Cortical Spreading Depression (A brief guide)

Cortical Spreading Depression
JuanitaHFNE

Juanita Agboola is the editor in chief of HFNE and an expert in mental health online. She has been writing about online behaviour, mental health and psychology issues since 2012. All Guides are reviewed by our editorial team which constitutes various clinical psychologists, PhD and PsyD colleagues.

In this guide, we will discuss what Cortical Spreading Depression means and some important aspects of CSD. 

Cortical Spreading Depression

Cortical spreading depression or CSD has been related to a wave of depolarization that is associated with a propagating wave of depolarization of neurons and glial cells that spreads across the cerebral cortex. The spreading of this wave is believed to activate the trigeminal nerve afferents, causing an inflammatory effect in pain-sensitive structures that lead to migraine headaches.

The brain is a very complex structure and researchers have attempted to unravel the relationship between anatomy and functioning but there is still a lot of research that needs to be done in the matter. 

The original description of CSD has been dated back to 1944 by Leao and extensive research and publications have attempted to characterize this phenomenon. There has been a lot of attention directed to CSD for over more than six decades but there are still many fundamental questions left unanswered associated with its initiation, propagation, functional consequences, and relationship to migraine and other conditions such as ischemia, seizures, and migraine variants still considered a mystery.

Cortical Spreading Depression (A brief guide)

In addition, there have been interesting advancements in genetics and imaging that have led to important insights into the basic mechanisms of Cortical spreading depression, with an increased attention on specific neuronal ion channels, neurotransmitters, and neuromodulators. 

Astrocytes and the vasculature may play an active role so there has been a growing interest in them, rather than considering they only have a passive or reactive role in Cortical spreading depression. Studies in humans in the area of brain injury provide important evidence that Cortical spreading depression can occur and have an important functional consequence in the human brain. 

As mentioned, this phenomenon is associated with the aura of migraine that occurs in humans and animals. Cortical spreading depression can be measured through imaging techniques which are considered an intrinsic optical signal. According to Haas et. al, (2009) “it is correlated to a Ca2+ increase in astrocytes, which can be simultaneously recorded.” 

In addition, researchers have demonstrated that cortical spreading depression, in the hippocampus, is accompanied by an astrocyte Ca2+ wave and that the astrocyte Ca2+ wave can be abolished in Ca2+-free, ethylene glycol tetraacetic acid (EGTA)-containing solution, while the spreading depression still occurs. This indicates that spreading depression triggers the astrocyte Ca2+ wave (Hass et. al., 2009).

Other researchers such as Ruthirago et. al., (2017) have indicated that “Several molecular cascades are activated by cortical spreading depression including the opening of pannexin-1 mega channels, the release of proinflammatory mediators.”

Cortical Spreading Depression (A brief guide)

This is believed to originate the aura altering the permeability of the blood-brain barrier, evoking and prolong the activation of trigeminal nociceptor that causes migraine headaches. In addition, “migraines without aura may be explained by the occurrence of this phenomenon in some parts of the brain where depolarization waves cannot be perceived.”

Cortical spreading depression (CSD) has been said to be an electrophysiological phenomenon that is characterized by a wave of excitation followed by inhibition in cortical neurons. As mentioned, “the aura phase that precedes migraine headache in about 20–30% of migraineurs may be a direct consequence of the events of cortical spreading depression (Borsook et. al., 2015).” 

However, the role of cortical spreading depression in patients that suffer from migraines but without aura is not well understood yet. Some studies have shown sub cortical spreading depression. Spreading depression may be the basis for neuroanatomical and functional (central hypersensitivity) changes observed in patients that suffer from migraines. 

Mechanisms of Cortical Spreading Depression

As it is known, neurons are the brain cells that use electrochemical energy to drive signaling in the brain. It has been described how they store the energy in the form of ion gradients across the cell membrane and it is said that the main ions involved in this process (neuronal excitability) are sodium, potassium, and chloride where the neuron needs only a small amount of this energy to fire the signal. 

Cozzolino et. al., (2018) indicate how “during an action potential, the flux of very few ions through specific membrane channels causes the membrane potential to rise and fall within the space in a millisecond. The activity of the Na/K-ATPase pump is crucial in restoring ion homeostasis. The brain consumes about 20% of the body’s basal energy and Na/K pumps use about half of this 20% share in maintaining ionic gradients.”

Cortical Spreading Depression (A brief guide)

Glial cells have also identified to play a crucial role, “serving to buffer K+ ions in the extracellular space and absorb the glutamate released from excitatory synapses, thereby avoiding excitotoxicity reactions.” 

However, it has been described how when there is a higher concentration of these molecules or if they exceed the threshold, neuronal and glial transporters can no longer cope with the efflux. This can result in massive extracellular accumulation of K+ and glutamate (neurotransmitter) and in large cell depolarization accompanied by loss of membrane resistance and large shifts in the intracellular and extracellular concentrations, that can in term prevent the generation of action potentials. 

In animal models, specifically in chick retina, Cortical Spreading depression “induced an initial increase in intracellular pH, which was associated with elevated levels of ADP, P-Creatine, lactate, and pyruvate. This was followed by an intermediary acid shift, increases in ATP values and decreases in ADP, a late alkaline rebound, a decrease in P-Creatine levels, and elevations in both ADP and lactate levels (Costa et. al., 2013).”

