Rethinking migraine with aura: Why cortical spreading depolarization (depression),not aura,causes headaches

Abstract

Cortical spreading depolarization (depression) underlies migrainous aura and is posited to cause its headache. At times, aura may start before headache, auras may start at the same time as, or shortly after headache onset, or sometimes without any headache at all. We suggest that the extent of spread and not the spread limited to eloquent cortex, is the key variable in the genesis of headache. Consistent with this notion, a first human case studied electrophysiologically showed that cortical spreading depolarization spreads extensively and silently

We propose a Buildup Hypothesis to explain headache generation in migraine with aura. Buildup occurs because cortical spreading depression releases noxious chemicals from cortical cells that accumulate in tissues and cerebrospinal fluid to reach levels sufficient to trigger pial afferents and cause pain. The extent of silent (or relatively silent) spread determines significant buildup. This Buildup Hypothesis helps to explain (1) typical and shorter latencies between end of aura and headache onset (approximately 0–20 minutes) and (2) why headache may not develop after aura (insufficient buildup), and also addresses temporal discrepancies such as headaches starting before an aura (i.e. subclinical spread with buildup in advance of aura). Hence, aura and headache are distinct consequences of cortical spreading depolarization.

Keywords

cerebrospinal fluid CGRP extra-axial inflammation trigeminovascular system visual aura

Introduction

Experimental animal models have been crucial for discovering new therapies and for developing hypotheses that promise a coherent understanding of migraine pathophysiology. Successful treatments for migraine critically depend upon these models and highlight the achievements of translational science; however, our understanding of underlying migraine pathophysiology has not kept pace, in part because of the painfully slow acquisition of new knowledge informing us about underlying brain events surrounding attacks in migraineurs. Consequently, isolated cases too infrequently emerge that confirm or challenge key principles, such as the recently reported electrophysiologic confirmation of cortical spreading depolarization (CSD) in a patient with migraine with aura (1). This case provides an opportunity to examine more closely the link between CSD and migraine with aura to conjecture about CSD as the only headache trigger for which there is experimental and human data, and the need for more experimental data to explore the hypothesis in this Viewpoint/Perspective.

CSD and migraine: the evidence mounts

Collective evidence from human and experimental studies suggests that CSD is the fundamental neurobiological event underlying migrainous aura and is often sufficient to activate the trigeminovascular system (2-5). Until recently, the most technically advanced demonstration of CSD came from a high-resolution magnetic resonance imaging (MRI) study published two decades ago in a patient who induced his attacks by intense exercise (6). The observed propagating BOLD (i.e. blood oxygenation level dependent) signal perturbation (2–6 mm per minute) was retinotopically matched to the patient's visual aura, providing a unique spatial and temporal correlation between the subjective aura and the underlying cortical event, comprising findings that remain unmatched by any other non-invasive technologies.

Confirming CSD in the human brain

Regardless of how persuasively the preclinical or clinical evidence implicates CSD, it is crucial to confirm defining characteristics by direct electroencephalographic recording, namely, by documenting its slowly propagating wave suppressing low voltage electrical activity, which is nearly impossible to record using scalp electrodes. However, confirmation was recently achieved using stereotactically placed microelectrodes providing a rare and instructive window into the details of a single episode in a migraineur's brain (1).

In this case, a 32-year-old woman with a history of migraine with visual aura was admitted for presurgical workup of intractable epilepsy. On the ninth day of her hospital stay, she experienced a typical visual aura affecting the right upper quadrant, followed by a headache commencing 31 minutes later. The event began abruptly and was marked by a slowly advancing suppression of low-voltage background activity, propagating at a rate of 3 mm per minute. This suppression, characteristic of CSD, was detected initially by the left mesial superior occipital microelectrode, and the spread continued long after the visual symptoms resolved. There was no evidence of pathology found on MRI and computed tomography scans after the attack.

