What does “aura” mean?
The term aura describes any neurological disturbance that appears shortly before or during the development of migraine headaches. Migraine with aura is a common type of migraine. The aura usually lasts less than 1 hour, and almost invariably fades away without long-lasting effects. The most common aura involves the vision, with hallucination/illusion of bright flashing lights and partial blindness.
Aura figure 1This shows the brain’s level of electrical activity. Reading from left to right, we can see the spreading of CSD of electrical activity (detectable as a reduction of the recorded signals to a straight line) and the subsequent return to normal electrical activity over a 9 minute period (Modified from Leão AAP, Journal of Neurophysiology, 1944, with permission from the American Physiological Society).
The first description of migraine aura is attributed to the German abbess Hildegard of Bingen, a truly remarkable woman who lived in Rhineland in the 12th Century. At the age of 32, she began to receive ‘holy visions’, but some neurologists attribute her descriptions to the classic symptoms of migraine with aura (See front cover). By 1941, the characteristic symptoms of the visual aura had been well described, and it was known to result from a disturbance of the visual cortex rather than from a malfunction of the eye retina. However, that year, Karl Spencer Lashley, an eminent psychologist working at Harvard who suffered from migraines published an article that later turned out to be extremely important. Through a careful analysis of the sketches of his visual illusions, and especially by following their development, with time he was able to propose that the visual aura probably results from a wave of intense excitation of the visual cortex (producing the visual illusion of scintillations or bright flashes) followed by complete inhibition of activity (resulting in temporary and partial blindness). These disturbances move at a rate of about 3 millimetres per minute across this cortical region in the brain.
What is cortical spreading depression?
The scientific term cortical spreading depression (CSD) describes a local disturbance of the brain function that is characterised by a transient and local suppression (depression) of the spontaneous electrical activity in thecortex (cortical) that moves slowly across this brain region (spreading). Aristides A.P. Leão, a Brazilian studying for a PhD at Harvard University was the first to describe this phenomenon in 1944 (Figure 1). He made this discovery while studying epilepsy. One year later, a better characterisation of CSD, especially of its progression, allowed Leão and his colleague R.S. Morison to propose, for the first time, that the malfunction of cortical nerve cells suspected to cause the aura might well be CSD. Indeed, both the suspected nervous malfunction and CSD shared surprisingly many common properties.
Aura figure 2Spreading suppression of cortical activation during migraine aura. A – in the top left corner is a drawing showing the progression of the aura symptoms, as described by the patient. B is the origin of this brain anomaly as seen by functional MRI (fMRI). (Modified from Hadjikhani and collaborators, Proceedings of the National Academy of Sciences of the United States of America, April 2001, with permission of the authors and the National Academy of Sciences of the USA).
The working brain
Under normal conditions, brain cells use a complex biochemical mechanism to maintain very different levels of several ions on each side of their cellular membrane. For example, the level of potassium is much higher within the cells than outside, whereas it is the reverse for sodium and calcium. This capability, called brain ion homeostasis, is vital to the brain’s electrical activity (Figure 2). It is now well established that a temporary failure of this cellular ion homeostasis occurs during CSD, with potassium suddenly leaking out of the cells, whereas sodium and calcium enter the intracellular space. Hence, the initial malfunction leading to the spreading, local suppression of electrical activity is actually a migrating local failure of brain ion homeostasis.
The progress of science
The link between migraine aura and CSD was confirmed in the early 1980’s, with the development of clinical methods for the imaging of cerebral blood flow in patients. These new methods allowed a team of researchers in Copenhagen to demonstrate that a unique pattern of changes in local cerebral blood flow was associated with an attack of migraine with aura. In particular, they were able to observe that, at the beginning of such an attack, cerebral blood flow decreased in the posterior part of the brain (which is concerned with visual perception), with the low flow regions subsequently spreading into the more frontal brain regions at the rate of 2 to 3 millimetres per minute. This was precisely the rate of CSD propagation that was measured in animal models, and reduced blood flow was already known to be associated with experimental CSD. The recent, spectacular advances in magnetic resonance imaging (MRI) of brain function have provided a definitive confirmation of these findings.
The value of knowledge
CSD is now attracting increasing interest from neuroscientists in both academia and the pharmaceutical industry. Firstly, 50 years after its discovery, it was finally agreed that this phenomenon plays a key role in the genesis of migraine attacks, possibly even when it is not preceded by an aura (migraine without aura is the common type). Indeed, it is currently suspected that CSD, depending on where it occurs in the cortex, may not always be associated with a perceived aura. Secondly, as CSD appears as the initial trigger of migraine attacks, the discovery of drugs capable of suppressing this nervous disturbance would potentially lead to the development of medicines to prevent the initiation of migraine (prophylactic treatment), in contrast to most current anti-migraine drugs that only treat the subsequent headache.
The Remaining Challenges
At present, the most important task is the discovery of drugs that can suppress CSD. These will have to be well tolerated (without side effects) if they are to be used to prevent migraine, because migraineurs will have to take them repeatedly over a long period, just as epileptic patients take drugs to prevent their seizures.
Improving our understanding of how CSD can lead to headache is another research strategy that will certainly help with the discovery of new anti-migraine drugs. So far, we know that this involves a complex cascade of events that ultimately leads to the activation of pain-sensitive fibres in the brain, but the overall picture is far from complete.
Most studies on CSD are carried out in models and tissue preparations where CSD is elicited experimentally using strong external stimuli such as the application of potassium chloride or electrical stimulation of parts of the brain. But, in the brains of people with migraine, the aura occurs without such strong external stimuli. Therefore, a key question is: what predisposes the brain of migraineurs to spontaneous CSD? It is likely that several anomalies of the complex machinery associated with the brain cell membrane can promote the occurance of CSD, and this certainly includes several types of genetic anomalies. The discovery of these altered genes will dramatically improve our understanding of the genesis of migraine attacks. This scientific knowledge may allow us to tailor the treatment of migraine to the specific genetic predisposition of a given group of patients.The possibility for such a gene-directed therapy of migraine is certainly a worthwhile long-term objective.
Acknowledgements
The authors are grateful to Louise Shepherd from the Library of the Institute of Neurology (London) for providing them with ‘historic’ scientific literature.
Authors
Tiho P. Obrenovitch is Reader in Neuroscience at the Bradford School of Pharmacy. Jens P. Dreier is a Neurologist at the Charité University Medicine in Berlin, Germany. Both are actively engaged in research focused on cortical spreading depression.
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