Aura and Head pain: relationship and gaps in the translational models

DOI: https://doi.org/10.1186/s10194- 019- 1042- 8

Abstract-Summary Cortical spreading depression (CSD) is recognized as the biological substrate of migraine aura and experimental animal studies have provided mechanisms that pos- sibly link CSD to the activation of trigeminal neurons mediating lateralized head pain.

Some CSD features do not match the clinical features of migraine headache and

there are gaps in translating CSD to migraine with aura.

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2 Mechanisms

Clinical features of migraine headache and results from research are critically evaluated; and consistent and inconsistent findings are discussed according to the known basic features of canonical CSD: typical SD limited to the cerebral cortex as it was originally defined.

Including thalamus, particularly reticular nucleus and higher order thalamic nuclei, which functions as a hub connecting the visual, somatosensory, language and motor cortical areas and subjects to modulation by brain stem projections into the CSD theory, would greatly improve our current understanding of migraine.

Extended: Cortical spreading depression (CSD) is a pathophysiological phenom- enon of gray matter characterized by sustained electrical silence and suppressed activity propagating in the cerebral cortex preceded by a brief shower of population spikes [236–238].

Introduction CSD has also been recognized as the biological substrate of migraine aura [239–241]. Experimental animal studies have provided mechanisms that possibly link CSD

to the activation of trigeminal neurons mediating lateralized head pain [242].

The probable mechanism between CSD and lateralized head pain in anesthetized rats is over-extrapolated to migraine without aura and a ‘silent aura’ theory is pro- posed for migraine without aura to explain headaches.

Some basic CSD features unfortunately do not match many clinical features of

migraine headache well.

What is the Functional Consequence of CSD at Cellular Level? The ‘depression’ or ‘silence’ is actually as a result of a state of sustained depolariza- tion where the membrane is captured/clamped at the depolarized potential with loss of excitability for a few minutes.

The CSD induced depolarization state is not associated with increased excitabil-

ity where action potentials fire, such as in epileptic discharges.

The depolarization process of CSD is a loss of excitability state lasting minutes and very similar to the ischemic depolarization resulting in loss of function [237, 238, 243].

Whole-cell recordings in vivo confirm the prolonged depolarization up to 345 s with neuronal silencing during CSD, which was followed by reduced spontaneous synaptic activity and AP firing.

The initial phase of CSD where the membrane resistance is lost and membrane potential is seized in depolarized state is a complete electrical silence that is unlikely to be associated with excitation of any cortical neuron leading to positive aura symptoms.

What is the Evidence Linking CSD to Head Pain? Any activation of meningeal perivascular trigeminal nociceptors by potassium, ara- chidonic acid or other molecules released during CSD, could initiate signal trans- mission orthodromically to the pain processing structures, while inducing antidromic neurogenic inflammation in the dura mater in experimental animals [242].

2.2 Biology

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The possible link between CSD and head pain was supported by the following findings in anesthetized rodent experiments; (1) Two dimensional blood flow imag- ing of both the cerebral cortex and the dura mater revealed that following CSD wave, blood flow in the middle meningeal artery (MMA) notably increased for an hour in a trigeminal nerve dependent manner [242].

CSD experiments in rodents showed the opening of pannexin 1 megachannels, MMP activation and BBB breakdown providing the possible mechanisms that explain how the intracellular nociceptive and vasoactive molecules induce neuroin- flammation and find a way to pass through the blood-brain barrier and reach to the perivascular trigeminal nociceptors in the dura mater [244–246].

Which Clinical Manifestations Suggest that CSD is the Underlying Mechanism of Migraine with Aura? 18% of 111 patients somatosensory aura was contralateral to the unilateral migraine headache [247].

Queiroz and others reported contralaterality of migraine headache with visual

aura in 8.2% of 122 patients [248].

Blood flow imaging studies in migraine with aura patients reported contralateral-

ity in most of the subjects, though the number of patients included was limited.

During regional cerebral blood flow (rCBF) evaluation via intracarotid injections of radioactive xenon, occipital hypoperfusion advancing anteriorly was detected in images captured in 15 min intervals in 8 out of 250 patients (7 patients had migraine, 6 with aura, 1 without aura) [239].

Occipital lobe hypoperfusion was reported during aura and before the onset of

headache in 4 migraine patients with aura [249].

Suppressed BOLD activation was detected as initial change in the occipital cor- tex in migraine patients independent of the presence of aura and progressed at a rate of 3–6 mm/min to adjacent cortex in 8 patients [250].

What are the Gaps in Translating CSD to Migraine with Aura? Aura symptoms originating from one hemisphere and unilateral migraine headache located to the other hemisphere were reported in many clinical studies.

a) In a detailed study of 111 migraine with aura patients, Peatfield and colleagues reported that somatosensory aura symptoms such as paresthesia were on the same side as headache in approximately half of the patients [247].

These findings are not compatible with the notion that aura symptoms and head-

ache are due to canonical CSD in one cerebral cortex.

Reports indicate that the theory of ‘typical CSD in human cerebral cortex cause unilateral headache via direct activation of overlying dural trigeminal nerve endings and trigeminal neurons in the same hemisphere’ has flaws to explain migraine with aura attacks in significant proportion of patients.

During the spontaneous attacks in migraine with aura patients, greater activation was detected in the occipito-parieto-temporal association cortices instead of pri- mary visual cortex, though, the visual stimulation induced activation was clearly seen in the occipital cortex [251].

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Alternative View to Explain Translational Gaps of CSD in Migraine The thalamus sends projections to almost all cerebral cortex, and the cortical region receiving projections from the thalamus, sends outputs to one or more thalamic nuclei, in return [252–254].

First-order thalamic nuclei, such as the lateral geniculate nucleus (LGN) and the ventral posterior (VP) nucleus, receive and relay inputs from ascending visual and somatosensory pathways to first order cortical areas [252, 253].

Higher-order thalamic nucleus, receive inputs principally from the 5th layer of

the cerebral cortex and relay information between different cortical areas [253].

Even if its propagation is blocked, such a cortical focus is sufficient to create a change in ongoing cortico-thalamic drive on thalamic relay nuclei and thalamic reticular nucleus.

Thalamic player in accordance with the cortex would enlighten positive aura symptoms and concurrent manifestation of different symptoms related to certain cortical areas such as visual, somatosensory, language and motor cortices connected through thalamic hub.

Conclusion Migraine headache is a heterogeneous complex disorder and it seems implausible to propose single mechanism to elucidate sufficiently all clinical manifestations.

More than one mechanism and multiple locations must be considered in the

development of migraine headache.

Including central pathways activated by thalamocortical dysfunction in the pro-

cess of headache development would improve our understanding of migraine.

Acknowledgement A machine generated summary based on the work of Bolay, Hayrunnisa; Vuralli, Doga; Goadsby, Peter J. 2019 in The Journal of Headache and Pain.

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