Comments on this case and why aura does not cause headache

This case is important because it provides the first electrophysiologic confirmation of CSD in a patient and provides evidence that CSD can propagate for long distances silently over parietal and temporal lobes, just as predicted by the wide-spread propagating blood flow decreases in occipital, temporal and parietal lobes measured by multiple modalities (3,7-10). Except for headache and its accompaniments and notable CSD propagation, this patient experienced only mild symptoms between the end of the visual aura and the last electroencephalographic recording. Her headache began 31 minutes after the onset of aura, which suggests a mechanism brewing in brain that is reasonably typical of the latency in most migraineurs.

We offer a caveat also shared by McLeod et al. (1): epilepsy may have lowered the CSD threshold for evoking it and enhanced its propagation into the frontal lobe. With caveats in mind and the acknowledged limitations of generalizations based on a single captured attack in a human, we offer explanations for what underlies the infrequent disconnect between the timing of aura and onset of headache. We take this opportunity to comment because such a well-documented case using stereotaxic electroencephalography is very unique indeed (Figure 1).

Figure 1.

Three scenarios relating cortical spreading depolarization (CSD), visual aura and timing of headache onset. (a) Headache beginning ≥0–20 minutes after the aura ends. CSD began and spread in eloquent visual cortex and then significantly into adjacent tissues until sufficient depolarization to generate headache. (b) Headache beginning at or before aura onset or during the aura. Requires extensive spread initiated in adjacent non-eloquent cortex before aura for earliest onset of headaches (even before aura). Headache beginning during the aura requires the above and extensive extra-striatal spread during it. (c) Migrainous aura without headache. Spread of depolarization confined mostly to primary visual cortex and provides an insufficient amount of depolarized tissue to generate a headache. Arrows represent the direction of CSD spread. Shaded area in posterior brain represents primary visual cortex. Graphic created by Marv Ruona (http://www.artandsciencegraphics.com).

First let us consider the 31-minute delay from the onset of aura to the headache phase, typical of many migraineurs. The “Buildup Hypothesis” posits that the extent and duration of CSD propagation determine the magnitude of released noxious mediators. These accumulate in tissues and cerebrospinal fluid (CSF) to influence the likelihood and timing of headache onset. Considering that aura onset started in this patient at or about the inferior wall of calcarine fissure (primary visual cortex), we surmise (using a 31 minute spread × 3.5 mm per minute) that the headache began sometime around when depolarization reached on or before 7.5 cm anteriorly from the first electrode in the left mesial superior occipital cortex to about the precuneus medially and the angular gyrus and anterior parietal cortex, laterally. Although a very gross estimate, this is a large volume of depolarized tissue that is consistent with the spatial distribution of spreading hypoperfusion in spontaneous or induced attacks (3,7-9). To explain a similar timing between the end of aura and headache, we posit that CSD spreads not only within Brodmann area 17 or primary visual cortex but simultaneously and silently within adjacent tissues to generate a critical volume of depolarized cells to cause headache (fig a).

From CSD onset, the brain solute released into tissues diffuses into the subarachnoid space and CSF challenged by edema but readily crosses the glial limitans reaching pia mater and CSF (11,12). In this model, the accumulating CSF solute then discharges local pial afferents after reaching critical threshold levels, and possibly even activates remote pain sensitive sites like trigeminal ganglia (12), as well as dura mater (11), the latter by extensive axon collaterals. The “Buildup Hypothesis” may help explain the typical headache latency after aura (fig a), as well as cases where aura occurs without headache (insufficient buildup) (fig c). As noted above, spread in this instance is best explained by CSD confined mostly to primary visual cortex. CSD may continue beyond the onset of headache as observed in this patient with a chronic epilepsy confound. If observed in more typical migraineurs, it could be a new therapeutic opportunity.

Depolarized cells release several noxious substances into tissues, including hydrogen and potassium ions, neurotransmitters including calcitonin gene-related peptide (CGRP) (12,13), serotonin and glutamate, tissue modulators such as nitric oxide, arachidonic acid, and prostaglandins (3,12 –15). CSD also induces a pro-inflammatory CSF proteome to significantly change CSF composition plus upregulated proinflammatory genes within trigeminal ganglia (12,16). Individually and especially together, these molecules (comprising an endogenous inflammatory soup) are sufficient to discharge primary afferents in pia mater. These events underlie the strong experimental evidence to suggest CSD as an activator of ipsilateral trigeminovascular system (2,11,12,15,17,18)

In instances where aura and headache begin almost simultaneously (19-22), we infer that CSD starts silently in areas remote and possibly near but not within eloquent cortex. Headache is caused when buildup is sufficient, and, in this instance, around the time or just before when CSD spreads into calcarine cortex. If headache does occur during the aura, it either requires simultaneous extra-striatal spread (outside primary visual cortex) or spread initiated before reaching eloquent cortex (fig b).

