injury

Cortical spreading depression (CSD) and depolarization waves are associated with dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells, increased energy metabolism and changes in cerebral blood flow (CBF). There is strong clinical and experimental evidence to suggest that CSD is involved in the mechanism of migraine, stroke, subarachnoid hemorrhage and traumatic brain injury. The implications of these findings are widespread and suggest that intrinsic brain mechanisms have the potential to worsen the outcome of cerebrovascular episodes or brain trauma. The consequences of these intrinsic mechanisms are intimately linked to the composition of the brain extracellular microenvironment and to the level of brain perfusion and in consequence brain energy supply. This paper summarizes the evidence provided by novel invasive techniques, which implicates CSD as a pathophysiological mechanism for this group of acute neurological disorders. The findings have implications for monitoring and treatment of patients with acute brain disorders in the intensive care unit. Drawing on the large body of experimental findings from animal studies of CSD obtained during decades we suggest treatment strategies, which may be used to prevent or attenuate secondary neuronal damage in acutely injured human brain cortex caused by depolarization waves.     

Effect of cortical spreading depression on synaptic transmission of rat hippocampal tissues

Cortical spreading depression (CSD) is believed to be a putative neuronal mechanism underlying migraine aura and subsequent pain. In vitro and ex vivo/in vitro brain slice techniques were used to investigate CSD effects on the field excitatory postsynaptic potentials (fEPSP) and tetanus-induced long-term potentiation (LTP) in combined rat hippocampus-cortex slices. Induction of CSD in combined hippocampus-cortex slices in which DC negative deflections did not propagate from neocortex to hippocampus significantly augmented fEPSP amplitude and LTP in the hippocampus. Propagation of CSD to the hippocampus resulted in a transient suppression followed by reinstatement of fEPSP with amplitude of pre-CSD levels. LTP was inhibited when DC potential shifts were recorded in the hippocampus. Furthermore, CSD was induced in anaesthetized rats and, thereafter, hippocampal tissues were examined in vitro. LTP was significantly enhanced in hippocampal slices obtained from ipsilateral site to the hemisphere in which CSD was evoked. The results indicate the disturbances of hippocampal synaptic transmission triggered by propagation of CSD. This perturbation of hippocampal synaptic transmission induced by CSD may relate to some symptoms occurring during migraine attacks, such as amnesia and hyperactivity.     

Spinal and cortical spreading depression enhance spinal cord activity

Cortical spreading depression (CSD) has been suggested to underlie some neurological disorders such as migraine. Despite the intensity with which many investigators have studied SD in the brain, only a few studies have aimed to identify SD in the spinal cord. Here we described the main characteristic features of SD in the spinal cord induced by different methods including various spinal cord injury models and demonstrated that SD enhances the spinal cord activity following a transient suppressive period. These findings suggest that SD may play a role in the mechanisms of spinal neurogenic shock, spinal cord injury, and pain. Furthermore, we studied the effect of CSD on the neuronal activity of the spinal cord. CSD was induced via cortical pinprick injury or KCl injection in the somatosensory cortex. CSD did not propagate into the cervical spinal cord. However, intracellular recordings of the neurons in the dorsal horn of C2 segment, ipsilateral to the hemisphere in which CSD was evoked, showed a transient suppression of spontaneous burst discharges, followed by a significant enhancement of the neuronal activity. This indicates a link between a putative cause of the neurological symptoms and the subsequent pain of migraine.     

Closing remarks: what future prospects can we expect in migraine management?

The future prospects that we can expect in migraine management are both exciting and challenging. Obviously, the future cannot be predicted fully; however, the science related to migraine pathogenesis, diagnosis and treatment has increased exponentially over the past two decades and continues to direct future research and clinical care. More than any time in the recent past, it now may be more possible to define better what migraine is and how it relates to other neurological disorders and other diseases. This overview will look at future prospects for management of migraine and how they relate to the migraine diathesis, and ways that might provide a better understanding of how it might be possible to calm the excitable brain. This meeting examined potential future developments in the management of migraine patients, with emphasis on disability, quality of life, and the role of patient personality in episodic and chronic migraine with substance/analgesic overuse. This meeting precedes the main theme of the seminar, which explores the relationships between pain, emotion and headache in light of recent findings, which show that pain and emotion are closely interrelated and contribute to the pathophysiology of headache. Thus, it is important to understand about future migraine management prospects in terms of known migraine pathophysiology, as current data provide support for the concept that migraine is a brain disorder.     

Reduced threshold for cortical spreading depression in female mice

The prevalence of migraine is much greater in female than male individuals. Cortical spreading depression (CSD) is thought to be a fundamental mechanism of migraine, and CSD in rodents is used as a model for migraine. We used optical intrinsic signal imaging and electrophysiological techniques to investigate CSD in C57Bl/6 mice. Using two different methods for induction of CSD, we found that female mice had a significantly reduced threshold for induction of CSD compared with male mice. These results suggest an increased cortical excitability in female mice that may be independent of the estrous cycle.     

Resting-state fMRI functional connectivity: a new perspective to evaluate pain modulation in migraine?

Resting-state (RS) functional magnetic resonance imaging (fMRI) is a relatively novel tool which explores connectivity between functionally linked, but anatomically separated, brain regions. The use of this technique has allowed the identification, at rest, of the main brain functional networks without requiring subjects to perform specific active tasks. Methodologically, several approaches can be applied for the analysis of RS fMRI, including seed-based, independent component analysis-based and/or cluster-based methods. The most consistently described RS network is the so-called “default mode network”. Using RS fMRI, several studies have identified functional connectivity abnormalities in migraine patients, mainly located at the level of the pain-processing network. RS functional connectivity is generally increased in pain-processing network, whereas is decreased in pain modulatory circuits. Significant abnormalities of RS functional connectivity occur also in affective networks, the default mode network and the executive control network. These results provide a strong characterization of migraine as a brain dysfunction affecting intrinsic connectivity of brain networks, possibly reflecting the impact of long lasting pain on brain function.     

Interaction of synchronized dynamics in cortex and basal ganglia in Parkinson's disease

Parkinson's disease pathophysiology is marked by increased oscillatory and synchronous activity in the beta frequency band in cortical and basal ganglia circuits. This study explores the functional connections between synchronized dynamics of cortical areas and synchronized dynamics of subcortical areas in Parkinson's disease. We simultaneously recorded neuronal units (spikes) and local field potentials (LFP) from subthalamic nucleus (STN) and electroencephalograms (EEGs) from the scalp in parkinsonian patients, and analysed the correlation between the time courses of the spike–LFP synchronization and inter‐electrode EEG synchronization. We found the (non‐invasively obtained) time course of the synchrony strength between EEG electrodes and the (invasively obtained) time course of the synchrony between spiking units and LFP in STN to be weakly, but significantly, correlated with each other. This correlation is largest for the bilateral motor EEG synchronization, followed by bilateral frontal EEG synchronization. Our observations suggest that there may be multiple functional modes by which the cortical and basal ganglia circuits interact with each other in Parkinson's disease: not only may synchronization be observed between some areas in cortex and the basal ganglia, but also synchronization within cortex and within basal ganglia may be related, suggesting potentially a more global functional interaction. More coherent dynamics in one brain region may modulate or activate the dynamics of another brain region in a more powerful way, causing correlations between changes in synchrony strength in the two regions.