Cortical Spreading Depression & Migraine: the 60 year war & the wave of the future

10194_2013_Article_306_Fig1_HTMLCortical Spreading Depression (CSD) is one of the more well supported and researched theories when it comes to the cause of migraine aura. When I first read about it in recently published articles and news reports it sounded new, however, CSD dates all the way back to 1944. Instead this has been a war of theories and experimental models that has spanned over 60 years.

What is Cortical Spreading Depression?

Cortical_spreading_depressionCortical Spreading Depression is a wave of depolarization of neurons. Essentially it is like lights dimming, as one fades the ones next to it do as well. This has been linked to visual aura based on how auras often expand, first documented by Lashley, a visual physiologist, in 1941 as he mapped out his own visual auras and tracked the time [1].

CSD also has been linked to a change in blood flow in the brain, vasospasm happened to be one of the most widely held theories in migraine causation until being disproven in the 1980s.

In a DANA article migraine researcher Richard Kraig defines CSD as “a spreading wave of electrical silence in which cortical neurons go quiet. There’s no firing at all.” [5]

The depolarization wave in neurons provides solid theory with a growing amount of evidence as a potential cause of migraine aura. The impact of CSD on blood flow in the brain and overall disruption in brain activity leads it to be a potential theory for migraine. This is important as it can give insight into why particular preventative treatments work for Migraine with Aura, and can help with identifying the causation of migraine as a whole.

In the Beginning aka the 1940s

visualauralashley

Ashley’s map of his migraine auras [1]

In 1941 Lashley mapped out his own migraine auras and how the disruption vision grew over time. Shortly thereafter in 1944 Leao describes how electrical activity decreased based on distance from an electronic stimulus [1]. Simultaneously he noted that there was vasodilation that followed the depressed activity. However, he was only studying rabbits and the prevailing migraine theory was based on vasospasm alone. Though in 1959 a researcher named Milner noted:

Attention should be drawn to the striking similarity between the time courses of scintillating scotomas and Leao’s spreading depression because, if there is a true correspondence between these phenomena, there is hope that some of the work done on spreading depression can be brought to bear on the problem of migraine. [1]

Hmmmm. That’s a vary curious comparison there! Yet, the thought would not be continued until well into the 1980s after the vasospasm theory of migraine was set aside in favor of neurological models of migraine pathogenesis.

CSD and Neurological models of migraine gain speed in the 1980s

In a study by Lauritzen in 1981 where they found that in patients with migraine with aura there was in half the cases an initial increase in blood flow, then in all cases the blood flow then decreased. Lauritzen then concluded that:

The results indicate that the vasospastic model of the migraine attack is too simplistic. Alteration in neuronal function, in the blood-brain barrier, or in some other brain process is more likely to be the primary event of the attack. [1]

Further research on CSD and neurological models if migraine conducted by Lauritzen, Olseen and others had a huge impact on. Further studies showed that along with a documented decrease in neuronal activity there was a dramatic increase in blood flow followed by a decrease in those with Migraine with Aura. This could not be found in Migraine without Aura and led to the two variants of migraine having separate classifications by the International Headache Society [1].

Moskowitz then led the charge in CSD research with a theory that focused on the interplay of neurogenic inflammation and the trigeminovascular system. However, in 2001 his theories were discredited due to what was essentially poor study design [2]. CSD appeared to have been put to bed until two new heroes emerged.

A theory that ties CSD and the rest of migraine together has begun to emerge

In 2005 Burstein and Jakubowski, our new heroes, wrote a paper regarding a central theory linking the forebrain to the nerve that is believed to be implicated in migraine pain, they observed that:

Many different known migrainous triggers are processed in several hypothalamic nuclei and other limbic areas, all connected to the superior salivatory nucleus (SSN), an important parasympathetic station pro- jecting, in turn, to meningeal vasculature via the sphenopalatine ganglion (SPG), and involved in the cascade of biochemical events leading to neurogenic inflammation and peripheral trigeminal activation. [2]

image005ln plain speak most migraine triggers are processed by the forebrain. Also a part of the forebrain is our flight/flight system which is believed to be the player in sickness behavior (when we want to just crawl in a dark cave and die). Also, near where migraine triggers are processed is a relay to the trigeminal nerve, which is the nerve that goes to the face and head and is believed to be responsible for migraine pain. Even more interesting is that the trigeminal nerve also feeds information to the forebrain which can create a feedback loop, explaining why migraine can appear to go on for days. [2]

Burstein and Jakubowski went on to put CSD back on the radar in 2010 with two studies which links CSD to activation of the trigeminal nerve and the meninges both of which are indicated in migraine pain. Furthermore they were able to bring Moskowitz back into relevance and creditability. Their study found that the same superficial laminae involved in the Moskowitz study was reproduced in their own using different methods [2].

In summary the forebrain is both where the most migraine triggers are processed, and where the pain in migraine is produced. There is also new research linking Cortical Spreading Depression to the triggering of the trigeminal nerve, there is also research showing that CSD can impact the forebrain. The sickness behavior is often a hallmark of migraine, as it is a condition where the sufferer often wants to be isolated in a dark quiet place during an attack.

All of these pieces are still only theoretic portions of a model, there is a reasonable amount of evidence supporting each piece and it seems with each subsequent study more of the pieces begin to slide into place.

Implications for treatment

10194_2013_Article_306_Fig2_HTML

Potential targets of medications based on current knowledge of CSD [4]

Knowing more about what causes migraine allows science to study current medications that are used for migraine prevention, and have a better understanding of how they work. Already there is a lot of curiosity around the apparent fact that there is no one class that appears to treat migraine. Out of the antidepressants it is debatably only Amitriptyline that has a solid track record. With the Anticonvulsants there are a few gold standards for Epilepsy which do nothing for migraine primarily Carbamazepine and it’s relatives. [4]

Through a better understanding of CSD there is the potential to understand why some medications in a class work, and others don’t. The Lamictal study openly muses on how the results with migraine aura may be due to how the drug mediates CSD. Ideally, these new insights into migraine will lead to new migraine specific treatment options which target the underlying cause.

CSD also explains why abortive medications do not work until the headache phase. The rapid up and down flow of neuronal activity and blood flow just do not cooperate. Abortives target the attack phase of a migraine where these changes in electrical activity and blood flow in the brain have settled. [3]

Though this extends past medication, and into potentially having a better understanding of why certain lifestyle changes often need to be made for migraine. Science is beginning to develop a complete picture of how migraine works, and the next ten years or so look like they will be filled with exciting new developments.

References

  1. History of migraine with aura and cortical spreading depression from 1941 onwards
  2. Cortical spreading depression and central pain networks in trigeminal nuclei modulation: time for an integrated migraine pathogenesis perspective
  3. Cortical Spreading Depression: A Model for Understanding Migraine Biology and Future Drug Targets
  4. Cortical spreading depression as a target for anti-migraine agents
  5. Theory Behind Migraine Emerges
  6. Lamotrigine reduces migraine aura and migraine attacks in patients with migraine with aura

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