It follows from the above that if aura is suppressed by a drug (ketamine) but does not impact the number of headache days, it probably did not block CSD propagation remote from eloquent cortex and a higher dose might deserve consideration (23). We also should be mindful that a precise relationship between the load of depolarized tissue and headache onset cannot easily be predicted partly because the tissue organization, composition and solute concentration may vary across different cortical regions and CSD does not always spread along all six cortical laminae. Other issues may be relevant such as the relatively few pial afferents whose density likely varies between regions plus CSF dynamics that reduce the likelihood of headache by CSF washing away and diluting solute. All of these factors need to be considered which reminds us that we need better tools to evaluate these parameters and greater knowledge of pia mater innervation and its neurophysiologic properties.

We should remind ourselves that migraine variability extends beyond auras and headaches. For example, just as in this patient, 1 in 4 migraineurs do not experience anticipatory or prodromal events prior to the onset of aura (22). Because a prodrome is not universally experienced, one could easily discount this phase in the genesis of attacks, as, for example, some have searched for alternatives as a cause of headache (i.e. because headaches do not always follow or conform to expectations about timing) (21). Thus, CSD, or any other brain-meningeal mechanism proposed to generate pain, presents a unique set of challenges in elucidating its role in migraine pathophysiology (17).

Based on the above and the following section, we do believe that headache following aura is a response to a significant noxious stimulus and not a misperception (19-22) or part of a parallel process (where exactly and what is in parallel is still unknown) (19). The imaging studies showing pathological features in migraineurs (24), do not support these alternative notions.

Headache and the trigeminal nerve

Consistent with the above, the location of headache is ipsilateral to the recorded CSD informing us that there is a stimulus sufficient to activate ipsilateral trigeminovascular afferents in migraine with auras and not by events driven within the affected hemisphere (that would cause contralateral headache). Blood flow data also show most commonly, that the accompanying hypoperfusion (a manifestation of CSD) is ipsilateral to the headache and contralateral to the aura symptoms (10). The headache may remain ipsilaterally (as in this patient), consistent with headaches that accompany structural brain lesions such as acute stroke, brain tumor or abscess. Hence, they probably all share the same anatomy of headache which involves the ipsilateral trigeminal nerve. What does not fit the anatomy of headache is the ipsilateral thalamocortical consequences postulated as an alternative cause of ipsilateral migraine headache following aura (21).

We are learning that migraine headaches have significant consequences. The trigeminal nerve at the skull base shows microstructural evidence consistent with inflammation and demyelination (24). Using 7T multimodal strategies (diffusion tensor imaging and functional MRI and integrated positron emission tomography (PET)/MRI), 60 migraineurs showed signs of neuroinflammation and demyelination especially on the most frequent side of headache not seen in 20 controls. Although admittedly, the cause for pathological changes in root or nerve remain to be determined, it most likely reflects repeated and sustained trigeminovascular overactivation, as suspected in patients with trigeminal neuralgia and temporomandibular disease. Without a downstream peripheral driver like CSD, we believe it is most unlikely that a purely central pain generator such as in brain stem or hypothalamus would produce such changes. In summary, wherever pertubations in brain may underlie migraine with or without aura, the trigeminovascular system (its nerve fibers, nerve, ganglion, root and central projections), serves as a final common pathway (17).

CSD and inflammation

Inflammation has been implicated in migraine supported by both elevated levels of circulating inflammatory markers such as cytokines, including tumor necrosis factor-α, interleukin-1β and interleukin-6 (25) and neurogenic inflammation (11). Although inflammation is a frequent companion of pain, inflammation is not a surrogate pain marker. Instead, inflammation may cause pain and pain may augment inflammation. CSD is a notable trigger of inflammation as well as pain.

