Understanding migraine as a cycling brain syndrome: reviewing the evidence from functional imaging

DOI: https://doi.org/10.1007/s10072- 017- 2866- 0

Abstract-Summary Due to the clinical picture and also based on early imaging data (Weiller and others Nat Med 1:658–660, [354]), the brainstem and midbrain structures have been intensely discussed as possible driving or generating structures in migraine.

Denuelle and others were the first to not only demonstrate significant activa- tions in the midbrain and pons but also in the hypothalamus, which, just like the brainstem activation in the first study, persisted after headache relief with sumatriptan.

Expanding these studies into f-MRI studies, refined the involvement of rostral

parts of the pons in acute migraine attacks.

They also focused on the preictal stage of NO-triggered and native human migraine attacks and suggested a predominant role of the hypothalamus shortly before the beginning of migraine headaches as well as alterations in hypothalamic functional connectivity.

The pathophysiology and genesis of migraine attacks is probably not just the

result of one single “brainstem generator”.

Spontaneous oscillations of complex networks involving the hypothalamus, brainstem, and dopaminergic networks lead to changes in activity in certain subcor- tical and brainstem areas, thus changing susceptibility thresholds and not only start- ing but also terminating headache attacks.

Extended: If one wants to interpret the most recent findings in migraine patho- physiology, it is important to again discuss the clinical presentation of all phases of a migraine attack.

Introduction Migraine is a multiphasic disorder and understanding of its pathophysiology starts with the acknowledgment that migraine is not simply a disease of intermittently occurring pain, but that it involves processes that affect the brain over time.

Effects on the brain (structure, neurochemistry, function) and neurovascular sys- tem have been widely documented during the different phases of migraine, and neuroimaging has played a significant role in the current understanding of patho- physiologic processes behind migraine [355].

These processes are still only partially understood, are likely multifactorial, and

involve several brain structures.

3.4 Neuroimaging

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The Clinical Presentation of Migraine Migraine is clinically characterized by various symptoms which are defined by the IHS classification [11].

The accompanying symptoms of nausea and photo-, and phonophobia are usu-

ally simultaneous to the headache.

Around 70–80% of migraine patients experience at least in some of these attacks, so-called migraine premonitory symptoms, including changes in appetite (food craving or nausea) and sleep–waking rhythms (yawning, fatigue, sleep disturbances).

Just as there are prodromal symptoms, a great percentage of patients experience a postdromal phase characterized as occurring after headache remission: fatigue and tiredness but also euphoria or dysphoria are frequent, next to alterations in appetite or osmoregulation [356–358].

The first one is that almost all symptoms of the premonitory phase including yawning, tiredness and mood changes [359] point towards hypothalamic involvement.

The Migraine Attack: Focusing on the Brainstem The patient developed a typical migraine attack and during this attack activation in the dorsal rostral brainstem was detected.

A strong indicator for an attack-generating function of this area is the fact, that a specific activation of this region could be shown for the premonitory phase of nitro- glycerine- triggered migraine attacks even before onset of migraine-like headaches in a recent PET study [360].

The commonly reported sustained activation of this area even after pain relief by sumatriptan strongly suggests attack-sustaining properties and that triptans do not terminate migraine attacks, but merely lead to a headache relief for a certain time. Although the original study by Weiller and others did not report the PAG specifi- cally as the brainstem region showing activation during attacks [354], the PAG was much discussed due to an earlier clinical study in which implementation of stimu- lating electrodes in the PAG of intractable pain patients resulted post-operative migraine-like headache in some patients [361].

Single activation changes in specific brain regions may be the correlate of spe- cific symptoms of headache, but do not easily explain any cycling change over time or indeed the generation of attacks.

Migraine Attacks Mediated by the Hypothalamus The orexinergic processing was suggested to be involved in migraine attack genera- tion and/or sustainment of migraine pain.

Recent neuroimaging studies in migraine patients undermine hypothalamic

involvement in the premonitory and acute pain phase of migraine [362, 363].

Maniyar and others investigated the (pain free) interval between initial headache after administration of NO as a human model of the premonitory phase and found increased activity of the hypothalamus and the dorsal rostral pons [360].

Increased hypothalamic activation was seen in the prodromal phase (within the last 24 h before migraine headache onset) as compared to the interictal state [364].

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The pain-related hypothalamic functional connectivity between the hypothala- mus and the spinal trigeminal nuclei was significantly increased during the preictal phase as compared to the interictal phase [364].

These data strongly suggest that the hypothalamus plays not only a crucial role

in generating premonitory symptoms, but also the migraine attack itself.

Migraine Attacks as a Change in Network Architecture? These changes involve certain networks including the hypothalamus and the dorsal rostral pons with a rather specific pattern during different stages of the migraine cycle.

The current understanding of migraine attack generation is developing from the hypothesis of one single migraine generator to a more complex perspective of oscil- in network lating neurotransmitter networks and connectivity.

time-dependent changes

Regarding BOLD-changes, a very recent study from our own group on one migraine patient scanned for 30 consecutive days including three untreated migraine attacks revealed alteration in pain-related hypothalamic functional connectivity.

A more complex picture of migraine attack generation is likely: spontaneous oscillations of complex networks involving the hypothalamus, brainstem, and dopa- minergic networks lead to changes in activity in certain subcortical and brainstem areas, thus changing susceptibility thresholds and not only starting but also termi- nating headache attacks.

Acknowledgement A machine generated summary based on the work of May, Arne. 2017 in Neurological Sciences.

Disconnectome of the migraine brain: a “connectopathy” model