Moreover, these changes are said to occur parallel to the changes of energy in the intracellular pH metabolite levels during CSD, which may be expressions of rapidly modifying metabolic activities of neurons and glial cells. The first alkaline shift was attributed to glial cells, whereas the intermediary acid shift was attributed to neurons. 

Reduction of Local Electrical Activity

Researchers have described how there is a reduction of electrical activity that tends to show up as a negative slow potential charge due to the propagating depolarization. This is believed to be a result of longitudinal gradients of depolarization along neurons. 

Cozzolino et. al. (2018) have stated that “In fact, neurons do not seem to be inactivated along their entire anatomy during the massive cell depolarization; instead they maintain their integrity and electrical function, except in the dendritic zone where ion channel opening allows large sustained influxes of small cations, such as sodium and calcium.”

Cortical Spreading Depression (A brief guide)

The zero to rest Intracellular potential gradients can be explained by a combination of shunted membranes and ion redistribution along with discrete cell subregions. This electrical activity suppression in Cortical spreading depression is said to rest on the reduction of synaptic currents that, in turn, reduces neuronal energy requirements, which is believed to be caused in the presynaptic process. 

The synaptic failure is said to be induced by a high extracellular levels of adenosine which is a breakdown product of ATP preventing the vesicular release of glutamate. The increased ATP consumption can be caused by high adenosine levels. For several minutes after repolarization, the electrical activity remains suppressed, meaning the neurons do not generate action potentials during this period. 

Some recent experiments have evidence that the large reduction in action potential firing observed after cortical spreading depression could be due to a shift in the excitation/inhibition ratio toward inhibition, showing that reduced action potential firing, like post-synaptic potential amplitude changes, lasted at least an hour after the depolarizing event (Cozzolino et. al., 2018). 

Cortical Spreading Depression in Migraine

Migraines are understood as a recurring neurological disorder that is characterized by unilateral, intense, and pulsatile headaches. It is believed that in one-third of these patients that suffer from migraines, these attacks are actually preceded by a visual aura described as a slowly-propagating scintillating scotoma (Cui, Kataoke and Watanabe, 2014). 

In addition, migraines are said to be the result of the neurovascular phenomenon of cortical spreading depression, a self-propagating wave of depolarization that spreads across the cerebral cortex. Experiments in animals have shown that cortical spreading depression causes intracranial neurogenic inflammation around the meningeal blood vessels, such as plasma protein extravasation and pro-inflammatory peptide release. 

In addition, it has also been reported that it can activate both peripheral and central trigeminal nociceptive pathways. Although several issues remain to be resolved, recent evidence suggests that cortical SD could be the initial trigger of intracranial neurogenic inflammation, which then contributes to migraine headaches via subsequent activation of trigeminal afferents (Cui, Kataoke and Watanabe, 2014).

Key aspects of Cortical Spreading Depression

According to Nature.com, here are some of the key aspects of Cortical Spreading Depression:

  • Cortical spreading depression is a slowly propagating wave of altered brain activity that involves dramatic changes in neuronal, glial and vascular function.
  • In Humans, it has been characterized extensively via recordings from the exposed brain surface in patients that have suffered a brain injury. 
  • The widely accepted hypothesis that CSD is the physiological mechanism underlying the migraine aura is supported by substantial evidence from animal models, but definitive proof in patients with migraine is still lacking.
  • In animal studies, it has been indicated that CSD can activate pain pathways, but the role of CSD as a potential trigger for migraine headache remains uncertain.
  • It is believed that CSD is a fundamental pattern of brain signaling that provides an opportunity for greater understanding of nervous system physiology, and for the identification of new therapies for migraine and other brain disorders

Why is this blog about cortical spreading depression important?

Cortical spreading depression is a phenomenon that is still being researched since there are a lot of unanswered questions around the association with its initiation, propagation, functional consequences, and relationship to migraine and other conditions such as ischemia, seizures, and migraine variants still considered a mystery.

The brain is a very complex structure and we still haven’t unraveled in total certain phenomena that are left understood at the moment. It is necessary then to conduct more research about this phenomenon so we can untangle the mysteries about Cortical spreading depression. Please feel free to comment in the comments section below. 

Recommended reading

References

Cui, Y., Kataoka, Y & Watanabe, Y. (2014) Role of cortical spreading depression in the pathophysiology of migraine. Neurosci Bull. 

Charles, A & Brennan, KC (2009) Cortical spreading depression New insights and persistent questions. Cephalalgia.

Cozzolino, O., Marchese, M., Trovato, F., Pracucci, E., Ratto, G.M., Buzzi, M.G, Sicca, F. & Santorelli, F.M (2018) Understanding Spreading Depression from Headache to Sudden Unexpected Death. Front. Neurol. https://doi.org/10.3389/fneur.2018.00019

Sciencedirect.com

Costa, C., Tozzi, A., Rainero, I. et al. Cortical spreading depression as a target for anti-migraine agents. J Headache Pain 14, 62 (2013). https://doi.org/10.1186/1129-2377-14-62

Nature.com

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