Recent clinical studies provide compelling evidence for meningeal neuroinflammation consistent with findings in animal models. A 2020 study utilizing simultaneously acquired PET and MRI imaging demonstrated a robust signal for the translocator protein TSPO, a widely used marker of inflammation, in the brain and meningeal tissues of individuals experiencing repeated migraine attacks with visual auras (26). Notably, increased TSPO binding was consistently observed in the occipital cortex and overlying dura mater (25), suggesting localized tissue inflammation. While the specificity of the TSPO ligand has been debated, the striking spatial distribution of the signal in three adjacent tissues supported by two distinct circulations supports a genuine tissue response rather than artifact (27), aligning with hypotheses of peripheral pain activation in migraine with aura (2).

Moreover, the REFORM study, a large cohort investigation, used quantitative MRI to assess inflammation in 300 migraineurs and 100 controls (28). The study found increased T2 signal in the pericalcarine cortex and left lateral occipital cluster of migraine with aura patients, indicative of elevated water or cell content, both consistent with markers of inflammation.

Collectively, findings from both animal models and human studies reach the conclusion that inflammation, particularly the fingerprints of CSD and meningeal pathology, is a key feature in migraine cases with aura.

General considerations

Our hypothesis does not suggest that CSD is a universal cause for headache among migraine subtypes such as migraine without aura. However, it seems prudent to rule out CSD or an equivalent event in a remote brain region that can support CSD but has not been rigorously investigated (e.g. cerebellum). Our formulation does not discount headache modulation by central mechanisms such as from the brain stem (22) or those leading to sensitization (2,18,29), nor the impact of ongoing pro- or antiinflammatory mechanisms associated with CSD (30,32) nor can we discount the potential contribution of a mechanism such as proposed recently following CGRP infusion (31). As important as they may be, they are not part of this hypothesis dealing with the relationship between CSD, aura and headache.

What our hypothesis does suggest however is the need for experiments to help clarify the relationship between CSD and migraine such as studies to measure CSF solute concentrations during an attack and to correlate real-time CSD mapping with headache onset (using genetically encoded calcium indicators together with electrophysiological recordings), difficult experiments to perform in both humans and experimental models at this time. However, published neuroimaging studies in aura patients should be reassessed to determine whether larger areas of cortical involvement (spreading hypoperfusion) correspond to a higher probability for headache.

Conclusions

In summary, recent findings from the literature reveal several key points that are consistent with CSD causing trigeminovascular activation and headache making it increasing impossible to accept the concept that CSD has little to do with the headache of migraine with aura. To provide a unifying theory of pain, we introduce the Buildup Hypothesis as a major contributor to headache generation. The hypothesis leads us to a core conclusion about the relationship between anticipatory events and headache, and provides plausible explanations for why this relationship between CSD and headache holds together so well, if the question is framed appropriately: “Does CSD cause headache?” So, put in simple terms, the headache of migraine with aura is caused by triggering of a “peripheral” trigeminal nerve by downstream events from a central nervous system perturbation (i.e. CSD), a paradigm that begins to reconcile the apparent confusion between whether migraine is a peripheral or central nervous system problem. It is both.

It is remarkable that since we first introduced the concept plus provided the first evidence that CSD triggers trigeminal activation, over 30 years ago (32), the field has been enriched by several important challenges and new hypotheses (33). My intent here was to revisit this question about CSD and headache by integrating new ideas and explanations that address and refute alternative viewpoints. Translating from animals to humans and from humans to humans is never easy but provides an essential step towards understanding the causes of headache and to improve upon its treatments.

Clinical implications

CSD causes aura from eloquent cortex but at the same time spreads relatively silently and extensively.

CSD causes pain by release of noxious chemicals by cortical cells that accumulate in CSF and reach levels to trigger pial afferents.

The volume load of those chemicals released into CSF determine in part, whether and when headache develops.

Migrainous auras and headache can begin at the same time when CSD spreads silently in remote cortex prior to reaching eloquent cortex.

Footnotes

Declaration of conflicting interests

The author declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The author received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Michael A. Moskowitz

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